ESPGHAN 1968 – 2018 Celebrating Years Jubilee Supplement50 A of ESPGHAN and its Contributions to Paediatric , and

Guest Editor Lawrence Weaver School of and Centre for the , University of Glasgow, Glasgow, Scotland, UK ESPGHAN Council 2018 and office staff from left to right are as follows: Kevin McCluskey – ESPGHAN Office, Iva Hojsak, Nicolette Moes, Katharina Ikrath – ESPGHAN Office, Christian Almuthe Hauer, Piotr Socha, Mary Fewtrell, Sarah Caillet – ESPGHAN Office, Raanan Shamir, Tena Niseteo, Annamaria Staiano, Gigi Veereman, Dominique Belli, Henkjan Verkade, Nikhil Thapar

ESPGHAN Council President Raanan Shamir General Secretary Gigi Veereman Treasurer Annamaria Staiano Education Secretary Iva Hojsak International Affairs Rep. Christina A. Hauer Scientific Secretary Piotr Socha Chair of Gastroenterology Committee Nikhil Thapar Chair of Hepatology Committee Henkjan Verkade Chair of Nutrition Committee Mary Fewtrell Chair of Local Organising Committee Dominique Belli Chair of Young ESPGHAN Committee Nicolette Moes Chair of Allied Health Professionals Committee Tena Niseteo JPGN Journal of Pediatric Gastroenterology and Nutrition A Journal of Clinical, Experimental, and Developmental Investigation in Pediatric Gastroenterology, Hepatology, and Nutrition www.jpgn.org The Official Journal of ESPGHAN 1968 – 2018 Celebrating Fifty Years Jubilee Supplement A History of ESPGHAN and its Contributions to Paediatric Gastroenterology, Hepatology and Nutrition

Guest Editor Lawrence Weaver School of Medicine and Centre for the History of Medicine, University of Glasgow, Glasgow, Scotland, UK

Editorial Committee and Co-Editors Michael Lentze Department of Paediatrics, University Hospitals, Bonn, Berthold Koletzko Ludwig-Maximilians-Universität Munich, Dr von Hauner Children’s Hospital, University of Munich Medical Center, München, Germany Olivier Goulet Division of Pediatric Gastroenterology-Hepatology-Nutrition, Hôpital Necker Enfants Malades, University Paris Descartes, Paris, France Martin Burdelski Universitats-Kinderklinik Hamburg-Eppendorf, Hamburg, Germany Olle Hernell Department of Clinical /, Umeå University, Umeå, Sweden Hania Szajewska Department of Paediatrics, The Medical University of Warsaw, Warsaw, Poland Dominique Belli Département Enfant et Adolescent, Service Pédiatrie Générale, Université de Genève, Switzerland JPGN Journal of Pediatric Gastroenterology and Nutrition Volume 66 The Official Journal of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and Supplement 1 the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition April 2018

Table of Contents S1 Introduction Lawrence T. Weaver S2 Chapter 1. The Historical Roots of Paediatric Gastroenterology, Hepatology, and Nutrition Lawrence T. Weaver S20 Chapter 2. ESPGHAN: 50 Years Memories—The Early Years Michael J. Lentze, Salvatore Auricchio, Samy Cadranel, Peter J. Milla, Deirdre Kelly, Alexander S. McNeish, Jean Rey, Jacques Schmitz, Birgitta Strandvik, Jan Taminiau, and Jarmo Visakorpi S29 Chapter 3. The European Society for Paediatric Gastroenterology, Hepatology and Nutrition in Recent Years Berthold Koletzko, Raanan Shamir, Ilse Broekaert, and Riccardo Troncone S44 Chapter 4. The Relationship Between the European and North American Societies for Pediatric Gastroenterology, Hepatology and Nutrition Carlos H. Lifschitz, Jon Vanderhoof, Harland Winter, Stefano Guandalini, William Klish, Richard Grand, Allan Walker, and Jay Perman S54 Chapter 5. Fifty Years of Paediatric Gastroenterology Olivier Goulet, Ricardo Troncone, Marku Makki, Jacques Schmitz, Isabel Polanco, Maria Luisa Mearin, Samy Cadranel, Sibylle Koletzko, Giuseppina Oderda, Alan Phillips, Simon Murch, John Walker-Smith, Frank Ruemmele, Jorge-Amil Dias, Sanja Kolacek, Yigael Finkel, John Puntis, Antonella Diamanti, Susan Hill, Florence Lacaille, Girish Gupte, Jean Francois Mougenot, Mike Thompson, Marc Benninga, Nikhil Thapar, Annamaria Staiano, Gigi Veereman, Yvan Vandenplas, Peter Milla, Jehan-François Desjeux, Alfredo Guarino, and Hania Szajewska S116 Chapter 6. ESPGHAN’s Contributions to Paediatric Hepatology Martin Burdelski, Etienne Sokal, Pilar Nannini, Anil Dhawan, Giorgina Mieli-Vergani, Diego Vergani, Nedim Hadzic, Giussepe Maggiore, Pietro Vajro, Giulia Paolella, Giovanna Alfano, Roderick Houwen, and Deirdre Kelly S144 Chapter 7. The Contributions of the ESPGHAN Committees on Nutrition to Paediatric Nutrition Olle Hernell, Peter Aggett, Mary Fewtrell, Berthold Koletzko, and Jean Rey S154 Chapter 8. 50 Years of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN): Captivating Witness Reports of a Success Story Salvatore Auricchio, Samy Cadranel, Stefano Guandalini, Deirdre Kelly, Berthold Koletzko, Michael J. Lentze, Alexander S. McNeish, Peter J. Milla, Jean Rey, Jacques Schmitz, Raanan Shamir, Birgitta Strandvik, Riccardo Troncone, and Jarmo Visakorpi S172 Chapter 9. Words From Partner Societies Barbara Golden, Tom Stiris, Julián Panés, Leyla Namazova-Baranova, André Van Gossum, Heiner Boeing, Zulfiqar A. Bhutta, Armando Madrazo, James E. Heubi, Nezha Mouane, Paul Fockens, and Berthold Koletzko

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Introduction

Lawrence T. Weaver

n 2014 I was asked by the President and Council of ESPGHAN pathophysiology and underlying genetic and environmental causes. to convene a small group of members to put together a ‘‘History ESPGHAN has played a significant part in the birth of paediatric ofI ESPGHAN’’ to mark its 50th anniversary. This is the result—a hepatology as a distinct branch of paediatrics, and Chapter 6 supplement that aims to give an account of the origins and founda- addresses some common diseases of the liver, the understanding tion of the Society, to record its activities, to celebrate its achieve- of which, through the collaborative efforts of members of ESP- ments, and to highlight its significant contributions to paediatric GHAN, have been central to this process. Chapter 7 explores the gastroenterology, hepatology, and nutrition (PGHAN). interface of paediatric gastroenterology and nutrition and how, from Growing from a meeting in 1968 of fewer than 40 people, it is the founding of ESPGHAN, interest in the nutrition of the newborn now an international organisation with hundreds of members, from played a central role in its activities, and its committees of nutrition all European countries and some further afield, committed to the became influential in European affairs in formulating guidelines for practice of PGHAN. The history of PGHAN and the history of feeding infants as well as defining nutritional requirements and ESPGHAN are intertwined and this supplement traces them both industrial standards. and offers insights into how modern medicine advances and the Chapter 8 is given to the past presidents of ESPGHAN, who forces that have driven and shaped it. The roots of PGHAN extend recollect and reflect on their terms of office, recording their back to the work of those who concerned themselves with the personal memories and professional achievements. They capture digestive ailments of children and wrote about them in the past, but the dynamic spirit of a society that has done so much to promote it only came of age as an independent clinical in the PGHAN in Europe. In Chapter 9, the presidents of our partner last half century. It is now one of the foremost fields of paediatrics, societies with which ESPGHAN shares common goals and mem- as this supplement proclaims. bers, pay tribute and offer congratulations at this historical mile- Chapter 1 outlines the roots of the modern clinical specialty stone. of PGHAN up the 1950s, to put the story of ESPGHAN in a How medicine is practised, how we care for sick children, historical context. The second chapter is an account of the founda- treat them and understand their diseases, has changed enormously tion of the Society by a small group of clinicians and scientists with over the last 50 years. Many members of ESPGHAN have contrib- a common interest in the digestive diseases of children, and how it uted to this publication, and this is reflected in the different styles, developed, nurtured, and fostered the growth of a new clinical approaches, and of course, subjects of the 9 chapters. The inclusion subspecialty in Europe. The third chapter illustrates the transition of of many photographs brings to life the personal involvement and ESPGHAN from a ‘‘family’’ of clinicians and researchers who professional dedication of members. It is hoped that this supplement gathered annually to share their personal experiences, into a large will be a record of the contributions of paediatricians and scientists, international organisation, embracing allied medical professionals, allied health professionals and industry, and significantly, European with its own journal, research, educational, and training pro- collaborations responsible for major advances in PGHAN, as well grammes. Chapter 4 outlines the close relationship between the as a history of a great medical Society on its 50th anniversary. European and North American Societies of PGHAN, marked by I want to acknowledge the encouragement of Birgitta Strand- memorable joint meetings. vik, editor of ESPGAN: 25 Years Memories 1968–1992 (Go¨teborg The next 3 chapters cover the contributions of ESPGHAN to 1993), who spoke then of 25 years as being ‘‘a time of growing and paediatric gastroenterology, hepatology, and nutrition, respectively. finding an identity’’ with ‘‘an optimistic prognosis for the future.’’ They are not intended to be ‘‘state-of-the-art’’ reviews, but accounts At 50 years, ESPGHAN has truly come of age and is now a securely of the involvement of ESPGHAN and its members in the develop- founded organization with a global reputation and influence. I am ment of a selection of areas of scientific research and clinical very grateful to my co-editors of this supplement, 5 of whom were practice. Chapter 5 concentrates on 13 clinical topics that have also lead authors of chapters, to all its contributors, including past attracted the special interests of members of ESPGHAN, and presidents of ESPGHAN, presidents of our partner societies, the describes how the Society has been a forum for the advance of European editor and managing editor of JPGN, and the host of the our understanding and treatment of them. Including both ‘‘com- 51st meeting of the Society, who so willingly and energetically mon’’ conditions, such as , and rarer diseases, like supported this project and brought it to fruition. It has been a truly congenital enteropathies, they illustrate the effectiveness of colla- European effort, illustrating the wonderful effects of international borations between paediatricians and scientists in elucidating their collaboration.

Lawrence Weaver, Guest Editor Copyright # 2018 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000001933

JPGN  Volume 66, Supplement 1, April 2018 S1 SUPPLEMENT

Chapter 1. The Historical Roots of Paediatric Gastroenterology, Hepatology, and Nutrition

Lawrence T. Weaver

ABSTRACT

The last 50 years have seen the establishment of paediatric gastroenterology, he purpose of this opening chapter is to provide the historical hepatology, and nutrition (PGHAN) as a well-recognised and thriving T context within which ESPGHAN’s contributions to PGHAN clinical specialty throughout most of Europe, and further afield. This has can be appreciated. Some key scientific and medical events, happened, in part, through the existence of the European Society for discoveries, and inventions in the prehistory of ESPGHAN are Paediatric Gastroenterology and Nutrition (ESPGHAN) as a forum for those listed alongside the venues of its annual meetings in Table 1. interested in this branch of children’s medicine. To illustrate the pan- Together with the text and figures, the table aims to give an idea European roots of PGHAN, some key scientific and medical events, of the origin, diffusion, and adoption of clinical and scientific discoveries, and inventions relevant to 3 common clinical problems— advances within and around Europe, and how new ideas spread diarrhoea, jaundice, and infant-feeding—have been chosen to survey the from one centre of medical innovation and were shared or devel- historical development of the ways in which each was understood and oped in others. From the Ancient World, to Southern Europe and treated within the changing thinking and practice of past times. Together then northwestwards, this was not an orderly process, but reflects they are used to trace the prehistory of ESPGHAN and provide a background major historical events that provoked step changes in how medicine against which to explain the genesis of the Society and how its spheres of was conceived, taught and practised, such as the Black Death, the clinical and scientific interest came to be defined. invention of the printing press, voyages of discovery, the French Revolution, the germ theory, and so on. Such ‘‘events’’ mark Key Words: gastroenterology, hepatology, history, nutrition transitions from one mode of thinking to another: from humoralism to experimentalism, from alchemy to chemistry, from miasmatism (JPGN 2018;66: S2–S19) to microbiology, from phenotypic to genotypic descriptions of disease, for instance. To illustrate the pan-European roots of PGHAN, this account is biographical, as well as thematic, and records the present-day countries of the people mentioned, highlighted in bold. Three common clinical problems—diarrhoea, jaundice, and milk-feeding—each from 1 of the 3 branches of PGHAN, have been chosen to survey the development of the ways in which each was understood and treated within the changing thinking and practice of past times.

Ancient, Medieval, and Renaissance Medicine

The deep roots of PGHAN, as we now know it, can be discerned in the writings and practice of the Ancients of the Greco-Roman worlds, whose medicine was holistic, treating the whole patient and seeking to prevent disease. Their approach to thecareofchildrenwasempirical, based on observation and informed by humoralism (Fig. 2). Children were regarded as moist and warm, and their diseases caused by disturbance in the balance of the humours. Hippocrates (460–370 BC) [Greece] taught that ‘‘the growing organism has the most innate heat and therefore requires more nourishment.’’ Galen (130–200 AD) [Turkey] regarded milk as the ideal food for infants ‘‘since they have a moister constitution than those of other ages’’ (1). FIGURE 1. Lawrence T. Weaver. Relaxation or contraction of pores in the body increased or diminished secretion leading to greater moisture or dryness. Received January 23, 2018; accepted January 29, 2018. Diarrhoea and vomiting were due to flux (flow) of the humours From the School of Medicine and Centre for the History of Medicine, downwards and upwards. Advice on childbirth and the care of the University of Glasgow, Glasgow, UK. young, particularly infant feeding and the treatment of common Address correspondence and reprint requests to Lawrence T. Weaver, MD, intestinal ailments such as stomatitis, thrush, and umbilical Centre for the History of Medicine, University of Glasgow, Glasgow G12 8QQ, UK (e-mail: [email protected]). hernia, was practical. Copyright # 2018 by European Society for Pediatric Gastroenterology, Galen formulated a physiology derived from the dissection of Hepatology, and Nutrition and North American Society for Pediatric animals and the actions of vital spirits, or pneuma. Food was taken Gastroenterology, Hepatology, and Nutrition into the stomach where it was turned into chyle and passed to the DOI: 10.1097/MPG.0000000000001917 liver via the portal vein. There it was converted into blood suffused

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TABLE 1. Some significant people, scientific and medical events, discoveries, and inventions in the prehistory of PGHAN before the 1960s when ESPGHAN was founded

Annual Meetings of ESPGHAN

Year Meeting Venue Country Significant people, scientific or medical events, discoveries or inventions of that country

2018 51st Geneva Switzerland Charles Chossat (1796–1875). Experimental researches into starvation, 1843. 2017 50th Prague Czech Republic Jan Purkinje (1787–1869). Anatomist who discovered Purkinje cells and fibres, 1839. 2016 49th Athens Greece Soranus (c 1st/2nd C AD). Advice on infant feeding and quality of breast milk. 2015 48th Amstedam Holland Herman Boerhaave (1668–1738). Aphorisms on child health and treatment of disease, 1709. 2014 47th Jerusalem Israel Aaron Ciechanover (b. 1947). Nobel Prize for Chemistry, 2004. 2013 46th London England Samuel Gee (1839–1911). who described clinical features of coeliac disease, 1888. 2012 45th Stockholm Sweden Nils Rosen von Rosenstein (1706–1773). Author of Diseases of Children and their Remedies, 1764. 2011 44th Sorrento Italy Giovanni Morgagni (1682–1771). Author of Seats and Causes of Disease Investigated by Anatomy, 1761. 2010 43rd Istambul Turkey Mary Wortley Montagu (1689–1762). Introduction of smallpox innoculation to England, 1717. 2009 42nd Budapest Hungary Ignaz Semmelweis (1818–1865). Prevention of puerpural fever by hand-washing, 1847. 2008 41st Iguassu Brazil Henrique Pinotti (1929–2010). Described oesophageal stenosis in Chagas Disease, 1988. 2007 40th Barcelona Spain Santiago Ramon y Cajal (1852–1934). Pathologist who identified nerve fibres in gut, 1890s. 2006 39th Dresden Germany Justus von Liebig (1803–1873). Chemist who pioneered analysis of composition of milks, 1830s–1840s. 2005 38th Porto Portugal Garcia de Orta (1501–1568). First European physician to describe symptoms of cholera, 1563. 2004 37th Paris France Claude Bernard (1813–1878). Experimental physiologist of digestion and sugar , 1860s. 2003 36th Prague Czech Republic Joseph Sˇkoda (1805–1881). Promoter and populariser of clinical percussion, 1839. 2002 35th Taormina Italy Santorio Santorio (1561–1636). Physiologist and pioneer of energy balance studies, 1614. 2001 34th Geneva Switzerland Paracelsus, aka Theophrastus von Hohenheim (1493–1541). Pioneering chemist and toxicologist. 2000 33rd Boston USA Thomas Rotch (1849–1914). Inventor of the percentage infant feeding method, 1910s. 1999 32nd Warsaw Poland Walery Jaworski (1849–1924). Gastroenterologist who described gastric bacteria Vibrio rugula, 1899. 1998 31st Toulouse France Louis Pasteur (1822–1895). Pasteurisation of milk, immunisation, and germ theory. 1997 30th Thessaloniki Greece Hippocrates (c 460–370 BC). Composed practical aphorisms for infant feeding and care. 1996 29th Munich Germany Robert Koch (1843–1910). Identified bacterial causes of tuberculosis and cholera, 1880s onwards. 1995 28th Jerusalem Israel Jesus of Nazareth (c 0–32). Healer and inspiration for foundation of many charitable hospitals. 1994 27th Houston USA William Beaumont (1785–1853). experimentation on gastric physiology, 1822. 1993 26th Gothenburg Sweden Olaus Rudbeck (1630–1702). Physician and anatomist who discovered the lymphatic system, 1652. 1992 25th Brussels Belgium Jules Bordet (1870–1961). Microbiologist and immunologist who discovered Bordatella pertussis, 1906. 1991 24th London England Francis Glisson (1597–1677). Described the capsule of the liver, and childhood rickets, 1651. 1990 23rd Amstedam Holland Antoine van Leeuwenhoek (1632–1723). Microscopist and observer of micro-organisms, 1670s. 1989 22nd Budapest Hungary Be´la Schick (1877–1967). Paediatrician who invented test for diphtheria, 1910. 1988 21st Copenhagen Denmark Harald Hirschsprung (1830–1916). Paediatrician who described Hirschsprung Disease, 1886. 1987 20th Lisbon Portugal Portuguese traders responsible for the adoption of cinchona bark for the treatment of malaria, 16th century. 1986 19th Edinburgh Scotland Thomas Dalziel (1861–1924). Surgeon who first described chronic interstitial enteritis in children, 1913. 1985 18th New York USA William Crosby (1914–2005). Inventor of suction biopsy capsule of small intestinal mucosa, 1957. 1984 17th Tampere Finland Arvo Ylppo¨ (1887–1992). Paediatrician who elucidated biochemistry of neonatal jaundice, 1913. 1983 16th Graz Austria Theodore Escherich (1857–1911). Paediatrician who discovered Bcoli,1885(E coli, 1919). 1982 15th Madrid Spain Severo Ochoa (1905–1993). Physician, biochemist and Nobel Prize winner for research in RNA, 1959. 1981 14th Bern Switzerland Guido Fanconi (1892–1979). Paediatrician responsible for characterisation of cystic fibrosis, 1934. 1980 13th Capri Italy Scuola Medica Salernitama. First late medieval European , 12th century. 1979 12th London England Thomas Barlow (1845–1945). Paediatrician who distinguished infantile scurvy from rickets, 1883. 1978 11th Paris France Charles Billard (1800–1832). Pioneering paediatrician, author of treatise on diseases of infancy, 1828. 1977 10th Utrecht Holland Willem-Karol Dicke (1905–1962). Paediatrican who developed gluten-free diet for coeliac disease, 1953. 1976 9th Weimar Germany Eduard Henoch (1820–1910). Described syndrome of purpura, bloody diarrhoea and arthralgia, 1868. 1975 8th Leuven-Brussels Belgium Andreas Vesalius (1515–1564). Anatomist and author of De Humani Corporis Fabrica, 1543. 1974 7th Verona Italy Giovanni Santorini (1681–1737). Described the accessory duct of the pancreas, 1724. 1973 6th Helsinki Finland Carl Ehrstrom (1803–1881). Pioneer of microbiological causes of infectious diseases, 1850s. 1972 5th Hamburg Germany Heinrich Finkelstein (1865–1942). Invented eiweissmilch (buttermilk) for ‘‘alimentary intoxication,’’ 1910. 1971 4th Birmingham England Harriette Chick (1875–1977). Showed roles of codliver oil and sunlight in preventng rickets, 1920s. 1970 3rd Lund Sweden Carl Linnaeus (1707–1778). Physician and botanist who invented binomial taxonomy, 1735. 1969 2nd Interlaken Switzerland Alexandre Yersin (1863–1943). Microbiologist who discovered plague bacillus Yersinia pestis, 1894. 1968 1st Paris France Antoine Lavoissier (1743–1794). Demonstrated role of oxygen in respiration and combustion, 1778.

with natural pneuma, which went to the heart where it passed (1088), Paris (1150), Oxford (1167), Cambridge (1209), Montpellier through ‘‘invisible pores’’ from right to left ventricle and was (1209), Padua (1222) [Italy, France, England], these writings, mixed with vital pneuma from the lungs. This vital blood went via elaborated by commentaries, were the basis of a bedside medicine, the aorta and carotid arteries to the brain, and thence by the nerves to taught from books that dealt with diseases a capitem ad calcem (from initiate motion and sensation (Fig. 3) (2). head to foot). When children were mentioned it was usually in With the decline of the ancient Greek and Roman civilisations, relation to infant care and feeding, with remedies such as ‘‘cooling many medical texts were preserved in Arabic translations and infused herbs’’ like mallow and plantain, rhubarb for constipation, and white with the works of Islamic scholars. Their rediscovery in the late vegetables, such as fennel, to stimulate mother’s milk. The aim of Middle Ages became the core of the teaching of newly founded treatment was to promote the flow or restore the balance of universities and medical schools. In Salerno (11th Century), Bologna the humours. www.jpgn.org S3 Supplement JPGN  Volume 66, Supplement 1, April 2018

FIGURE 2. The 4 humours, with their characteristic properties and associated elements.

During the Renaissance humoural thinking continued to inform conceptions of the causes of disease and approaches to treatment, but ‘‘new’’ , reaching Europe from ‘‘voyages of discovery’’ to Africa, the Orient and New World, and along trade routes, such as the Silk Road, introduced cinchona (Peruvian bark), and spices and herbs with supposed therapeutic properties, like cinnamon, pepper, cloves, and ginger. The ‘‘Black Death,’’ or bubonic plague, also reached Europe from the east and reduced its population by around a third. Medical knowledge was disseminated throughout Europe in the common lingua franca of Latin, and the invention of the printing press in the 1450s facilitated the circulation of copies of the works of ancient writers, and also new treatises on the diseases of children, such as Libellus de Egritudinibus Infantum (3) by Paulo Bagellardo (c 1450–1494) [Italy] and Ein Regiment de Jungen Kinder (1473) (4) by Batholomew Metlinger (c 1450–1492) [Germany]. Such texts generally restated the teachings of the Ancients, broadly under 3 headings—pregnancy, the care, rearing and feeding of infants, and FIGURE 3. Galen’s ‘‘physiological system.’’ the diseases of children. Their focus was on treatment, rather than diagnosis or , with plant-based remedies, along with observance of rules of , healthy living, and the healing that many diseases came from the outside and that specific power of nature. Texts took the form of aphorisms—short, pithy medicines were indicated for specific diseases, such as mercury statements: on ‘‘flux of the belly’’ (de fluxi and de vomitu) and on for syphilis. ‘‘stopping of the belly’’ (constipation) (5). Hippocrates (c 460–270 Didactic poems, such as Paedotrophia (6), the Art of Nursing BC) [Greece], for instance: and Rearing Children, written in Latin by Scevole de St Marthe (1536–1623) [France], and later translated into French and  They that have their belly much moved and good digestion are English, circulated and were ‘‘read in the most famous universities the healthier; they that have scant movement, and being gross of Europe with the same veneration as the works of the Ancients.’’ feeders are not nourished in proportion, are sickly. Combining practical advice with humoral theory, the treatment of  They that often pass bloody and undigested stools from the constipation, for instance, was ‘‘to mix liquid honey with his food; belly are especially liable, amongst the symptoms of fever, for of the laxatives that art bestows, none has been so fitted to expel to drowsiness. bad humours and to make the infant well.’’ For diarrhoea; ‘‘to brace the bowels the infant needs Cyperus brown, mixed with poppy seeds The humanism of the Renaissance rejected medieval scho- and myrtle berries that warm the stomach. Pound these together and lasticism and stressed the significance of the individual. A spirit of when fitly bruised, in milk infuse the grateful loquor, which will enquiry informed many spheres of practical activity, including new health produce and o’er his slender body strength diffuse.’’ chemistry. The processes of distillation and evaporation were used With the foundation of printing houses in Venice, Antwerp, by Paracelsus (1492–1541) [Switzerland] to extract, concentrate, Paris, Amsterdam, London, and other cities, texts translated into and purify the ‘‘essences’’ of plants and mineral ores (including vernacular languages circulated around Europe, such as Thomas arsenic, lead, and mercury) to produce medicines. While he Phayre’s Boke of Chyldren (7) [England] that deals with ‘‘feeble- also sought the elixir of life using alchemical methods, he taught ness of the stomacke and vomiting,’’ teaching that ‘‘colyke and

S4 www.jpgn.org JPGN  Volume 66, Supplement 1, April 2018 Supplement rumblings of the guttes cause the child restlessness. He crieth and The teachings of Christianity inspired the foundation of frettish himself and many times also makes urine by reason of winde foundling hospitals and other charitable institutions for the that oppresseth the neck of the bladder.’’ abandoned, sick, and infirm. Run by holy orders, they provided nursing care, refuge, and protection, but were not the locus of medical teaching or professional development. There were no Scientific Revolution and Enlightenment children’s hospitals, nor paediatricians, in the modern sense. (1550–1800) Physical examination was rudimentary, but ‘‘stool-watching’’ was keen. Jean Astruc (1684–1776) [France] wrote that ‘‘as to The ‘‘new anatomy’’ of Andreas Vesalius (1514–1564) the nature of the evacuations, diarrhoea is of four species: [Belgium] ‘‘corrected ancient errors’’ and challenged received stercoral (whitish, greenish, yellowish or bilious, viscid), coeliac ideas of how the body was formed, but offered few insights into (‘‘milky whitish humour – chyle that could not enter the the causes of disease. Humoural physiology still served to explain lacteals’’), lienteric (undigested food), and dysenteric (bloody) physiological processes, such as digestion, absorption, excretion (8). External agents, especially worms, were found in the and lactation. Bartholomew Metlinger (c 1450–1492) [Germany] stool. Hippocrates had taught that they were generated by taught that human milk was produced from the blood of the mother putrefaction in the bowel, and ‘‘are produced in the child yet flowing through the veins into the breast (4). in utero’’ (1). ‘‘Children’s physic’’ continued to regard children as ‘‘wet’’ The transition from scholastic, bookish medicine to clinical and ‘‘warm,’’ and that their medicines should soothe and cool them, practice based on observational and experimental evidence and be gentle, innocent and simple. ‘‘Strong medicines,’’ bleeding involved a shift from a physiology of ‘‘vital spirits,’’ ‘‘invisible and purging, were to be avoided. Walter Harris (1647–1742) pores,’’ and alchemy, to one of mechanism, materialism, and [England], wrote in De Morbis Acutis Infantum (8), that ‘‘together chemistry. ‘‘Number, weight, and measure’’ became the watch- with their thin diet, their redundancy of humours, and almost words of the new Natural Philosophy. The adoption of technology mucous state of solids, everybody will allow that the constitution and experiment to investigate how the body worked generated of infants is of the moistest kind. ...moist and soft bodies are far mechanical, chemical, and haemodynamic explanations of muscle more susceptible of any kind of impression than those endued with contraction (Giovanni Borelli 1608–1679) [Italy], cardiac function the contrary qualities.’’ He noted the seasonal incidence of acute (William Harvey 1578–1657) [England], respiration (Robert diarrhoea: ‘‘From the middle of July to the middle of September the Boyle 1627–1691) [Ireland], metabolism (Santorio Santorio epidemical gripes of children are so rife every year that more of 1561–1636) [Italy], digestion (Jean-Baptiste Helmont 1577– them usually die in one month than in three of four at any other 1644) [Belgium] and reproduction (Franc¸ois Mauriceau 1637– time.’’ The ‘‘seasonal flux’’ was viewed as due to deficient quality 1709) [France]. With the assistance of the microscope, single or quantity of milk, or as Sylvius Francisco (1614–1672) [France] and multicellular organisms, muscle fibres, spermatozoa, and blood wrote, ‘‘gripes of the belly [are] due to wind or from sour and sharp cells were observed (Robert Hooke 1635–1703) [England], humours.’’ Antoine van Leeuwenhoek (1632–1723) [Holland], (Marcello Children were deemed worthy of care, protection, and edu- Malpighi 1628–1694) [Italy], and by human dissection the cere- cation in accord with humanistic and enlightenment thinking. The bral, placental and foetal circulations (Thomas Willis 1621–1675) babies of the well-to-do were often reared by wet nurses. Sick [England], (Frederik Ruysch 1638–1731) [Netherlands] were children were generally cared for at home, by their parents, demonstrated (Fig. 4). sometimes attended when seriously ill by a physician or clergyman This iatrophysical and chemical conception of the living (to care for the soul as well as body). Healing and recovery from body as a machine made up of smaller machines operating accord- illness may be brought about by Nature (vis medicatrix naturae), ing to scientific laws, informed a ‘‘new’’ physiology, that was under the command of God and the assistance of the physician. shared by many in Europe who wrote about children’s diseases. But With the help of the 6 ‘‘Non-Naturals’’—excretion, sleep, food, remained dominated by humoural thinking, with emetics, passions, air, and exercise, the ‘‘natural spirits’’ would expel bad cathartics and aperients. Nils Rosen von Rosenstein (1706–1773) humours and redress their balance. Choice of food reflected the [Sweden], for instance, wrote in his Diseases of Children and their ‘‘chain of being,’’ in which fowls stood higher than meat, than fish, Remedies (10): than vegetables in their capacity to restore the ‘‘innate heat’’ and ‘‘radical moisture,’’ which constituted health. Diarrhoea (‘flux of yellow humours downwards’) may arise from Herman Boerhaave (1668–1738) [Netherlands] continued whatever occasions a greater quantity to remain in the bowels than to teach that the ‘‘child in the womb has its nourishment and growth normal, or by anything causing the humours to be discharged in too from the mother’s humours; it seems very probable that in the last great a plenty, or from anything preventing the vasa bibula months of pregnancy the milk is carried to the uterus and to the (absorptive pores) from absorbing these liquids, and by whatever fetus’’ (9). But as a physician Boerhaave collected clinical cases, increases the peristaltic action. ...By eating and drinking in too great based on careful questioning, observation, and inspection, and quantities, the stomach and intestines are unable to digest the food shared them with other practitioners by correspondence, through and from thence will arise indigestions and crudities, which by their journals and published lecture notes, facilitating the spread of activity, irritate in part and increase the motus peristalticus, and in knowledge of children’s diseases, even though within a small part occasion a greater flux of humours. network of , with court appointments, university posi- tions, charitable dispensaries, or postal practices. Texts on the While medical thinking remained imbued with humoral natural of diseases, such as those by Thomas Sydenham language and concepts, the idea that disease was an independent (1624–1689) [England], were accompanied by classifications of entity, separable from the patient, permitted the compilation of diseases (nosologies), based on symptoms (eg, itch, gripes, cough) descriptions of cases of disease and taxonomies that included and external signs (eg, rickets, measles, pox), grouped generically ‘‘causes’’ as well as ‘‘symptoms.’’ ‘‘The saliva which is swallowed as dolores, spasmii, fluxes, cachexiae and so on. Such system- promotes peristalsis and prevents the excrements from becoming atisation reflected the organisation of information within quasi- hard.’’ ‘‘The gall is diluted by that humour (saliva) which the Linnaean taxonomies (Carl Linnaeus 1707–1778) [Sweden]. sweetbread (pancreas) separates from the blood, promotes the www.jpgn.org S5 Supplement JPGN  Volume 66, Supplement 1, April 2018

FIGURE 4. The Anatomy Lesson, by Frederik Ruysch (1683). digestions and stools.’’ Von Rosenstein classified diarrhoea into bodies, but in other animals, several of which I have seen from an fourteen species; the twelfth was Fluxus Coeliacus: ox,’’ observed an unknown 18th-century English physician, who reported that ‘‘a certain woman complains of weariness and itching Children are subject to another kind of diarrhoea, which physicians of the skin. Her urine is like dark beer, the faeces ash coloured. The have termed fluxus coeliacus. Those who have this disease are white of her eyes, skin and nails are tinged yellow.’’ Seeking to affected with gripes and violent purging, which is not continued, but understand the causes, or seats, of disease George Armstrong comes on now and then. Sometimes the excrements have an (1719–1789) [England] performed an autopsy and reported in insupportable stench, and at other times are void of any; their colour his Account of the Diseases Most Incident to Children (11) that: is various, as grey, yellow, red, brown, and sometimes tinged with blood. The appetite at times is very great, and sometimes changes In a child which I opened a few years ago, that died at the age of ten into disgust for food. The patient looks pale, is lean, pines away, and months, of obstructions in its bowels, which occasioned want of loses his strength; his hands and feet swell, the stomach is puffed up digestion and in consequence thereof a marasmus; the gall in the and feverish symptoms come on; the child is troubled with wind; the vesica fellea [gall-bladder] was as thick and ropy as a strong mesenteric glands are obstructed, and when the humours become mucilage of quince feeds, and of a deep saffron colour. The child was more corrupt, the liver, spleen and the large gland lying behind the never thriving from birth, had been ill a month before I saw him and stomach [pancreas] swells and grows hard. The cause of this disease was very much reduced. He had a slow fever almost constantly upon seems therefore to consist of a of the whole mass of blood, him, and his complexion was very sallow, like a person’s in the but more especially the digestive humours, because when they are beginning of the jaundice. His urine was high coloured, his stools vitiated, they injure the support in the intestines and make the whitish, very tenacious and offensive to the smell; and he was stomach and bowels lose their strength. generally inclined to be costive [constipated], except when laxatives were given him. When opened, the abdominal viscera appeared very Setting aside exactly what the diagnosis was, the description sound, nor could anything be discovered to account for his combines observation on the course of the disease with inspection complaints, except the above viscid quality of the bile in the gall- of the stools, examination of the abdomen, and post-mortem bladder, which had tinged the neighbouring parts of a deep orange findings. The effects of mechanical obstruction of the biliary colour. system on the flux of yellow bile was also understood by Von Rosenstein, who wrote: ‘‘As to the causes of jaundice, we shall find Such a clear account of the pathological findings post- them to be such which effect the stoppage in the channels that carry mortem and the symptoms and signs of the child before he died the gall or bile from the liver, the ductus hepaticus, ductus represents an advance from purely humoural thinking. Careful choledocus, so that the bile is prevented from being freely dis- observation and dissection located ‘‘morbid matter’’ in particular charged in the duodenum. ...Stones in the gall bladder do not cause organs, rather than viewing it as due to an imbalance of the a jaundice unless they are retained in the ductus choledocus and humours. Scrutiny of urine, stools, vomit, and bile from a purely shut up that passage’’ (10). humoral point of view was giving way to careful descriptions of Such assertions were corroborated by the dissection of their colour and nature. Comparison of the colour of urine with that animals: ‘‘stones are bred in the gall bladder, not only of human of wines, beers and spirits (by ‘‘piss-prophets’’), and minute

S6 www.jpgn.org JPGN  Volume 66, Supplement 1, April 2018 Supplement observation of stools (‘‘stool watching’’) informed diagnosis and supposed effects in promoting health and well-being. Foods made treatment. Armstrong recorded many cases of sick children with up of a single substance, such as gelatine (derived from animal diarrhoeal diseases, writing: ‘‘As to vomiting and green stools, bones) led to the marketing of proprietary foods, which claimed there are few infants that are not subject to them at times. The health benefits. Such substances were recommended for the nour- disease has been called the watery gripes, from the stools being as ishment of children. The inferiority of plant sources for infant feeds thin as water, attended by violent gripes. Sometimes they are (in accordance with the hierarchy of food substances) was con- colourless, sometime mixed with little streaks of blood, and some- firmed by the observation of the indigestibility of ‘‘vegetable times of a brownish cast, like a kind of putrid sanies, of a very strong aliment.’’ Cereals with a lot of starch (representing respiratory and offensive smell, but always very thin.’’ The character of the of combustible ingredients) were noted to lack the ‘‘plastic ingre- stools was a guide treatment, as Michael Underwood (1737–1820) dients’’ and to be associated with the accumulation of starchy [England], taught in his Treatise of Diseases of Children (12): deposits along the lining of the infant gut. The production and marketing of ‘‘special foods,’’ mineral Regard is to be paid to the kind of stools that come away, which are waters, alcoholic spirits, and nutritious beverages with purported seldom healthy and natural, and are usually distinguished into the health benefits, was accompanied by the promotion of spas, cures, sour and curdled, slimy, mucous, green, pale, clayey, watery, over- regimen, and diets for the sick. A convergence of gastroenterology tenacious, and bloody, some of which are at times fetid. Under some and gastronomy, and of commerce and chemistry, informed the of these, and particularly the latter two, some powerful purgative, recommendations of medical men, replacing humoural classifica- such as senna tea, is generally necessary, if the child is not very tion of foods and their purported health-promoting properties and young. True, bloody stools are less common in infants than adults, therapeutic effects with dietary advice based on ‘‘scientific prin- and seldom occur but in the last stage of disease; but a few streaks of ciples.’’ Handbooks of childcare, texts on the physiology of diges- blood may sometimes be mixed with the faeces, which arising only tion, and articles in scientific and medical journals reported the from the haemorrhoidal veins is a matter of no consequence. chemical analysis of foods, the percentages of different nutrients within them, and made recommendations for their choice and use— Rejecting bookish aphorisms in favour of direct inspection, such as Antoine Fourcroy’s (1755–1809) [France] Encyclope´die remedies composed from many sources; herbs, minerals, and Me´thodique Me´decine (13), and William Buchan’s (14) [England] animals, chosen to transform the stools to normal, were recom- Domestic Medicine (1769). mended. Late Modern Period (1800–1900) When the stools appear very slimy, and more especially sour or curdled, or when the child is much disposed to the cough, the Foundling Hospitals had been established in many European magnesia and other absorbent powders, are calculated to afford towns as early as the 15th century: in Florence, Rome, Paris, peculiar assistance, and may be warmed by any suitable aromatic. Montpellier, and Nuremburg, they provided for the care of children When the stools are very green, or white or clayey, a drop or two of whose parents had died, had abandoned, or disowned them. But the aqua kali [alkali] may be occasionally put into the other they were places of refuge and confinement, rather than of medical medicines, or a little almond soap be dissolved in the clysters treatment and care (Fig. 5). Although a few children’s hospitals [enemas], which are essentially necessary when much griping attends were founded earlier in some European cities, these were small, this complaint. Some light cordial is also frequently useful, and the charitable institutions which, responding to a local concern for the child’s belly may be rubbed with a little warm brandy, or be plight of sick children, were neither long-lasting nor influential in fomented with a decoction of chamomile flowers or white poppy shaping the way paediatrics came to be practised and sick children heads (12). were cared for. The taking of the great Paris hospitals of the ancien re´gime Such remedies, and foods and drinks, were classified into into public ownership after the French Revolution, in 1794, the those that were hot, cold, wet, and dry, chosen to redress humoral appointment of salaried staff, the allocation of hospitals to specific imbalance, and also to alter the chemistry of the gut. Rather than clinical specialties, and thereby the concentration of patients with regarding foods as ‘‘unitary’’ substances with humoral qualities similar diseases together, led to a new and powerful opportunities to practitioners sought to define their character and to distinguish the understand disease (Fig. 6). The collection of disease statistics and properties of vegetable matter and animal flesh. Floury and sugary analysis of the outcomes of particular treatments (‘‘methode numer- foods derived from plants were observed to be subject to digestion ique’’), and the use of diagnostic aids, such as the stethoscope by and fermentation, while animal foods tended towards putrefaction. Rene´ Laennec (1781–1826), the thermometer by Carl Wunderlich The former were described as ‘‘gelatinous’’ and the latter ‘‘muci- laginous.’’ Digestion was thought to be a form of decomposition, akin to the fate of kept foods, which tended to become ‘‘spiritous,’’ ‘‘acetous,’’ or ‘‘putrefactive.’’ Milk was regarded as an intermedi- ate substance, which combined both gelatinous and mucilaginous properties. Moreover, as a fluid, it was high in a hierarchy of other humours or fluids—blood, semen, urine, bile, saliva, and so on. Milk was also high in the hierarchy of plant—animals—man: as a substance elaborated by man (woman) and close to a perfect food, it promoted health and defended against disease. Adopting the methods used in the manufacture of alcoholic drinks, the techniques of distillation, fermentation, and so on were used to analyse the composition of fluids and food, including milk. The processes that regulated their transformation, combination, and separation, and that combated acidity or promoted digestion, drove FIGURE 5. Ospedale degli Innocenti (foundling hospital) in Florence, the search for the essence of substances, and their demonstrable or Italy. www.jpgn.org S7 Supplement JPGN  Volume 66, Supplement 1, April 2018

FIGURE 6. Paris Hospitals in 1804.

(1822–1895) [Germany] and weighing scales by Franc¸ois Chaus- opportunity thus afforded to examine by dissection all their organs, sier (1746–1828) [France], all contributed to the application of this and ascertain the causes and seat of each disease.’’ ‘‘clinico-anatomic method’’ to the diseases of children (15). Billard argued that ‘‘it appears that it is not after birth only, as Careful observation through dissection had demonstrated has been asserted by philosophers, that man for the first time that in many cases the precise location of disease could be deter- experiences that set of maladies which afflicts his race, but the mined (localism), often in a solid organ (solidism). The physician origin must be sought in a much more remote source; it commences and anatomist Giovanni Morgagni (1682–1771) [Italy] had pro- with the organisation...as soon as the ovum, the embryo, the fetus, posed that most diseases were not due to disturbance of the and the adult become more perfect in their organisation, their humours, but to be found in specific organs, or metastasise between functions undergo a peculiar change in a state of health, and whence them. Based on the records of more than 600 dissections, many present corresponding peculiarities of symptoms in disease, the prefixed with symptoms, his De Sedibus et Causis Morborum per forms of which will change according to the different phases of Anatomen Ingegatis (16) published in Latin in 1761 (translated into organisation. The alterations of the functions, or the diseases French in 1765, English in 1769, and German in 1771), deals with resulting from any disturbance in the organs, vary equally according the anatomy of diseased organs, from head to foot. Symptoms to the different subjects [organs] affected, and according to the ceased to be the core of disease classification, but were viewed as different epoch [stage] in the life of the same subject.’’ ‘‘the cries of suffering of diseased organs.’’ The conception of disease as due to derangement of the In the L’Hoˆpital des Enfants Malades, established in 1803, organisation of the growing child was a development from Xavier this ‘‘new Paris medicine,’’ which stressed observation, experi- Bichat’s (1771–1802) [France] assertion in his Recherches Phy- ment, and the correlation of symptoms and signs with post-mortem siologiques sur la Vie et la Mort (18) that ‘‘Life is that set of pathology, was applied to children. Cases of diarrhoea, typhoid functions which resist death,’’ which he elaborated further as ‘‘there fever, and exanthemata (eruptive fevers) were common on the is a superabundance of life in the child. In the child the reaction of wards, and children with these conditions were the subject of study the system is superior to the action, which is made upon it from by Charles Michel Billard (1800–1832), physician at L’ Hoˆpital des without. ...In living bodies, such in fact is the mode of existence; Enfants Trouve´s, who described in his Traite´ des Maladies des that whatever surrounds them tends to their destruction.’’ By the Enfants Nouveau-Ne´seta` la Mamelle (17) that ‘‘in reading 1830s the new clinico-anatomic method recognised tissues and Morgagni I was particularly struck how this ‘distinguished membranes as ‘‘seats of disease,’’ and embryology and develop- observer’, after having enumerated the affections to which newborn ment as shaping their expression in children. Billard’s book was children are liable,’’ complained of the little progress that has been succeeded by a more substantial text by 2 physicians, Fre´de´ric made in their pathology. Therefore ‘‘I availed myself of the Rilliet (1814–1861) and Antoine Barthez (1811–1891) [France],

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FIGURE 7. Tableau Synoptique du Plan de L’Ouvrage, from Rilliet & Barthez’s Traite´ Clinique et Pratique de Maladies des Enfants (1843) (19). whose Traite´ Clinique et Pratique de Maladies des Enfants (19) and are followed by ne´vroses, fie`vers, tuberculisations (occupying constructed a nosology of children’s disease based primarily on the the whole of volume 3), and entozoaires (gut parasites) (Fig. 7) (19). nature of the pathological lesions discovered at autopsy. Diarrhoeal diseases (catarrhales), with and without fever, and The Tableau Synoptique du Plan de L’Ouvrage of the first non-diarrhoeal disease of the stomach and intestines, were classi- edition (1843) summarises how Rilliet and Barthez chose to classify fied without indication of pathological causes—‘‘inconnue’’ or children’s diseases: by organ and nature. Internal ‘‘organs’’ are ‘‘irritants locaux’’ (Fig. 8) (19). The second edition of Rilliet et chest (encompassing bronchi, lungs and heart); mouth, nose, and Barthez (1853) reflects developments in physiology and experi- throat; abdomen (encompassing stomach and intestines, liver, and mental medicine, by Franc¸ois Magendie (1783–1855) [France] and kidneys); brain and spinal cord; and external organs; joints, skin, Claude Bernard (1813–1878) [France], and in the German-speak- and genitalia. These 5 ‘‘divisions by organ’’ are cross-tabulated by ing states (Wilhelm Camerer, 1842–1909) [Germany], where the 8 ‘‘divisions by nature.’’ The first 4 have labels that echo humoral chemistry of Justus von Liebig (1803–1873) [Germany] formed categories—phlegmasies, hyrdropsies, he´morrhagies, gangre`nes, the basis of physiology, , and metabolism. Chapters www.jpgn.org S9 Supplement JPGN  Volume 66, Supplement 1, April 2018

FIGURE 8. Classement des Maladies Gastro-Intestinales, from Rilliet & Barthez’s Traite´ Clinique et Pratique de Maladies des Enfants (1853) (19).

devoted to particular diseases, such as Ente´ro-Colite Chronique, The division of the ingredients of foods, including milks, into which has sections on anatomie pathologique, symptoˆmes, com- sugar, fat, and protein, based on the proportions and properties of plications, prognostic, diagnostic, e´tiologe, and traitement. But for these substances, was established by Justus von Liebig (1803–1873) the liver ‘‘he´patite est une affection fort rare chez les enfants.’’ [Germany] who sought to explain how food may power and nourish With the rise of laboratory science, the alliance of laborato- the body through study of the overall balance of the bodily ingesta ries and scientific institutes alongside hospitals, the growing use of (food), excreta (faeces), and respiratory gases (breath) and thereby the instruments such as the stethoscope, thermometer, microscope, and conservation of matter. ‘‘All vital activity arises from the natural weighing scales to extend and deepen the ‘‘clinical gaze,’’ com- action of the oxygen of the atmosphere and the elements of the food,’’ bined with measurement and quantitation, charting and tabulation, he argued, coining the term ‘‘metabolism’’ (20). Elaboration of the collection and preservation, illustration and reproduction generated constituents of food resolved them into ‘‘nutrient’’ groups—gelatin, and disseminated a mass of new information and ideas that albumin and fibrin, sugars, and fat with specific properties—calor- informed medicine and were tested and exploited in the clinic ificant or combustible matter (sugars and fats); plastic or nitrogenous (Fig. 9). Simple chemistry was applied to the analysis of bodily matter (proteoids); and mineral matter (ash) or salts. Steggall’s fluids (urine, blood) and foods (including milk) in ward side-rooms, Manual for Students (21) reflects this integration: dissection and vivisection were performed in nearby laboratories, and histopathological examination of morbid tissues undertaken  Animal and vegetable bodies are formed by compounds, with the microscope. Nevertheless, materia medica remained - named proximate principles consisting of 4 elements, namely tially empirical, employing remedies with specific indications, such oxygen, hydrogen, carbon, and nitrogen. as digitalis for the heart, calomel for the bowels and bark for fever,  Organic bodies are distinguished by the impossibility of but with no understanding of their mechanisms of action. imitating them by the chemical art. Antoine Lavoisier (1743–1794) [France] had shown that  Pancreatic juice resembles saliva, contains in addition albumin animals use and reconstitute atmospheric air in the same way as a and osmazome (nitrogenous extracts), and is distinguished burning body: oxygen is consumed, carbon dioxide is generated and from saliva by not containing sulphocyanic acid. respiration produces heat. Using an ice calorimeter he showed that ‘‘animal heat’’ was the chemical equivalent of slow combustion The shift in focus of the medical gaze, from whole bodies (Fig. 10). His student, Franc¸ois Magendie (1783–1855) [France], (humoralism), to organs (solidism) (Giovanni Morgagni 1682–1771) demonstrated the requirement of the body for nitrogen, in the form of [Italy], to tissues (Xavier Bichat 1771–1803) [France], to cells protein, and the German metabolists, Carl Voit (1831–1908) and Max (Theodor Schwann 1810–1882) [Germany], drove the quest for a Rubner (1852–1932) [Germany], using calorimetry and balance general physiology applicable to all living things, consistent with the studies, later linked respiration with combustion, disposing of vitalistic doctrine that cells were the building blocks and functional units of explanations of life. Physiology was embracing chemistry, comple- plants and animals (Rudolf Virchow 1821–1902) [Germany]. Tissue menting the mechanistic concepts that had explained the circulation of growth and development were explained by cell multiplication— the blood and alimentary functions such as peristasis, linking the ‘‘omnis cellula e cellula’’—and with the use of the microscope, properties of food with their actions within and upon the body. microtome and tissue-specific stains, the new sciences of histology

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FIGURE 9. The ‘‘new’’ instruments of clinical medicine—the stethoscope, thermometer, weighing scales and microscope.

and embryology revealed, in bright colour, the fine structure of the than independent function of the vital organs—heart, lungs, liver, tissues in health, development, and disease (Fig. 11). brain—as key to health. William Prout (1785–1850) [England] A mechanistic and materialistic conception of the body as a reported in 1823 the function of hydrochloric acid in the stomach, machine in which the ‘‘physiological basis of life’’ was situated in and Claude Bernard (1813–1878) [France] showed the role of the the cells, was expanded and substantiated by experiment, spawning liver in sugar metabolism and the pancreas in digestion, arguing that a chemical physiology that saw coordinated ‘‘organisation,’’ rather ‘‘a complex organism should be viewed as an assemblage of small organisms, which are the anatomical elements that live in the liquid milieu inte´rieur’’ (22). Location of ‘‘combustion/respiration’’ within the cell and the chemical reactions that generated energy and thereby mediated muscle action, for instance, became clearer with Louis Pasteur’s 1822–1895) [France] work on fermentation and moulds. The application of the microscope, laboratory study of moulds (Louis Pasteur 1822–1895) [France], the mapping of the social demogra- phy of diseases (Rudolph Virchow 1821–1902) [Germany], and identification of the tubercle bacillus by Robert Koch’s (1843– 1910) [Germany] in 1882. This was followed by the characterisa- tion of other agents, responsible for cholera (1883) and typhoid (1884), and the gradual acceptance of the ‘‘germ theory’’ of infectious disease, which transformed the practice of ( 1827–1912) [England], midwifery (Ignaz Semmel- weis 1818–1865) [Hungary], and paediatrics. Efforts to understand and tackle typhoid fever and ‘‘summer diarrhoea’’ (cholera infantum), illustrate the ways in which the ‘‘germ theory,’’ coupled with developments in nutritional chemis- try, physiology, and came to be applied to the care of sick children in the clinic and community. Pierre Louis (1787– 1872) [France] identified distinctive lesions in the Peyer’s patches of the small intestine in patients with ‘‘gastric fever’’ (typhoid), Carl Wunderlich (1822–1895) [Germany] distinguished distinctly different patterns of temperature change in patients with typhoid and typhus, and William Budd (1811–1880) [England] concluded that typhoid fever was spread by contaminated water; ‘‘the sewer is the direct continuation of the intestine.’’ This new understanding of the microbiology and epidemiol- ogy of infectious diseases had little immediate impact on the sustained high mortality rates of infants (150 or more per 1000 live births) that had persisted throughout Europe for centuries. The link between diarrhoeal diseases and ‘‘improper feeding’’ kindled a ‘‘clean milk movement’’ that sought to address the stubbornly high and well-documented death rates of young children. In 1858, The FIGURE 10. Ice calorimeter used by Lavoisier and Laplace to measure Lancet championed the cause with an editorial entitled ‘‘The ‘‘animal heat’’ (1783). Murder of the Innocents’’ (23): www.jpgn.org S11 Supplement JPGN  Volume 66, Supplement 1, April 2018

(Fig. 12) (24). , the medicalisation of antenatal and postnatal care, infant-feeding (so critical for infant survival), cre`ches, and legislation to protect children from dangerous employ- ment, recognised the importance of maternal and child health. International congresses in Europe’s capital cities, on infantile mortality, , rickets, tuberculosis and syphilis, brought together paediatricians, public health physicians and scientists, and forged networks of like-minded professionals who shared their clinical discoveries, discussed new treatments, and strategies for preventing disease. The massively higher mortality of artificially fed infants during of summer diarrhoea (cholera infantum, a fre- quently lethal disease of bottle-fed babies), was depicted graphi- cally by Pierre Budin (1846–1907) [France] in the 1890s (Fig. 13) (25). There was a shift from a primary concern for mothers, to infants and children, who became recognised as patients. Among a range of welfare services initiated for babies, consultations de nourissons, Gouttes de Lait and infant milk depots, designed to provide ‘‘pure, clean milk for babies’’ were promoted. Breast- feeding was (and always had been) the dominant way in which mothers have fed their babies. Nevertheless, alternatives for mother’s milk were badly needed and sought. Justus von Liebig’s (1803–1873) [Germany] baby food, composed of wheat flour, cow’s milk, malt flour, and potassium bicarbonate, was launched in 1867, setting in motion an infant food industry that was to become global within 2 decades. Henri Nestle´ (1814–1890) [Switzerland] developed ‘‘farine lacte´e’’—‘‘a whole- some Swiss milk and cereal component baked by a special process of my invention’’— in 1868. Varying in composition, but designed to mimic human milk or meet the special nutritional needs of babies, these milk formulas were seen as the answer to the high rates. Recipes for graduated mixtures of cow’s milk, cream, sugar and water, developed by Philippe Biedert (1847–1916) [Germany] were popularised throughout Europe by both physicians and commercial entrepreneurs in efforts to ‘‘humanise’’ cow’s milk, culminating in Thomas Rotch’s (1849–1914) [USA] absurdly com- plex ‘‘percentage feeding method’’ (26). Franz von Soxhlet (1848– 1926) [Germany] invented a means for ‘‘pasteurising’’ cow’s milk for babies and the provision of clean, sterilised, modified formulae for babies (Fig. 14). The mother and child welfare movements were an impetus for the collection of data on infant growth. Mothers were encour- aged to bring their babies for weekly weighing, without which artificial feeds were not supplied (Fig. 15). Growth standards were FIGURE 11. Histological sections of the intestinal mucosa. pioneered by statisticians, such as Adolph Quetelet (1796–1874) [Belgium] in the 1830s, who argued that ‘‘the study of diseases and of the deformities to which they give place, has shown the benefits Meat, potatoes, often gin; scant nourishment drawn from the breasts derivable from corporeal measurements; but in order to recognise whose secretive power cannot eliminate milk from a half- starved whatever is an anomaly, it is essentially necessary to have estab- frame, and the unwholesome diluted milk of unhealthy badly-fed lished the type constituting the normal or healthy condition’’ (27). cows; such is the nourishment afforded to thousands of children on The growth standard, just like the temperature chart, became an this day of an enlightened age, in this capital city of a civilised essential tool of clinical research as well as medical care, in the country [England]. hospital ward and welfare clinic. An alliance of social reformers (Louis-Rene´ Villerme´ 1782– Coming of Age of Paediatrics (1900–1950) 1863) [France], Edwin Chadwick 1800–1890 [England] and Rudolf Virchow 1821–1902) [Germany] with philanthropists, The alliance of hospitals with universities, and the appli- politicians, social reformers, and public health authorities, con- cation of science and technology to clinical practice stimulated cerned with the high premature death rates of children, their clinical specialisation. This was the birth-time of paediatrics as an exploitation in mines, and their mothers in textile mills, inspired independent ; first in Germany and France, and by an atmosphere of social justice, liberal nationalism, and munici- then in other European countries and North America. The foun- pal charity, and at the end of the century by a fear for the strength of dation of university departments, of children’s hospitals, of the armed forces of the imperial powers through the unfitness of journals and textbooks, and of national societies of paediatrics, recruits, led to the development of childcare in dispensaries, clinics all contributed to the creation of clinical specialists with the and hospitals, and the social, or public health care of children dedicated interest in the diseases of children (Fig. 16). This

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FIGURE 12. Maps showing locations of children’s hospitals in Europe, 1802 to 1847 (24). professionalisation of paediatrics is well illustrated by an image of Escherich and Moro took special interests in the colonic Theodore Escherich (1856–1911) [Germany] who is represented bacteria of children. The ‘‘species of diarrhoea’’ formerly clas- as the ‘‘chief’’ of a team of clinicians, scientists and teachers. He sified according to the character of the stools, were to be better stands beside a sick child lying on the trolley. On his left is distinguished using the new sciences of histopathology and Meinhard von Pfaundler (1872–1947) [Germany], his assistant microbiology. Samuel Gee (1839–1911) [England] had noted and soon to be professor of paediatrics in Munich, who listens to in 1888 that the coeliac affection ‘‘is met with in persons of all the heart of the child, wielding that potent symbol of the modern ages, yet it is especially apt to affect children between one and clinician, the stethoscope. On the right of the chief stands Ernst five years old,’’ and is marked by the postmortem finding of Moro (1874–1951) [Germany] injecting a rabbit held by a ‘‘atrophy of the glandular crypts of the intestine’’ (28). Henry technician, symbolising ‘‘medical experimentation.’’ The scene Koplik (1858–1927) [USA], in his Diseases of Infancy and is set in a lecture theatre where 3 attentive students signify the Childhood (29), stated that ‘‘the various forms of acute gastro- integration of clinical teaching with scientific research and medi- enteritis may be divided into ‘‘those whose source of infection cal care (Fig. 17). lies outside the body (‘ectogenous’), and those in which the www.jpgn.org S13 Supplement JPGN  Volume 66, Supplement 1, April 2018

FIGURE 13. The mortality of breast-fed and artificially fed infants in Paris during an of summer diarrhoea (cholera infantum) in 1898 (25). elements of infection are pre-existent in the body (‘endogenous’), alliance of laboratory with clinic, as exemplified by the ways in which ...which, in the opinion of Theodore Escherich (1856–1911) diseases of the gastrointestinal tract were understood and investi- [Germany] and Antoine Marfan (1858–1942) [France], may gated. However, although the chemist and pharmacist were replacing under favourable conditions increase to enormous numbers and the apothecary, therapeutics still comprised recipes primarily become virulent.’’ designed to relieve symptoms. For instance ‘‘Acute Catarrh (diar- The magisterial 4 volume, multi-author Handbuch der Kin- rhoea) of the Small Intestine generally occurs as a result of marked derheilkunde (30) edited by Meinhard von Pfaundler (1872–1947) indiscretions in diet. ...The treatment is relatively simple and and Arthur Schlossmann (1867–1932) [Germany] (translated into generally successful, ...with a strict diet of weak, sweetened tea, a English in 1908), based on physiological and developmental princi- hot pack to the abdomen, and an astringent medicine, for example’’: ples, represented the state-of-the-art of paediatrics at the start of the 20th century. The integration of the sciences of microbiology, a thin mucilage, I Gm. (15 gr.) to 100 c.c (3 oz.) water may be given , serology, biochemistry, and signal the close containing zinc sulphate 0.1 Gm. (1.5 gr.), extract opii 0.2 Gm (1/3

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to 25 drops in equal doses, tannigen 0.25 to 0.4 Gm. (4 to 6 gr.) three times a day; tannalabin in equal doses or in the form of tannalabin chocolate, bismuthose, and similar preparations. ‘‘After the intestines have become quiet, diluted milk is given, best added to the tea; later to cereal waters, slowly, with constant regard to the condition of the tongue, the previous normal diet is again resumed.’’ Such complicated and carefully com- pounded prescriptions, containing tinct. opii and syrup cinnamomi were hardly changed from those recommended by Michael Under- wood (1737–1820) [England] a century before (12). Treatment was directed at prevention—‘‘nursing bottles when emptied by the infant should be filled with a saturated solution of sodium bicarbonate, allowed to stand for a few hours and then carefully washed inside and out with a bristle brush’’—but if diar- rhoea is persistent or progressive, rectal enemas were indicated to ‘‘remove any residue of faeces that may have collected and to stimulate peristalsis and thereby favour evacuation, and to stimulate the heart and add to the body an amount of normal solution [saline] to compensate for the drain caused by the diarrhoea. ...The injection of normal salt solution under the skin (hyperdermoclysis) is indicated only in severe cases in which the course of the disease is rapid and prostration extreme,’’ wrote Henry Koplik (1858–1927) [USA] (29). The search for pathogenic microorganisms was paramount, especially in cases of summer diarrhoea or cholera infantum. Streptococcus enteritidis attracted the greatest attention. However ‘‘the treatment of chronic disturbances of digestions requires much patience.’’ In tackling colitides and dysenteries, determination of the microorganisms involved employed the new science of immu- nology. Gaston Variot (1855–1930) [France] in his Traite´ Pratique des Maladies des Enfants du Premier Age (31) says ‘‘avec Rilliet et Barthez nous re´servons le terme de dysenterie, a` une maladie FIGURE 14. Soxhlet’s Milk Steriliser (1891). sporadique ou e´pide´mique caracte´rise´e cliniquement par des selles fre´quentes, muco-purulentes et sanguinolentes, et anatomiquement gr.) and syrup althaea 10 Gm. (2 dr.), teaspoonful every two hours; or par des le´sions ulce´reuses, sie´geant dans le gros intestin. ...Pour extract haematoxylin 5 Gm. (11/4dr.) to 100 c.c (3 oz.) water, tinct. e´tablir le diagnostic, il faudra tenir compte des conditions e´tiolo- catechu 3 Gm. (45 gr.), tinct. opii 20 to 25 drops, syrup cinnamomi giques, et recourir surtout aux proce´de´s de laboratoire. ...L’agglu- 15 Gm. (1/2 oz.); a teaspoonful every two hours; or extract Colombo tination due bacilli dysente´rique par le se´rum du malade a e´te´ utilize´ 2.5 to 3.5 Gm. (2/3 to 1 dr.) to 100 c.c (3 oz.) water with tinct. opii 20 pour le diagnostic.’’

FIGURE 15. L’Oeuvre de la Goutte de Lait showing Gaston Variot in the Bellville Dispensary, Paris. Print after Jean Geoffroy 1901. www.jpgn.org S15 Supplement JPGN  Volume 66, Supplement 1, April 2018

FIGURE 16. Cover of Jahrbuch fur Kinderheilkunde (1909) showing international European editors, including Biedert, Escherich, Finkelstein, Jacobi, Henoch, Hirschprung, and von Pirquet.

FIGURE 17. Theodore Escherich with his colleagues and students in Graz in 1902.

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variable des fausses membranes forme´e de mucin et de divers e´le´ments e´pithe´liaux et microbiens,’’ identified by microscopical examination of the mucus membrane. The same year the use of barium sulphate as a radio-opaque contrast medium to outline the luminal structure of the gut was pioneered by Paul Krause (1871– 1934) [Germany] (Fig. 18) (33). Biochemistry, microbiology, and radiology made the pipette, Petri dish and photo-plate essential tools of paediatrics. Describing chronic interstitial enteritis in children for the first time in 1913, Kennedy Dalziel (1861–1924) [Scotland] suspected it to be due to tuberculosis; but ‘‘a careful search has failed to reveal microorgan- isms of any kind’’ (34). He drew attention of ‘‘chronic bacterial enteritis of cattle, called pseudotuberculosis, in which the histolog- ical characters and naked-eye appearances are as similar as may be those we have found in man.’’ The tuberculin test (1906), invented by Clemens von Pirquet (1874–1929) [Austria] helped to detect exposure to the tubercle bacillus, but 40 years on from its identifi- cation, the debate between Robert Koch (1843–1910) [Germany] and Leon Calmette (1863–1933) [France] on the portal of its entry to the body of the (via respiratory or gastrointestinal tract) remained unresolved. Efforts to understand the metabolic disturbances associated with chronic diarrhoea and malnutrition—variously termed atro- phy, dystrophy, decomposition, athrepsia, intestinal intoxication— through competitive and collaborative research during the 1920s and 1930s. In Pfaundler and Schlossmann’s expanded 5-volume edition of the Diseases of Children of 1935, the ‘‘theories of the origin of dystrophy’’ were summarised under the headings of Ferment Deficiency Theory, Intoxication Theory, Demineralisation Theory, Inanition Theory, focusing on disturbances of milk diges- FIGURE 18. Radiogram of barium meal in 3-week-old infant with tion, ‘‘alimentary-toxic or infectious-toxic injury,’’ salt and water congenital stenosis of the duodenum (33). losses, and malabsorption and maldigestion. Heinrich Finkelstein’s (1865–1942) [Germany] in his Lehrbuch der Sa¨uglingskrankhei- Serology was required to identify and distinguish between ten (35), promoted eiweissmilch (casein-enriched milk). This was species of ‘‘bacille typhique’’ (George Widal 1862–1929) used to treat coeliac disease, also known as intestinal infantilism, [France] (test 1896), and ‘‘l’examen microscopique des selles’’ which was distinguished from pancreatic infantilism (cystic fibro- for amoeba. A vaccine for typhoid fever had been developed in sis) by microscopy of the stool: the excess of fat or its derivatives in 1896 by Almroth Wright (1861–1947) [England], and ‘‘le se´rum the former, and of unaltered starch in the latter. In 1936 Guido antidysente´rique (polyvalent),’’ along with ‘‘les purgatifs – huile Fanconi (1892–1927) [Switzerland] drew together the clinical de ricin, calomel, sulfate de soude ou magnesia, ...et ‘lavages de features and presentation of meconium ileus (Carl von Rokitansky l’intestin avec de l’eau de guimauve ou des solutions antiseptiques’’ 1804–1878) [Austria], bronchiectasis and chronic diarrhoea into were recommended as treatment. In Maladies du Tube Digestif,de the diagnosis of cystic fibrosis. La Pratique des Maladies des Enfants (32) edited by Rene´ Cruchet The diseases of the liver in children are allocated only 8 out (1875–1959) [France], Colite Muco-Membraneuse ‘‘est charac- of more than 600 pages in Henry Koplik’s Diseases of Infancy and te´rise´e par l’e´mission de selles glaireuses, contenant en proportion Childhood (29): jaundice and congenital obstruction of the bile

FIGURE 19. Method of palpating the projection of the liver below the ribs (29). www.jpgn.org S17 Supplement JPGN  Volume 66, Supplement 1, April 2018

FIGURE 20. Children with rickets outside the Royal Hospital for Sick Children, Glasgow. ducts, cirrhosis, fatty degeneration, syphilis, abscess, and tumours, in the inter- and post-world war periods championed the interests of to which are added 25 years later, in Wilfrid Sheldon’s Diseases of sick children. National societies of paediatrics had gastrointestinal Infancy and Childhood (1936), Von Gierke’s Disease (Fig. 19). sections, and international links between fellow clinicians were Apart from the biochemistry of jaundice (Jarmo Ylppo¨ 1887–1992) strengthened through the exchange of trainees, research collabora- [Finland] and the treatment of icterus, with calomel, enemas fresh tions and personal friendships. Medical insurance schemes and air and daily alkaline baths, no treatments of children’s liver national health services expanded access to hospital care, and diseases were specified. growth surveillance, vitamin supplementation, school health The aetiology of childhood rickets, long recognised as a and immunisation programmes improved the health of all children. disease of children (Francis Glisson 1599–1677) [England], and The discovery and clinical use of antibiotics, corticosteroids, vita- particularly prevalent in northern European cities, appeared unre- mins, new anaesthetics, and rational fluid management transformed sponsive to scientifically formulated dietary , until, as a the fortunes of many sick children in hospital. result of animal experimentation (Edward Mellanby 1884–1955 Endoscopy, special feeds and diets, parenteral nutrition, [England]), clinical trials (Harriette Chick 1875–1977 [England], functional diagnostic tests, luminal contrast studies, for instance, Clemens von Pirquet 1874–1929 [Austria], Kurt Huldschinsky all required laboratory support and expertise, stretching the capa- 1833–1940) [Germany]), and biochemistry (Frederick Gowland bilities of general paediatricians. Children’s hospitals and paediatric Hopkins 1861–1947) [England], it was shown to be due to vitamin departments facilitated the trend towards clinical specialisation, D deficiency (Fig. 20). This discovery was followed by the identi- driven by technological advances, such as the sweat test in 1953 fication of a series of other ‘‘accessory food factors’’ and the (Paul di Sant’ Agnese 1914–2005) [USA] and jejunal biopsy characterisation of a number of vitamin-deficiency diseases. capsule in 1957 (William Crosby 1914–2005) [USA]. The first use of the biopsy capsule in children by Jack Sakula (1908–1982) and Margot Shiner (1923–1998) (37) [England, Germany], CONCLUSIONS ‘‘made a very big difference to intestinal studies and gave paediatric The enormous advances in our understanding of infectious gastroenterology a quantum leap,’’ according to Charlotte Ander- diseases and nutritional disturbances to the health, welfare, growth, son (1915–2002) (38) [], opening the way to tissue and development of children between 1850 and 1950, when paedi- diagnosis as well as to the study of the gut mucosa in health and atrics was born and came of age, made the gastrointestinal tract, as disease (39). the organ of nutrition, of vital interest to paediatricians (36). The foundation of ESPGAN in 1968 by a small group of Although the aetiology of many children’s digestive diseases were European paediatricians and biochemists sharing their personal determined, and scientifically based treatments were available, clinical knowledge, skills, and expertise, coincided with a transition improvements in , hygiene, nutritional support, and food from a medicine based on classical physiology, biochemistry, and supplementation were the chief contributors to their prevention and histopathology into one in which evidence-based medicine bol- better outcome. stered by technology, multiprofessional teams, noninvasive imag- International and European organisations, including the ing and systematic reviews, disseminating the latest advances in the International Paediatric Association, WHO, and UNICEF, formed application and outcomes of clinical trials, molecular ,

S18 www.jpgn.org JPGN  Volume 66, Supplement 1, April 2018 Supplement , biologic therapies, and designer drugs. ESP- 18. Bichat MFX. Recherches Physiologiques sur la Vie et la Mort. Paris: GHAN has been the parent, child, and midwife of a new clinical Brosson, Gabon; 1800. specialty, and the next chapters tell the story of its origin, growth, 19. Rilliet F, Barthez A. Traite´ Clinique et Pratique de Maladies des Enfants. and development, and give accounts of the contributions of its Paris: Germer Baillie`re; 1843:1853, 1863. members to the recent history of the science and practice of 20. Liebig J. Animal Chemistry or Organic Chemistry in its Application to paediatric gastroenterology, hepatology, and nutrition. Physiology and Pathology (trans Gregory W). Cambridge: John Owen; 1842. 21. Steggall J. A Manual for Students Preparing for Examination at Acknowledgments: I thank John Walker-Smith, Olle Hernell, Apothecaries Hall. London: John Churchill; 1838. Michael Lentze, and Malcolm Nicolson for their helpful comments, 22. Bernard C. Introduction a` L’etude de la Me´decine Expe´rimentale. Paris: and the Wellcome Trust for permission to reproduce Figure 13. J-B Baillie`re; 1865. 23. Anon. Editorial. The murder of the innocents. Lancet 1858;i:345–6. REFERENCES 24. Schneider D, Macey SM. Historical geography of medical care and 1. Still GF. The History of Paediatrics. Oxford: Oxford University Press; facilities for infants and children. Focus on Geography 2004;48:9–17. . 1931. 25. Budin P. Le Nourisson. Paris: O Doin; 1900 2. Bynum WF. The History of Medicine: A Very Short Introduction. 26. Rotch T. Pediatrics: the Hygiene and Medical Treatment of Children . Oxford: Oxford University Press; 2008. Philadelphia: JB Lippincott; 1896 3. Bagellardo P. Libellus de Egritudinibus Infantum. Padua: 1472. 27. Tanner JM. A History of the Study of Human Growth. Cambridge: 4. Metlinger B. Ein Regiment der Jungen Kinder. Augsburg: 1473. Cambridge University Press; 1981. St Bartholomew’s Hospital Reports 5. Ruhrah J. Pediatrics of the Past. New York: Paul Hoeber; 1925. 28. Gee SJ. On the coeliac affection. 6. St Marthe S. Paedotrophia or the Art of Nursing and Rearing Children 1888;24:17–20. (trans Tytler HW). Edinburgh: Bell and Bradfute; 1798. 29. Koplik H. The Diseases of Infancy and Childhood. London: Henry 7. Phayre T. The Boke of Chyldren. London: 1545. Kimpton; 1910. 8. Harris W. De Morbis Acutis Infantum (trans Cockburn W). London: 30. Pfaundler M. Arthur Schlossmann A, eds. Handbuch der Kinderheilk- unde (trans Shaw HLK, La Fe´tra L) Sam Clement; 1689. . London: JB Lippincott; 1908 ´ 9. Garrison FH. History of Pediatrics. In: Abt IA, ed. Abt’s Paediatrics. 31. Variot G. Traite Pratique des Maladies des Enfants du Premier Age. . Philadelphia: Saunders; 1923. Paris: Libraire Octave Doin; 1921 ` 10. Rosenstein NR. The Diseases of Children and their Remedies (trans 32. Cruchet R. La Pratique des Maladies des Enfants. Paris: J-B Bailliere; . Sparrman A). London: T Cadell; 1776. 1910 11. Armstrong G. Account of the Diseases Most Incident to Children. 33. Thomson J, Findlay L. The Clinical Study and Treatment of Sick . London: T. Cadell; 1783. Children. Edinburgh: Oliver & Boyd; 1933 12. Underwood M. Treatise on the Diseases of Children. London: Callow 34. Dalziel TK. Chronic interstitial enteritis. BMJ 1913;2:1068–70. ¨ and Wilson; 1827. 35. Finkelstein H. Lehrbuch der Sauglingskrankheiten. : Verlag von 13. Buchan W. Domestic Medicine. Edinburgh: Balfour, Auld, Smellie; Julius Springer; 1924. History of Pediatrics 1769. 36. Nichols BL, Ballabriga A, Kretchmer N (Eds): 14. Fourcroy A. Encyclope´die Me´thodique Me´decine. Paris: Chez Panck- 1850–1950. Raven Press: New York; 1991. oucke; 1789. 37. Sakula J, Shiner M. Coeliac disease with atrophy of the small-intestine 15. Weaver LT. The coming of children’s hospitals. In: Hutchison I, mucosa. Lancet 1957;2:876–7. Nicolson M, Weaver LT, eds. A History of Glasgow’s Royal Hospital 38. Walker-Smith J. The role of small intestinal biopsy in the development Gastro- for Sick Children. Glasgow: Scottish History Press; 2015:3–25. of paediatric gastroenterology in Britain. In: Bynum WF, ed. 16. Morgagni GB. De Sedibus et Causis Morborum per Anatomen Inga- enterology in Britain. London: Wellcome Institute for History of . gatis. Venice: Typographica Remondini; 1761. Medicine; 1997:124–33 17. Billard C-M. Traite´ des Maladies des Enfants Nouveau-Ne´seta` la 39. Walker-Smith J, Walker WA, eds. A Concise History of Paediatric Gastroenterology Mamelle. Paris: J-B Baillie`re; 1828. . Plymouth: Bladon Medical Publishing; 2004.

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Chapter 2. ESPGHAN: 50 Years Memories— The Early Years

Michael J. Lentze, ySalvatore Auricchio, zSamy Cadranel, §Peter J. Milla, jjDeirdre Kelly, ôAlexander S. McNeish, #Jean Rey, #Jacques Schmitz, Birgitta Strandvik, yyJan Taminiau, and zzJarmo Visakorpi

ABSTRACT

Thirty-six founding members from Europe were present in 1968, when the European Society of Paediatric Gastroenterology (ESGA) had its first meeting in Paris. The aim was to create a forum for presentations and discussions of research activities in paediatric gastroenterology in Europe. At the second meeting of ESGA 1969 in Interlaken, an important landmark was set for all gastroenterologists in the world. In this conference, the first ever criteria for ‘‘the Diagnosis of Coeliac Disease’’ (CD) were established. In 1990, the revised criteria for the diagnosis of CD were published. After the introduction of new noninvasive techniques, like tissue transglutaminase 2- antibodies and the HLADQ2/HLADQ8 determinations in blood, ‘‘new’’ criteria for the diagnosis of CD were published in 2012 by the European society of Paediatric Gastroenterology, Hepatology and Nutrition (ESP- GHAN). Close collaboration of ESPGHAN and the North American Society of Paediatric Gastroenterology, Hepatology and Nutrition led to mutual meetings. The first combined meeting was 1978 in Paris, followed by meetings in New York, Amsterdam, Houston, and last in Toulouse. The first World Congress of Paediatric Gastroenterology took place in Boston 2000 followed by congresses in Paris, Iguazu, Taipeh, and Toronto. The creation of specialised committees (Nutrition Committees, GI-Committee, and Hepatology-Committee) enabled the society to elaborate numerous guidelines for standards in the diagnosis and treatment of diseases within the . The Journal of Paediatric Gastroenterology and Nutri- tion, as organ of ESPGHAN and the North American Society of Paediatric Gastroenterology, Hepatology and Nutrition since 1991, serves as the voice for these worldwide accepted guidelines. Growing educational activities with summer schools, the Young Investigator Forum and the creation of working groups have distributed our current knowledge among the younger generation and led to fruitful reports, guidelines, and syllabus. In 1992, ESPGHAN was 1 of the founding 7 members of the United European Gastroenterology Federation (UEGF), which developed into a successful FIGURE 1. Michael J. Lentze. organisation for gastroenterology in Europe. This year we celebrate the 50th anniversary of ESPGHAN at our annual Meeting in Geneva. Key Words: ESPGHAN, early years, 50th anniversary pecialisation in the field of paediatrics was a much slower process after the Second World War than that in internal (JPGN 2018;66: S20–S28) medicine.S Organ-related subspecialties in paediatrics developed in the 1950s and 1960s, among them paediatric gastroenterology.

Received January 24, 2018; accepted January 29, 2018. From the Department Paediatrics, University Hospitals, Bonn, Address correspondence and reprint requests to Michael J. Lentze, MD, Germany, the yDepartment Paediatrics, University of Naples Emeritus Professor of Paediatrics, Department Paediatrics, University Federico II, Italy, the zDepartment of Paediatric Gastroenterology, Queen Hospitals, Bonn, Germany, Adenauerallee 119, D-53113 Bonn Fabiola University Children’s Hospital, Bruxelles, Belgium, the §UCL (e-mail: [email protected]). Institute of Child Health, University College, London, the jjLiver Unit, The authors report no conflicts of interest. Birmingham Childrens Hospital and University, the ôInstitute of Child Copyright # 2018 by European Society for Pediatric Gastroenterology, Health, , Birmingham, UK, the #Hoˆpital Necker Hepatology, and Nutrition and North American Society for Pediatric Enfants Malades-University Paris Descartes, France, the Department of Gastroenterology, Hepatology, and Nutrition Bioscience and Nutrition, Karolinska Institutet, Novum, Stockholm, DOI: 10.1097/MPG.0000000000001912 Sweden, the yyAMC, University of Amsterdam, Netherlands, and the zzDepartment Paediatrics, University of Tampere, Finland.

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Although some meetings and conferences devoted to topics in paediatric gastroenterology took place in paediatric departments in Europe, the need for more regular meetings of paediatricians and researchers with common interests in paediatric gastroenterology to provide a mutual platform for the exchange of experiences and ideas, was growing. The initiative to build this platform was taken by Dolf Weijers (Fig. 2) in November 1967, by inviting Bertil Lindquist and Jean Rey to Utrecht to discuss the foundation of a society for paediatric gastroenterology. Dolf Weijers was perhaps the first paediatric gastroenterologist in Europe. The trigger for his initiative was probably the initiation of the European Society for Paediatric by Harm Tiddens, his colleague, at the Wilhelmina Children’s Hospital in Utrecht (The Netherlands). Dolf Weijers’ colleague, Jan van de Kamer, was also present at the meeting (incidentally). He was a pharmacist of great talent and had described a method for the determination of fat in faeces named after him, working closely with Weijers on the fat absorption in the healthy and in patients with coeliac disease (Fig. 3). Jan van de Kamer was not only a pharmacist, but also a musician and ‘‘musi- cologist.’’ At the time of the meeting he was working on ‘‘The Magic Flute.’’ The main item on the agenda was to agree on the aims of the proposed Society and the criteria for membership. The structure and constitution of the Society were also discussed.

AIM OF THE SOCIETY The aim was to create a forum for the presentation and discussion of the research activities being pursued in paediatric gastroenterology in Europe. Because of the close relationship between research in gastroenterology and nutrition, it was agreed that the Society should concern itself with clinical nutrition as well as gastroenterology. Both disciplines were therefore included in the constitution as fields of interests of the Society from its beginning. For the sake of simplicity, however, it was decided that the name of

FIGURE 3. Dolf Weijers at his PhD thesis defence, with Jan van de Kamer, in 1950. Photo: Jan Taminiau.

the Society should reflect the discipline in which, at that time, research was most active: paediatric gastroenterology. It was further agreed that the society should carry some responsibility for the dissemination of knowledge in paediatric gastroenterology and clinical nutrition throughout Europe. This objective of the society—its ‘‘missionary function’’—remained a subject of debate by the membership for many years. At a council meeting in 1975, it was agreed that the selection of papers for presentation at meetings should be based solely on scientific criteria and not on its ‘‘missionary function.’’ In later years, however, the ‘‘missionary function’’ was recognised by the publications of numerous guidelines and the European society of Paediatric Gastro- enterology, Hepatology and Nutrition (ESPGHAN) summer schools.

MEMBERSHIP AND ATTENDANCE AT MEETINGS It was agreed that anyone working in paediatric gastroenter- ology and/or clinical nutrition should be allowed to attend the meetings of the Society, either as a member or their guests. It was further agreed that membership should not be strictly confined to researchers but also include those whose main interest was clinical paediatric gastroenterology. This decision was reached because, at that time, clinical and basic research in the gastroenterology and FIGURE 2. Dolf Weijers, First President 1968–1972. Photo: Jean Rey. nutrition was not being pursued in all European countries. It was www.jpgn.org S21 Supplement JPGN Volume 66, Supplement 1, April 2018 regarded as important for the Society to represent all of these the constitution, it was decided that the Society’s membership countries. In this way the Society hoped to promote the extension would also be open to colleagues from basic sciences (biochemistry, of research and knowledge in paediatric gastroenterology and physiology, pathology, etc) with close professional links with the clinical nutrition throughout Europe. clinical group. To the first Council of ESPGA were elected Dolf Weijers (President), Bertil Lindquist (Secretary), Charlotte Anderson, Sal- FOUNDER MEMBERS vatore Auricchio, and Jean Rey. Gunnar Meeuwisse was appointed It was decided that letters of invitation for founder member- Assistant Secretary. The scientific part of the meeting lasted 2 days, ship would be sent, by those present in Utrecht, to paediatricians in which 20 oral presentations were given, each 25 minutes with 5 recognized for their scientific contributions to paediatric gastroen- minutes of discussions. Two of the 5 sessions were dedicated to terology and/or clinical nutrition. In order to avoid geographical coeliac disease, which played from the start a major role within our exclusiveness, it was agreed to approach some well-known chair- society. The abstracts of the first ESPGA meeting were published in men of major paediatric departments in Europe requesting propos- Acta Paediatrica Scandinavica 1969 (1). als for membership of colleagues with excellent qualifications and a deep interest in the disciplines served by the Society. THE EARLY YEARS Bertil Lindquist volunteered to do the secretarial work of In the very first years the Council meetings were held ‘‘Chez setting up the new society. Thirty-four colleagues were offered les Weijers’’ in Utrecht, where everyone was made to feel part of founder membership and invited to the first meeting of the Society, the family. It was sometimes difficult to reach majority decisions, as which Jean Rey agreed to organise in Paris 1968. The 36 founder in general 4 Council members were present (Charlotte Anderson, members, who all attended the first meeting in Paris in 1968, were Dolf Weijers, Bertil Lindquist, and Jean Rey). To resolve the Charlotte Anderson (England), Salvatore Auricchio (Italy), problem of majority—and as a last resort—the secretary, Bertil Ephraim Eggermont (Belgium), Jean Frezal (France), Rolf Gru¨ttner Lindquist, said on one occasion that if the assistant secretary, (Germany), Beat Hadorn (Switzerland), Aaron Holzel (England), Gunnar Meeuwisse, had been present at the meeting, he would Pirkko Immonen-Pelkonen (Finland), Jiri Jodl (Slovakia), Joseph certainly have voted as he (Bertil) did. It should be mentioned that at Jos (France), Jan van de Kamer (Netherlands), Herbert Kayden that time Gunnar Meeuwisse was an Associate Professor in Bertil (USA), Peter Krasilnikoff (Denmark), Maurice Lamy (France), Lindquist’s department (Figs. 4 and 5). Thor Lindberg (Sweden), Bertil Lindquist (Sweden), June Lloyd In 1969, at the second meeting of ESPGA in Interlaken, an (England), Helmut Loeb (Belgium), Gunnar Meeuwisse (Sweden), important landmark was set for all gastroenterologists, paediatric Sergio Nordio (Italy), Daniel Nu¨ssle´ (Switzerland), Wolfgang and adult, in the world. In a round table conference, chaired by Dolf Plenert (DDR), Claude Polonovski (France), Andrea Prader Weijers, the first ever criteria for ‘‘the Diagnosis of Coeliac (Switzerland), Jean Rey (France), Ettore Rossi (Switzerland), Pierre Disease’’ were established. For the conference Jarmo Visakorpi Royer (France), Armido Rubino (Italy) Otto Saxl (Czechoslovakia), prepared an international inquiry of 33 centres on the topic (2). The David Shmerling (Switzerland), Arne Sto¨ren (Norway), Jarmo diagnostic criteria agreed at this conference have come to be Visakorpi (Finland), Erik A.K. Wauters (Netherlands), Dolf Wei- referred worldwide by scientists and clinicians as the ‘‘Interlaken jers (Netherlands), Lars Wranne (Sweden), and Giorgio Zoppi Criteria of Coeliac Disease’’ and were published 1970 (3). Since (Italy). that time the topic of coeliac disease has always been a major focus of ESPGHAN. In 1977, a follow-up round table workshop, dedi- FIRST EUROPEAN SOCIETY FOR PAEDIATRIC cated to our first President Dolf Weijers who died in 1972, was GASTROENTEROLOGY MEETING IN PARIS organised in Utrecht at the annual meeting. The second round table workshop consisted of David Shmerling, Karsten Harms, Sandy IN 1968 McNeish, Jarmo Visakorpi, and John Walker-Smith. After a survey The first meeting of the new society was planned to take of 51 centres in Europe, conducted by David Shmerling, a com- place in Paris in October 1968. However, in the springtime of that mentary was prepared by Sandy McNeish on ‘‘The Diagnosis of year no one was sure whether it could really occur. In the middle of May the whole of France was on strike. Barricades were erected each night and the petrol pumps were dry. However, the petrol suddenly began to flow again on the eve of Whit Sunday. The French were able to leave for the weekend. The first meeting of European Society for Paediatric Gastroenterology (ESPGA) became possible and happened. Based on the discussions in Utrecht and consultation with some of the founding members, proposals for a constitution had been prepared and were accepted on the October 4, 1968 by those assembled in Paris. It was agreed that the new society should be called the ‘‘European Society for Paediatric Gastroenterology’’ (ESPGA). The constitution was hardly discussed at all. Not because no one was interested in discussing it, but because the organizer of the Paris meeting, Jean Rey, did not give participants time to open their mouths. ‘‘Have you any comments or questions on the constitu- tion?’’ he asked. A short silence. ‘‘No?’’ An even shorter silence. ‘‘The constitution is adopted,’’ he declared, banging his fist on the table, like an auctioneer delighted to have got rid of a knick-knack. FIGURE 4. Informal discussion between Dolf Weijers and Bertil Lind- None of the members present have got over it. (Yet many feel that quist walking in the Wilhelmina Park at the Council Meeting in Utrecht Jean was more democratic than Bertil.) As an addition to the rules in 1970. Photo: Jean Rey.

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Paris, the revised criteria for the diagnosis of coeliac disease, prepared by John Walker-Smith (Fig. 6) were published in 1990 (5). Discussion of the diagnostic criteria for coeliac disease within the working group of ESPGHAN continued over the years, owing to new noninvasive techniques like tissue transglutaminase 2-antibodies and the HLADQ2 and HLADQ8 determinations in blood. This led to the publication of the ‘‘new’’ criteria by the working group of coeliac disease of ESPGHAN in 2012 (6). In 1978, the first European Society for Paediatric Gastroen- terology and Nutrition (ESPGAN) meeting together with our American colleagues from the North American Society for Paedi- atric Gastroenterology (NASPG) took place in Paris. The main topic was gastroenteritis. John Fordtran, Mike Field, Henry Binder, and John Rhode were establishing the role of bacterial toxins producing massive diarrhoea. John Rhode demonstrated the application of basic GI-Physiology to the treatment of a lethal condition, that is, FIGURE 5. Dolf Weijers, Bertil Lindquist, and Charlotte Anderson at an cholera. When John Rhode was a research fellow in Calcutta during intermission of the Council Meeting in the Wilhelmina Park Pavilion, a massive outbreak of cholera, his wife told him that, if he believed Utrecht, May 1970. Photo: Jean Rey. in his research, he should load an aeroplane full of oral rehydration solution and take it to those afflicted. Other eminent paediatric Coeliac Disease.’’ A commentary on the current practices of gastroenterologists and nutritionists from both sides of the Atlantic, members of ESPGA was published 1979 (4) with the conclusion, including John Harries, Jean Rey, Bertil Lindquist, Margot Shiner, that the Interlaken Criteria, which stated ‘‘the only decisive criteria Dick Grand, Charlotte Anderson, Brian Wharton, Armido Rubino, are an abnormal pathology of the small intestinal mucosa, its and Anne Ferguson took part in the meeting (Figs. 7–11). In 1990, normalization on gluten withdrawal and the reaction on reintroduc- the Annual General Meeting (AGM) in Amsterdam decided to add tion of gluten,’’ were still useful. But not all centres were conduct- the ‘‘H’’ for hepatology into the name of ESPGAN, since when ing the full gluten challenge procedure. In addition, the so-called ‘‘2 ESPGHAN has been the official name of the Society. years rule,’’ which says that a normal jejunal biopsy after 2 years of a normal diet excluded coeliac disease, was in fact not correct. Some patients had been reported to relapse after that period. NUTRITION COMMITTEE These objections to the Interlaken Criteria let to the creation At the annual meeting in Verona in 1974, Bertil Lindquist of a working group on coeliac disease under the presidency of suggested the formation of a nutrition committee. The first Com- Salvatore Auricchio. A third round table workshop discussion on mittee of Nutrition (CoN) consisted of Bertil Lindquist (chairman), diagnostic criteria of coeliac disease was conducted in 1989 in Jarmo Visakorpi (secretary), Beat Hadorn, Sergio Nordio, Jean Rey, Budapest. The speakers were Stefano Guandalini, Luigi Greco, and Otto Wolff. Later Angel Balabriga, Wolfgang Plenert, and Tadeusz Zalewski, Isabel Polanco, Jacques Schmitz, David Shmer- Eberhard Schmidt joined the committee and June Lloyd was ling, and Jarmo Viskorpi. After a subsequent committee meeting in appointed permanent adviser. The first task was to lay down

FIGURE 6. Committee for the revision of the diagnostic criteria of coeliac disease, meeting in Paris on 14th October 1989. Picture taken at the home of Jacques Schmitz. From left Stefano Guandalini, David Shmerling, John Walker-Smith, Jacques Schmitz and Jarmo Visakorpi. Photo: Jarmo Visakorpi. www.jpgn.org S23 Supplement JPGN Volume 66, Supplement 1, April 2018

FIGURE 7. Giorgio Semenza and John Harries, Paris 1978. Photo: Jean Rey. guidelines on infant nutrition. The CoN between 1974 and 1976 had numerous meetings throughout Europe. Altogether the committee FIGURE 9. Margot Shiner (middle) and Dick Grand (right), Paris members travelled 250,000 km. 1978. Photo: Jean Rey. The second major achievement during the early years of ESPGHAN was set by this Committee of Nutrition. The first part of guidelines in the field of child nutrition (see Chapter 7). The the guidelines was almost ready in 1976 and published as ‘‘Recom- concepts and scientific standards developed by the CoN over 4 mendations for the Composition of an Adapted Formula’’ in 1977 decades have had a major impact on the feeding practice of infants (7). Part II: ‘‘Recommendations for the Composition of Follow-up and young children in Europe and the world. formula and Beikost,’’ and Part III: ‘‘Recommendation for Infant Feeding’’ followed in 1981 (8) and (1982) (9). June Lloyd did the COMMITTEE OF GASTROENTEROLOGY AND enormous work of translating the ‘‘committee’’ English into ‘‘stan- dard’’ English. At the annual meeting in Weimar in 1976 it was COMMITTEE OF HEPATOLOGY agreed that the Society’s name would be changed to ESPGAN. The enormous success of the publications in nutrition and on In 1979 during a committee meeting in Du¨sseldorf, a com- coeliac disease led to intensive discussion on how to facilitate mittee was appointed to prepare guidelines on the enteral feeding of clinical and scientific knowledge by writing and publishing author- low birth weight infants. The members, Hans Bremer, Oliver itative commentaries of clinical and scientific relevance to pertinent Brooke, Marcello Orzalesi, Guy Putet, Niels Ra¨iha¨, Jacques Sen- questions in paediatric gastroenterology and hepatology. In 2004, terre, Jonathan Shaw, and Brian Wharton (chairman) published in the Committees of Gastroenterology and Hepatology were formed 1987 an extensive review on the nutritional needs and feeding and started their work in this direction with the promotion of high- recommendations for preterm infants as a supplement in Acta quality research and training in paediatric gastroenterology, by Paediatrica Scandinavica (10), which had a worldwide impact. organising workshops, scientific meetings, and training courses. 1986 to 1989 were the years of the ‘‘Second’’ Nutrition Committee of ESPGAN, established during the presidency of Salvatore Auricchio (1986–1989) with Jean Rey as chairman and Peter Aggett as secretary. Since that time the CoN has contin- ued its successful work and published up to today 48 statements and

FIGURE 10. Charlotte Anderson and Brian Wharton, Paris 1978. FIGURE 8. Jean Rey and Bertil Lindquist, Paris 1978. Photo: Jean Rey. Photo: Jean Rey.

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The working group on coeliac disease created a subcommit- tee (John Walker-Smith, Stefano Guandalini, David Shmerling, and Jarmo Visakorpi), which published the revised criteria for the diagnosis of coeliac disease in 1990 (4) (Fig. 6). In 1993, the subcommittee (Jarmo Visakorpi, Luigi Greco, and Markku Ma¨ki) published the results of a multicenter study on the of coeliac disease in Europe in a book (Common Food Intolerance 1: Epidemiology of Food intolerance, Karger). The working group for food published ‘‘Diagnostic criteria for food allergy with predominantly intestinal symptoms’’ in 1992 (11). The hepatology working group discussed the status of sclerosing cholangitis in Copenhagen in 1989 with the intention of encouraging cooperative studies in different centres. This was discussed at the 1990 meeting in Amsterdam and in Brussels in 1992 there was an excellent summary of the outcome of hepatitis B infection and the efficacy of interferon therapy. Between 1989 and 1992 the number of working groups increased every year. At the annual meeting in Brussels in 1992, 7 working groups presented their work in work- shops: coeliac disease (J. Visakorpi), IBD treatment (J. Taminiau), gastro-esophageal reflux (Y. Vandenplas), hepatology (A. Mowat), Helicobacter pylori (S. Cadranel), congenital transport defects (Jean-Francois Desjeux), and oral rehydration (John A. Walker- Smith). In the 24 years, thereafter the number of working groups steadily increased to 22 altogether (gastroenterology 11, hepatology 6, nutrition 5). See reference at: http://www.espghan.org/about- espghan/committees/groups/.

SUMMER SCHOOLS AND YOUNG INVESTIGATORS Charlotte Anderson and Sandy McNeish organised a course on FIGURE 11. Armido Rubino and Anne Ferguson, Paris 1978. Photo: paediatric gastroenterology in the early 1970s on behalf of the British Jean Rey. Council. In 1985, there was a second British Council course in Birming- hamorganisedbySandyMcNeish.JohnHarrieshaddiedtheyearbefore so Sandy invited Peter Milla to be the co-organiser of that course. Altogether both committees have published 17 position papers or Already by 1988 educational and training activities of ESP- guidelines on various topics within the 2 subspecialties. The posi- GAN were discussed in council meetings. At the Council meeting in tion papers and guidelines have gained high international reputa- Vevey in 1988, Peter Milla proposed the first postgraduate ‘‘Sum- tions and are cited widely in the scientific literature (see: http:// mer School,’’ together with Sandy McNeish, which was approved www.espghan.org/guidelines/gastroenterology and http://www.esp- enthusiastically at the AGM in Copenhagen in 1988. Held in ghan.org/guidelines/hepatology/) Birmingham 1990 during the time of the football world champion- ship in Italy, the first ‘‘Summer School’’ was a great success. All participants and teachers were invited to Sandy McNe- WORKING GROUPS ish’s house for dinner on the evening of the semifinal game between Between 1982 and 1989 a number of lively discussions took England and Germany. To pay tribute to the football fans a small place at annual meetings. Some groups of members, who were television set was put up in a small room. When Sandy McNeish’s pursuing common areas of research, felt the need to discuss mother came into the dining room asking: ‘‘Who is this crazy problematic technical issues among themselves. There was great German Professor (Michael J. Lentze) shouting all the time,’’ interest in this form of discussion for the interchange of information. everyone joined the ‘‘crazy’’ football fan in the small room watch- The rest of the Society found it attractive, in spite of its irrelevance ing this exciting game, which was won by Germany after a penalty to many of them. The original group of members had only intended shoot-out 4:3. Since the start of that summer school a large number the exchange of methodological information. This resulted in of schools followed over the years and master classes and eLearning discussions during council meetings on the future life of the society. classes within our subspecialties were developed. Stimulated by the success of the definition of the criteria for the In addition to the postgraduate trainings activities at summer diagnosis of coeliac disease and the guidelines for infant nutrition, schools held in ‘‘Western’’ Europe, an Eastern European Summer members of Council were convinced that in many other fields the School was initiated by Jacques Schmitz to bring educational ESP- Society could play an important role in defining guidelines for the GAN activities to countries that were experiencing the political diagnosis and treatment of diseases, conducting epidemiological changes that followed the break-up of the Soviet Union. The first surveys and standardizing diagnostic procedures. Following the Eastern European Summer Schools took place in 1994 in Budapest original suggestion of Salvatore Auricchio and Jacques Schmitz and Bialystok (Poland). Council appointed an additional member the creation of working groups was proposed. At the AGM in responsible for the organization of the Eastern Summer Schools. The Copenhagen in May 1988 the creation of 3 working groups was Eastern European representatives in the early years were Andrzej agreed: Diagnostic Criteria for Coeliac Disease (chairman Jarmo Radzikowski, Hedvig Bodansky, Tamara Vucovic, Hania Szajewska, Visakorpi), Diagnostic Criteria for Protein Sensitization (chairman Sanja Kolacek, Andras Arato, and Dusanka Micetic-Turk. In later Erkki Savilahti), and Liver Disease (chairman Alex Mowat). years, the Eastern European Summer Schools were integrated into the www.jpgn.org S25 Supplement JPGN Volume 66, Supplement 1, April 2018

Summer Schools. These Eastern Summer Schools achieved great popularity within our Society in former Soviet countries and were followed by an increase in memberships from this part of Europe. In 2009, the title of the portfolio of council member respon- sible for these teaching activities was changed by Council to ‘‘International Affairs.’’ Louisa Me´arin and Jerney Dolinsek repre- sented it in Council, extending ESPGHAN teaching meetings in Indonesia and Africa. The vision of many presidents and council members, that teaching should not be restricted to Europe but focus on global teaching activities, has led to various international teaching activities in Asia and Africa.

YOUNG INVESTIGATOR FORUM Based on the success of the Young Investigator Forums (YIF) in the United States, Deirdre Kelly, who experienced them during her time in Omaha, came up with the idea to start a similar activity within ESPGHAN. She and Hans Buller initiated them in 1994. The forums were sponsored by Nutricia and later Danone and were always held in the Netherlands at different venues in 1996, 1997, 1999, 2000, and later every 2 years. They were designed to nurture academic development in the Society and foster collabora- tions among the emerging generations of academics and clinicians. Over the years YIF has seen many individuals, their juniors and team members develop into established academics and clinicians as well as foster warm friendships and collaborations across Europe. In 2007 the organisation of YIFs was taken over to Alan Phillips and Louisa Me´arin and later to Nikhil Thapar, Lissy de Ridder, and Florence Laicaille. FIGURE 12. Alex Mowat 1935–1995.

ESPGHAN PRIZES annual meeting thoroughly and made the memories of the John Harries Prize ‘‘Mowats’’ unforgettable. Alex Mowat died much too early in John Harries had worked successfully at The Hospital for 1995 during a lecture tour in Chile. To remember one of the Sick Children at Great Ormond Street and the Institute of Child founders of paediatric hepatology the Alex Mowat Prize was Health as a paediatric gastroenterologist (Fig. 7). He had joined initiated in 1997. Since then 20 prizes have been awarded for ESPGHAN, which he loved very much, early in his career. He the best presentation in paediatric hepatology at annual meetings. inspired many young men and women within the Society, who in later years rose to the highest positions as academics, clinicians, and scientific investigators. Shortly after his premature death in 1983, Jean Rey Prize the John Harries Memorial Fund was established. At the 1985 Six years after the foundation of ESPGHAN in 1968 the first meeting in New York, the Society proposed that the most appro- Nutrition Committee was created at the seventh annual meeting in priate use of this memorial fund would be the endowment of a prize Verona 1974. Jean Rey and Bertil Lindquist, who were both for the best presentation at the annual meeting by a young investi- founding members of our Society, joined the nutrition committee gator. The first John Harries Prize was awarded at the annual together with Jarmo Visakorpi, Beat Hadorn, Sergio Nordio, Otto meeting in Edinburgh in 1986 to Irene Axelsson. Since then 31 Wolf, Angel Balabriga, June Lloyd, Wolfgang Plenert, and Eber- more prizes for the best presentation in paediatric gastroenterology hardt Schmidt, until 1986. In the same year the ‘‘new’’ Nutrition have been awarded. Committee was established with Jean Rey as chairman until 1994. Overall, Jean Rey served successfully in the nutrition committees of Alex Mowat Prize ESPGHAN for 20 years. To honour his long outstanding and productive work in the field of paediatric nutrition, the Jean Rey Alexander Parker Mowat (Fig. 12), born in Cullen, Banff- Prize was instituted in 1994. Since then 24 prizes have awarded for shire, was proud of his Scottish ancestry. After his medical educa- the best presentation in paediatric nutrition at annual meetings. tion in Aberdeen and clinical appointments in the 1960s in Aberdeen, Hong Kong, and New York, he joined the Kings College Hospital in 1970 as consultant paediatrician and paediatric hepa- JOURNAL OF PAEDIATRIC tologist. In 1993, he became head of the Department Child Health, GASTROENTEROLOGY AND NUTRITION King’s College Hospital. Although there had previously been no In 1982, Prof Emanuel Lebenthal together with Prof. Ettore sustained academic interest in liver disorders in children in Britain, Rossi founded the Journal of Paediatric Gastroenterology and Mowat developed a first-class clinical unit for children who expe- Nutrition as the first scientific journal in this subspecialty. Nine rienced these rare conditions. He joined ESPGHAN early in his years later the journal became the official organ of 2 distinguished career and was ‘‘the’’ representative of paediatric hepatology for societies representing our subspecialties, ESPGHAN and the North many years within the Society. His medical unit at Kings achieved American Society of Paediatric Gastroenterology, Hepatology and broad international recognition and many members of the Society Nutrition (NASPGHAN). The first Editors from ESPGHAN and were trained under his supervision. He and his wife Ann enjoyed our NASPGHAN were Michael J. Lentze and William F. Balistreri,

S26 www.jpgn.org JPGN Volume 66, Supplement 1, April 2018 Supplement followed over the years by Allen W. Walker (1995), Judith Sond- of clinical expertise in the treatment of gastrointestinal-related heimer (2001), Eric Sibley (2005), and Melvin Heyman (2010) on disease (12). Today ESPGHAN is involved in numerous UEGF the American side of the office and by John Walker-Smith (1995), initiatives, with representation in the Scientific, Education, and Jehan-Francois De´sjeux (2001), Alfredo Guarino (2005), David Future Trends Committee and the General Assembly. Branski (2010), Raanan Shamir (2013), and Hania Szajewska (2015) on the European side of the office. The last 26 years of JPGN as organ of ESPGHAN and NASPGHAN have been a story THE EUROPEAN SOCIETY OF PAEDIATRIC of success. To become the leading journal in paediatric gastroen- GASTROENTEROLOGY, HEPATOLOGY AND terology, hepatology, and nutrition is the result of endless hard work NUTRITION ‘‘FAMILY’’ by members of the 2 societies. Thanks to them and the thoughtful In the early years of the Society, the number of members was guiding work of all chief editors and associated editors from both small and attendance for nonmembers was restricted by invitation. sides of the Atlantic, the journal has its place in the scientific The constitution at that time stated: ‘‘A member wishing to introduce community and is firmly established. Numerous guidelines in our a guest at a meeting will submit the name of the guest and the title of subspecialties published in JPGN have established highly respected his/her paper, if any, to the organizer of the next meeting at least three standards as to diagnose and treat children in the world. months prior to the meeting.’’ In order to become a member the candidate had to present 2 oral papers to the annual meeting of the Society. So the Society at that time was more or less a closed shop and UNITED EUROPEAN GASTROENTEROLOGY the number of attendees at the annual meeting could always fit into FEDERATION one room at the farewell dinner. Everyone knew each other well and The foundation of UEGF, with its first scientific meeting in this created a close family feeling among the members and guests. Athens 1992, was a big step forward to a European Gastroenterol- Like in a big family there were often different views, always settled ogy Institution comparable to the American DDW. Seven sister amicably by rigorous debate. Social events centred around the annual societies belonged to that foundation. ESPGHAN was one of them meetings and played an important role in the cohesion of the Society. and played an important role in the development of the UEGF. One afternoon of the annual meeting was free and everyone was ESPGHAN is the only paediatric member association and, during entertained somewhere outside, enjoying some typical culture of the the 26 years since its inception, the relationship between the 2 host country. Many of these gatherings are unforgettable and should organisations has matured. Knowledge exchange and networking be mentioned briefly. Music performed by members played an between paediatric and adult gastroenterologists has become a more important role in our Society. At the annual meeting in Graz 1983 vital activity due to the enhanced understanding of gastrointestinal Beat Hadorn, as president of the meeting, sang (he is a professional infections, the impact of nutrient deficiencies and chronic diseases opera singer) and Bertil Lindquist played the piano. When Beat such as coeliac disease, IBD, and metabolic diseases linked with Hadorn was introducing the performance he said: ‘‘I am a lucky man obesity. Direct exchange between the 2 organisations has developed today, because it is my 50th birthday and I always wanted to celebrate with invitations to ESPGHAN member to present at UEGW, and my birthday with so many people.’’ He performed again at the annual UEGF members taking part in ESPGHAN Annual Meetings, meeting in Amsterdam 1990, where he sang with the general paedia- ensuring an important translation of basic science and exchange trician, Nel Beervliet from Paramaribo Dutch Guyana, some Mozart

FIGURE 13. ESPGHAN Indoor Football Match at the farewell dinner at the ESPGHAN meeting in Dresden 2006 during the world football championship in Germany. From left to right standing: Ramon Tormo-Carnice´ (Spain), Jorge Amil-Dias (Portugal), Sanja Kolacek (Croatia), Jean- Pierre Olives (France), Hania Szajewska (Poland), Deirdre Kelly (UK), behind Olle Hernell (Sweden), Jon Vanderhoof (USA), Riccardo Troncone (Italy), kneeling Dominique Belli (Switzerland), Ulysses Fagundes-Neto (Brazil), Hans Hoekstra (Netherlands), Yuichiro Yamashiro (Japan), and lying Jobst Henker (Germany). Olle Hernell won the ESPGHAN football championship cup! Photo: Michael J. Lentze. www.jpgn.org S27 Supplement JPGN Volume 66, Supplement 1, April 2018 opera duets and 3 songs by Maurice Ravel of the Don Quichotte to article (13). In the current report of the early years, we have tried to Dulcinee´. cover the memorable events of our society, but we could not include At the annual meeting in Tampere, in 1984, we enjoyed the all details. Please accept our apologies if something that individual free afternoon with some Finnish customs, like Wellington boots readers deem important was excluded. throwing and the smoked sauna jumping with black bottoms naked into the neighbouring lake. Jarmo Visakorpi opened the main REFERENCES farewell dinner with the words: ‘‘In Finland on occasions like this, 1. Proceedings of Pediatric Societies. European Society for Pediatric the traditional dishes will be either cold salmon and hot reindeer or Gastroenterology Acta Paediat Scand 1969;58:305–14. hot salmon and cold reindeer. Today you will have cold salmon and 2. Visakorpi JK. An international inquiry concerning the diagnostic cri- hot reindeer.’’ teria of coeliac disease. Acta Paediatr Scand 1970;59:463. Two years later in 1986, at the annual meeting in Edinburgh, 3. Meuwisse GW. Diagnostic criteria in coeliac disease. Acta Paediatr Sandy McNeish toasted the ‘‘Haggis’’ with a wonderful ode by Scand 1970;59:461. Robbie Burns, before we ate the traditional Scottish dish. In 4. McNeish AS, Harms HK, Rey J, et al. The diagnosis of coeliac disease. Gotenburg, when Birgitta Strandvik was president, we all remember A commentary on the current practices of members of the European Society for Paediatric Gastroenterology and Nutrition (ESPGAN). Arch the farewell dinner, held in a traditional old building, where we sat Dis Child 1979;54:783–6. in the main hall and on an upper balcony. All of a sudden paper 5. Revised criteria for diagnosis of coeliac disease. Report of Working planes were flying around and people from the upper floor were Group of European Society of Paediatric Gastroenterology and Nutri- shooting them down and vice versa for at least an hour enjoying the tion. Arch Dis Child 1990;65:909–11. ‘‘battle’’ very much. In Munich at the annual meeting in 1996 6. Husby S, Koletzko S, Korponay-Szabo´ IR, et al., ESPGHAN Working Michael J. Lentze, in the clothes of a typical Bavarian, taught the Group on Coeliac Disease Diagnosis; ESPGHAN Gastroenterology whole ESPGHAN ‘‘family’’ to sing the traditional Munich song: Committee; European Society for Paediatric Gastroenterology, Hepa- ‘‘In Mu¨nchen steht ein Hofbra¨u-Haus,’’ and let members of the tology, and Nutrition. European Society for Paediatric Gastroenterol- Society blow into an alp-horn. In Dresden 2006, the year of the ogy, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr 2012;54:136–60. world football championship in Germany, an ESPGHAN football 7. ESPGAN Committee on Nutrition. Guidelines on infant nutrition. I. match took place at the farewell dinner, where Olle Hernell from Recommendations or the composition of an adapted formula. Acta Sweden won the cup (Fig. 13). These social events are a vital part of Paediatr Scand Suppl 1977;262:1–20. the history of our Society and will be unforgettable memories of the 8. ESPGAN Committee on Nutrition. Guidelines on infant nutrition. II. early years of ESPGHAN and explain that ‘‘family’’ like feeling, Recommendations for the composition of follow-up formula and enjoyed when attending our annual meetings. Beikost. Acta Paediatr Scand Suppl 1981;287:1–25. The creation of these personal contacts, especially among 9. ESPGAN Committee on Nutrition. Guidelines on infant nutrition. III. young scientists and clinicians in ESPGHAN, has very often been Recommendations for infant feeding. Acta Paediatr Scand Suppl the beginning of deep friendships and a fruitful base for future 1982;302:1–27. 10. Nutrition and feeding of preterm infants. Committee on Nutrition of the scientific collaboration, helping very much the development of Preterm Infant, European Society of Paediatric Gastroenterology and individual careers and the happy feeling that membership of this Nutrition. Acta Paediatr Scand Suppl 1987;336:1–14. ESPGHAN ‘‘family’’ engendered. 11. Diagnostic criteria for food allergy with predominantly intestinal symptoms. The European Society for Paediatric Gastroenterology Acknowledgments: The authors thank all the people having and Nutrition Working Group for the Diagnostic Criteria for Food contributed to this article with photos and comments. We thank Allergy. J Pediatr Gastroenterol Nutr 1992;14:108–12. 12. UEG. Advancing gastroenterology care. Twenty years on...The story of them for their invaluable information. For revisions of the article we UEGF and UEGW. Available at: https://ueg.eu/fileadmin/ueg/UEG_ thank Lawrence Weaver and Peter Milla. Special thanks go to History_Brochure/index.html. Accessed November 27, 2017. Birgitta Strandvik, who gave the lead to the history of 13. Strandvik B. 1993 ESPGAN: The European Society for Paediatric ESPGHAN with her booklet published at the 25th birthday of Gastroenterology and Nutrition: 25 Years Memories 1968–1992. ESPGHAN in 1993, which served as invaluable source for this Gotenborg: Tryckt and Bunden; 1993.

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Chapter 3. The European Society for Paediatric Gastroenterology, Hepatology and Nutrition in Recent Years

Berthold Koletzko, yRaanan Shamir, zIlse Broekaert, and §Riccardo Troncone

ABSTRACT

The European Society for Paediatric Gastroenterology, Hepatology and Nutrition has experienced an amazing development in the 50 years of its existence. It grew from a small group of 36 friends who held an informal meeting with some 20 oral presentations to share and discuss their clinical and research work, to a large, multiprofessional society that sets widely recognized standards for clinical care and policy and hosts the world’s largest congress of Paediatric Gastroenterology, Hepatology and Nutrition with more than 4500 delegates from 100 countries. However, the Society’s mission has remained the same: to promote the health of children with special attention to the gastrointestinal tract, liver, and nutritional status, through knowledge creation, the dissemination of science based informa- tion, the promotion of best practice in the delivery of care and the provision of high-quality education. The European Society for Paediatric Gastroen- terology Hepatology and Nutrition’s success is based on the enthusiasm and engagement of its membership that contribute extensive volunteer work to support child health, while maintaining a positive spirit of collaboration and friendship, which characterises this Society. This article aims at describing recent developments and the current situation of the European Society for Paediatric Gastroenterology Hepatology and Nutrition. Key Words: child health, code of conduct, codes of ethics, digestive health, nongovernmental organization, nonprofit organization, standard of care, volunteers

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FIGURE 1. Berthold Koletzko. Received January 24, 2018; accepted January 29, 2018. From the Dr von Hauner Children’s Hospital, University of Munich he European Society for Paediatric Gastroenterology Hepa- Medical Center, LMU—Ludwig-Maximilians-Universita¨t Munich, tology and Nutrition (ESPGHAN) started as a group of 36 Mu¨nchen, Germany, the ySchneider Children’s Medical Center, Petah Tfriends who held an informal meeting with some 20 oral presentations Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, to share what they were working on in the clinic and in the laboratory, Israel, the zChildren’s Hospital, University of , Cologne, and it grew to a now extremely strong, highly professional and § Germany, and the Department Medical Translational Sciences and globally impactful organisation dedicated to research and clinical European Laboratory for the Investigation of Food Induced Diseases, care related to gut, liver, and nutritional health of infants, children, University Federico II, Naples, Italy. Address correspondence and reprint requests to Berthold Koletzko, MD, and adolescents. We are both happy and proud that ESPGHAN is in a Professor of Paediatrics, LMU—Ludwig-Maximilians-Universita¨t Mu- very healthy situation, stronger, and more active now than ever before nich, Dr von Hauner Children’s Hospital, Univ. of Munich Medical in the 5 decades since its foundation. ESPGHAN hosts the largest Center, Lindwurmstr. 4, 80337 Mu¨nchen, Germany congress in the field worldwide, with attendance of more than 4500 (e-mail: offi[email protected]). delegates from all 5 continents. ESPGHAN also maintains an exu- Supplemental digital content is available for this article. Direct URL berant level of activity throughout the year through its Committees, citations appear in the printed text, and links to the digital files are Special Interest and Working Groups and associated research net- provided in the HTML text of this article on the journal’s Web site works that support international research collaborations, guidance for (www.jpgn.org). clinical care, and state-of-the-art education, often with marked B.K. is the Immediate Past President of ESPGHAN; R.S. is the current President, ESPGHAN; I.B., in Young ESPGHAN Committee; and R.T. is international impact on clinical practice and standards in Europe past President of ESPGHAN. and worldwide. The basis of the success of ESPGHAN is the Copyright # 2018 by European Society for Pediatric Gastroenterology, enthusiasm and engagement of its membership that donates extensive Hepatology, and Nutrition and North American Society for Pediatric volunteer work and outstanding contributions to the Society and to Gastroenterology, Hepatology, and Nutrition supporting child health, while maintaining a positive spirit of col- DOI: 10.1097/MPG.0000000000001913 laboration and friendship so characteristic of ESPGHAN.

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ESPGHAN TODAY the Society’s journal, The Journal of Pediatric Gastroenterology The European Society for Paediatric Gastroenterology, and Nutrition, the website editor, the e-learning editor, chairs of Hepatology and Nutrition is a multiprofessional nonprofit organi- further committees, Special Interest Groups and Working Groups, sation seated in Geneva, Switzerland. ESPGHAN’s mission is to and others. promote the health of children with special attention to the gastro- ESPGHAN has 3 main standing committees focusing on intestinal tract, liver, and nutritional status, through knowledge PGHAN (Fig. 2). They aim at promoting child health and increasing creation, the dissemination of science-based information, the pro- the understanding and treatment of disease states. ESPGHAN motion of best practice in the delivery of care and the provision of members are also involved in a large number of currently 30 high-quality education for paediatric gastroenterology, haepatol- Special Interest Groups and Working Groups that focus on particu- ogy, and nutrition professionals in Europe and beyond. The consti- lar aspects of child care and/or disease states, for example, celiac tution and an operational guide, the ESPGHAN Rules and disease, inflammatory bowel disease, endoscopy, liver transplanta- Regulations document, are available on the website of the associa- tion, clinical malnutrition, and early nutrition research, to name just tion, at www.espghan.org. ESPGHAN provides representation for a few (Table 2). The Allied Health Professional Committee aims to all professionals involved in Paediatric Gastroenterology, Hepatol- enhance the multidisciplinary approach towards PGHAN in Europe. ogy and Nutrition (PGHAN), promotes basic, translational, and The Young ESPGHAN Committee promotes and supports special- clinical research; lobbies for stronger support of research and high ist training and guides trainee members, within the first 5 years after standards of care; and offers the highest standards of education to entering subspecialty training, towards full membership of ESP- members and all professionals involved in PGHAN. ESPGHAN GHAN. ESPGHAN promotes scientific exchange among research dedicates particular attention to new investigators and trainees to groups in Europe and among trainees, young doctors, and scientists ensure they are supported and encouraged. ESPGHAN also aims to through PGHN Schools, Young Investigator Forums, Monothe- serve as a source of competent advice for governments, interna- matic Meetings, Master Classes, International Schools, and Eastern tional agencies, and relevant stakeholders. European Schools. The Annual General Meeting of full ESPGHAN members is the ultimate decision-making body that elects the President, Gen- THE ESPGHAN MEMBERSHIP eral Secretary and Executive Treasurer (who together form the ESPGHAN is an association of members; the members are Executive Committee), 6 additional council members, and the the Society. While membership was initially restricted to estab- chair of the Local Organizing Committee of the annual congress lished academic leaders in the field, over the years the Society has (Fig. 2). Table 1 presents a list of the Presidents, Secretaries, and become more and more inclusive. After the recent change of Treasurers of ESPGHAN. The chairs of the Young ESPGHAN membership criteria, adopted in 2013, membership is now open Committee and of the Allied Health Professionals Committee, and to all health care professionals dedicated to PGHAN. Consequently, the President Elect or Past President (for 1 year each) also attend the number of members has been steadily increasing to now more the council meetings. Additional volunteers serve as the Editor of than 800 active and fully paid members (Fig. 3), with an increasing

FIGURE 2. Organisational structure of ESPGHAN.

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TABLE 1. List of ESPGHAN presidents, secretaries, and treasurers

President Secretary Treasurer

Prof Dolf Weijers (The Netherlands) 1968–1972 Prof Bertil Lindquist 1968–1972 Not nominated Prof Bertil Lindquist (Sweden) 1972–1977 Prof Jarmo K. Visakorpi 1972–1976 Not nominated Prof Jean Rey (France) 1977–1980 Prof Alexander S. McNeish 1976–1981 Prof Helmuth Loeb 1976–1979 Prof Jarmo K. Visakorpi (Finland) 1980–1983 Prof Eberhard Schmidt 1979–1984 Prof Alexander S. McNeish (UK) 1983–1986 Prof Armindo Rubino 1981–1984 Prof Salvatore Auricchio (Italy) 1986–1989 Prof Jacques Schmitz 1984–1986 Prof Michael Lentze 1984–1990 Prof Birgitta Strandvik (Sweden) 1989–1992 Prof John Walker Smith 1988–1991 Prof Jacques Schmitz (France) 1992–1995 Prof Isabel Polanco 1989–1992 Prof Samy Cadranel (Belgium) 1995–1998 Prof Peter Milla 1994–1996 Prof Dominique Belli 1995-2005 Prof Stefano Guandalini (Italy) 1998–2001 Prof Markku Maki 1996–2000 Prof Peter Milla (UK) 2001–2004 Dr Jan Taminiau 2000–2003 Prof Michael Lentze (Germany) 2004–2007 Prof Jean-Pierre Olives 2003–2006 Dr Jorge Amil Dias 2005–2011 Prof Deirdre Kelly (UK) 2007–2010 Prof Riccardo Troncone 2006–2009 Prof Riccardo Troncone (Italy) 2010–2013 Prof Hania Szajewska 2009–2012 Prof Berthold Koletzko (Germany) 2013–2016 Prof Sanja Kolacek 2012–2015 Prof Alan Phillips 2012–2015 Prof Raanan Shamir (Israel) 2016–2019 Prof Gigi Veereman 2015–2018 Prof Annamaria Staiano 2016–2019 proportion of young members and allied health care professionals with modern web design and much enhanced functional capabili- such as nurses, dieticians, psychologists and others (Fig. 4). It is ties. Social media share buttons are integrated. The ‘‘MyESP- particularly encouraging to see a rising proportion of young col- GHAN’’—section offers personalized pages and additional leagues joining ESPGHAN (Fig. 5). Women comprise 40% of the information for members. Since 2017, members can also post members, with a particularly high proportion among younger questionnaires and job posting on our website. It is encouraging members. While most members are from Europe, the membership to note great acceptance and high usage of our improved website. has become truly global, currently representing 72 different coun- We also introduced in 2014 a new, interactive electronic newsletter, tries (Fig. 6). which is sent out monthly to all members and provides regular updates on news, current developments and opportunities, and DIGITAL INFORMATION SHARING upcoming events. With the increasing and global membership, digital sharing and exchange of information has become an important priority to STANDARDS OF PRACTICE: THE ESPGHAN serve the needs of members. Therefore in 2015 we launched a new CODE OF CONDUCT and markedly improve website (Fig. 7) after investing 2 years of ESPGHAN is dedicated to excellence and integrity in scien- intensive work of the president, treasurer, website editor and tific and medical clinical practice aiming at generating and con- council. We are proud of an intuitive and easy to navigate website solidating trust at all levels. Therefore, we started an initiative to

TABLE 2. ESPGHAN Working Groups and Special Interest Groups 2017

WG / SIG Chair

Gastroenterology Motility and Neurogastroenterology Silvia Salvatore Paediatric and Adolescent Inflammatory Bowel Diseases Dan Turner Eosinophilic Gastrointestinal Diseases Jorge Amil Dias Helicobacter pylori Infection Patrick Bontems Cystic Fibrosis and Pancreatic Disease Michael Wilschanski Esophageal atresia Frederic Gottrand Epigenetics: Epigenetics in Paediatric Gastroenterology, Matthias Zilbauer Hepatology And Nutrition (EPaedGHAN) Paediatric Polyposis Warren Hyer GENIUS (GENetically determined ImmUne-mediated EnteropathieS) Frank Ruemmele Special Interest Group: Endoscopy Mike Thomson Special Interest Group: Coeliac Disease Carmen Ribes Koninckx Hepatology Hepatology Interest Group Henkjan Verkade/Florence Lacaille Internat. Registry of Porto Systemic Shunts Valerie McLin Intestinal Failure – Associated Liver Disease Special Interest Group Girish Gupte/Florence Lacaille GIGOLO - Graft Injury after LTx Deirdre Kelly Nutrition Pre and Probiotics Hania Szajewska / Zvi Weizman Clinical Malnutrition Jessie Hulst Early Nutrition Research Berthold Koletzko Working Group on Outcomes in Nutrition Trials Hania Szajewska NEOMUNE: Newborn immunity, gut and brain Hans Van Goudoever www.jpgn.org S31 Supplement JPGN Volume 66, Supplement 1, April 2018

critical open discussion in our organisation, focussing on the interest of our patients and their families.

THE ANNUAL CONGRESS OF ESPGHAN The ESPGHAN annual congress (Fig. 8A–F) is the largest meeting in PGHAN in the world, with an attendance in 2017 that exceeded 4500 delegates from almost 100 countries on all 5 continents. The congress offers an excellent platform for members and nonmembers to exchange new research findings in the different fields of our specialty, to hear updates on the state of the art in research, clinical practice, and policy, and to meet key opinion leaders and colleagues from all over the world. It also gives FIGURE 3. Growth of the ESPGHAN membership. ESPGHAN members opportunities for working group meetings and postgraduate courses. The number of abstracts submitted has been steadily increasing and has now reached close to 1000 develop a comprehensive document to address these important abstracts per year. To serve the interest of the large number of issues, which ESPGHAN adopted in 2015 as its ‘‘Code of clinical practitioners attending the meeting, in 2014 we introduced a Conduct’’ (see Supplementary Material 1, Supplemental Digital new Clinical Practice Track and in 2015 a new hands-on learning Content 1, http://links.lww.com/MPG/B282). The document sum- zone in endoscopy, which have all been highly appreciated and marizes the ethical foundations of ESPGHAN’s obligation to ensure successful. The use of digital tools is continuously expanded, with that paediatricians and allied health care professionals acquire and an interactive congress app for handheld devices, ePosters, a Virtual maintain knowledge, skills, and values that are central to paediatrics Meeting Site, and a Website on Demand, which enhance informa- and child health without undue due to financial or commercial tion sharing and convenience for delegates, for example, by acces- interests. The ESPGHAN Code of Conduct analyses the ethical sing handouts and webcasts of presentations. Since 2015 our annual challenges that can be posed when ESPGHAN members who congress is joined by a variety of patient and parent organisations at organize, teach, or serve other roles in have the congress with whom we wish to closely collaborate to achieve financial relationships with companies that have a direct interest in our goal to optimally support patients and their families. Our recommendations. It also illustrates strategies for mitigating the members can enjoy the added privileges of the ESPGHAN Mem- potential of such financial relationships to influence professional bers Lounge to meet or enjoy a quiet moment, and the newly education in undesired ways. ESPGHAN’s Code of Conduct introduced Young ESPGHAN Lounge. The annual Members Din- also governs the relationship between ESPGHAN and industry ner at the congress provides a unique opportunity for meeting representatives involved in the support of research and educational friends and colleagues in a relaxed atmosphere, and to enjoy a activities in the field of PGHAN. Besides identifying the principles programme of great fun. of transparency, independence and accountability, the Code of Conduct provides a practical approach to how to maintain the independence and integrity of ESPGHAN’s related professional COMMITTEES, SPECIAL INTEREST GROUPS, education while promoting a trustworthy relationship between AND WORKING GROUPS ESPGHAN and commercial companies. We are conscious that ESPGHAN’s main Committees on Gastroenterology, Hepa- the ethical conduct of our association must go beyond the sole tology and Nutrition, and the many other Committees (Table 3) development and adoption of this Code of Conduct, but that we also and Special Interest and Working Groups (Table 2) engage in need to foster a culture of integrity, responsibility, transparency, and numerous activities throughout each year, such as developing

FIGURE 4. Members per category 2017.

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and related research (Fig. 9). The Public Affairs Committee also engages in interaction with international agencies such as the World Health Organisation, the European Medicines Agency (6), and the Codex Alimentarius where ESPGHAN has been accepted as a registered observer organisation in 2003 and ever since has proac- tively contributed to the development of standards for dietetic food products for infants and young children (5,7). The Public Affairs Committee coordinates the close collaboration of ESPGHAN with patient and parent associations related to paediatric digestive health, which is considered to be a key strategic priority. The History Committee was newly formed in 2014 with the goals to compile the history of PGHN and of ESPGHAN, and to build an ESPGHAN archive with records of the foundation of the Society, annual meetings, and other activities. This very publication FIGURE 5. Age distribution of ESPGHAN members 2017. on the occasion of the 50th anniversary of ESPGHAN is a result of the successful work of this Committee. recommendations and clinical guidelines on pertinent topics in the field, facilitation, and execution of collaborative research studies, YOUNG ESPGHAN and engagement in educational and training activities. Many ESP- The Trainee Committee was formed in November 2009 GHAN guidelines have set global standards for practice, clinical during the United European Gastroenterology (UEG) Congress care, policy and regulatory decisions not only in Europe but in London with the vision to involve and support trainees throughout the world and are highly cited, for example, 799 in PGHAN within ESPGHAN. One of the first meeting reports citations of the guideline for the diagnosis of coeliac disease concludes: ‘‘The ESPGHAN Trainee committee is currently sur- 2012 (1), 408 citations of the ESPGHAN Comment on Comple- veying the trainees to identify how training is carried out in the mentary Feeding 2008 (2), 372 citations of the guideline on enteral member countries. From this we may be able to ascertain areas of nutrient supply for premature infants (3), 285 citations of the training which need targeting, this may include practical procedures comment on dietary products for infants treatment and prevention and log books, theoretic knowledge, mentoring or the identification of food allergy (4), 229 citations of the global standard for infant of training leads.’’ The Society encouraged the Young ESPGHAN formula composition (5), and 204 citations of the comment on Committee to expand the group and facilitated the involvement of breastfeeding (Web of Science, October 26, 2017). Trainee Members with ESPGHAN, for example, by becoming With the increasing role of ESPGHAN in influencing members of the other standing committees. In 2015, the name of research and clinical practice, the need to discuss issues of impor- the Committee was changed to ‘‘The Young ESPGHAN Commit- tance to child health, conditions of clinical care, and research with tee: Committee for Trainees and Young Investigators’’ to indicate political decision makers particularly at the European level has that all young members within the first 5 years after joining the become more pressing. Therefore, in 2013 we created the new society should be represented, including nonclinical scientists and Public Affairs Committee to raise awareness for themes related to early career clinicians who already finished their training. Today paediatric digestive health, with a particular focus on the European young ESPGHAN members comprise the fastest growing member- Commission and European Parliament where repeated meetings ship category within ESPGHAN. The Young ESPGHAN Commit- and events were held to lobby for greater support for child health tee meets face-to-face twice yearly and reaches out to its members

FIGURE 6. Geographical distribution of ESPGHAN members 2017. www.jpgn.org S33 Supplement JPGN Volume 66, Supplement 1, April 2018

FIGURE 7. Snapshot from the ESPGHAN website 2017.

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FIGURE 8. A, 48th ESPGHAN Congress 2015, Amsterdam. B, Prof Marc Benninga at the opening cabaret, 48th ESPGHAN Congress 2015, Amsterdam. C, Prof Bert Koletzko at the reception for Patient and Parent Organisations, ESPGHAN Congress. D, Prof Luigi Dall’Oglio (far right) teaching at the Endoscopy Learning Zone, ESPGHAN Congress. E, The abstract presentations of new results through posters, e-posters, and oral presentations are the core of ESPGHAN congresses and always draw a lot of attention. F, Prof Raanan Shamir presenting the ESPGHAN Distinguished Service Award 2017 to Prof Olivier Goulet. via e-mail, LinkedIn, and Twitter, with the last one being very skills, and during the last members’ dinners the committee attracted popular during the annual conferences. It channels its members’ ESPGHAN members by rewarding the ‘‘best behaving’’ monkey concerns via surveys and round table discussions at the annual group and the ‘‘cleverest pilot’’! In 2016, a group of 5 Young conferences. Furthermore, the committee is actively involved with ESPGHAN members received the FISPGHAN expert team award e-learning, ESPGHAN summer schools, and endoscopy/motility at the WCPGHAN in Montreal, Canada, and produced a very learning zones at the annual conferences and promotes these instructive teaching video on treatment of acute gastroenteritis, activities to its membership. During the annual conference, Young which is now available at www.fispghan.org. The Young ESP- ESPGHAN has held its own workshop on career development GHAN committee has reached out to the Young NASPGHAN www.jpgn.org S35 Supplement JPGN Volume 66, Supplement 1, April 2018

TABLE 3. ESPGHAN Committees 2018

Chair Term of Chair

Committee on Gastroenterology Nikhil Thapar 2015–2019 Committee on Hepatology Henk Jan Verkade 2017–2019 Committee on Nutrition Mary Fewtrell 2015–2018 Young ESPGHAN – Trainee Committee Nicolette Moes 2015–2018 Allied Health Professionals Committee Tena Niseteo 2015–2018 Scientific Committee Piotr Socha 2015–2018 Finance & Investment Committee Annamaria Staiano 2016–2019 Public Affairs Committee Deirdre Kelly 2017–2020 Publication Committee Berthold Koletzko 2016–2019 Ethics Committee Martin Burdelski 2015–2018 History Committee Lawrence Weaver 2015–2018

Committee, Young Talent Group UEG and Young ECCO. In 2017, financial and other means of support for research, including col- the society and Young ESPGHAN have started a mentoring pro- laborative and multidisciplinary research. Research priorities have gram for its new Young members. Young ESPGHAN is also recently been defined (8). The strong and active networks of leading working on optimizing transition from Young to Full ESPGHAN experts in different areas of PGHAN provides excellent opportu- membership. The Young ESPGHAN thanks for tremendous support nities for scientific collaboration and successful multicentric it has received from the ESPGHAN Presidents Deirdre Kelly, research grant applications. This should be illustrated by the Riccardo Troncone, Berthold Koletzko, and Raanan Shamir. following recent examples of success of funded research consortia Over the years, Young ESPGHAN has established itself with that have arisen out of ESPGHAN collaborations. The Paediatric an important role within ESPGHAN, and its activities have been European Digestive Diseases Clinical Research Network (http:// very well received and greatly appreciated. The ongoing enthusiasm www.espghan.org/about-espghan/research/paediatric-european- and engagement of Young ESPGHAN in the ESPGHAN activities digestive-diseases-clinical-research-network-peddcren/) coordi- and the support from the ESPGHAN members and its Council nated by Nick Croft was established in 2013 with financial support provide an excellent basis for a bright future of ESPGHAN! from UEG to form a network of clinical trials for studying and ultimately providing effective medicines for infants, children, and adolescents with disorders in the area of PGHAN. The European RESEARCH NETWORKS AND Network Study on Malnutrition and Outcome in Hospitalized COLLABORATIONS ARISING OUT OF ESPGHAN Children in Europe coordinated by Berthold Koletzko received a One of the core goals of ESPGHAN is to promote basic, network grant from the European Society for Clinical Nutrition and translational, and clinical science in our field, and to enhance Metabolism (www.espen.org) and was established with the

FIGURE 9. The ESPGHAN Public Affairs Committee meets with members of the European Parliament and representatives of the European Commission in the European Parliament building to discuss the need for stronger research funding in the area of paediatric gastroenterology, hepatology, and nutrition.

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ESPGHAN working group Clinical Malnutrition to explore the prevalence and effects of undernutrition among more than 2500 hospitalised children in 12 countries, and it also studies opportu- nities for nutrition screening (9,10). The European Commission (EC) funded ‘‘PreventCD’’ project (http://www.preventcd.com) coordinated by Maria Luisa Mearin studied the natural history of coeliac disease and the effects of infant feeding on disease mani- festation (11). The ‘‘Early Nutrition Project’’ coordinated by Berthold Koletzko and also funded by the EC (www.project-ear- lynutrition.eu) explores long-term effects of early nutrition on later health, with a focus on opportunities for prevention of obesity and associated disorders (12). The EC funded ‘‘Paediatric Inflammatory Bowel Disease network for Safety, Efficacy, Treatment and Quality Improvement of Care’’ (http://cordis.europa.eu/project/ rcn/199745_en.html) coordinated by Frank Ruemmele aims to establish a long-term inception cohort of paediatric IBD patients and to perform a randomised clinical therapeutic trial. The EU funded regional project ‘‘Focus in CD – Innovative coeliac disease learning model for health care professionals in the Danube region’’ FIGURE 10. Dr Dan Turner (Jerusalem) presents at an ESPGHAN (http://www.interreg-central.eu/Content.Node/Focus-IN-CD.html) Update Course for the Middle East in Istanbul in 2013, jointly orga- coordinated by Jasmina and Jernej Dolinsek aims at strengthening nised with the Pan Arabian Society for Paediatric Gastroenterology, knowledge and awareness on coeliac disease among health care Hepatology, and Nutrition. professionals and the general public. The Erasmus Plus programme in Capacity Building in Higher Education funded the ‘‘Early Nutrition eAcademy South East Asia’’ coordinated by Berthold end of the Cold War, these links have been proactively strength- Koletzko focusses on eLearning in paediatric nutrition for health ened and dedicated ESPGHAN summer schools were held at least care professionals in Malaysia, Thailand, and neighbouring coun- once a year in Central and Eastern Europe. These courses have tries, in close collaboration with ESPGHAN’s eLearning pro- attracted many highly talented colleagues from this part of the gramme. Many more opportunities exist for successful research world to join ESPGHAN, a number of which today are among the and education activities based on the strong ESPGHAN network. thought leaders of our society. Training activities have also been Following previous successes, in 2018 ESPGHAN provides 3 organized outside of Europe to support areas with special needs, grants of 50,000 Euros each to support and enable the creation for example, the ESPGHAN Update Course for colleagues from of more successful networks. the middle east countries held in Istanbul, Turkey, in 2014 (Fig. 10), the Training Course for Rising Stars from Latin America hosted by LASPGHAN in Cancun, Mexico, in 2014 EDUCATION in collaboration with ESPGHAN and NASPGHAN, or the Inter- ESPGHAN strives to develop an up-to-date, independent, national Paediatric Nutrition School in Thailand in 2016 orga- high-quality educational programme for health professionals that nized jointly by ESPGHAN and the Society of Paediatric caters to their immediate and changing needs. ESPGHAN seeks to Nutrition of Thailand (Fig. 11). Perhaps the most successful continuously improve its educational programme and to present training outside of Europe has been the regular ‘‘ESPGHAN additional courses and educational materials that cover niches or goes Africa’’ diploma course for African colleagues, with two complement existing training opportunities and products. In addi- 1-week courses per year held in Cape Town from to 2012 to 2015, tion, ESPGHAN believes it has a responsibility for the education of in close collaboration with the Universities of Cape Town and of underprivileged areas outside Europe where the needs for education Stellenbosch, South Africa (Fig. 12). About 120 paediatricians and training are more urgent, although learning and research from the whole Sub-Saharan African region received intensive priorities may be substantially different. The ESPGHAN training training in paediatric gastroenterology, hepatology, and nutrition activities are guided by the European Training Syllabus in Paediat- based on lectures, case presentations with intense discussions, e- ric Gastroenterology, Hepatology and Nutrition that was updated in learning, visits to local hospitals, and final examinations. ESP- 2014 (13) and defines minimum requirements for training to GHAN provided financial support to more than 20 of the partici- support recognition as a European Specialist in paediatric gastro- pating colleagues to attend the reciprocal ‘‘Africa goes enterology, hepatology, and nutrition, along with a logbook on ESPGHAN’’ event held at the 49th Annual Congress of ESP- necessary achievements. The Education Task Force, established in GHAN at Athens in 2016. 2017, aims to integrate all core activities within a 5-year cycle. The ESPGHAN Summer Schools for trainees and fellows have become regular events and a huge success story ever since EDUCATION PARTNER PROGRAMME the inception of the first Gastroenterology School in 1990 and the To further stabilize and strengthen the numerous regular first Nutrition School in 1991. The combination of high-quality education activities, we launched in 2015 the ESPGHAN Education training with an informal, communicative atmosphere, and the Partner Programme that aims at ensuring the on-going development close interaction of delegates and a small resident faculty creates and implementation of an up-to-date, independent, high-quality an unforgettable learning experience for participants, many of educational programme for health care professionals. It is designed whom have become active ESPGHAN members. Since its begin- and implemented in full compliance with current professional and ning ESPGHAN has established close links between western, Continuing Medical Education (CME) standards and with our Code central and eastern Europe and has built bridges and strong links of Conduct, to promote confidence in independence, integrity and across Europe. After the fall of the boundary dividing former credibility of ESPGHAN and its industry partners. The key target ‘‘Western Europe’’ and the ‘‘Warsaw Pact Countries’’ and the groups include Trainee Members and other young health care www.jpgn.org S37 Supplement JPGN Volume 66, Supplement 1, April 2018

FIGURE 11. Participants of the Paediatric Nutrition course organized jointly by ESPGHAN and the Paediatric Nutrition Society of Thailand in 2016. professionals (addressed primarily by the ESPGHAN Summer The joint ESPGHAN / NASPGHAN Travel Award, USD/ Schools and the Young Investigator Forum), established specialists EUR 5,000. (addressed by the new Master Classes introduced in 2015 that are offered exclusively for ESPGHAN members), as well as health care professionals from less privileged areas (Eastern European Summer The highest honour of the Society is the ESPGHAN Distin- Schools, International Schools). In 2017, 7 sponsors (www.espgha- guished Service Award that was inaugurated in 2010 (14). It is n.org/education/) each donated 50 000 Euro to support the training presented annually to an individual who has made a major contri- courses listed in Table 4. bution to the development of paediatric gastroenterology, hepatol- ogy, or nutrition. The selection criteria include

ESPGHAN AWARDS AND GRANTS Outstanding scientific achievements related to paediatric ESPGHAN provides numerous grants, awards, and prizes to gastroenterology and/or hepatology, and/or nutrition, usually members and nonmembers, including documented by the candidate’s publication and citation record Annual Research and Networking Grants, EUR 50,000 (3 per Outstanding contributions to the standards, practice, and year). training in the fields of paediatric gastroenterology and/or Charlotte Anderson Travel Award, EUR 3000. haepatology and/or nutrition Outstanding contributions to ESPGHAN as a society ESPGHAN International Exchange, EUR 3000 (7 per year). Personal integrity. Young Investigator Awards (YIA) for abstract presenters at the ESPGHAN, UEG and WCPGHAN conferences up to EUR 1000. This special honour has been awarded to Profs John Walker- John Harries, Alex Mowat, and Jean Rey Prizes (best abstract Smith in 2010 (14), Salvatore Auricchio in 2011, Martin Burdelski presentations at the ESPGHAN congress in the fields of in 2012, David Branski in 2013 (15), Peter Milla in 2014 (16), Olle gastroenterology, hepatology, and nutrition, respectively), Hernell in 2015 (17), Deirdre Kelly in 2016 (18), and Olivier Goulet EUR 2500. in 2017 (19).

FIGURE 12. Participants of a ‘‘ESPGHAN goes Africa’’ Training Course in Cape Town, South Africa, jointly organised by Prof Michael Lentze (first row, 4th from right) and Prof Jan Taminiau from ESPGHAN and Dr Liz Goddard, University of Cape Town (first row, 2nd from right), and Dr Etienne Nel, University of Stellenbosch (first row, 3rd from right).

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TABLE 4. Training activities under the ESPGHAN education partner- 2000 onwards (see below), a large number of joint guidelines ship programme in 2017 and position papers, and not the least joint engagement in the ESPGHAN Paediatric Nutrition Summer School: Beyond the Nutrients co-owned journal. ESPGHAN Danube/Balkan Summer School ESPGHAN Allied Health Professional Summer School THE JOURNAL OF PEDIATRIC ESPGHAN Young Investigator Forum GASTROENTEROLOGY AND NUTRITION ESPGHAN Paediatric Gastrointestinal Motility Hands-On Training Course A visible manifestation of the close and trusting collabo- ESPGHAN Gastroenterology Summer School ration of ESPGHAN and NASPGHAN is the Journal of Pediatric ESPGHAN Master Class on Gastrointestinal Immunology Gastroenterology and Nutrition (JPGN; www.jpgn.org). The jour- ESPGHAN 3rd Paediatric Inflammatory Bowel Disease Masterclass nal was founded by Dr Emanuel Lebenthal and became the ESPGHAN Monothematic Conference: Chronic Liver disease in children official journal of both societies in 1991. This only journal treatment and follow-up dedicated to PGHAN today is managed jointly by an ESPGHAN editor (currently Hania Szajewska, Warsaw) and a NASPGHAN editor (currently Mel Heymans, San Francisco). The current (2016) journal Impact Factor is 2.799, after 2.298 in 2011, COLLABORATION WITH OTHER 2.196 in 2012, 2.873 in 2013, 2.625, in 2014 and 2.400 in ASSOCIATIONS 2015. Our Journal is valued as one of the top paediatric subspe- ESPGHAN has engaged in partnering with several other cialty journals and has established itself as a leading platform for associations with joint interests (Table 5). For a number of years, publishing research articles related to PGHAN as well as guidance representatives of the national PGHN societies across Europe on clinical practices, such as the guidelines of ESPGHAN and have met with the ESPGHAN officers at the ESPGHAN Con- NASPHAN and the working group conclusions of FISPGHAN. gress to discuss issues of common interest and opportunities for JPGN publishes original papers and reviews dealing with all harmonization. To strengthen the collaboration of the national aspects of PGHAN, including normal and abnormal functions associations across Europe among each other and with ESP- of the alimentary tract, the liver, and associated organs. Particular GHAN, we formally established the ESPGHAN National Socie- emphasis is devoted to developmental aspects, and to infant and ties Forum in 2015 as a platform for sustained collaboration and childhood nutrition. JPGN offers fast-track publication available joint activities with all Presidents of National PGHAN societies for selected articles of general scientific or public health impor- across Europe to act as a bidirectional link between ESPGHAN tance. Accepted original manuscripts are posted as Publish Ahead and the National Societies. As a first project, a joint standard for of Print (PAP) within 3 of 5 days of acceptance and indexed in implementing training in PGHAN is supposed to be developed, PubMed within a few days. The full text is available to all based on the ESPGHAN Training Syllabus (13), aiming towards ESPGHAN and NASPGHAN members, online and in print, enhanced harmonization and quality assurance of subspecialty and to numerous institutions worldwide. Articles are open to training across Europe. the public 1 year after publication.

COLLABORATION WITH THE NORTH THE CREATION OF FISPGHAN AND THE AMERICAN SOCIETY OF PEDIATRIC WORLD CONGRESS SERIES GASTROENTEROLOGY Building on the success of the combined NASPGHAN- The most long-standing and closest collaboration of ESP- ESPGHAN meetings and the attendance of colleagues from around GHAN probably is that with its North American sister society, the world, in 1998 the ESPGHAN president Stefano Guandalini which actually was established after the model of the European initiated a discussion about expanding these into global World society by Jon Vanderhoof after he participated in the ESPGAN Congresses to address PGHAN issues and colleagues from all parts (then still without Hepatology in the name) conference in 1986 in of the globe. Obviously he was very convincing, since a first World Edinburgh. The close collaboration is facilitated by a number Congress was successfully held in Boston, when also the global of individuals that are members of both ESPGHAN and NASP- Federation of International Societies on Paediatric Gastroenterol- GHAN, regular participation of European and North American ogy, Hepatology and Nutrition (FISPGHAN; www.fispghan.org) colleagues, respectively, in the annual congresses on the other side was created by the sisters in the Asian and Pacific region (APPSP- of the Atlantic, a series of successful joint congresses held in GHAN), Europe (ESPGHAN), Latin America (LASPGHAN), and 1978 in Paris, 1985 in New York, 1990 in Amsterdam, 1994 in North America (NASPGHAN), with additional associate member- Houston, and 1998 in Toulouse, which laid the ground for ship of the Commonwealth Association (CAPGAN) and since 2016 the creation of the World Congresses on PGHAN held from also of the Pan Arabian (PAPGHAN) societies. The Second World

TABLE 5. Close partner societies of ESPGHAN

National Societies All national paediatric gastroenterology, hepatology and nutrition societies across Europe FISPGHAN Federation of International Societies of Pediatric Gastroenterology, Hepatology, and Nutrition NASPGHAN North American Society for Pediatric Gastroenterology, Hepatology and Nutrition LASPGHAN Latinamerican Society for Pediatric Gastroenterology, Hepatology and Nutrition APPSPGHAN Asian Pan Pacific Society for Pediatric Gastroenterology, Hepatology, and Nutrition CAPGHAN Commonwealth Association of Paediatric Gastroenterology & Nutrition UEG United European Gastroenterology EAP European Academy of Paediatrics EPA/UNEPSA European Paediatric Association, the Union of National European Paediatric Societies and Associations www.jpgn.org S39 Supplement JPGN Volume 66, Supplement 1, April 2018

Congress in Paris, France in 2004 was co-hosted by Prof Olivier Goulet and ESPGHAN. The next world congress will be jointly hosted by FISGHAN and ESPGHAN in Copenhagen in June 2020. In addition to the World Congresses, FISPGHAN also maintains expert working groups that develop position and guideline papers with global perspectives.

UNITED EUROPEAN GASTROENTEROLOGY ESPGHAN was 1 of the 7 sister associations that jointly discussed the idea of creating an umbrella organisation to repre- sent all aspects of digestive health in Europe and in 1990 formally created the United European Gastroenterology (UEG). The first UEG congress, then called the UEG week, was held in 1992 at Athens. UEG has since experienced an enormous growth and success. UEG now incorporates 20 European gastroenterological subspecialty societies and 49 national gastroenterological socie- ties. The annual UEG congress attracts more than 14,000 dele- gates from all over the world, including also an ever-increasing attendance of North American delegates. Many ESPGHAN members attend the UEG congress regularly not only because ESPGHAN is one of the ‘‘founding sisters’’ of UEG, but also because it is a prime opportunity to exchange with our adult colleagues on recent trends in clinical gastroenterology and related basic science. ESPGHAN is a very active contributor to the activities of UEG through its proactive FIGURE 13. Brochure on Pediatric Digestive Health jointly developed representation in the Meeting of Members, Education Committee, and distributed at the European Parliament and Commission by Scientific Committee, Public Affairs Committee, and the Research ESPGHAN and United European Gastroenterology. Board. ESPGHAN members held positions at the Executive level (UEG treasurer) and currently, our immediate past president Berthold Koletzko is the UEG Council representative for the 11 Medical COLLABORATION WITH OTHER PAEDIATRIC Gastroenterological Associations that are members in UEG. ESP- GHAN benefits from the UEG collaboration in many aspects, ASSOCIATIONS including for example significant support for educational activities ESPGHAN regularly collaborates with a variety of European through educational grants, and added leverage in European and national paediatric associations, for example, with joint ses- activities through joining forces with the large and professional UEG sions addressing paediatric digestive health at the respective con- infrastructure. For example, UEG and ESPGHAN jointly developed a gresses. ESPGHAN has a permanent representation at the European brochure and performed extensive, targeted lobbying activities at the Academy of Pediatrics (EAP) to represent PGHAN at the European European parliament and European Commission level to raise aware- Union of Medical Specialists (UEMS) and currently chairs their ness and support of key challenges in paediatric digestive Tertiary Care Committee. UEMS is the oldest European medical health, including liver health and nutrition (Fig. 13). There are some organisation created in 1958 that defines the standards of medical first indications that our voices have been heard at least to some education and training and subspecialty accreditation in the Euro- extent, given that some of the proposed opportunities have been pean Union. ESPGHAN also regularly contributes to the pro- incorporated into the work programmes of the Horizon 2020 research gramme planning of the biannual EAP congress. It is also funding. partners with the European Paediatric Association – Union of European Paediatric Societies and Associations (EPA-UNEPSA) that was founded in 1976 and serves as an umbrella organisation of DISTANCE LEARNING (E-LEARNING) IN 49 national paediatric associations. ESPGHAN has provided the COLLABORATION WITH UNITED EUROPEAN chair of the Scientific Committee coordinating the programme GASTROENTEROLOGY development of the 8th Europaediatrics Congress in Bucharest in 2017 (Tables 6 and 7). An example of very fruitful collaboration between ESP- GHAN and UEG is the establishment of a programme for electronic distance learning, which has become a standard educational tool in FUTURE OPPORTUNITIES AND CHALLENGES medical schools around the world. e-Learning is a valuable element As ESPGHAN has gone from strength to strength during the that helps meeting the great needs for up-to-date, evidence-based, last 5 decades; it appears to be well prepared to looking forward to and applicable information of health care professionals, who are the future and to prepare for the challenges and opportunities that often challenged by time and budget constraints. e-Learning enables the years to come may bring. We continue to strive for further easy access from the workplace or from home or abroad, self-paced improving our ability to promote child health, to treat and prevent learning, no travel and onsite costs, and interactivity. Since 2012, challenges to digestive health in children and adolescents, and to ESPGHAN has started to build an e-learning programme that is strengthen the knowledge base that is required to do so. Close embedded in ESPGHAN’s PGHAN specialist training syllabus collaboration among all health professionals involved in this area, (13), supported by the technical and logistic infrastructure of along with patients, families, and the many involved stakeholders UEG (https://www.ueg.eu/education/online-courses/). ESPGHAN and decision makers, will be key to achieving our goals. ESPGHAN has also partnered with the Early Nutrition eAcademy to jointly provides a strong platform and great opportunity for such a fruitful develop and implement courses related to nutrition in early life collaboration. The increasing number of young and trainee mem- (http://www.early-nutrition.org/en/enea/). bers in recent years is very impressive and ensures that ESPGHAN

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TABLE 6. List of ESPGHAN annual congresses

Year Meeting Location

2016 2016 4th FISPGHAN World Congress Montreal, Canada 2017 50th Annual Meeting Prague, Czech Republic 2016 49th Annual Meeting Athens, Greece 2015 48th Annual Meeting Amsterdam, Netherlands 2014 47th Annual Meeting Jerusalem, Israel 2013 46th Annual Meeting London, UK 2012 Update Meeting Stockholm, Sweden 2011 44th Annual Meeting Sorrento, Italy 2010 43rd Annual Meeting Istanbul, Turkey 2009 42nd Annual Meeting Budapest, Hungary 2008 41st Annual Meeting and 3rd FISPGHAN World Congress Iguassu Falls, Brazil 2007 40th Annual Meeting Barcelona, Spain 2006 39th Annual Meeting Dresden, Germany 2005 38th Annual Meeting Porto, Portugal 2004 37th Annual Meeting and 2nd FISPGHAN World Congress Paris 2nd World Congress 2003 36th Annual Meeting Prague, Czech Republic 2002 35th Annual Meeting Taormina, Italy 2001 34th Annual Meeting Geneva, Switzerland 2000 33rd Annual Meeting and 1st FISPGHAN World Congress Boston, MA, USA 1999 32nd Annual Meeting Warsaw, Poland 1998 31st Annual Meeting and 5th Joint Meeting with NASPGHAN Toulouse, France 1997 30th Annual Meeting Thessaloniki, Greece 1996 29th Annual Meeting Mu¨nchen, Germany 1995 28th Annual Meeting Jerusalem, Israel 1994 27th Annual Meeting and 4th Joint Meeting with NASPGHAN Houston, TX, USA 1993 26th Annual Meeting Gotenburg, Sweden 1992 25th Annual Meeting Brussels, Belgium 1991 24th Annual Meeting London, UK 1990 23rd Annual Meeting and 3rd Joint Meeting with NASPGHAN Amsterdam, The Netherlands 1989 22nd Annual Meeting Budapest, Hungary 1988 21st Annual Meeting Copenhagen, Denmark 1987 20th Annual Meeting Lisbon, Portugal 1986 19th Annual Meeting Edinburgh, UK 1985 18th Annual Meeting and 2nd Joint Meeting with NASPGHAN New York City, NY, USA 1984 17th Annual Meeting Tampere, Finland 1983 16th Annual Meeting Graz, Austria 1982 15th Annual Meeting Madrid, Spain 1981 14th Annual Meeting and Joint Meeting with ESPR, ESPHI, EPRS Bern, Switzerland 1980 13th Annual Meeting Capri, Italy 1979 12th Annual Meeting London, UK 1978 11th Annual Meeting and 1st Joint Meeting with NASPGAN Paris, France 1977 10th Annual Meeting Utrecht, Sweden 1976 9th Annual Meeting Weimar, German Democratic Republic 1975 8th Annual Meeting Leuven-Brussels 1974 7th Annual Meeting Verona, Italy 1973 6th Annual Meeting Helsinki, Finland 1972 5th Annual Meeting Hamburg, Federal Republic of Germany 1971 4th Annual Meeting Birmingham, UK 1970 3rd Annual Meeting Lund, Sweden 1969 2nd Annual Meeting and Joint Meeting with ESPR Interlaken, Switzerland 1968 1st Annual Meeting Paris, France

remains a young society, but more efforts are needed to support the com/MPG/B282) has been developed based on thorough and growth also of allied health professional members and to provide detailed discussions amongst thought leaders of the Society gath- attractive offers for this important group of members, such as the ered at the annual ESPGHAN strategy days and the ESPGHAN first ESPGHAN allied health professional summer school held council, with subsequent discussion with and input from the whole in 2017. membership. Our Strategy Plan defines our mission, our strategic The ESPGHAN Strategy Plan 2016–2019 (see supplemen- priorities, and the actions to achieve those and provides a roadmap tary material 1, Supplemental Digital Content 1, http://links.lww. for the actions to be implemented by the Society in the years after its www.jpgn.org S41 Supplement JPGN Volume 66, Supplement 1, April 2018

TABLE 7. Presidents of the Federation in International Societies for A major achievement of our Society in recent years has Pediatric Gastroenterology, Haepalogy and Nutrition been the adoption of the ESPGHAN Code of Conduct that defines the ethical standards and resulting guidelines for the Stefano Guandalini Chicago (2000–2004) practices and dealings of ESPGHAN. A number of other Euro- Geoff Cleghorn Brisbane (2004–2008) pean associations have looked at the ESPGHAN Code of Mei-Hwei Chang Taipeh (2008–2012) Conduct and have started to develop similar standards. For Kathy Schwarz Baltimore (2012–2016) example the BioMed-Alliance, an umbrella organisation of 26 Berthold Koletzko Munich (2016–2020) European biomedical associations, including ESGPGHAN, that aims to improve the health and well-being of all citizens of Supplemental Material 2, Supplemental Digital Content 2, http:// Europe through promoting excellence in European biomedical links.lww.com/MPG/B283. research and advocating for increased funding in favour of biomedical research, in 2016 adopted a Code of Conduct that follows very similar concepts as the one adopted by ESPGHAN adoption. Among the identified immediate key goals are that in 2015. However, it does not suffice to adopt and publish a ESPGHAN should provide broad representation for all profes- written Code of Conduct. Day by day it is of utmost importance sionals involved in our field; promote basic, translational, and to strongly support and defend a culture of honesty, transpar- clinical science; lobby for stronger support of research; offer the ency, of resistance against opportunism and against financial highest standards of education to members and all professionals allurements that may conflict with our ethical goals, and to involved in our field; support and defend the health and interests of support and strengthen and open debate and civil courage children, with a special emphasis on gastrointestinal, liver, and within ESPGHAN. nutritional health; and serve as a source of competent advice for ESPGHAN has a strong tradition of tolerance and inclusion institutions and international agencies. Very good progress is being of diversity, and of applying and promoting equality. However, made in all of these areas, thanks to the enthusiastic volunteer work despite the high and rapidly growing proportion of female collea- of many members. gues particularly amongst our younger members, their representa- ESPGHAN takes pride in its Guidelines and Position Papers. tion in the council and the executive council has been less than In recent years the number of these generated by Committees, SIGs satisfactory and should be improved. In the now 50 years of and WGS has markedly increased. To enable maintenance of high ESPGHAN’s existence we had only 2 female presidents. We need quality standards of our guidelines and position papers, we estab- to get better here. lished rules for a transparent process of their creation and review. ESPGHAN has a very strong tradition of collegial friendship, ESPGHAN has a strong tradition in empowering young support and collaboration that has its foundation in the spirit of a small colleagues and facilitating their qualification in clinical compe- society of experts where everyone pretty much knew each other. It is a tences and research capability, and it is committed to continue to do challenge to maintain this high level of identification of members so. However, we face challenges due to increasing economic with their society, which may be the reason for the very large degree pressures on health systems across Europe, and in particular tertiary of volunteer work that members commit, in a rapidly growing society paediatric care and academic paediatrics. The reality of tertiary and with a now huge congress. The Summer Schools for young members academic paediatrics is more and more dictated by the income in training provide an opportunity to create close and lasting friend- raised from clinical services, while training and academic activities ships and for building strong links of young colleagues to ESPGHAN, are often not adequately considered and come under pressure, which but we probably need to keep investing in opportunities for full has at times endangered the quality of training and discouraged members to meet and interact such as the ESPGHAN working groups talented colleagues to pursue a career in research. Along with other that are accessible for members only, the annual members dinner, and paediatric and medical associations, ESPGHAN must make its the ESPGHAN master classes. Maintaining and strengthening the voice heard and will have to continue lobbying for providing high level of dedication of members to ESPGHAN will also be a adequate resources and infrastructures subspecialty medical care, prerequisite for preserving the high level of volunteer work of our in particular for children. members for the association, even at times when pressures at the Today’s medicine is based on what science has discovered workplace tend to increase and the challenge to achieve a work-life- before, and today’s science is tomorrow’s medicine. We cannot be balance may be greater than ever. satisfied with our current ability to support patients because we do The prerequisites for continued importance and success of not yet have satisfactory diagnostic and therapeutic strategies ESPGHAN are very good, not the least because our core mission is available for too many children; hence we must keep moving the as current as ever: we aim to promote child health through increased borders of our knowledge forward. Much of the progress in our field understanding, prevention strategies and treatment of diseases. The has previously been driven by talented and dedicated physician future developments and strengths of ESPGHAN will most likely scientists that could build a bridge from bench to bedside. The have a considerably impact on the lives of children and on economic pressures in the medical care system make it increasingly their future. difficult to protect time for clinicians’ work in research unless additional grant funding is available. At the same time, research methodology rapidly has become more complex and sophisticated, REFERENCES and it is now difficult if not impossible for a clinician to achieve 1. Husby S, Koletzko S, Korponay-Szabo´ IR, et al., ESPGHAN Working major progress for her/his patients by doing research work on its Group on Coeliac Disease Diagnosis; ESPGHAN Gastroenterology own after the regular work hours. There is a real need for close Committee; European Society for Pediatric Gastroenterology, Hepatol- ogy, and Nutrition. European Society for Pediatric Gastroenterology, interdisciplinary collaboration and for attracting outstanding basic Hepatology, and Nutrition guidelines for the diagnosis of coeliac scientists from various disciplines to get involved in the many disease. J Pediatr Gastroenterol Nutr 2012;54:136–60. burning questions in PGHN. ESPGHAN must strive to attract such 2. Agostoni C, Decsi T, Fewtrell M, et al., ESPGHAN Committee on scientists to its meeting and the Society to facilitate this essential Nutrition. Complementary feeding: a commentary by the ESPGHAN bidirectional exchange from bench to bedside. Committee on Nutrition. J Pediatr Gastroenterol Nutr 2008;46:99–110.

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3. Agostoni C, Buonocore G, Carnielli VP, et al., ESPGHAN Committee 10. Hecht C, Weber M, Grote V, et al. Disease associated malnutrition on Nutrition. Enteral nutrient supply for preterm infants: commentary correlates with length of hospital stay in children. Clin Nutr from the European Society of Paediatric Gastroenterology, Hepatology 2015;34:53–9. and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr 11. Vriezinga SL, Auricchio R, Bravi E, et al. Randomized feeding inter- 2010;50:85–91. vention in infants at high risk for celiac disease. N Engl J Med 4. Host A, Koletzko B, Dreborg S, et al. Dietary products used in infants 2014;371:1304–15. for treatment and prevention of food allergy. Joint Statement of the 12. Koletzko B, Brands B, Chourdakis M, et al. The Power of Programming European Society for Paediatric Allergology and Clinical Immunology and The Early Nutrition Project: opportunities for by (ESPACI) Committee on Hypoallergenic Formulas and the European nutrition during the first thousand days of life and beyond. Ann Nutr Society for Paediatric Gastroenterology, Hepatology and Nutrition Metab 2014;64:141–50. (ESPGHAN) Committee on Nutrition. Arch Dis Child 1999;81:80–4. 13. D’Antiga L, Nicastro E, Papadopoulou A, et al. European Society for 5. Koletzko B, Baker S, Cleghorn G, et al. Global standard for the composi- Pediatric Gastroenterology, Hepatology, and Nutrition syllabus for tion of infant formula: recommendations of an ESPGHAN coordinated subspecialty training: moving towards a European standard. J Pediatr international expert group. J Pediatr Gastroenterol Nutr 2005;41:584–99. Gastroenterol Nutr 2014;59:417–22. 6. Turner D, Koletzko S, Griffiths AM, et al. Use of placebo in pediatric 14. Phillips A, Kelly D, Troncone R. ESPGHAN presents first Distin- inflammatory bowel diseases: a position paper From ESPGHAN, guished Service Award at AGM 2010. J Pediatr Gastroenterol Nutr ECCO, PIBDnet, and the Canadian Children IBD Network. J Pediatr 2011;53:124–5. Gastroenterol Nutr 2016;62:183–7. 15. Troncone R, Shamir R. Presentation of the 2013 ESPGHAN distin- 7. Koletzko B, Bhutta ZA, Cai W, et al. Compositional requirements of guished service award to professor David Branski. J Pediatr Gastro- follow-up formula for use in infancy: recommendations of an interna- enterol Nutr 2014;59:1–2. tional expert group coordinated by the Early Nutrition Academy. Ann 16. Koletzko B. ESPGHAN Distinguished Service Award 2014 to Professor Nutr Metab 2013;62:44–54. Peter John Milla, MSc, MBBS. J Pediatr Gastroenterol Nutr 2015; 8. Koletzko B, Kolacek S, Phillips A, et al. Research and the promotion of 60:285–6. child health: a position paper of the European Society for Paediatric 17. Koletzko B. ESPGHAN Distinguished Service Award 2015 to Professor Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol C. Olle E. Hernell. J Pediatr Gastroenterol Nutr 2016;62:793–4. Nutr 2014;59:274–8. 18. Koletzko B. ESPGHAN Distinguished Service Award 2016 to Professor 9. Chourdakis M, Hecht C, Gerasimidis K, et al. Malnutrition risk in Deirdre Kelly. J Pediatr Gastroenterol Nutr 2017;64:169–70. hospitalized children: use of 3 screening tools in a large European 19. Shamir R. ESPGHAN Distinguished Service Award 2017 to Professor population. Am J Clin Nutr 2016;103:1301–10. Olivier Goulet. J Pediatr Gastroenterol Nutr 2017;65:487–8.

www.jpgn.org S43 SUPPLEMENT

Chapter 4. The Relationship Between the European and North American Societies for Pediatric Gastroenterology, Hepatology and Nutrition

Carlos H. Lifschitz, yJon Vanderhoof, zHarland Winter, §Stefano Guandalini, jjWilliam Klish, zôRichard Grand, z#Allan Walker, and zJay Perman

ABSTRACT

This chapter is based on the memories of those who shaped the relationship his chapter is based on the memories of those who shaped the between the European and the North American Societies for Pediatric T relationship between the European (ESPGHAN) and the Gastroenterology, Hepatology and Nutrition. The first joint meeting of North American Societies for Pediatric Gastroenterology, Hepa- the 2 Societies took place in Paris in 1978, followed by 1 in New York tology and Nutrition (NASPGHAN). Of note is that neither in 1985, 1 in Amsterdam in 1990, 1 in Houston in 1994, and the last one in Society had at its origins an ‘‘H’’ in its acronym, as Hepatology Toulouse in 1998. The formation of the Federation of the International was not part of either; the liver at that time was not considered to Societies for Pediatric Gastroenterology, Hepatology and Nutrition (FISP- be important or nobody knew enough about it as to deserve to GHAN) preceded the First World Congress of all Societies, which took place have it included. No one remembers or will admit to knowing the in Boston in 2000. The success of this meeting was followed by world reason why haepatology was omitted. That changed with time, of congresses in Paris in 2004, Iguassu in 2008, Taiwan in 2012, and Montreal course, and the ‘‘H’’ was added to the name of both Societies, in 2016. NASPGHAN and ESPGHAN jointly took on the direction of the which is why in this chapter you may see in some places Journal of Pediatric Gastroenterology and Nutrition in 1991. Communica- ESPGAN and in others ESPGHAN. The same is true for the tion between the 2 Societies is extremely active, with members participating ‘‘N’’ for ‘‘Nutrition’’ in the North American Society; Europeans in many joint projects. on the other hand always knew the importance of Nutrition, at least from around 1971. However, at its beginning, the European Key Words: ESPGHAN, NASPGHAN, pediatric gastroenterology society was known as ESPGA. NASPGHAN got all letters of its acronym in 2001. (JPGN 2018;66: S44–S53)

ESPGAN as Inspiration for the North American Society of Pediatric Gastroenterology

In 1986, Dr Jon Vanderhoof, as President of what was then called the North American Society for Pediatric Gastroenterology (NASPG) attended for the first time the annual ESPGAN meeting in Edinburgh, Scotland, as the official representative from North America. Until that time, members of the NASPG met as a group (The Pediatric Gut Club) at one of the national meetings. Dr Vanderhoof, greatly impressed with the ESPGAN meeting, returned to the USA with the strong conviction that NASPG should have a similar, independent meeting in North America. Subse- quently, the NASPG Council authorized the very first Society meeting in Chicago in 1989, largely patterned upon the ESPGAN meeting. Organizing such a meeting was challenging because funding was not available and the members of Digestive Disease Week (DDW) were not interested in including pediatric gastroen- terology. However, the quality of the ESPGAN meetings served as the inspiration and impetus for what has become the successful FIGURE 1. Carlos Lifschitz. annual NASPGHAN meeting.

Received January 24, 2018; accepted January 29, 2018. From the Hospital Italiano, Buenos Aires, Argentina, the yHarvard Medical Address correspondence and reprint requests to Carlos H. Lifschitz, Associ- School, Gastroenterology at Boston Children’s Hospital, the zHarvard ate Physician, Hospital Italiano, Buenos Aires, Argentina Medical School, Boston, MA, the §Section of Pediatric Gastroenterology, (e-mail: [email protected]). University of Chicago, Chicago IL, the jjBaylor College of Medicine, Copyright # 2018 by European Society for Pediatric Gastroenterology, Houston, TX, the ôCenter for Inflammatory Bowel Disease, Boston Hepatology, and Nutrition and North American Society for Pediatric Children’s Hospital, Boston, MA, the #Mucosal Immunology and Biol- Gastroenterology, Hepatology, and Nutrition ogy Research Center, Massachusetts General Hospital for Children, DOI: 10.1097/MPG.0000000000001914 Boston, MA, and the University of Maryland, Baltimore, MD.

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JOURNAL OF PEDIATRIC Second Joint ESPGHAN-NASPGHAN Meeting GASTROENTEROLOGY AND NUTRITION The Second Joint Meeting was organized in New York by Dr In 1982, the Journal of Pediatric Gastroenterology and William Balistreri, who was Program Chairman. He worked with Nutrition was founded by Dr Emanuel Lebenthal and was run as a Drs Jean Rey, Peter Milla, and Beat Hadorn. Dr Richard Grand, private journal. Also, during the time when Dr Jon Vanderhoof from Boston, succeeded Dr Balistreri as NASPGHAN President was president of NASPG, several members of the American and chaired the meeting, which took place in 1985 at the now Society approached him with concerns that the only journal defunct Barbizon Plaza Hotel. At that time, the rate of exchange devoted exclusively to pediatric gastroenterology and nutrition was such that the dollar was extremely expensive for Europeans had an affiliation with neither of the major academic Societies. and many people complained about the high costs. That at least was Despite the fact that most of the published papers were written by not under the control of the organizers. The Farewell Dinner members of NASPG or ESPGAN, there was no editorial input took place at the Essex House Hotel. The Barbizon Hotel went from either Society to publication decisions. The issues involved bankrupt shortly after the meeting and NASPGHAN never got a in changing the status of the Journal were of concern to both bill for that. That was the first time NASPGHAN’s budget showed NASPG and ESPGAN. Discussions were initiated with Dr Bir- a positive balance. Since then, NASPGHAN has tried to hold its gitta Strandvik, President of ESPGHAN, and eventually with meetings at hotels likely to go bankrupt, but so far has been members of the respective Society Councils, to approach the unsuccessful and other sources of revenue have had to be found. Founding Editor, Dr Lebenthal, regarding affiliations. Negotia- The Post Graduate Course was then created which became a source tions by the Societies’ Presidents, Dr Birgitta Strandvik and Dr of revenue. Jon Vanderhoof, and subsequently Dr Jay Perman, as well as the The European view of this Jointmeetingissummarizedin publisher, Raven Press, and Dr Lebenthal were challenging due to the following paragraphs, taken from the report of the 1985 competing priorities. Eventually, in 1991 an agreement was Annual General Meeting presented by Dr Sandy McNeish’s, signed in Vevey, Switzerland, and The Journal of Pediatric President of ESPGAN at that time. His wittiness and sense of Gastroenterology and Nutrition became the official journal of humour are reflected. This document was provided by one of the ESPGHAN and NASPGHAN. In 1995, the other 2 regional authors (S.G.): ‘‘The (ESPGAN) Annual General Meeting Societies, the Latin American (LASPGN) and Asian Pan Pacific (AGM) in 1985, a joint meeting with NASPGN, was certainly (APPSPGN), became affiliates with representation on the edito- uniquely memorable, both in its preparation and at the meeting rial board. The Journal has grown steadily and now receives itself. First, the USA organizers had to dismiss the professional manuscripts from clinical and basic research physicians and conference organizer for incompetence less than one year before scientists worldwide. The Societies publish guidelines, position the date of the meeting. His replacement was a fast-talking New papers, supplements from major meetings, abstracts from York lady who appeared to have everything in hand. In fact, the national meetings, and opinions from leaders. The quality of company she represented went bankrupt during the meeting and the articles reflected in the rising impact factor is a major reason only sterling work by the local committee saved the day. The for the establishment of pediatric gastroenterology as a distinct scientific programme was of an exceptionally high standard and specialty in the international medical community. showed, to this biased observer at least, that European paediatric gastroenterologists can at least hold their own with their Amer- ican cousins. The symposium on ‘brain-gut peptides’ gave me a First Joint ESPGAN-NASPGAN Meeting headache, not only because of its very high scientific standard, but also because it took place the morning after the welcome The First Joint Meeting took place in Paris in 1978. cocktail party. At that party, held at the Asia Society on Park A photo is witness of one of the moments at that meeting Avenue, our hosts had prepared 5 g of food and 1 kg of alcohol (Fig. 2). for each person. The lunches and the formal banquet on the

FIGURE 2. Gala dinner at the First Joint Societies Meeting in Paris, May 1978. From left to right: Dr Jacques Schmitz, Mrs Louise Morin, Dr Jehan- Francois Desjeux, unidentified, Dr Hans Hildebrand, Mrs Marie France Desjeux, Dr Richard Grand, Dr Andree Weber, and Dr Claude Morin. www.jpgn.org S45 Supplement JPGN Volume 66, Supplement 1, April 2018 penultimate night confirmed that the thinking American (or at The first new member admitted (by special arrangement) was least the about-to-be bankrupt conference organizer) can eat Professor Rolf Zetterstrom (editor of Acta Pediatrica Scandina- only chicken and pasta. But the final night was superb - an vica), boyish in outlook but certainly not a teenager. Nevertheless, informal supper in Manhattan, accompanied by 1920’s piano. It the guidelines have become successfully adopted, as can be seen by is only about good friends that you can joke. The 1985 joint scanning the auditorium or the dance floor during our recent annual meeting was such a success that we agreed unanimously at the meetings. Despite these stringent bylaws, Drs Jon Vanderhoof, AGM to repeat the joint meeting regularly. Amsterdam 1990 Allan Walker, and Dr Carlos Lifschitz who had (and still do) enjoy followed and, even as I write, we are all looking forward to ESPGHAN meetings immensely but did not work in Europe, were Houston 1994.’’ accepted as members. Although the following pertains more to ESPGHAN proper than to joint relations of the 2 Societies, this document, also Third Joint ESPGHAN-NASPGHAN Meeting transcribed from Dr McNeish’s report, was elaborated at the time of the Joint meeting in New York. Because more than 30 years have The site selection was summarised like this by the main elapsed and problems have not changed, we believe it is interesting organizer, Jan Taminiau: ‘‘I liked the New York meeting in 1985, to include it. The following was adopted unanimously at the AGM went immediately with Hugo Heymans to John Vanderhoof and in New York: Dick Grand, proposed Amsterdam that was it.’’ The meeting took 1 PREAMBLE place in 1990 in downtown Amsterdam at the hotel Krasnapolsky. 1.1 Paediatric gastroenterology has grown and developed Three hundred people were registered but 600 participants showed well in Europe in the past decade, largely because of the up, 300 without any prior notification. According to the organizer efforts of members of ESPGAN. Our activities have caught Dr Taminiau, the reason was because the weather was nice! the interest of young workers, and increasing numbers feel Instantly 2 infant milk formula companies came up with the sufficiently committed to paediatric gastroenterology to wish additional budget needed. Old times! to become members of the Society. One of the social events took place at the old Binnegasthuis 1.2 Superficially this can be seen to create a conflict between (former Academic Children’s Clinic) and the Dutch Youth Orches- those who wish to keep the Society small (with the real tra and the imploding piano organized by Werner Herbers, from the benefits of easy communication and mutual understanding) Concertgebouw orchestra, performed and one of ESPGHAN mem- and those who wish to allow into membership all who might bers, Beat Hadorn sang opera arias with Ms Nel Biervliet, general benefit us. pediatrician from Paramaribo, Dutch Guyana. One was ‘‘La`ci 1.3 Council believes that the guidelines for membership of darem la mano’’ from Mozart’s Don Giovanni. There was also a ESPGAN should be revised to take account of these trends. tour to the open aircraft museum in Enkhuizen with buses and back by boat over the Ijsselmeer to Volendam for dinner at Spanjer hotel. The final dinner took place at the 3-story restaurant at Rokin, and 2 PROPOSED OBJECTIVES became a standing dinner, as the only way to accommodate the 2.1 To maintain, or better to increase, the scientific standards crowd. of the Society. 2.2 To offer membership to young workers of high achievement and potential—‘‘to catch them while they are Fourth Joint Meeting of ESPGHAN and still young.’’ NASPGHAN

3 REVISED GUIDELINES During the period of 1992 to 1994, the relationship between 3.1 The applicant should be working in Europe. NASPGHAN and ESPGHAN evolved and became closer, due in 3.2 Published evidence of active participation in research of large part to the interaction of Dr Allan Walker with European high scientific merit. This is likely to include several papers in colleagues. The NASPGHAN Board of Directors discussed refereed international journals. the possibility of holding another joint meeting between the 2 3.3 At least 1 personal presentation of a paper to the Society. Societies in the United States. Dr William Klish, who at that time 3.4 No lower or upper age limit will be set. However, it is was President of NASPGHAN, had offered to hold the meeting unlikely that strong candidates for membership will be more in Houston, Texas. He solicited the help of Dr Carlos Lifschitz than 45 years old. and with the tremendous help of Margaret Stallings, who 3.5 Basic scientists, and those in disciplines related to worked for the company called SLACK, they began the process paediatric gastroenterology and nutrition, will be welcomed. of finding a hotel large enough to hold a meeting which could attract 400 to 500 participants. Five hundred and thirteen people attended. 4 ADVANTAGES OF THE NEW GUIDELINES For the 1994 Joint Meeting, there were 186 abstracts sub- 4.1 The introduction of new blood, new ideas, new science. mitted by NASPGHAN members and 200 from European collea- 4.2 Some young colleagues will mature as active members of gues. Seventy-four abstracts were accepted for presentation. A the Society to the point where they are ready to assume nurses’ program was included. The meeting was held in October responsibility as Council members and officers when still and was extremely successful, including participants from South young. American and Asia. The entertainment was decidedly Texan and included a live private rodeo and Texas barbeque. The rodeo opened 5 POSSIBLE DISADVANTAGES to the delight of everyone, with the traditional parade led by Dr 5.1 The membership could increase to a size, which would William Klish on horseback and Dr Jacques Schmitz, President of cause the AGM to become impersonal. ESPGHAN, riding a very large Texas longhorn steer. Tequila shot 5.2 This could be minimized by either (a) limiting the number girls circulated and line dance with instructors put everyone on the of guests allowed to each member or (b) limiting guests of dance floor. A special tour and dinner at the National Aeronautic new members for (say) the first 3 years of membership. and Space Agency (NASA) was arranged for the farewell dinner.

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FIGURE 3. Representatives of all societies agree to the First World Congress in Denver in 1997. From left to right: Drs Ron Sokol, Samy Cadranel, Ulysses Fagundes Neto, Yuichiro Yamashiro, and Harland Winter.

Some people complained that the meeting was getting too large and meetings hosted by ESPGHAN (2004), LASPGHAN (2008), and impersonal. That meeting attracted 513 participants, today they are APPSPGAN (2012). The agreement between the societies was that over 4000! each would cancel its annual meeting during the year of the World Congress. Although CAPGAN was not 1 of the 4 sponsoring Fifth and Last Joint Meeting of ESPGHAN and societies, Dr Peter Sullivan, CAPGAN President, graciously agreed to cancel the already planned meeting in 2000 in order to participate NASPGHAN in the World Congress. The Mission Statement of the First World Congress stated: ‘‘The purpose of this first World Congress of This was held in Toulouse in 1998, organized by Jean Pierre Pediatric Gastroenterology, Hepatology and Nutrition is to bring Olives at the Centre de Congre`s Pierre Baudis. 900 participants together, for the first time, physicians, scientists and other health attended from 37 countries around the world. The Honorary Presi- professionals interested in child health from all over the world to dent was Jean Rey, NASPGN President was Ron Sokol, and share clinical advances and scientific and technologic develop- ESPGHAN President was Samy Cadranel. The highlights of the ments in the fields of paediatric gastroenterology, hepatology and Scientific Program were lectures on ‘‘Pathogenesis of gastrointes- nutrition.’’ tinal and liver disease in cystic fibrosis’’ by Claude Roy with a Dr Guandalini became ESPGHAN President in 1998 and his presentation and award by Richard Grand, and ‘‘Coeliac disease vision was that the World Congresses should be the pinnacle of a today: new faces of an old disorder’’ by Jarmo Visakorpi. There larger federation that should include the 4 major International were 250 original presentations, consisting of 51 oral and 199 Societies for pediatric gastroenterology. He thus began working posters. Social Events included a Welcome reception at the City at this project first within ESPGHAN but immediately also with the Hall, a concert in the Basilique Saint Etienne, a medieval evening in NASPGHAN leadership: in 1998, Dr Richard Colletti became the old city of Revel and a Farewell Dinner in the ‘‘Cloitre des President-elect of NASPGHAN and joined Drs Sokol and Winter Augustins,’’ where Stefano Guandalini was elected the next in organizing the World Congress. Thus, after much discussion that ESPGHAN President. included Ulysses Fagundes Neto and Geoff Cleghorn, the bylaws of First World Congress this new Federation were drawn and eventually signed in a cere- mony held in 2000 in Boston during the World Congress. FISP- Building on the success of the Combined NASPGHAN- GHAN (The Federation of the International Societies for Pediatric ESPGHAN meetings and the attendance of colleagues from Gastroenterology, Hepatology and Nutrition) was officially created, throughout the world, the leadership of the Asian Pan Pacific with the mission to not only be a stable organization to organize all Society of Pediatric Gastroenterology and Nutrition (APPSP- subsequent World Congresses, but also to form international teams GHAN), Latin American Society of Pediatric Gastroenterology, (‘‘Working Groups’’), to bring together investigators from each and Nutrition (LASPGHAN), and the Commonwealth Association Society to work together and develop in specific areas of clinical of Paediatric Gastroenterology & Nutrition (CAPGAN) began practice, updated statements on the current state of knowledge, and discussions about organizing a World Congress. Dr Ron Sokol needs for future research. was President of NASPGHAN from 1996 to 1998 and Dr Harland The organizational aspects of the World Congress were Winter was elected President-elect in 1996. Dr Ulysses Fagundes approved. The host society would retain all the revenue from the Neto was a key figure in the development of this project. Each Post-Graduate Course and, in addition, 40% of the profit from the Society made a presentation about hosting the Congress, and at a meeting. The remaining 60% would be divided among the other 3 meeting in Denver in 1997 (Fig. 3), the Presidents decided to hold sponsoring Societies. The meeting was organized by SLACK, a the First World Congress of Pediatric Gastroenterology, Hepatol- company that worked with NASPGN in the past to raise funds for ogy and Nutrition in Boston, to be followed every 4 years by the annual meeting and manage all the logistics. About a year prior www.jpgn.org S47 Supplement JPGN Volume 66, Supplement 1, April 2018

FIGURE 4. President’s reception at the home of Harland Winter and Susan Weinstein-Winter. Seated, from left to right: Drs Mei Hwei Chen, Mrs Milla, Hans Buller, unidentified. Standing: Dr Richard Grand, Ms Jan Sharkey (worked with Margaret Stallings to organize the meeting), Dr Geoffrey Davidson, Dr Peter Milla, Mrs Myra Grand. to the meeting, unexpectedly SLACK decided to sell their meeting In addition, the HEC was responsible to the IEC for (i) selection of business. The President, Harland Winter along with NASPGN meeting site and management company, (ii) budget management, leadership negotiated with SLACK to remove NASPGN from and (iii) oversight of the social activities. A Local Organizing inclusion in the sale and Peter Slack agreed to allow Margaret Committee was responsible for the social events and local programs Stallings to get out of her ‘‘non-compete’’ contract and leave at the meeting. SLACK to become NASPGN Executive Director. Jan Sharkey, The 20 working groups, which included a member from each who continued to be employed at SLACK, worked with Margaret of the 5 societies, served as a mechanism for members to interact. Stallings to raise the funds, organize the meeting, and handle all the Each group presented its conclusions during a session at the meeting. logistics. These 2 women did the work of an entire company and There were 1138 abstracts submitted as both oral and poster pre- saved the First World Congress. Margaret started what has become sentations that were reviewed by members from each society by a the NASPGHAN home office, and she remains the highly valued committee chaired by Dr Mitchell Cohen. Celiac disease had the Executive Director of NASPGHAN. highest number with 95 abstracts, followed by Helicobacter pylori As said earlier, the meeting was organized to emphasize with 92, oesophageal disorders with 82, inflammatory bowel disease scientific interactions and friendships. The objectives were as follows: to improve the digestive health and nutrition of infants, children, and adolescents worldwide by: 1. creating an international forum for communication of the latest scientific, clinical, pharmacological, and technological advances; 2. initiating and promoting global collaboration, education, and communication among health professionals; 3. fostering basic and clinical research in pertinent issues that impact the paediatric patient, family, and environment; 4. encouraging young researchers to pursue scientific investiga- tion into relevant areas.

There were 3 committees that organized the meeting. The International Executive Committee (IEC) that had responsibility for the choice of speakers, selection, and the final approval of the entire scientific program and the marketing of the meeting. The IEC was composed of the current President and President-elect of each of the FIGURE 5. President’s reception at the home of Harland Winter and Sponsoring Societies. The Host Executive Committee was com- Susan Weinstein-Winter, First World Congress, 2000: from left to right posed of officers and Host Society members who worked with the seated Mrs Samy Cadranel, Drs Jean-Pierre Olives, Carlos Lifschitz, IEC to organize specific programs, raise funds for the meeting, and unidentified, Ivor Hill, Mrs. Markku Maki. Standing: Drs Samy Cadra- insure that Continuing Medical Education requirements were met. nel, Jose Cervetto, Markku Maki, Rafael Jimenez Garcia.

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FIGURE 6. Dinner at the First World Congress, John Fitzgerald Kennedy Library, Boston, MA, August 2000. Seated, from left to right: unidentified, Drs Jan Taminiau, Ron Sokol, unidentified, Olivier Goulet. Standing: William Balistreri, Eve Roberts, Geoffrey Cleghorn, Jon Vanderhoof, unidentified. with 79, endoscopy with 69, hepatitis with 66, liver transplantation 1. Alan Guttmacher, MD, Senior Clinical Advisor to the Director with 57, and cholestatic liver disease with 47. Twelve abstracts were National Human Genome Research Institute, NIH The Human presented at plenary sessions, 125 were oral presentations, and 971 Genome Project on ‘‘Genetics and Gastroenterology in the 21st were posters. Plenary State of the Art lectures were given by: Century’’

FIGURE 7. Editors of the publication committee of the Journal of Pediatric Gastroenterology and Nutrition at the time of the First World Congress Sitting, from left to right: Drs John Walker-Smith, Judy Sondheimer, Emanuel Lebenthal, Michael Lentze, W. Allan Walker, Jehan Francois Desjeux, William Balistreri. www.jpgn.org S49 Supplement JPGN Volume 66, Supplement 1, April 2018

FIGURE 8. Society presidents at the World Congress August 2000: Drs Ron Sokol (NASPGN), Stefano Guandalini (ESPGHAN), Harland Winter (NASPGN), John Walker-Smith (ESPGHAN), Mei-Hwei Chang (APPSPGAN), Yuichiro Yamashiro (APPSPGAN), Roberto Rodriguez Calva (LASPGN), Geoffrey Cleghorn (APPSPGAN), Richard Colletti (NASPGN), Olivier Goulet (ESPGHAN).

2. Jay Hoofnagle, MD, Director, Division of Digestive Diseases program. They were acknowledged at the very successful exhibit and Nutrition, NIH on ‘‘Global View of Hepatitis in Children’’ hall which most of the over 2000 attendees from 80 countries 3. Benjamin Caballero, MD, The Johns Hopkins School of visited. Allocating funds to bring colleagues from resource-poor Hygiene and Public Health on ‘‘The Contributions of Nutrition countries was an important aspect of the meeting and was unani- in Child Health: A View from the Global Village’’ mously supported by the NASPGN Council and the IEC. Resources from the meeting provided funding for 150 young investigators and 50 International Outreach Awards to bring colleagues from Africa, Decisions about the program were made by the officers of Asia, Eastern Europe, and Latin America including 12 physicians each society by teleconference and at meetings held in airport from Cuba. Many of these physicians participated for the first time conference centres. Industry was a true partner in the meeting, in a professional international meeting. There was a lunch hosted by providing financial support without requesting any influence on the the leadership of NASPGN at which representatives from countries

FIGURE 9. Members of all 4 societies at the First World Congress. Seated from left to right: Drs Jose Cervetto, Ulysses Fagundes Neto, Roberto Rodriguez Calva, John Watkins, unidentified, unidentified, unindentified, William Balistreri, Geoffrey Cleghorn, unidentified. Standing: Drs Richard Coletti, Judy Sondheimer, Frederick Suchi, unidentified, unidentified, William Klish, Birgitta Strandvik, Michael Lentze, Jon Vanderhoof, Salvatore Auricchio, Jehan Francois Desjeux, Samy Cadranel, Stefano Guandalini, Ron Sokol, John Walker-Smith, Emanuel Lebenthal, Yuichiro Yamashiro, Harland Winter.

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(Fig. 6), and the Membership Dinner was held at the Boston Aquarium. Live fish was not part of the menu. The Farewell Dinner was at the Museum of Science where Sue, the Tyrannosaurus Rex, greeted everyone and international food stations were located throughout the museum. The First World Congress provided an opportunity for members and leaders in pediatric gastroenterology from every continent to meet and share experiences. In addition, the editors of the Publication Committee of the Journal of Pediatric Gastroenterology and Nutrition had a meeting (Fig. 7) and the presidents of the World Societies (Fig. 8) and members (Fig. 9). Subsequent World Congresses

The second World Congress, in Paris in 2004, the third in Brazil in 2008, the fourth in Taiwan in 2012, and the fifth in Montreal in 2016, complete the global cycle. Members of NASP- GHAN and ESPGHAN actively contributed with their experience to the organization of forthcoming World Congresses. Figures 10– 14 are mementos of the Paris meeting. FIGURE 10. At the opening ceremony of the Second World Congress held in Paris July 4 to 9, 2004, Professor Olivier Goulet, Congress’ CONCLUSIONS President, drives Professor Stefano Guandalini, ESPGHAN President, in As one (C.L.) who has attended the first ESPGAN meeting his 1972 Cinquecento at the Opening Ceremony in the Palais des in Madrid in 1981 and all but 4 since, and comparing them to the Congre`s. NASPGHAN meetings, I was always particularly impressed by 4 things about the ESPGHAN meetings: (1) the large number of topics in nutrition that were presented; (2) the interest- ing cities where the meetings took place; (3) the social pro- in the Middle East met together to discuss the creation of a regional grams; and (4) the comradery that existed among members. At society inclusive of all countries in the region. NASPGHAN there was only a business lunch. Unfortunately, In addition to the scientific program, there was an entertain- regulatory guidelines, costs, and the large number of attendees ing social program. The Opening Ceremony featured the Boston have restricted social events and time for informal exchanges Ballet II, the young professional arm of the parent company. A at ESPGHAN! reception for organizers was held in the backyard of the home of What started as a small project has evolved into an interna- Harland Winter and Susan Weinstein-Winter (Figs. 4 and 5), the tional meeting where colleagues from around the world can interact President’s Dinner was held at the John Fitzgerald Kennedy Library and learn from one another. The leadership of ESPGHAN and

FIGURE 11. Second World Congress in Paris, 2004. President’s dinner at the Hoˆtel d’Evreux, Place Vendoˆme, Paris, France. ‘‘The French Connection’’: from left to right Drs Jacques Schmitz, Jean Rey, and Olivier Goulet accompanied by their wives. www.jpgn.org S51 Supplement JPGN Volume 66, Supplement 1, April 2018

FIGURE 12. Second World Congress in Paris, 2004. Farewell Dinner. Muse´e des Arts Forains. The Congress President, Dr Olivier Goulet (left), and the future ESPGHAN President, Dr Berthold Koletzko.

FIGURE 13. Second World Congress in Paris, 2004. Farewell Dinner. Muse´e des Arts Forains. Drs Mike Thomson, Bhupinder Sandhu, and Hania Szajewska.

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FIGURE 14. Second World Congress in Paris, 2004. Farewell Dinner. Muse´e des Arts Forains. Drs Deidre Kelly and Peter Milla.

NASPGHAN continue to work with colleagues throughout the Acknowledgments: The authors wish to thank Margaret world to support . Unlike most long-lasting relations, Stallings, Drs Ulysses Fagundes Neto, Yen-Hsuan Ni, Jean Pierre this one has been relatively problem free and extremely produc- Olives, Olivier Goulet, and Jan Taminiau for their contributions. We tive. Hopefully newer generations will continue the traditions and also want to recognize Dr Sandy Mc Neish for the insightful and collaboration. witty minutes of an ESPGHAN Council meeting.

www.jpgn.org S53 SUPPLEMENT

Chapter 5. Fifty Years of Paediatric Gastroenterology

Olivier Goulet, yRicardo Troncone, zMarku Makki, §Jacques Schmitz, jjIsabel Polanco, ôMaria Luisa Mearin, #Samy Cadranel, Sibylle Koletzko, yyGiuseppina Oderda, zzAlan Phillips, §§Simon Murch, jjjjJohn Walker-Smith, ôôFrank Ruemmele, ##Jorge-Amil Dias, Sanja Kolacek, yyyYigael Finkel, zzzJohn Puntis, §§§Antonella Diamanti, jjjjjjSusan Hill, ôôôFlorence Lacaille, ###Girish Gupte, Jean Francois Mougenot, yyyyMike Thompson, zzzzMarc Benninga, §§§§Nikhil Thapar, jjjjjjjjAnnamaria Staiano, ôôôôGigi Veereman, ####Yvan Vandenplas, §§§§Peter Milla, Jehan-Franc¸ois Desjeux, yyyyyAlfredo Guarino, and zzzzzHania Szajewska

L isting of Chapter 5 Chapter 5.2.4 - Intestinal transplantation: on a long and uneven road Chapter 5.0 - 50 years of Paediatric Gastroenterology from the past to the future Chapter 5.1.1 - Coeliac Disease Chapter 5.3.1 - ESPGHAN History of Gastrointestinal Paediatric Chapter 5.1.2 - Infectious Diarrhoea Manuscript Endoscopy Chapter 5.1.3 - Forty Years of Helicobacter Pylori in ESPGHAN Chapter 5.3.2 - Some things have moved in the world of motility Chapter 5.1.4 - Pediatric Immune Related Enteropathies Chapter 5.3.3 - The story of gastro-oesophageal reflux that became Chapter 5.2.1 - Short Bowel Syndrome: half a century of progress a disease Chapter 5.2.2 - From the syndrome of intractable of infancy Chapter 5.4.1 - Acute Diarrhea to molecular analysis and cell : 50 years of evolution Chapter 5.4.2 -ESPGHAN made the gastrointestinal microbiota Chapter 5.2.3 - Parenteral nutrition and home parenteral nutrition grow changed the face of paediatric gastroenterology

Received January 27, 2018; accepted January 29, 2018. From the Divison of Pediatric Gastroenterology-Hepatology-Nutrition. Nutrition, National Reference Center for Rare Digestive Disease, Refer- Hoˆpital Necker-Enfants Malades. University Cite´-Paris Sorbonne. Paris ence Center for Home Parenteral Nutrition, Hoˆpital Necker Enfants Descartes Medical School. Paris, France, the yDepartment of Translational Malades, Paris, France, the ###XXX, the Hospitals Robert Debre´ Medical Sciences and European Laboratory for the Investigation of Food- and Necker-Enfants Malades, AP Paris, France, the yyyySheffield Chil- Induced Diseases (ELFID), University of Naples Federico II, Naples, Italy, dren’s Hospital NHS Foundation Trust, Sheffield, UK, the zzzzDepartment the zCenter for Child Health Research, University of Tampere and of Paediatric Gastroenterology and Nutrition, Emma Children’s Hospital/ Tampere University Hospital, Tampere, Finland, the §Hoˆpital Necker- Academic Medical Centre, Amsterdam, The Netherlands, the §§§§Divi- Enfants malades University Paris-Descartes, Paris, France, the jjFacultad Division of Neurogastroenterology & Motility, Department of Paediatric de Medicina. Universidad Auto´noma de Madrid, Spain, the ôDepartment Gastroenterology, Great Ormond Street Hospital, London, UK, the of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands, jjjjjjjjDepartment of Translational Medical Science, Section of Paediatrics, the #Queen Fabiola Children’s Hospital, Free University of Brussels, University of Naples Federico II, Naples, Italy, the ôôôôPediatric Gastro- Belgium, the Dr. von Hauner Children’s Hospital, University Hospital, enterology and Nutrition, University Hospital Brussels, Free University LMU Munich, Munich, Germany, the yyUniversita` del Piemonte Orien- Brussels, Belgium, the ####Department of Pediatrics, UZ Brussel, Vrije tale, Novara, Italy, the zzUCL Emeritus Professor of Paediatric Gastro- Universiteit Brussel, Brussels, Belgium, the Acade´mie nationale enterology, UCL Medical School, London, UK, the §§Warwick de me´decine, Paris, France, the yyyyyDepartment of Translational Medical University; University Hospital Coventry & Warwickshire, the Science, Section of Pediatrics University of Naples Federico II, Naples, jjjjUniversity of London, London, UK, the ôôNecker Enfants Malades Italy, and the zzzzzDepartment of Paediatrics, The Medical University of Hospital, Pediatric Gastroenteroloy, Universite´ Paris Descartes—Sor- Warsaw, Warsaw, Poland. bonne Paris Centre, Paris, France, the ##Hospital S. Joa˜o, University of Address correspondence and reprint requests to Olivier Goulet, MD, Porto, Portugal, the University Department of Pediatrics, Referral PhD, Hoˆpital Necker University of Paris Descartes, Paris, France Center for Pediatric Gastroenterology and Nutrition, Children’s Hospital, (e-mail: [email protected]). Zagreb, Croatia, the yyyDepartment of Gastroenterology, Karolinska Copyright # 2018 by European Society for Pediatric Gastroenterology, Institutet, Stockholm, Sweden, the zzzLeeds Teaching Hospitals NHS Hepatology, and Nutrition and North American Society for Pediatric Trust, London, UK, the §§§Artificial Nutrition Unit, ‘‘Pediatric Hospital Gastroenterology, Hepatology, and Nutrition Bambino Gesu`,’’ Rome, Italy, the jjjjjjDepartment of Paediatric Gastro- DOI: 10.1097/MPG.0000000000001915 enterology, Great Ormond Street Hospital NHS Foundation Trust, London, UK, the ôôôDepartment of Paediatric Gastroenterology-Hepatology-

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Chapter 5.0. 50 Years of Paediatric Gastroenterology

Olivier Goulet

promoted in every field of clinical practice and medical science. Nowadays, PedGI ‘‘generalists’’ and PedGI ‘‘specialists’’ are facing. Indeed, what is common to outstanding motility specialists as the authors of the following papers, and the PedGI immunol- ogists who deal with IBD and ‘‘immune related congenital entero- pathies’’ (IRCE) [I do prefer this wording to the term ‘‘very early onset IBD’’]. A number of centres in the world have the privilege of developing to a high level in all aspects of PedGI. This gives them the obligation to share and diffuse the knowledge acquired through their own publications and, within the ESPGHAN frame- work, by their investment in the formation and promotion of young people through post-graduate courses, workshops, working groups, statements etc. Most, but not all, of the diverse faces of PedGI are covered in these papers. Much progress and many advances are stressed. Great dynamism and enthusiasm is released from these various lines, but some fundamentals deserve to be underlined. With huge clinical demands related to digestive functional disorders, together with parental pressure, clinicians, who we are first, must avoid the multiplication of investigative procedures, and for some, to fall into merchandizing attitudes, the so called ‘‘GI business.’’ Our medical care should be based first on clinically well-established hypotheses, or in some settings be part of a clinical research protocol. In the same way, the development of the internet demands new attitudes and generates requests for treatments. Fortunately, Evidence Based Medicine (EBM) makes it possible to establish guidelines, as shown in a growing number of recommendations by ESPGHAN (eg, acute diarrhoea, management of functional intesti- FIGURE 1. Olivier Goulet. nal disorders, probiotics, prebiotics, etc). Intestinal failure (IF) has become a very distinct field within PedGI. It links clinical gastroenterology, therapeutic nutrition, t is an immense pleasure and a great honour to present this immunology, genetics, and cell biology. In that field, EBM for chapter devoted to Pediatric Gastroenterology (PedGI). During most purpose cannot be achieved. This medicine is based on myI training in this field I was privileged to have several mentors, the physiology, experience and common sense as well as collabora- ESPGHAN members Jean Rey, Claude Ricour, and Jacques tions. More than any other domain of PedGI, IF requires interdisci- Schmitz. I thank them very warmly. In addition, during my forma- plinarity, involving neonatalogists, pediatric surgeons and many tion, I had the chance to meet wonderful ESPGHAN colleagues and other organ specialist, and multi-professionalism, including nurses, friends who are, many of them, involved in these PedGI selected dieticians, pharmacists, psychologists, and social workers. Every- topics and papers. I am sorry to have been unable to involve as many one who is invested in this discipline must perceive that they are not colleagues as I should have wished. Editing so many different alone and that they cannot be alone. This is one of the most beautiful papers, with 2 to 5 authors, was not easy, but I hope it was aspects of this medical field. IF constitutes the essence of ‘‘rare successful. For me all the papers are excellent, fitting perfectly digestive diseases.’’ It is a topic that should not be a closed, with the wishes of the ESPGHAN History Committee. I would like protected field, or of the ‘‘aristocracy of the rare diseases,’’ but, to thank, from the depth of my heart, all the authors who gave their on the contrary, to lead always to open dynamic research interac- time and energy to achieve this. tions. In addition, IF can lead to very challenging situations, such as Fifty years ago, both ESPGHAN was born, and the indivi- end-stage liver disease, intestinal transplantation failure, humanly dualisation of PedGI within Paediatrics grew. During the following with dark horizons sometimes, even if important progress has been years, PedGI became very diverse, as reflected by the different accomplished during the last 50 years in both diagnosis and papers in this short historical overview. With the onset of technol- management of these rare conditions. We must have, even more ogy (endoscopy, imaging, recording devices), microbiology, than in other field of PedGI, great empathy and ethical sensitivity, to immunology, genetics and cell biology, excellence has been deal effectively with chronic diseases, and moreover to cope with major human problems (shaken families, divorce, eating disorders, Received January 27, 2018; accepted January 29, 2018. financial problems) emotional strength, openness, and humility are Copyright # 2018 by European Society for Pediatric Gastroenterology, required. Hepatology, and Nutrition and North American Society for Pediatric Modernity and the evolution of lifestyles have their limits. Gastroenterology, Hepatology, and Nutrition The burden of IBD is a perfect illustration. Who would have DOI: 10.1097/MPG.0000000000001915 predicted in 1968 that we would become submerged by this

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FIGURE 2. Walker’s pediatric gastrointestinal disease textbook. increasing wave, which we know not where it will lead. It touches This retrospective review of 50 years of PedGI made me each and everyone, irrespective of age, sex, origin, social status or happy and very grateful with respect to its pioneers and my senior ethnicity. It constitutes for me a priority in public health. Outstand- colleagues. I would like to especially recognise Professor Alan ing research and RCTs, mostly promoted by the wonderful and very Walker, for inviting Ian Sanderson and myself to be European co- active Porto ESPGHAN working group, have been improving IBD editors of the famous Walker’s Pediatric Gastrointestinal Disease management. Treatments are increasingly focused but expensive textbook for the GI part and Giorgina Mieli-Vergani for Hepatology and not always effective, nor are they always free of dangers, both (Fig. 2). It obliges us to continue to promote constant progress as short and long term. Can we hope that the demonstrated role of the they did. Thank you, once again, my colleagues who contributed to intestinal microbiota will change current therapeutic attitudes and this Journal of Pediatric Gastroenterology and Nutrition 50th move us back to a more ‘‘ecological’’ approach as is the ‘‘nutri- anniversary special. Thank you Lawrence Weaver, who has been tional’’ management promoted a long time ago (1987) by Ian so confident a conductor of this Hepatology-Gastroenterology- Sanderson (1). In addition, Ian was the first to provide a clinical Nutrition ‘‘concert of the century.’’ (phenotypical) description of the, nowadays, well-recognized My best wishes for the next ESPGHAN 50 years and my very IRCE, well before the genetics of IL-10 receptor deficiency, which warm regards to all my ESPGHAN friends and colleagues. followed 18 years later! (2). Do not believe that I am reactionary, but just careful vis-a`-vis this therapeutic, hopefully evidence based progress, which makes doctors shine and delights the phar- REFERENCES maceutical industry. I believe that classical IBD, mainly related to 1. Sanderson IR, Udeen S, Davies PS, et al. Remission induced by an lifestyle, dietary habits and possible intestinal microbiota predators, elemental diet in small bowel Crohn’s disease. Arch Dis Child requires a basic reflection on its prevention, maybe as early as birth 1987;62:123–7. (might Caesarean sections, antibiotics, proton pump inhibitors, 2. Sanderson IR, Risdon RA, Walker-Smith JA. Intractable ulcerating breast feeding, healthy further feeding be involved?). enterocolitis of infancy. Arch Dis Child 1991;66:295–9.

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Chapter 5.1.1. Coeliac Disease

Markku Maki, Maria Luisa Mearin, Isabel Polanco, Jacques Schmitz, and Riccardo Troncone

o other disease parallels the history of ESPGHAN as coeliac 1990 criteria were still largely applied throughout Europe, but also disease (CD) does. For a long time it has been considered that was time for a change. The new criteria (6) published in 2012 by N‘‘the disease’’ of ESPGHAN. This goes back to the time CD was a a committee chaired by Steffen Husby introduced significant disease of childhood manifesting only in the first 2 years of life, changes in the very definition of the disease emphasising its mainly with chronic diarrhoea, distended belly, and failure to thrive. systemic nature, with enteropathy being only one of its features, The Dutch paediatrician W.K. Dicke, working in Utrecht together and the value of CD-associated autoantibody in some situations able with one of the founders of ESPGHAN, Dolf Weijers, was the first to replace the demonstration of mucosal damage. to demonstrate the harmfulness of gluten on the basis of experi- Diagnosis has been not the only area in CD where a joint ments based on standardised diets and fat absorption assessment. effort by ESPGHAN members has brought significant progress. Other ESPGHAN members posed milestones in the history of the Epidemiology has been another area of strong cooperation. Impor- CD; among them Margot Shiner, who, with the development of tant cooperative work was conducted by some ESPGHAN members methods for peroral biopsy of the small intestinal mucosa, rendered (Jarmo Visakorpi, Isabel Polanco, Salvatore Auricchio) at the end possible to define the histological lesions, and Anne Ferguson, with of 1980s to assess the prevalence of CD among first-degree relatives her seminal studies on gut intraepithelial lymphocytes (1). It is then of CD patients. A few years before the antireticulin antibody, not surprising that until now (in recent years only IBD seems to subsequently replaced by endomysial and antitransglutaminase parallel the interest among members) CD has been the disease most antibody, was shown to have a very high positive predictive value investigated in ESPGHAN, as shown by the number of abstracts for the diagnosis of CD (7); the prevalence found in families where presented at the annual meetings. Those contributions are not only almost all members were biopsied approached 9% (8), but more the result of the work of brilliant researchers, but in many important importantly this was one of the first studies indicating how screen- cases, of the cooperative effort of more members made possible by ing based on CD-associated autoantibodies allowed the identifica- networking in ESPGHAN. tion of the vast majority of previously unrecognised cases. There is no doubt that the area where ESPGHAN as Society In the same years the ESPGHAN working group on CD has been more linked to CD is the formulation of diagnostic criteria. promoted a multicenter study of the epidemiology of the disease, Already in the second annual meeting of ESPGHAN (ESPGA at whose results were discussed at the 24th annual meeting in London that time) a round table was organised to create a consensus (June 1991) and in a special meeting organised in Capri by especially concerning the permanency of gluten intolerance. Jarmo Salvatore Auricchio and Jarmo Visakorpi. The study was the largest Visakorpi remembers (2) that an inquiry made to prepare the ever conducted involving 38 centres from 15 European Countries; conference showed that at that time only a minority of patients there were contributions also from outside Europe, including North was treated with a gluten-free diet lifelong. The first diagnostic Africa and South America, and significant variation in the incidence criteria for CD laid down by ESPGAN in Interlaken had the merit of emerged (9). Environmental factors, including type and amount of including the concept of the permanent gluten intolerance (3). They cereals, hypothesised to cause the different figures of prevalence in introduced the need to demonstrate an abnormal morphology of the different countries. That was a critical time for epidemiology, as, small intestinal mucosa, its normalisation on gluten-free diet and thanks to the development of serological methods, the whole the relapse following reintroduction of gluten, and of the 3 biopsies spectrum was displayed, from silent cases, to atypical cases (with- procedure (3). These strict criteria were soon applied by paedia- out gastrointestinal symptoms), to cases with minor enteropathy. tricians throughout Europe: an enquiry conducted by ESPGHAN The detection of cases with positive autoantibody and mild member David Shmerling in 51 centres showed that the great enteropathy (or no enteropathy at all) represents today one of the majority applied the criteria and treated all patients lifelong. An main problems. A starting point of latency in CD, that is, the disease ESPGHAN working group on CD was founded under the presi- is existing but not manifest at the mucosal level, came from the dency of Salvatore Auricchio; in its context the need for a revision Tampere group in 1990 (10). This publication, and many to come, of diagnostic criteria emerged in the late 1980s; after a workshop question the same definition of CD and poses significant questions organised at the annual meeting in Budapest (1989), a subcommit- in terms of management. In a similar context are patients who tee (Jacques Schmitz, John Walker-Smith, Stefano Guandalini, received a diagnosis of CD and show no villous atrophy even after a David Shmerling, Jarmo Visakorpi) published in 1990 a revision long period of gluten-containing diet (11). Prospective randomised of the criteria where the obligatory provocation was abandoned in controlled studies are necessary to define the natural history, assess typical cases and for the first time the value of determination of the risk they are exposed if on normal gluten-containing diet and to specific CD serum antibodies was emphasised (4). The rest is decide about the need of excluding gluten. history of these days. A further revision has been published, after The central role played by HLA-restricted gliadin-specific T a long work initiated by a meeting in Tampere promoted in 2006 by cells is nowadays fully recognised. Other 2 important concepts have Markku Maki. An inquiry led by Carmen Ribes (5) showed that the emerged in the last decades: the activation of innate immunity and the autoimmune nature of the disease. Both came from within Received January 27, 2018; accepted January 29, 2018. ESPGHAN. The recognition of the biological activity of the A Copyright # 2018 by European Society for Pediatric Gastroenterology, gliadin peptide 31–43 (12) and its role in triggering mucosal innate Hepatology, and Nutrition and North American Society for Pediatric immunity (13), both emerged from organ culture studies. Operating Gastroenterology, Hepatology, and Nutrition autoimmune mechanisms were first postulated in 1991, with DOI: 10.1097/MPG.0000000000001915 ingested gluten as the environmental insult (14) and the hypothesis

JPGN  Volume 66, Supplement 1, April 2018 S57 Supplement JPGN  Volume 66, Supplement 1, April 2018 for autoimmune mechanisms were presented and discussed at the 5. Ribes-Koninckx C, Mearin ML, Korponay-Szabo´ IR, et al. Coeliac sixth International Symposium on Coeliac Disease held at Trinity disease diagnosis: ESPGHAN 1990 criteria or need for a change? College, Dublin, in 1992 (15). Results of a questionnaire. J Pediatr Gastroenterol Nutr 2012;54: An important area where major efforts are being concentrated 15–9. is prevention. The increasing knowledge about genetic factors (HLA 6. Husby S, Koletzko S, Korponay-Szabo IR, et al. European Society for and non-HLA) involved in CD and hence the possible identification Pediatric Gastroenterology, Hepatology and Nutrition Guidelines for the diagnosis of celiac disease. J Pediatr Gastroenterol Nutr 2012;54: of at risk subjects, together with the information about environmental 136–60. factors involved, may open the way to strategies for prevention. A 7. Ma¨ki M, Ha¨llstro¨m O, Vesikari T, et al. Evaluation of a serum IgA class first effort based on the possibility of inducing tolerance by feeding reticulin antibody test for the detection of childhood celiac disease. J small amount of gluten has involved many ESPGHAN members, Pediatr 1984;105:901–5. coordinated by Luisa Mearin (16). Another similar study (17) has 8. Auricchio S, Mazzacca G, Tosi R, et al. Coeliac disease as a familial been conducted in Italy involving other ESPGHAN members led by condition: Identification of asymptomatic coeliac patients within family Carlo Catassi. Altogether, these data have been translated in ESP- groups. Gastroenterol Int 1988;1:25–31. GHAN guidelines for infant nutrition (18). More importantly, these 9. Greco L, Ma¨ki M, Di Donato F, et al. Epidemiology of coeliac disease in studies have paved the way for other prospective randomised inter- Europe and the mediterranean area. A summary report on the multi- centre study by the European Society of Paediatric Gastroenterology vention studies, reinforcing the hope that CD and its complications and Nutrition. In: Auricchio S, Visakorpi JK, eds. Common Food might be delayed, or even prevented, with interventions in the first Intolerances 1: Epidemiology of Coeliac Disease. Dyn Nutr Res, Basel, year of life in genetically susceptible individuals. Karger 1992; 2:25-44. Today CD is very much changed in comparison to the disease 10. Ma¨ki M, Holm K, Koskimies S, et al. Normal small bowel biopsy known when ESPGHAN moved its first steps; it is no more a followed by coeliac disease. Arch Dis Child 1990;65:1137–41. disease of childhood and is not restricted to Europe. The attention 11. Matysiak-Budnik T, Malamut G, de Serre NP, et al. Long-term by adult gastroenterologists is increasing worldwide and new follow-up of 61 coeliac patients diagnosed in childhood: challenges are faced. The progress in the comprehension of the evolution toward latency is possible on a normal diet. Gut 2007;56: molecular basis of CD has allowed the identification of possible 1379–86. 12. de Ritis G, Auricchio S, Jones HW, et al. In vitro (organ culture) studies targets for therapy (19). supplement therapy using bacterial of the toxicity of specific A-gliadin peptides in celiac disease. Gastro- endopeptidases has been proposed to promote complete digestion of enterology 1988;94:41–9. cereal proteins and thus destroy T-cell multipotent epitopes. The 13. Maiuri L, Ciacci C, Ricciardelli I, et al. Association between innate identification of specific epitopes may also provide a target for response to gliadin and activation of pathogenic T cells in coeliac immunomodulation of antigenic peptides. Other promising areas disease. Lancet 2003;362:30–7. include inhibition of the adaptive immune response activated by 14. Ma¨ki M, Ha¨llstro¨m O, Marttinen A. Reaction of human non-collage- gliadin peptides, preventing gliadin presentation to T cells by nous polypeptides with coeliac disease autoantibodies. Lancet blocking HLA binding sites or use of TG2 inhibitors. So far trials 1991;338:724–5. have involved mostly adult CD patients, but it is easy to predict that 15. Ma¨ki M. Autoantibodies as markers of autoimmunity in coeliac disease pathogenesis. In: Feighery C, O’Farrelly C, eds. Gastrointestinal paediatric gastroenterologists will soon be involved and that ESP- Immunology and Gluten-sensitive Disease. Dublin: Oak Tree Press; GHAN members will give their contribution thank to their consoli- 1994:246–52. dated ability to work together. 16. Vriezinga SL, Auricchio R, Bravi E, et al. Randomized feeding inter- vention in infants at high risk for celiac disease. N Engl J Med 2014;371:1304–15. REFERENCES 17. Lionetti E, Castellaneta S, Francavilla R, et al., SIGENP (Italian Society 1. Ferguson A, Murray D. Quantitation of intraepithelial lymphocytes in of Pediatric Gastroenterology, Hepatology, and Nutrition) Working human jejunum. Gut 1971;12:988–94. Group on Weaning and CD Risk. Introduction of gluten, HLA status, 2. Visakorpi J. ESPGAN: 25 years 1968–1992. and the risk of celiac disease in children. N Engl J Med 2014;371:1295– 3. McNeish AS, Harms HK, Rey J, et al. The diagnosis of coeliac disease. 303. A commentary on the current practices of members of the European 18. Szajewska H, Shamir R, Mearin L, et al. Gluten introduction and the risk Society for Paediatric Gastroenterology and Nutrition (ESPGAN). Arch of coeliac disease: a position paper by the European Society for Dis Child 1979;54:783–6. Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gas- 4. Revised criteria for diagnosis of coeliac disease. Report of Working troenterol Nutr 2016;62:507–13. Group of European Society of Paediatric Gastroenterology and Nutri- 19. Kurada S, Yadav A, Leffler DA. Current and novel therapeutic strategies tion. Arch Dis Child 1990;65:909–11. in celiac disease. Expert Rev Clin Pharmacol 2016;9:1211–23.

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Chapter 5.1.2. Infectious Diarrhoea

Alan Phillips, Simon Murch, and John Walker-Smith

n the 50 years since ESPGHAN’s inception the field of intestinal immune based identification tests; subsequently, molecular biologi- infectious diarrhoea has changed considerably. It is important to cal analysis using polymerase chain reaction methods provided rapid rememberI that ESPGHAN was a small society at the beginning and and sensitive viral identification and has become the method of it is only in the last few years that the membership has expanded to choice. 800 plus including trainees and allied health professionals (and an expanding emeritus category). There has been a huge expansion in Contribution of Intestinal Biopsies the numbers of nonmembers attending the annual ESPGHAN meetings, dramatically changing the more informal atmosphere Although Bishop et al performed small intestinal biopsies in of earlier years to the formality of a major scientific congress. children with acute diarrhoea, in clinical practice intestinal biopsy Around the 1980s and beyond ESPGHAN was largely driven by was restricted to cases of chronic (>14 days) diarrhoea (2). The leading figures in centres of excellence, each with their own mix of application of EM to an abnormal biopsy from a case of chronic areas of interest, which they independently investigated and funded diarrhoea in 1980 demonstrated a distinctive microvillous-effacing having to satisfy their own Institutions’ demands of scientific activity lesion at sites of bacterial adhesion (4). The bacteria were identified and output. ESPGHAN’s strength at that time, in terms of infectious as enteropathogenic Escherichia coli (EPEC). The observation that diarrhoea, was largely as a network of clinical expertise, a platform to host cell actin accumulated at sites of EPEC (and enterohaemor- present research for debate, rather than a source of funding or a rhagic E coli (EHEC) infection both in vivo and in vitro, provided a stimulus of novel research. So it is not surprising that there was an host, cell-based virulence test, which handed to molecular biolo- uneven scientific interest in infective diarrhoea, which did not match gists the key that unlocked the incredible bacterial processes the more widespread commitment to clinical areas of research such as underlying pathogenesis (5) (Fig. 2). Another major advance was coeliac disease. However, the Group led by John Walker-Smith at the the finding in the early 1980s that EHEC produced Shiga toxin Queen Elizabeth Hospital for Children in London had been involved explaining the association of haemorrhagic colitis and the haemo- in the field of infectious diarrhoea from an early stage. In recent years, lytic uraemic syndrome with infection (6). Advances were also the ESPGHAN Gastroenteritis Working group, involving especially made in the identification and understanding of a range of other Hania Szajewska and Alfredo Guarino, provided important work for bacterial toxins (7). establishing guidelines (see Chapter 5.4.1). In terms of parasites, although Giardia lamblia is a frequent stool and intestinal biopsy finding, the identification of Cryptospo- THE PRE-ESPGHAN PERIOD ridium as a cause of acute and chronic infectious diarrhoea was perhaps a more important finding (8) (Fig. 3). Evidence of Viral Diarrhoea In 1968 no viral causes of acute diarrhoea had been identified and presumed cases were called nonbacterial gastroenteritis. This was Geographical and Interdisciplinary Approach a result of using isolation and culture when viral culture was It is clear that infectious diarrhoea is a particular problem in impossible. Coincidentally, the outbreak of acute diarrhoea from developing countries and is integral to the downward spiral of which the Norwalk Agent was detected, occurred in 1968, but the infection and malnutrition that blights populations and is responsible virus was not identified until 1972 when immune electron microscopy for high levels of morbidity and mortality. In Europe, a direct interest was applied to stored faecal samples (1). Shortly afterwards Bishop et in these areas is particularly fostered by historical links with countries al used thin section electron microscopy to study small intestinal in the process of development, for example, the British Common- biopsies taken from children with acute diarrhoea and identified viral wealth, the French-speaking North African countries, and to popula- particles (rotavirus) within enterocytes (2). It was also found that tion centres where immigration of people from these countries was negative staining stool electron microscopy could be used on crude prevalent. The Commonwealth Association of Paediatric Gastroen- faecal extracts to identify viral particles (3) (Fig. 1). This paved the terology and Nutrition (CAPGAN) was founded to develop clinical way for rapid viral diagnosis, and allowed several morphologically and research links between developing and developed communities. distinct viruses to be identified (rotavirus, adenovirus, astrovirus, Through FISPGHAN a similar interest was catalysed at the world small round structured viruses (Norwalk-like), small round viruses, congresses by ESPGHAN, and working group reports were published and coronavirus). From a clinical point of view, having the ability to for the 2004 and 2008 World Congress meetings (9,10). It is clear that make rapid viral diagnoses gave an understanding of the prevalence major advances are made when there is a high degree of interaction of viral diarrhoea, especially rotavirus-related, permitted an analysis between clinicians and other disciplines with microbiological, basic of whether there were particular diagnostic clinical associations and scientific, and molecular biological expertise. gave an important analytical tool in children with the postenteritis syndrome. Stool electron microscopy (EM) was taken over by THE ESPGHAN PERIOD Received January 27, 2018; accepted January 29, 2018. Protracted Diarrhoea, Malnutrition, and Copyright # 2018 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Immune System Gastroenterology, Hepatology, and Nutrition By the time of the founding of ESPGHAN, the relationship DOI: 10.1097/MPG.0000000000001915 between repeated cycles of gastrointestinal infection and

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FIGURE 1. Rotavirus. Left—negative staining EM (from stool sample) and Right—Transmission EM showing epithelial cell containing rotavirus particles (human infection).

FIGURE 2. Enteropathogenic E coli: Left—scanning EM of in vitro organ culture infection. Right—in vivo infection of small intestine in child with chronic traveller’s diarrhoea returning to UK from India.

FIGURE 3. Showing extent of chronic diarrhoea duration in children with cryptospridiosis. From Phillips et al Gut 1992;33:1057–61.

S60 www.jpgn.org JPGN  Volume 66, Supplement 1, April 2018 Supplement malnutrition diseases was just becoming appreciated (11). Although severely dehydrated cases, intravenous rehydration therapy. immune mechanisms were acknowledged, the importance of Compared to the more individual Institution based studies on the lymphoid system was not then recognised. In the next 2 decades, aetiology and pathogenesis, ESPGHAN has taken a more active the natures of T cells and B cells were clarified, and important involvement in studies on the management of acute diarrhoeal peptide mediators of inflammation and the changes in malnutrition disease. and chronic diarrhoea were discovered, such as interleukin (IL-1), IL-6, and tumor necrosis factor (12). Oral Rehydration Therapy Collaboration between ESPGHAN and CAPGAN members in centres, including the Medical Research Council (MRC) Unit in In 1978 The Lancet stated that a method of rehydrating The Gambia, contributed to changes in the nutritional management patients with acute diarrhoea by mouth was ‘‘potentially the most of infants with chronic diarrhoea (13), and identified that persistent important medical advance in this century’’ (29). This method was increase in gut epithelial permeability predicted nutritional failure based upon the discovery that glucose stimulated sodium transport and death (14), associated with an unchecked TH1 immune response across a piece of rat ileum (30). This approach was called Oral within the mucosa and failure of T regulatory responses (15). Rehydration Therapy (ORT). ‘‘It was a remarkable example of Consistent with this, it was confirmed that an elemental diet induced theoretical scientific knowledge being applied directly to a clinical better weight gain than a traditional weaning diet (16). More problem’’ (31). The effectiveness of this approach in practice was recently, there has been recognition of the important role of the dramatically demonstrated in a cholera epidemic in Bangladesh, microbiome in malnutrition enteropathy (17). Thus, there has been a with a dramatic fall in mortality (32,33). change of emphasis, away from a simple concept of undernutrition, In Europe, there was concern about the relatively high towards recognition that mucosal immune responses and immune sodium levels of the original oral rehydration solution (ORS). tolerance are critical players in determining outcome of infants with This was at a time when hypernatraemic dehydration was an chronic diarrhoea in resource poor countries. important problem for the children of Europe with gastroenteritis. In the UK, both Sandy McNeish and John Walker-Smith Unlike children of the developing world who were malnourished, encouraged younger scientists and electron microscopists (Alan such children were often obese and fed with high solute milks. Phillips and Stuart Knutton) to get involved in clinical concerns There was pressure upon paediatricians in developed countries and this mentorship stimulated laboratory studies in viral, EPEC such as those of Europe to set an example to their colleagues or Clostridium difficile diarrhoea which were presented at ESP- by using ORS but there were safety anxieties at a time when GHAN meetings; it also helped clinicopathological studies in mortality from childhood gastroenteritis had fallen to low levels. viral, bacterial, parasitic, and traveller’s diarrhoea observations at ESPGHAN addressed these issues and the matter was discussed in Queen Elizabeth Hospital for Children, London (18–21). These detail at a workshop at the ESPGAN meeting in Copenhagen in observations were of relevance to developing and developed 1988 (34). communities as the hospital served a deprived community in east London with significant numbers of immigrant children and children of immigrants, especially from the Indian subcontinent ESPGHAN Gastroenteritis Working Group and Bangladesh. Extensive work achieved understanding in E coli–related infectious diarrhoea. This arose in part from national There were 2 outcomes of this Copenhagen symposium in and international collaboration between like-minded individuals 1988. Firstly, an ESPGHAN working group was established as a with a balance of expertise and contacts. While not directly collaboration between 13 ESPGHAN members from across Europe. resulting from ESPGHAN initiatives, those involved benefited This led to the publication of ESPGHAN recommendations for the from an understanding of the clinical importance of the diseases composition of ORS for the children of Europe (35) promoting a caused by Ecoli, the access to clinical material (intestinal biopsy solution containing 60 mmol/L sodium ‘‘to minimize the risk of samples) from cases being investigated for unrelated conditions, hypernatraemia.’’ Secondly, intestinal perfusion models at St. and the ESPGHAN annual meeting platform to present research to Bartholomew’s Hospital in London permitted physiological studies intellectual scrutiny. The work itself used molecular biological, of ORT (30). This led to modifications of ORS composition in order cell culture, in vitro human intestinal organ culture, biochemical, to maximise water and electrolyte absorption. Basically hypo- and morphological techniques to gain an understanding of the osmolar solutions were recommended and they are now recom- molecular basis of the interaction between enteropathogenic, mended worldwide by the WHO, effectively removing the risk enterohaemorrhagic, and enteroaggregative Ecoliwith the intes- of hypernatraemia. tine (22–27). Multicentre study with 18 collaborators across Europe Light was also thrown onto the postenteritis syndrome, that established the value of early feeding in children with gastroen- is, chronic diarrhoea as an apparent sequel to acute infection (28). teritis. The ESPGHAN gastroenteritis working group continued Evidence was presented at ESPGHAN meetings of cow’s milk and a medical position paper concerning recommendations for sensitive enteropathy as a sequel to gastroenteritis, as well as feeding in childhood gastroenteritis were published in JPGN in persistent EPEC infection, and intercurrent and/or superimposed 1997 (36). A further collaborative ESPGHAN study investigated viral infections causing enteropathies and prolonging diarrhoeal the value of adding lactobacillus GG to ORS (37) reporting some, episodes (28). This work alerted ESPGHAN members that there but not dramatic, reduction of duration of diarrhoea. In a follow-up were important causes of small intestinal enteropathy apart from study, the group reported the practical success of the new recom- coeliac disease. mendations for early feeding in gastroenteritis in a large Europe wide study (38). Other ESPGHAN studies in acute diarrhoea have included compliance with treatment guidelines (2001) (39), rota- ESPGHAN CONTRIBUTION IN virus (2008) (40), recommendations for management GASTROENTERITIS MANAGEMENT in Europe (2008, 2014) (41,42), and on the use of probiotics (2014) In reality, identifying the aetiology of the acute diarrhoeal (43) (see Chapter 5.4.1). episode did not, in the majority of cases, alter management. 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FIGURE 4. A, Team representatives at royal free hospital. B, John Walker-Smith at Dresden 2005 ESPGHAN annual Congress.

in children proceed to the production of effective vaccine treatment. there is a place for stimulating research, either by highlighting areas ESPGHAN has been active in guiding management of acute of concern to attract the consideration of funding bodies, or by gastroenteritis and has members that have been involved in directly funding studies which would require significant financial advances in aetiology, pathogenesis, and physiologically based backing and an increase in the philosophy of looking outside its own treatment. As ESPGHAN increases in size and influence perhaps geographical borders.

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FIGURE 5. A, Mike Thomson, Simon Murch, Rob Heuschkel. B, Fun at ESPGHAN meeting Sorrento. C, EPEC PIs in India: S. Knutton, G. Frankel, and Alan Phillips.

Addendum: We join to this ESPGHAN history of infectious 13. Hoare S, Poppitt SD, Prentice AM, et al. Dietary supplementation and diarrhoea some pictures of many of those who contributed in the rapid catch-up growth after acute diarrhoea in childhood. Br J Nutr work at the Royal Free Hospital and in the world in Fig. 4A and B 1996;76:479–90. and Fig. 5A–C. 14. Lunn PG, Northrop-Clewes CA, Downes RM. Intestinal permeability, mucosal injury, and growth faltering in Gambian infants. Lancet 1991;338:907–10. REFERENCES 15. Campbell DI, Murch SH, Elia M, et al. Chronic T cell-mediated 1. Kapikian AZ, Wyatt RG, Dolin R, et al. Visualization by immune enteropathy in rural west African children: relationship with nutritional electron microscopy of a 27 nm particle associated with acute infectious status and small bowel function. Pediatr Res 2003;54:306–11. non-bacterial gastroenteritis. J Virol 1972;10:1075–81. 16. Amadi B, Mwiya M, Chomba E, et al. Improved nutritional recovery on 2. Bishop RF, Davidson GP, Holmes IH, et al. Virus particles in epithelial an elemental diet in Zambian children with persistent diarrhoea and cells of duodenal mucosa from children with acute nonbacterial gastro- malnutrition. J Trop Pediatr 2005;51:5–10. enteritis. Lancet 1973;2:1281–3. 17. Blanton LV, Barratt MJ, Charbonneau MR, et al. Childhood under- 3. Flewett TH, Bryden AS, Davies H. Diagnostic electron microscopy of nutrition, the gut microbiota, and microbiota-directed therapeutics. faeces. II Acute gastroenteritis associated with reovirus-like particles. J Science 2016;352:1533. Clin Pathol 1974;27:608–14. 18. Calabi E, Calabi F, Phillips AD, et al. Binding of Clostridium difficile 4. Ulshen MH, Rollo JL. Pathogenesis of Escherichia coli gastroenteritis surface layer proteins to gastrointestinal tissues. Infect Immun in man – another mechanism. N Engl J Med 1980;302:99–101. 2002;70:5770–8. 5. Knutton S, Baldwin T, Williams PH, et al. Actin accumulation at sites of 19. Walker-Smith JA, Phillips AD. Is prolonged rotavirus infection a bacterial adhesion to tissue culture cells: basis of a new diagnostic test common cause of protracted diarrhoea? Arch Dis Child 1999;81:189. for enteropathogenic and enterohemorrhagic Escherichia coli. Infect 20. Salim AF, Phillips AD, Walker-Smith JA, et al. Sequential changes in Immun 1989;57:1290–8. small intestinal structure and function during rotavirus infection in 6. Karmali MA, Steele BT, Petric M, et al. Sporadic cases of haemolytic- neonatal rats. Gut 1995;36:231–82. uraemic syndrome associated with faecal cytotoxin and cytotoxin- 21. Chan KN, Phillips AD, Knutton S, et al. Enteroaggregative Escherichia producing Escherichia coli in stools. Lancet 1983;1:619–20. coli: another cause of acute and chronic diarrhoea in England? J Pediatr 7. Fasano A. Toxins and the gut: role in human disease. Gut 2002;50(suppl Gastroenterol Nutr 1994;18:87–91. 3):iii9–14. 22. Hicks S, Candy DC, Phillips AD. Adhesion of enteroaggregative 8. Phillips AD, Thomas AG, Walker-Smith JA. Cryptosporidium, chronic Escherichia coli to pediatric intestinal mucosa in vitro. Infect Immun diarrhoea and the proximal small intestinal mucosa. Gut 1992;33: 1996;64:4751–60. 1057–61. 23. Phillips AD, Navabpour S, Hicks S, et al. Enterohaemorrhagic Escher- 9. Salazar-Lindo E, Allen S, Brewster DR, et al., Latin American Society ichia coli O157:H7 target Peyer’s patches in and cause attach- for Pediatric Gastroenterology, Hepatology and Nutrition. Intestinal ing/effacing lesions in both human and bovine intestine. Gut infections and environmental enteropathy: Working Group report of the 2000;47:377–81. second World Congress of Pediatric Gastroenterology, Hepatology, and 24. Frankel G, Phillips AD. Attaching effacing E. coli and paradigms of Tir- Nutrition. J Pediatr Gastroenterol Nutr 2004;39(suppl 2):S662–9. triggered actin polymerisation: getting off the pedestal. Cell Microbiol 10. Bhutta ZA, Nelson EA, Lee WS, et al., Persistent Diarrhea Working 2008;10:549–56. Group. Recent advances and evidence gaps in persistent diarrhea. J 25. Schuller S, Frankel G, Phillips AD. Interaction of Shiga toxin from Pediatr Gastroenterol Nutr 2008;47:260–5. Escherichia coli with human intestinal epithelial cell lines and explants. 11. Scrimshaw NS, Taylor CE, Gordon JE. Interactions of nutrition and Stx2 induces epithelial damage in organ culture. Cell Micro 2004;6: infection. Monogr Ser World Health Organ 1968;57:3–329. 289–301. 12. Tracey KJ, Cerami A. Tumor necrosis factor in the malnutrition 26. Garmendia J, Phillips AD, Carlier MF, et al. TccP is an enterohaemor- (cachexia) of infection and cancer Am J Trop Med Hyg 1992;47 (1 rhagic E. coli O157:H7 type III effector protein that couples Tir to the pt 2):2–7. actin-cytoskeleton. Cell Microbiol 2004;6:1167–83.

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27. Frankel G, Phillips AD. Attaching effacing Escherichia coli and para- 37. Guandalini S, Pensabene L, Zikri MA, et al. Lactobacillus GG admi- digms of Tir-triggered actin polymerisation: getting off the pedestal. nistered in oral rehydration solution in children with acute diarrhoea: Cell Microbiol 2008;10:549–56. a multi-centre European Trial. J Pediatr Gastroenterol Nutr 2000;30: 28. AD Phillips. Microscopical studies in chronic diarroea. PhD thesis, 54–60. University of London; 1991. 38. Szajewska H, Hoekstra H, Sandhu BK. Management of Acute Diarrhoea 29. Water with sugar and salt. Lancet 1978;2:300–1. in Europe and the impact of new recommendations. A multi-centre 30. Schultz SG, Zalusky R. Ion transport in isolated rate ileum. II. The study. J Pediatr Gastroenterol Nutr 2000;30:522–7. interaction between active sodium and active sugar transport. J Gen 39. Hoekstra H. European Society of Paediatric Gastroenterology, Hepatol- Physiol 1964;47:1043–59. ogy and Nutrition Working Group on Acute Diarrhoea. Acute gastro- 31. Walker-Smith JA, Sandhu BK, Isolauri E, et al., Guidelines prepared by enteritis in industrialized countries: compliance with guidelines for the ESPGAN Working Group on Acute Diarrhoea. Recommendations treatment. J Pediatr Gastroenterol Nutr 2001;33:S31–5. for feeding in childhood gastroenteritis. European Society of Pediatric 40. Vesikari T, Van Damme P, Giaquinto C, et al., Expert Working Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr Group; European Society for Paediatric Infectious Diseases/European 1997;24:619–20. Society for Paediatric Gastroenterology. Hepatology, and Nutrition 32. Mahalanabis D, Choudhuri AB, Bagchi NG, et al. Oral fluid therapy of evidence-based recommendations for rotavirus vaccination in cholera among Bangladesh refugees. Johns Hopkins Med J Europe: executive summary. J Pediatr Gastroenterol Nutr 2008;46: 1973;132:197–205. 615–8. 33. Farthing MJG, Walker-Smith JA. Oral rehydration solutions for children 41. Guarino A, Albano F, Ashkenazi S, et al., European Society for of Europe Proceedings of a workshop held at XXI Annual Meeting of Paediatric Gastroenterology, Hepatology, and Nutrition/European So- ESPGAN Copenhagen 1988. Acta Paediatr Scand Suppl 1989; 364:1– ciety for Paediatric Infectious. Diseases evidence-based guidelines for 50. the management of acute gastroenteritis in children in Europe. J Pediatr 34. Elliott EJ, Watson AJM, Walker-Smith JA, et al. Search for the ideal oral Gastroenterol Nutr 2008;46(suppl 2):S81–122. rehydration solution: studies in a model of secretory diarrhoea. Gut 42. Guarino A, Ashkenazi S, Gendrel D, et al., European Society for 1991;32:1314–24. Paediatric Gastroenterology. Hepatology, and Nutrition/European So- 35. Booth I, Cunha Ferreira R, Desjeux J-F. Recommendations for compo- ciety for Paediatric Infectious Diseases evidence-based guidelines for sition of oral rehydration solutions for the children of Europe. ESPGAN the management of acute gastroenteritis in children in Europe: update Working Group on Oral Rehydration. J Pediatr Gastroenterol Nutr 2014. J Pediatr Gastroenterol Nutr 2014;59:132–52. 1992;13:113–5. 43. Szajewska H, Guarino A, Hojsak I, et al., European Society for Pediatric 36. Sandhu BK, Isolauri E, Walker-Smith JA, et al. A multicentre study on Gastroenterology, Hepatology, and Nutrition. Use of Probiotics for behalf of the European Society of Paediatric Gastroenterology and Management of Acute Gastroenteritis: A Position Paper by the ESP- Nutrition Working Group on Acute Diarrhoea. Early feeding in child- GHAN Working Group for Probiotics and Prebiotics. J Pediatr Gastro- hood gastroenteritis. J Pediatr Gastroenterol Nutr 1997;24:522–7. enterol Nutr 2014;58:531–9.

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Chapter 5.1.3. Forty Years of Helicobacter Pylori in ESPGHAN

Samy Cadranel, Giuseppina Oderda, and Sibylle Koletzko

n 1892, Bizzozero reported the presence of microorganisms in working group with Sibylle Koletzko as chair, Samy Cadranel and the stomach of dogs (1). Although some other investigators had Guiseppina Oderda as co-chairs and Francis Me´graud as Honorary describedI bacteria in the stomach of humans with gastric cancer the Chair. gastric milieu continued to be believed to be sterile. In 1983, the The group gathers twice per year, at the annual ESPGHAN dogma on the sterility of the gastric cavity fell tumbling down due to meeting and the 2 days prior the European H pylori study group the discovery by Robin Warren and Barry Marshall (2) (awarded the congress. The 21st paediatric H pylori meeting was held in Sep- Nobel prize for medicine in 2005) of the Gram-negative, spiral- tember 2017 in Bordeaux. During the past 20 years, several multi- shaped microaerophilic microbe with unipolar flagellae they first centre studies were implemented by the group on critical issues, named Campylobacter pyloridis, then C pylori and finally the new including the accuracy of different noninvasive tests (6), the species, Helicobacter pylori. Soon after they succeeded in cultivat- prevalence of antibiotic resistance (7) the frequency of H pylori ing the strain, H pylori hit the stage in 1984 as a main factor causing infection as cause of peptic ulcer disease compared to other gastric inflammation and peptic ulcer. The infection was soon aetiologies (8,9), and the efficacy of different treatment regimens. reported in children with epigastric pain and peptic ulcer disease Short but regular sessions were organized during our annual meet- in the absence of other causes of ulceration and almost simulta- ings in order to communicate our research topics and results to the neously published in prestigious European and American reviews members of ESPGHAN. (3,4). After reports of a correlation between the prevalence of the TREATMENT OF H PYLORI IN PEDIATRICS: A infection and gastric cancer in various populations, WHO declared in 1994 H pylori, a microbe that infects half of the world’s CHALLENGE population, a class I carcinogen. Therefore, it took some time to So Many Different Treatment Regimens accept the idea of H pylori infecting children although, as early as One of the first questions the group tried to answer was how 1974 antral nodularity (a reliable endoscopic sign of chronic H H pylori was treated throughout Europe. A registry (10) was pylori gastritis in children) was endoscopically recognized. How- established on the ESPGHAN website and information on 597 ever, the abstract reporting this, submitted in 1979 to ESPGAN in children were entered by 23 European Centers, but only data of 518 London, was not accepted. Eventually the paper ‘‘H pylori associ- treated children was complete enough to analyse. One amazing ated gastritis in children’’ was presented at the ESPGAN 1986 finding was that European paediatricians entering data in the meeting in Edinburgh. A correlation was also found between age register used 27 different regimens. Bismuth containing therapies and prevalence of infection although the majority acquires the resulted in higher eradication rate. Omeprazole containing triple infection before school age (5). therapies were the most used, although their efficacy was low. At the first specific European meeting on H pylori, organized Therapies recommended for adults did not appear to be suitable for in 1988 in Bordeaux by Francis Me´graud, a few paediatricians were children. Overall eradication rates were unacceptably low with a present who subsequently regularly attended the following annual mean of 65.6%, with higher rates in children with ulcer disease meetings of this new ‘‘European Helicobacter pylori study group’’ compared to those with gastritis only (79.7% vs 63.9%). When (EHPSG). The paediatric abstracts presented in specific workshops given as first treatment bismuth-containing triple therapies were demonstrated the epidemiological importance of the primo-infec- more efficacious than those without (77% vs. 64%); however, tion of H pylori acquired early in childhood. At the 1996 meeting of numbers in subgroups were small. Since neither dose nor duration EHPSG in Copenhagen the authors of this paper decided to develop or adherence to therapy and most importantly results of suscepti- the Paediatric Task Force. bility testing, were considered the results must be interpreted with The first task force meeting, supported by EHPSG council caution. The data were confirmed by a systematic review and meta- members Colm O’Morain and Francis Me´graud, was organized in analysis carried on the paediatric literature (11) revealing that data 1997 by Samy Cadranel (S.C.) and Giuseppina Oderda (G.O.) in in the literature were scarce and the need for more and better Estoril, Portugal. It was regularly followed by yearly meetings held designed trials. An important issue to be addressed before designing prior to the EHPSG congress and by short meetings of the working multicentre studies on treatment efficacy was to ascertain suscepti- group at the annual ESPGHAN meetings with reports to Council bility to clarithromycin and metronidazole of H pylori strains presented at the AGM by the steering committee (S.C., G.O., and harboured by children. soon also Sibylle Koletzko). In 2006, at the meeting in Kliczko´w Castle, Poland, the group voted to become an official ESGPHAN Emergence of Antibiotic Resistances

Received January 27, 2018; accepted January 29, 2018. The next task was to assess the prevalence of antibiotic Copyright # 2018 by European Society for Pediatric Gastroenterology, resistance. In a large prospectively multicentre study carried out Hepatology, and Nutrition and North American Society for Pediatric from 1999 to 2002 our group collected data on antibiotic suscepti- Gastroenterology, Hepatology, and Nutrition bility of H pylori strains obtained from 1233 infected children living DOI: 10.1097/MPG.0000000000001915 in 14 European countries, 1037 of them were treatment naı¨ve (7).

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Overall primary resistance rates in children were very high with breath test, stool antigen test, or serology) and to treat in case of a 23% for metronidazole, 20% for clarithromycin, and 5% for double positive result, the so-called ‘‘test and treat strategy’’. In countries resistance. After failed therapy these figures increased to 35%, 42%, where H pylori infection is still quite common an H pylori positive and 15%, respectively. Children living in Southern compared to gastritis without peptic ulceration may be found incidentally during Northern Europe had a more than 2 times higher risk of being upper endoscopy. While in adult patients treatment should be infected with clarithromycin resistant strains (7). offered even in asymptomatic persons the benefit-risk ratio in Since second and third line antibiotics for H pylori infection children is different. used in adults are not recommended, and even contraindicated in children (eg, levofloxacin, tetracycline), the working group mem- Beneficial Effects of H Pylori? bers evaluated the eradication rate in children with resistance to both antibiotics with a 14-day triple therapy of high-dose amoxi- There is accumulating body of evidence from epidemiologi- cillin, metronidazole, and esomeprazole, which was successful in cal studies in human and experimental animal studies that H pylori 66% in intention to treat and 73% per protocol (12). Then high protects against childhood-onset asthma, probably through the eradication rate was reported both in adults and in Italian children gastric recruitment of regulatory T cells (21). H pylori infection with sequential therapy consisting in a 10-day therapy where in the is negatively associated with other immune mediated disorders first 5 days amoxicillin was associated with a proton pump inhibiter including inflammatory bowel disease (22) and celiac disease (PPI) to lower the bacterial load, and the second 5 days PPI was (23). There is now major interest on the effect of the infection continued and amoxicillin was substituted by clarithromycin and and its treatment on the gastric and intestinal microbiome. Current metronidazole (13). To ascertain if such a high eradication rate was projects of the working group will include these aspects in the trials. achievable in other European countries, members of the working group reported their results in a smaller (n ¼ 77) (14) and a larger REFERENCES cohort (n ¼ 209) (15) of previously untreated children. The previ- 1. Figura N, Oderda G. Reflections on the first description of the presence ously reported high eradication rates of the randomised controlled of Helicobacter species in the stomach of mammals. Helicobacter trial from Italy could not be confirmed. The results of both pub- 1996;1:4–5. lications are reflected in the most recent guidelines that sequential 2. Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of therapy cannot be recommended except in children infected with a patients with gastritis and peptic ulceration. Lancet 1984;1:1311–5. strain susceptible to both clarithromycin and metronidazole (16). 3. Cadranel S, Goossens H, De Boeck M, et al. Campylobacter pyloridis in children. Lancet 1986;1:735–6. 4. Drumm B, Sherman P, Cutz E, et al. Association of Campylobacter GUIDELINES AND FUTURE DEVELOPMENTS pylori on the gastric mucosa with antral gastritis in children. N Engl J Med 1987;6:1557–61. Working Groups and Transatlantic Consensus 5. Oderda G, Vaira D, Holton J. Age-related increase of Helicobacter In 1998, at the paediatric H pylori meeting in Budapest, a pylori frequency in symptom-free and dyspeptic children. Lancet decision was made for the first consensus on the management of H 1992;ii:671–2. pylori infection in children, as it was recognized that adult guidelines 6. Megraud F. Comparison of non-invasive tests to detect Helicobacter may not apply to children in many aspects. The consensus was pylori infection in children and adolescents: results of a multicenter published in 2000 and focused on the indications for investigating European study. J Pediatr 2005;146:198–203. children for H pylori, and the role of noninvasive tests in clinical 7. Koletzko S, Richy F, Bontems F, et al. Prospective multicenter study on practice (17) Shortly thereafter the H pylori group of NASPGHAN antibiotic resistance of Helicobacter pylori strains obtained from chil- dren living in Europe. Gut 2006;55:1711–6. (18) and in 2004 the Canadian working group published their 8. Kalach N, Bontems P, Koletzko S, et al. Frequency and risk factors of paediatric guidelines also giving recommendations for therapy in gastric and duodenal ulcers or erosions in children: a prospective 1- H pylori–infected children (19). The first combined guidelines of month European multicenter study. Eur J Gastroenterol Hepatol ESPGHAN and NASPGHAN followed the strict methodology of 2010;22:1174–81. evidence guidelines based with a systematic review of the literature 9. Bontems P, Kalach N, Vanderpas J, et al. Helicobacter pylori Infection in published from 2000 until 2009, by constructing evidence tables with European children with gastro-duodenal ulcers and erosions. Pediatr grading per the Oxford system, and a Delphi process with anonymous Infect Dis J 2013;32:1324–9. voting of the members of the guideline group (20). The guidelines 10. Oderda G, Shcherbakov P, Bontems P, et al. Results from the pediatric included recommendations for the following 4 areas: Who should be European register for treatment of Helicobacter pylori (PERTH). He- licobacter 2007;12:150–6. tested? What tests should be used? Who should be treated? What 11. Khurana R, Fischbach L, Chiba N, et al. Meta-analysis of Helicobacter treatment regimens are most appropriate? These combined ESP- pylori eradication treatment efficacy in children. Aliment Pharmacol GHAN and NASPGHAN guidelines were a huge step forward to Ther 2007;25:523–36. guidance for physicians working on both sides of the Atlantic. Five 12. Schwarzer A, Urruzuno P, Iwanczak B, et al. New effective treatment years later the combined guidelines have been updated (16). The main regimen for children infected with a double-resistant Helicobacter changes consider the increasing rates of antibiotic resistance and the pylori strain. J Pediatr Gastroenterol Nutr 2011;52:424–8. falling eradication rates. To reach the goal of a primary eradication 13. Francavilla R, Lionetti E, Castellaneta SP, et al. Improved efficacy of rate of at least 90% it is recommended to perform antibiotic suscepti- 10-Day sequential treatment for Helicobacter pylori eradication in bility testing and tailor treatment accordingly in children. Compared children: a randomized trial. Gastroenterology 2005;129:1414–9. 14. Bontems P, Kalach N, Oderda G, et al. Sequential therapy versus to previous guidelines it is now recommended to use higher drug tailored triple therapies for Helicobacter pylori infection in children. doses and a treatment duration of 14 days (16). J Pediatr Gastroenterol Nutr 2011;53:646–50. 15. Schwarzer A, Bontems P, Urruzuno P, et al. Sequential therapy for Strong Recommendation Against ‘‘Test and Helicobacter pylori infection in treatment-naive children. Helicobacter 2016;21:106–13. Treat Strategy’’ 16. Jones N, Koletzko S, Goodman KJ, et al. Joint ESPGHAN /NASPGHAN guidelines for the management of Helicobacter pylori in children and A clear recommendation is made against screening of chil- adolescents (update 2016). J Pediatr Gastroenterol Nutr 2017;64: dren with abdominal pain with a non-invasive test (13) C-urea 991–1003.

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17. Drumm B, Koletzko S, Oderda G. Helicobacter pylori infection in 20. Koletzko S, Jones NL, Goodman KJ, et al. Evidence-based guidelines children: a consensus statement. European Paediatric Task Force from ESPGHAN and NASPGHAN for Helicobacter pylori infection in on Helicobacter pylori. J Pediatr Gastroenterol Nutr 2000;30: children. J Pediatr Gastroenterol Nutr 2011;53:230–43. 207–13. 21. Blaser MJ. Heterogeneity of Helicobacter pylori. Eur J Gastroenterol 18. Gold BD, Colletti RB, Abbott M, et al. Helicobacter pylori infection in Hepatol 2012;Suppl 1:S3–6. children: recommendations for diagnosis and treatment. J Pediatr 22. Sonnenberg A, RM. Low prevalence of Helicobacter pylori Gastroenterol Nutr 2000;31:490–7. infection among patients with inflammatory bowel disease. Aliment 19. Jones NL, Sherman P, Fallone CA, et al. Canadian Helicobacter Study Pharmacol Ther 2012;35:469–76. Group Consensus Conference: update on the approach to Helicobacter 23. Lebwohl B, Blaser MJ, Ludvigsson JF, et al. Decreased risk of celiac pylori infection in children and adolescents—an evidence-based eva- disease in patients with Helicobacter pylori colonization. Am J Epide- luation. Can J Gastroenterol 2005;19:399–408. miol 2013;178:1721–30.

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Chapter 5.1.4. Paediatric Immune–related Enteropathies

Frank M. Ruemmele, John Walker-Smith, Jorge-Amil Dias, Olivier Goulet, and Simon Murch

ver the last 50 years, major insights into the different (chromosome Xp11.23–Xq13.3) coding for a DNA-binding protein aetiologies of severe diarrhoea of infancy have been gained, of the forkhead family. FOXP3 is expressed predominantly in leadingO to the discovery of various distinct of the CD4 þ CD25 þ regulatory T cells, where it may function as a intestinal mucosa and to treatment plans with significantly transcriptional repressor and key modulator of regulatory T cell improved outcome (see Chapter 5.2.2). One key advance in the fate and function. Clinically, boys with IPEX syndrome manifest understanding and the treatment of children suffering these dis- most commonly with severe protein-loosing diarrhoea despite orders has been the development of supportive nutritional care, complete bowel rest, early onset of insulin-dependent diabetes such as parenteral nutrition (see Chapter 5.2.3), as well as the use of mellitus, thyroid disorders, eczema, and high immunoglobulin E new treatments such as immunosuppressive therapy and, even levels (5–7). haematopoetic stem cell transplantation (HSCT). With improved A collaborative effort (9) allowed for the first time to the survival, distinct clinical pictures have been identified in parallel identification of 2 different phenotypes of patients with IPEX with the development of new analytic tools, such as immune- syndrome; the originally described systemic form with haemato- histology of intestinal and colonic mucosal biopsies, immunologi- logical, endocrinological, and intestinal involvement, and a second cal, and more recently, genetic investigations. In the year of form combining autoimmunity with severe allergic manifestations ESPGHAN’s birth almost none of the diseases described in this (severe food allergy and atopic eczema, hyper-IgE and eosino- paper were known, except in the field of inflammatory bowel philia). Molecular analyses revealed an almost complete defect of diseases (IBD), mainly from adult experience. From the 1970s regulatory T cells functions in these patients (9,10). The first onwards, many ESPGHAN members described ‘‘new rare dis- systematic analysis of regulatory T cells functions in 11 children eases’’ and contributed to the classification of paediatric immune- with AIE was published in 2010 by the Paris-Necker group, giving related congenital enteropathies (IRCE). additional insight into the complexity of regulatory T cell functions in patients with AIE (10). In this work, we identified FOXP3- AUTOIMMUNE ENTEROPATHY AS ONE OF THE dependent and independent forms of autoimmune enteropathy with or without defective regulatory T-cell functions (10). Recent col- ANCESTORS laborative research trough the ESPGHAN Genius working group ESPGHAN has been involved in uncovering autoimmune (see below), as well as other groups allowed to identify several enteropathies (AIE) from the very beginning; the first report of AIE molecular defects causing distinct forms of autoimmune enteropa- in the literature goes back to 1978 (1). The term ‘‘autoimmune thy, such as mutations in MALT1 (11), IL2 Ralpha (12), STAT1 enteropathy’’ was introduced by Unsworth and Walker-Smith (2) in (13), CTLA4 (14), and others. London, UK, for severe persistent diarrhoea in the absence of Given the increasing number of genes and the overlapping immune deficiency or signs of coeliac disease, but associated with clinical pictures, it is helpful to separate 3 distinct clinical entities autoimmune disorders and the presence of specific complement- (see above) based on the clinical pictures (5–7). The diagnosis of fixing circulating antibodies directed against small intestinal and AIE is based on the combination of clinical, immunological, colonic epithelial cells. It was speculated that quantitative and histological, and eventually genetic data (5–7,15–17). The hall- qualitative variations of human leucocyte antigen product expres- mark of AIE is severe often bloody diarrhoea with a marked protein- sion in the gut epithelium of children could reflect the severity of the losing enteropathy in the presence of autoimmune signs (anti- autoimmune process underlying the clinical picture (3). Powell et al enterocyte or anti-75 kDa antigen antibodies, which have a high (4) observed 17 boys with various autoimmune disorders over 3 specificity for AIE (18). On histological analysis, severe inflam- generations in the same family, suggesting an X-linked mode of mation with lymphocytic infiltration and epithelial cell apoptosis is transmission. However, some rare cases of girls presenting with characteristic, but an almost completely destroyed intestinal AIE were reported. Based on further advances in the genetics of mucosa is often observed in severe forms (16). Signs of autoim- AIE, as well as the pathophysiology and clinical presentation, 3 munity can be observed in virtually all organ systems, most often in distinct types of AIE were classified: immune dysregulation, poly- the endocrine, haematological, nephrological, and skin compart- endocrinopathy, enteropathy, X-linked (IPEX)-syndrome (AIE type ments. Testing of basal immune functions, as well as phenotyping 1), IPEX-like, FOXP3-independent AIE (AIE type 2) and other of lymphocytes including staining for CD25 and FOXP3 is manda- forms of AIE (type 3) (5–7). tory if AIE is suspected. Functional tests of regulatory T cells complete the diagnostic workup, but these are only available in few IPEX SYNDROME research laboratories, but well represented among ESPGHAN IPEX syndrome is a severe systemic immune disorder with members (5–7). Genotyping of FOXP3 or other genes so fare an extremely severe intestinal involvement in the majority of identified will confirm the initial diagnostic hypothesis. Treatment patients. It is caused by mutations in the FOXP3 gene (8) strategies for patients with AIE depend on the type and severity of the disease. Usually, all patients require stabilization with cortico- Received January 27, 2018; accepted January 29, 2018. steroid- and immunomodulator-based (5–7,19). Unfor- Copyright # 2018 by European Society for Pediatric Gastroenterology, tunately, mortality remains high in patients with IPEX-syndrome, Hepatology, and Nutrition and North American Society for Pediatric except if HSCT with an optimal donor is possible. The first HSCT in Gastroenterology, Hepatology, and Nutrition a boy with IPEX-syndrome was performed at Necker Enfants DOI: 10.1097/MPG.0000000000001915 Malades Hospital in Paris in 2000 (20).

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VERY EARLY ONSET INFLAMMATORY BOWEL TGFbeta-2 as efficient in promoting mucosal healing (35). With DISEASE time and more frequent use of exclusive enteral nutrition, the Paris group confirmed the efficacy of EEN in CD not only by tube Distinct forms of IRCE are the so-called ‘‘very early onset feeding, but also when taken orally (36). This allowed to increase inflammatory bowel diseases’’ (VEO-IBD). First described by Ian acceptance rates by teenagers of this therapy and thus positioning Sanderson, London, as intractable enterocolitis (21), over the last EEN as first-line induction therapy for luminal CD. decade the concept of VEO-IBD truly emerged. The initial reports of A second major initiative for studying IBD in ESPGHAN Crohn disease (CD) or CD-like diseases starting in the first year of life was the creation of a collaborative group of clinicians dedicated to (21,22) indicated a parallel to classical IBD with 2 major differences, IBD, the so-called Porto IBD group (Fig. 1) by Hans Bu¨ller and most patients did not respond to classical IBD medication, such as the Hans Hildebrand in 2002. Several major projects came out of this use of immunomodulators or more recently biologics and some productive group over the last 15 years, such as the EUROKIDS patients developed during infancy or early childhood often lethal registry (37), the Porto diagnostic criteria of pediatric inflamma- lymphomas (23). The discovery of CD-like patients related to tory bowel disease (PIBD) and its revision (38), the growth study, mutations in one the IL10 receptor genes brought the breakthrough cancer and mortality study (39), the Paris classification (40) and in the understanding of the pathophysiology of these children suffer- more recently studies on the use of new biologics, such as vedo- ing from severe colitis and perianal fistulising disease, resistant to lizumab (41). In collaboration with ECCO, ESPGHAN took the medical therapy, but healed by HSCT (24). A collaborative study world-lead in creating the first paediatric-specific guidelines in involving some ESPGHAN members gathered evidence of mutations how to treat paediatric CD (42) and ulcerative colitis (43,44), in genes encoding the IL10R subunit proteins in patients with early- followed by surgical guidelines for CD and more recently guide- onset enterocolitis, involving hyperinflammatory immune responses lines on nutritional and endoscopic aspects in the care of children in the intestine (25,26). The GENetically determined ImmUne- with IBD (to be published). mediated enteropathieS (GENIUS) working group of ESPGHAN collected infants with a proven defect of the IL10 axis for accurate phenotyping of disease presentation and evolution (26). PERSPECTIVES The recent discovery at Necker Enfants Malades, Paris, of a Research over the last 50 years allowed advancing markedly particular vulnerability to develop a T cell lymphoma of patients with in the field of PIBD and immune-mediated intestinal diseases of defective IL10 sensing due to mutations in one of the 2 IL-10 infants and children. In 2018, we have distinct new diagnostic, as receptors completed the initial report of the Londoner group (27). well as therapeutic approaches for our patients requiring often But not only the IL10 axis is of importance in the control of intestinal expert knowledge. To share and spread this clinical experience, immune responses to maintain a balanced situation, mutations in collaborative groups, such as the ESPGHAN Porto Group for IBD, XIAP (28,29), TTC7A (30), or genes causing chronic granulomatous and the GENIUS working group of ESPGHAN for genetically diseases are frequently seen in our patients with VEO-IBD (31). determined immune-mediated intestinal disorders were created. The productivity over the last years proved already how important INFLAMMATORY BOWEL DISEASES and helpful these collaborative exchanges within EPSGHAN are. ESPGHAN’s contribution in this field is enormous and not Given the large panel of diseases and overlapping phenotypes, the all aspects can be detailed. However, several important issues may challenge is to translate research approaches, such as a systematic be remained. One major issue is the use of enteral nutrition as first- diagnostic work-up with a gene panel for VEO-IBD combined with line induction therapy in children with CD. In Europe, Sanderson whole exome sequencing into clinical routine. The potential et al first reported in children enteral tube feeding as first-line correlation (or not) of clinical phenotype and genotype, requires treatment of CD instead of steroids (32). It opened the door to a new a secured database, such as the recently created by the GENIUS and nutritional approach of CD, meanwhile largely confirmed by working group, allowing all ESPGHAN members to share these several meta-analysis (33,34). rare patients. This collaborative effort will help to improve diagno- Once more, the London group by Walker-Smith et al first sis as well as therapy and ultimately outcome for our young patients reported the benefits of a special polymeric diet containing suffering from immune-mediated GI disorders.

FIGURE 1. The Porto IBD Group of ESPGHAN during their 2016 meeting in Porto, Portugal. www.jpgn.org S69 Supplement JPGN Volume 66, Supplement 1, April 2018

REFERENCES 24. Glocker EO, Kotlarz D, Boztug K, et al. Inflammatory bowel disease 1. McCarthy DM, Katz SI, Gazze L, et al. Selective IgA deficiency and mutations affecting the interleukin-10 receptor. N Engl J Med associated with total villous atrophy of small intestine and an organ- 2009;361:2033–45. specific anti-epithelial cell antibody. J Immunol 1978;120:932–8. 25. Begue B, Verdier J, Rieux-Laucat F, et al. Defective IL10 signaling 2. Unsworth DJ, Walker-Smith JA. Auto-immunity in diarrheal disease. J defining a subgroup of patients with inflammatory bowel disease. Am J Pediatr Gastroenterol Nutr 1985;4:375–80. Gastroenterol 2011;106:1544–55. 3. Mirakian R, Hill S, Richardson A, et al. HLA product expression and 26. Pigneur B, Escher J, Elawad M, et al. Phenotypic characterization of lymphocyte subpopulations in jejunum biopsies of children with idio- very early-onset IBD due to mutations in the IL10, IL10 receptor alpha pathic protracted diarrhoea and enterocyte autoantibodies. J Autoimmun or beta gene: a survey of the Genius Working Group. Inflamm Bowel Dis 1988;1:263–77. 2013;19:2820–8. 4. Powell BR, Buist NRM, Stenzel P. An X-linked syndrome of diarrhea, 27. Neven B, Mamessier E, Bruneau J, et al. A Mendelian predisposition polyendocrinopathy, and fatal infection in infancy. J Pediatr 1982;100: to B-cell lymphoma caused by IL-10R deficiency. Blood 2013;122: 731–7. 3713–22. 5. Ruemmele FM, Brousse N, Goulet O. Autoimmune enteropathy: mo- 28. Aguilar C, Lenoir C, Lambert N, et al. Characterization of Crohn disease lecular concepts. Curr Opin Gastroenterol 2004;20:587–91. in X-linked inhibitor of apoptosis-deficient male patients and female 6. Ruemmele FM, Moes N, de Serre NP, et al. Clinical and molecular symptomatic carriers. J Allergy Clin Immunol 2014;134:1131–41. aspects of autoimmune enteropathy and immune dysregulation, poly- 29. Latour S, Aguilar C. XIAP deficiency syndrome in humans. Semin Cell endocrinopathy autoimmune enteropathy X-linked syndrome. Curr Dev Biol 2015;39:115–23. Opin Gastroenterol 2008;24:742–8. 30. Lemoine R, Pachlopnik-Schmid J, Farin HF, et al. Immune deficiency- 7. Kapel N, Roman C, Caldari D, et al. Fecal tumor necrosis factor-alpha related enteropathy-lymphocytopenia-alopecia syndrome results from and calprotectin as differential diagnostic markers for severe diarrhea of tetratricopeptide repeat domain 7A deficiency. J Allergy Clin Immunol small infants. J Pediatr Gastroenterol Nutr 2005;41:396–400. 2014;134:1354–64. 8. Wildin RS, Ramsdell F, Peake J, et al. Clinical and molecular features of 31. Uhlig HH, Schwerd T, Koletzko S, et al. The diagnostic approach to the immunodysregulation, polyendocrinopathy, enteropathy, and X- monogenic very early onset inflammatory bowel disease. Gastroenter- linked (IPEX) syndrome. J Med Genet 2002;39:537–41. ology 2014;147:990–1007. 9. Torgerson TR, Linane A, Moes N, et al. Severe food allergy as a variant 32. Sanderson IR, Udeen S, Davies PS, et al. Remission induced by an of IPEX syndrome caused by a deletion in a noncoding region of the elemental diet in small bowel Crohn’s disease. Arch Dis Child FOXP3 gene. Gastroenterology 2007;132:1705–17. 1987;62:123–7. 10. Moes N, Rieux-Laucat F, Begue B, et al. Reduced expression of FOXP3 33. Zachos M, Tondeur M, Griffiths AM. Enteral nutritional therapy for and regulatory T-cell function in severe forms of early-onset autoim- induction of remission in Crohn’s disease. Database Syst Rev mune enteropathy. Gastroenterology 2010;139:770–8. 2007;(1):CD000542. 11. Charbit-Henrion F, Jeverica AK, Be`gue B, et al., GENIUS Group. 34. Heuschkel RB, Menache CC, Megerian JT, et al. Enteral nutrition and Deficiency in mucosa-associated lymphoid tissue lymphoma transloca- corticosteroids in the treatment of acute Crohn’s disease in children. J tion 1: a novel cause of IPEX-like syndrome. J Pediatr Gastroenterol Pediatr Gastroenterol Nutr 2000;31:8–15. Nutr 2017;64:378–84. 35. Fell JM, Paintin M, Donnet-Hughes A, et al. Remission induced by a 12. Caudy AA, Reddy ST, Chatila T, et al. CD25 deficiency causes an new specific oral polymeric diet in children with Crohn’s disease. Nestle immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like Nutr Workshop Ser Clin Perform Programme 1999;2:187–96. syndrome, and defective IL-10 expression from CD4 lymphocytes. J 36. Rubio A, Pigneur B, Garnier-Lengline´ H, et al. The efficacy of exclusive Allergy Clin Immunol 2007;119:482–7. nutritional therapy in paediatric Crohn’s disease, comparing fractio- 13. Uzel G, Sampaio EP, Lawrence MG, et al. Dominant gain-of-function nated oral vs. continuous enteral feeding. Aliment Pharmacol Ther STAT1 mutations in FOXP3 wild-type immune dysregulation-polyen- 2011;33:332–9. docrinopathy-enteropathy-X-linked-like syndrome. J Allergy Clin Im- 37. de Bie CI, Buderus S, Sandhu BK, et al., EUROKIDS Porto IBD munol 2013;131:1611–23. Working Group of ESPGHAN. Diagnostic workup of paediatric patients 14. Kuehn HS, Ouyang W, Lo B, et al. Immune dysregulation in human with inflammatory bowel disease in Europe: results of a 5-year audit of subjects with heterozygous germline mutations in CTLA4. Science the EUROKIDS registry. J Pediatr Gastroenterol Nutr 2012;54:374–80. 2014;345:1623–7. 38. Levine A, Koletzko S, Turner D, et al. ESPGHAN revised porto criteria 15. Halabi-Tawil M, Ruemmele FM, Fraitag S, et al. Cutaneous manifesta- for the diagnosis of inflammatory bowel disease in children and tions of immune dysregulation, polyendocrinopathy, enteropathy, X- adolescents. J Pediatr Gastroenterol Nutr 2014;58:795–806. linked (IPEX) syndrome. Br J Dermatol 2009;160:645–51. 39. de Ridder L, Turner D, Wilson DC, et al., Porto IBD Working Group of 16. Patey-Mariaud de Serre N, Canioni D, Ganousse S, et al. Digestive ESPGHAN. Malignancy and mortality in pediatric patients with in- histopathological presentation of IPEX syndrome. Mod Pathol flammatory bowel disease: a multinational study from the porto pedia- 2009;22:95–102. tric IBD group. Inflamm Bowel Dis 2014;20:291–300. 17. Hill SM, Milla PJ, Bottazzo GF, et al. Autoimmune enteropathy and 40. Levine A, Griffiths A, Markowitz J, et al. Pediatric modification of the colitis: is there a generalised autoimmune gut disorder? Gut Montreal classification for inflammatory bowel disease: the Paris clas- 1991;32:36–42. sification. Inflamm Bowel Dis 2011;17:1314–21. 18. Kobayashi I, Imamura K, Yamada M, et al. A 75 kDa autoantigen 41. LedderO,AssaA,LevineA,etal.Vedolizumabinpaediatricinflammatory recognized by sera from patients with X-linked autoimmune enteropathy bowel disease: a retrospective multi-centre experience from the paediatric associated with nephropathy. Clin Exp Immunol 1998;111:527–31. IBD Porto Group of ESPGHAN. J Crohns Colitis 2017;11:1230–7. 19. Sanderson IR, Phillips AD, Spencer J, et al. Response to autoimmune 42. Ruemmele FM, Veres G, Kolho KL, et al., European Crohn’s, Colitis enteropathy to cyclosporin A therapy. Gut 1991;32:1421–5. Organisation, European Society of Pediatric Gastroenterology, Hepa- 20. Baud O, Goulet O, Canioni D, et al. Treatment of the immune tology, Nutrition. Consensus guidelines of ECCO/ESPGHAN on the dysregulation, polyendocrinopathy, enteropathy, and X-linked syn- medical management of pediatric Crohn’s disease. J Crohns Colitis drome (IPEX) by allogeneic bone marrow transplantation. N Engl J 2014;8:1179–207. Med 2001;344:1758–62. 43. Turner D, Levine A, Escher JC, et al. Management of pediatric 21. Sanderson IR, Risdon RA, Walker-Smith JA. Intractable ulcerating ulcerative colitis: joint ECCO and ESPGHAN evidence-based consen- enterocolitis of infancy. Arch Dis Child 1991;66:295–9. sus guidelines. European Crohn’s and Colitis Organization; European 22. Ruemmele FM, El Khoury MG, Talbotec C, et al. Characteristics of Society for Paediatric Gastroenterology, Hepatology, and Nutrition. J inflammatory bowel disease with onset during the first year of life. J Pediatr Gastroenterol Nutr 2012;55:340–61. Pediatr Gastroenterol Nutr 2006;43:603–9. 44. Ruemmele FM, Turner D. Differences in the management of pediatric 23. Thapar N, Shah N, Ramsay AD, et al. Long-term outcome of intractable and adult onset ulcerative colitis—lessons from the joint ECCO and ulcerating enterocolitis of infancy. J Pediatr Gastroenterol Nutr ESPGHAN consensus guidelines for the management of pediatric 2005;40:582–8. ulcerative colitis. J Crohns Colitis 2014;8:1–4.

S70 www.jpgn.org SUPPLEMENT

Chapter 5.2.1. Short Bowel Syndrome: Half a Century of Progress

Olivier Goulet, Yigael Finkel, Sanja Kolacˇek, and John Puntis

he year 1968 is often considered to be one of the most 28 patients. The preliminary results have been reported as a turbulent in the 20th century. It began with the Tet Offensive communication in the Sixth International Congress of Dietetic. Tin the midst of the second part of the Vietnam War, it was followed However the methods used and the indications for ‘constant rate by the assassination of Dr Martin Luther King, Jr, and soon after by enteral nutrition,’about 12 cases of SBS, have been described. It is a that of Robert F. Kennedy. Mass socialist movements grew not only very important nutritional approach, combined or not with total in the United States but also in most of European countries. The parenteral nutrition. It is not a ‘new method’ of treatment of SBS, most spectacular manifestation of this was the May 1968 protests in however, as Christie and Ament have stated’’ (6). Indeed, PN has France, in which students linked up with wildcat strikes of up to 10 become the key therapeutic tool for managing SBS patients. Its aim million workers, and for a few days the movement seemed capable is to achieve normal growth and development during the period of of overthrowing the government. Another event of 1968 was in time to full intestinal autonomy. August, when the Soviet army entered Prague, the capital of Another key ESPGHAN member, Michael Lentze, published Czechoslovakia. However, behind those events, important happy in 1989 an important review on physiology of intestinal adaptation occurrences, such as the birth of ESPGHAN and the first publica- after intestinal resection (7). He concluded the paper as follows: tion, from Stanley Dudrick and Douglas Wilmore, reporting the ‘‘From a practical point of view, some of the substances involved successful management of short bowel syndrome in neonates using such as enteroglucagon, prostaglandins and plerocercoid growth parenteral nutrition (PN) (1). It started a revolution in the manage- factor show some promise for future application in the management ment of short bowel syndrome-related intestinal failure (SBS-IF). of the short-bowel syndrome. However, although adequate nutri- tional support and H2-receptor blocking agents can be adminis- THE PIONEERS tered, we still seem to be rather far away from being able to offer a In 1967 Rickham reported his experience in Liverpool, UK, more complete drug therapy to our patients suffering from short where only 7 of 17 newborns with less than 75 cm or remaining bowel syndrome.’’ small bowel survived long term (2); these data were later confirmed in follow-up in collaboration with the Swiss group (3). In Rick- WHAT IS SHORT BOWEL SYNDROME ham’s unit at Alder Hey Hospital, PN was being used from 1962, SBS is the leading cause of paediatric intestinal failure (IF). comprised of Intralipid, 10% amino acid solution and 10% to 15% SBS-IF is characterized by a compromised bowel absorptive carbohydrate (glucose or fructose solution). Only a modest energy capacity due to severely reduced mucosal surface resulting in intake could be achieved, but in some cases it allowed time for gut diarrhoea, water-electrolytes imbalance, and protein-energy mal- adaptation to occur such that weaning to full enteral feeding nutrition. SBS usually follows extensive surgical resection leaving became possible. the bowel length below a critical value necessary for adequate Rickham also described using a probiotic (lactobacillus) in nutritional supply (8). short bowel patients, and experimental work he undertook in rats Not surprisingly, the conditions giving rise to SBS have not and piglets to investigate the phenomenon of small bowel adapta- really changed, although the relative importance in relation to each tion. Subsequent work on gut adaptation by Hughes et al (4) showed other has altered. Common causes still include small bowel atresia, that in dogs total PN/compete gut rest lead to mucosal hypoplasia, complex gastroschisis, mid gut volvulus, neonatal necrotising and that this could be prevented by giving daily injections of enterocolitis (NEC), and long segment Hirschsprung disease. cholecystokinin and secretin, possibly through a trophic effect of The precise anatomy of the small intestine causing IF is an impor- pancreatico-biliary secretions. tant predictor of the final outcome of SBS (Fig. 1). Before the advent of PN, short bowel syndrome (SBS) While the proportion of very preterm infants surviving has carried a dismal prognosis. In the late 1960s, following Dudrick gone up the incidence of NEC has not diminished (9), generating and Wilmore, yet another pioneer in the promotion and develop- more cases with massive gut resection resulting in SBS. A striking ment of nutritional management of pediatric SBS patients in Europe increase in the incidence of gastroschisis has been noted in a range was Claude Ricour, an active pediatrician and ESPGHAN member. of countries (10), with a small proportion of cases being compli- As early as 1976 he published this letter in Journal of Pediatrics (5): cated by intestinal atresia, or antenatal/perinatal bowel infarction. ‘‘The continuous infusion technique for management of short bowel Data from the UK show a fourfold rise from 1993 to 2012 in syndrome (SBS) is very interesting. At the Hospital Necker-Enfants numbers of long-term intestinal failure patients, with an increase in Malades in Paris, we have used it for six years. We have employed the proportion with SBS rising from 27% to 50% (11). this nutritional program in 170 children; 36 of them had a subtotal resection of the small intestine and a complete recovery ensued in WHAT CHANGED IN THE MANAGEMENT? During the 1980s, many children dependent on PN for long Received January 27, 2018; accepted January 29, 2018. periods of time experienced high rates of sepsis, cholestatic liver Copyright # 2018 by European Society for Pediatric Gastroenterology, disease, bone disease, and mortality. The high rate of mortal Hepatology, and Nutrition and North American Society for Pediatric complications raised serious doubts about the safety of PN which Gastroenterology, Hepatology, and Nutrition ultimately led to intestinal transplantation being considered as the DOI: 10.1097/MPG.0000000000001915 final solution for the SBS-IF. With the advent of the

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FIGURE 1. Anatomy of small intestine causing intestinal failure in childhood. following decade saw the onset of the European perspective in on PN prescribing functions, and the development of computer- intestinal transplantation (see Chapter 5.2.4). assisted PN prescribing facilitated the provision of individualised Nevertheless, following the pioneer period, an increasing feeding regimens (22). An evaluation of children referred for number of infants and children survived after extensive intestinal consideration of intestinal transplantation (mostly with SBS) sug- resection (12). Case report and cohort follow-up studies from USA gested that those who had been cared for in a medical unit without and Europe allowed identification of factors influencing the out- NST were less well nourished, had more CVC related complications come: the underlying diagnosis, the type of segments preserved a and experienced greater early mortality than those cared for by a long-term stoma versus a primary anastomosis, the presence of the multidisciplinary team (23). Quality standards in some countries ileo-caecal valve and the age of the patient at the time of surgery such as the UK now dictate that specialist gastroenterology services (13–19). Goulet from the team of Claude Ricour in Paris (13) have to include an NST. reported outcomes in 87 patients with major gut resection; they were divided into group 1 with less than 40 cm remaining bowel, and group 2 with 40 to 80 cm. Underlying disorders included 36 CONTROVERSIES IN SHORT BOWEL atresia, 22 volvulus, 10 gastroschisis, 11 NEC, and 8 with other SYNDROME FEEDING MANAGEMENT conditions. Survival was 92% in group 2 and 67% in group 1; The management of SBS aims to promote the adaptation of overall more than 90% survived. Outcome was better after 1980 the remnant intestine, which is a physiological process. The role of following the introduction of a home PN service. PN is to maintain optimal nutritional status during the time required Nutritional support teams (NST) developed in response to the for the intestinal adaptation to achieve intestinal autonomy. The GI increasing sophistication of medical interventions, in order to share tract should be used for feeding as much and as early as possible knowledge and skills, provide management advice and act as an since it is the most physiological and safest route to provide expert resource across different departments (20). The care of nutrition. However, PN should not be stopped until adequate intake children with SBS was aimed at maintaining growth and develop- and growth can be achieved with oral feeding (OF) and/or enteral ment while promoting adaptational changes in the gut that would tube feeding (ETF). The optimal strategy for enteral feeding, OF facilitate eventual weaning from PN, as well as avoiding recognised versus ETF and bolus versus continuous, remains a matter of debate complications such as catheter-related blood stream infection and (24). A European group of expert agreed in promoting as much OF intestinal failure–associated liver disease. NST commonly brought as possible allowing the maintenance of sucking and swallowing together nurse, dietician, gastroenterologist, surgeon, and pharma- functions along with the interest and enjoyment associated with cist with clinical chemist, speech and language therapist, and eating thus helping to prevent eating disorders (24). Moreover, OF interventional radiologist also closely involved. The ‘‘nutrition promotes the release of epidermal growth factor (EGF) from nurse specialist’’ was crucial, and often the starting point of the salivary glands and increases gastrointestinal secretion of trophic team, being a novel appointment employed solely to foster effective factors (25). As emphasized by the Rotterdam group, breast-feeding nutritional support. This role was shown to be cost effective through should be encouraged (26). Human milk (HM) contains a number of having an important impact on complications such as catheter- factors supporting the developing neonate’s immune system includ- related blood stream infection (21). Nutrition nurse specialists ing nucleotides, EGF, immunoglobulin A, and leucocytes (27). subsequently played a key role in the development of home PN Very few studies involved the choice of an ‘‘ideal’’ formula for SBS services, training carers, coordinating with community services, patients. In Europe, only Ksiazyk et al provided data showing the and supporting families at home. In some centres, pharmacists took tolerance and efficiency of polymeric diets (28). However they are

S72 www.jpgn.org JPGN  Volume 66, Supplement 1, April 2018 Supplement not usually used. Extensively hydrolysed formulas are preferred discomfort, intestinal distension, and loss of self-regulation of with the advantage of containing short peptides easily absorbed as intake leading to eating disorders. IFALD occurrence is a strong well as medium-chain triglycerides (MCT) (24). Amino acid–based limiting factor in continuing PN. Fish oil–based lipid emulsions formulas (AABF) are generally used in the treatment of food have been shown to reverse cholestasis (42–44), and the studies on or in case of milk protein hydrolysate intolerance. True their efficacy have been recently reviewed by the ESPGHAN food allergies have been rarely documented in children with SBS Committee on Nutrition providing recommendations for their use (29). In spite of 2 retrospective studies reporting that the use of an in chronic IF patients (45). Both their availability and SBS-IF AABF was associated with earlier weaning off PN and also a management improvements might explain why, in Europe, the rate reduced rate of allergies (30,31), the very small sample sizes and of end stage IFALD leading to death or liver-intestine transplanta- the lack of control groups do not support the recommendation of tion is much lower than reported by the US Intestinal Failure using AABF in SBS patients. The small number of SBS patients as consortium (46). well as their heterogeneity precludes the design of randomized controlled trials investigating both, the type of the diet and the mode of its administration. Therefore, the current clinical practice is based Dysbiosis as a New Paradigm more on expert opinion and experience based on large cohorts, than The evolution of knowledge on the gut microbiota leads to on evidence-based medicine. The European view has been pub- changes in paradigms and terminology. SIBO should not be lished by ESPGHAN members, d’Antiga and Goulet (32), and the neglected or confused with what it is now referred to as ‘‘intestinal ESPGHAN Working Group on Intestinal Failure (33). dysbiosis.’’ Available data are limited, but the study by Joly et al has opened this field by showing ‘‘imbalances’’ in the gut micro- INTESTINAL MICROBIOTA: THE BLACK BOX biota of adults with SBS, therefore suggesting ‘‘intestinal dysbio- sis’’ (47). Two recent European studies have been conducted in The Yin and Yang of the Colon children with SBS (48,49). The faecal microbiome of children with The role of the colon, as well as the intestinal microbiota, are SBS was different from that of controls with a significant abun- crucial for the prognosis of the SBS by reducing loss of energy and dance of gamma-proteobacteria and bacilli (48). Overall, these by producing trophic factors (34). In animal models, supplementa- studies seem to report a decreased bacterial diversity associated tion of an elemental diet with pectin, which is fermented to short- with a reduction or dominance of some bacterial species. These chain fatty acids in the colon, improved adaptation of the small characteristics appear to be correlated with the level of PN depen- intestine and the colon in SBS (35). PN with short-chain fatty acids dence and the use of gastrointestinal decontamination. reduced mucosal atrophy and intestinal immune dysfunction fol- Ulcerations in the small intestine in the vicinity of ileoco- lowing massive small bowel resection (36). Interesting results have lonic anastomosis are rare and relatively unknown complication of been obtained by Finkel et al by infusing pectin-supplemented SBS, especially in children, as reported by 2 groups from Paris elemental diet (37). However, clinical manifestations such as (50,51). These ulcerations appear as externalized or occult gastro- abdominal distension, bloating and nausea—due to fermentation intestinal hemorrhages (hypochromic microcytic anemia). The in the colon—may impair daily life and should be monitored. They pathophysiology is not known but it could be caused by dysbiosis are the consequences of the intestinal malabsorption leading to huge and, perhaps by a specific bacterium. The role of NOD2/CARD15 load of undigested CHO reaching the colon. This condition may be mutations has been suggested (51). worsened by hyperphagia or aggressive tube-feeding with the risk of developing D-lactic acidosis, a rare complication of the colonic hypermetabolism (38). HOW TO ENHANCE BOWEL ADAPTATION AND INTESTINAL AUTONOMY Small Intestinal Bacterial Overgrowth and Do Surgeons Have the Answer? Cholestasis Surgical approaches aimed at maximising gastrointestinal digestive and absorptive function are crucial to the management of Cholestatic liver disease (CLD) has been shown to be more SBS. These include stoma closure and restoration of bowel conti- frequent in the SBS patients than in any other IF conditions (39). It nuity together with resection of strictures and closure of fistula. is generally accepted that CTF offers the advantages of optimal There are situations where surgical interventions aimed at reducing digestion and absorption rate (26). However, continuous infusion stasis in very dilated bowel, possibly decreasing SIBO (with its changes the intestinal motility pattern by missing fasting period negative effects on digestion, absorption, and the liver) in the (40). Significant dysmotility—impairing intestinal bacterial clear- process and increasing contact time between luminal nutrients ance—leads to small intestinal bacterial overgrowth (SIBO) with and mucosa might improve overall absorption. The most common subsequent enterotoxin release or Gram-negative sepsis. SIBO and procedures are Longitudinal Intestinal Lengthening and Tapering cholestasis are common, especially in patients without ileo-caecal (LILT) developed by Adrian Bianchi in Manchester, UK (52) and valve and in those with abnormal motility (eg, intestinal atresia, Serial Transverse Enteroplasty (STEP) mostly used in North Amer- gastroschisis, NEC). Aggressive continuous ETF is often attempted ica (53). The precise indications and the potential benefits of these with the aim of weaning the child off PN, thought to be the cause of procedures remain a matter of debate (54,55). LILT involves liver injury. These patients present with dilated loops of bowel longitudinal splitting of the small bowel remnant along its mesen- containing residual nonabsorbed nutrients. This strategy results in teric and anti-mesenteric border, ending up with 2 tubes of bowel of increasing SIBO that can cause mucosal inflammation and identical length each with their own blood supply, which are then increased permeability leading to sensitisation and allergy as well joined together (52). STEP is a newer and less complex technique as bacterial translocation, sepsis, and cholestasis (32) (Fig. 2). that involves serial transverse application of a stapler, from opposite Interestingly, a group of Finish paediatric surgeons demonstrated, directions to create a zig-zag channel (53); unlike LILT, no recently, the link between small bowel dilation, mucosal damage, anastomosis is needed, and the mesenteric blood supply is not bowel-derived bloodstream infections, and hepatic injury (41). In put at risk. If the bowel re-dilates, a further STEP procedure can be addition, overaggressive ETF may also result in abdominal undertaken. Unfortunately there are no surgical techniques that can www.jpgn.org S73 Supplement JPGN  Volume 66, Supplement 1, April 2018

FIGURE 2. Cover of JPGN February 2013 illustrating the concept of SIBO causing gastrointestinal and nutritional disorders as well as liver disease. reliably increase small bowel surface area, and by so doing rapidly Despite some decrease in PN requirements during treatment these achieve more than the background process of gut adaptation. trials showed little benefit on body composition and mucosal Plasma citrulline is a marker of small bowel enterocyte mass absorption in the long term. Glucagon-like peptide 2 (GLP-2) is (56,57). It increases significantly within the first weeks following produced by the L-cells of the terminal ileum in response to luminal the STEP procedure (58), suggesting that, by reducing SIBO, it nutrients and has a trophic effect on the intestine, promoting restores small intestinal mucosa integrity and improves villous size. absorption and adaptation (61). Clinical trials suggest it has the Surgical bowel-lengthening should be considered in any chronically potential to decrease PN dependency in patients with SBS when PN-dependent patient when there is substantial bowel dilatation and given as a daily subcutaneous injection. A 12-week, open-label symptoms of SIBO, regardless of the remaining bowel length. study, involving the Great Ormond Street Hospital in London, enrolled SBS PN-dependent patients aged 1–17 years (62). It has been concluded that Teduglutide (GLP-2 analogue) was well Hormonal Therapy tolerated at 0.025 or 0.05 mg/kg per day and was associated with trends toward reductions in PN requirements and advancements in The role of recombinant human growth hormone (rhGH) enteral feeding. However, study limitations included its short-term, alone or in combination with glutamine has been investigated by open-label design, small sample size and heterogeneity of both ESPGHAN members in PN-dependent children with SBS (59,60). patients and management because of the multicentre study.

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Monocenter trials are required for addressing recommendations and 8. Goulet O, Ruemmele F. Causes and management of intestinal failure in extend the use of GLP-2 analogue (eg, Teduglutide Revestive) at a children. Gastroenterology 2006;130(2 suppl 1):S16–28. dose of 0.05 mg/kg per day. 9. Lin PW, Stoll BJ. Necrotising enterocolitis. Lancet (London, England) The research group of Shamir has shown oral insulin to be 2006;368:1271–83. beneficial in animal models (63), and some preliminary observa- 10. Mastroiacovo P, Lisi A, Castilla EE. The incidence of gastroschisis: tional trials have shown beneficial effects in children with SBS (64). research urgently needs resources. BMJ 2006;332:423–4. 11. Barclay AR, Henderson P, Gowen H, et al. The continued rise of It might be interesting to use other trophic factors such as EGF, paediatric home parenteral nutrition use: Implications for service and insulin-like growth factor-1 (IGF-1) or GLP-1 in SBS-IF. the improvement of longitudinal data collection. Clin Nutr 2015;34: 1128–32. 12. Ricour C, Duhamel JF, Arnaud-Battandier F, et al. Enteral and par- CURRENT PERSPECTIVES enteral nutrition in the short bowel syndrome in children. World J Surg Tremendous progresses have been achieved during the last 1985;9:310–5. half a century, changing the face of SBS-IF. Significant contribu- 13. Goulet OJ, Revillon Y, Jan D, et al. Neonatal short bowel syndrome. tions have been provided by both sides of the Atlantic Ocean, even J Pediatr 1991;119:18–23. if clinical practices often differ (8,24,26,32,65,66). SBS-IF moved 14. Iacono G, Carroccio A, Montalto G, et al. Extreme short bowel syndrome: a case for reviewing the guidelines for predicting survival. from a high mortality condition to a model of intestinal physiology J Pediatr Gastroenterol Nutr 1993;16:216–9. and PN efficiency promoting new concepts and paradigms for the 15. Quiros-Tejeira RE, Ament ME, Reyen L, et al. Long-term parenteral daily clinical practice, lending special importance on preserving nutritional support and intestinal adaptation in children with short bowel oral skills and improving the . Nevertheless, some syndrome: a 25-year experience. J Pediatr 2004;145:157–63. patients still remain at risk of developing irreversible IFALD due to 16. Spencer AU, Neaga A, West B, et al. Pediatric short bowel syndrome: extremely short bowel or type 1 SBS, mostly caused by very long redefining predictors of success. Ann Surg 2005;242:403–9. segment Hirschsprung disease. In spite of availability and safety of 17. Goulet O, Baglin-Gobet S, Talbotec C, et al. Outcome and long-term home-PN improving their quality of life, those patients are candi- growth after extensive small bowel resection in the neonatal period: a dates for hormonal treatment that is already available, intestinal survey of 87 children. Eur J Pediatr Surg 2005;15:95–101. 18. Infantino BJ, Mercer DF, Hobson BD, et al. Successful rehabilitation transplantation that showed limits or tissue engineering that might in pediatric ultrashort small bowel syndrome. J Pediatr 2013;163: be one hope for the future. 1361–6. As management strategies of these patients are aimed at 19. Diamanti A, Conforti A, Panetta F, et al. Long-term outcome of home preventing the need for small bowel transplantation by avoiding the parenteral nutrition in patients with ultra-short bowel syndrome. life-threatening complications of PN, effective interventions to J Pediatr Gastroenterol Nutr 2014;58:438–42. reduce the incidence of NEC and congenital bowel defects will 20. Smallman S, Handy D, Puntis JW, et al. The nutrition team in a be needed to reduce the numbers of patients with SBS. Progress may children’s hospital. Nutr Health 1987;5:137–44. come from further understanding of molecular and genetic influ- 21. Keohane PP, Jones BJ, Attrill H, et al. Effect of catheter tunnelling and a ences on congenital gastrointestinal anomalies, recently reviewed nutrition nurse on catheter sepsis during parenteral nutrition. A con- trolled trial. Lancet 1983;2:1388–90. (67). Gene regulatory factor X6 (RFX6) is possibly linked with 22. Ball PA, Candy DC, Puntis JW, et al. Portable bedside microcomputer intestinal atresias, while gastroschisis may be due to improper system for management of parenteral nutrition in all age groups. Arch closure of a body fold impeding the merging of the yolk sac stalk Dis Child 1985;60:435–9. with the connecting stalk, resulting in the intestine rather than the 23. Beath SV, Booth IW, Murphy MS, et al. Nutritional care and candidates umbilical cord herniating into the amniotic cavity with the vitelline for small bowel transplantation. Arch Dis Child 1995;73:348–50. duct. Polymorphisms in genes for intracellular adhesion molecule 1 24. Goulet O, Olieman J, Ksiazyk J, et al. Neonatal short bowel syndrome as (ICAM1), endothelial nitric oxide synthetase 3 (NOS3), atrial a model of intestinal failure: physiological background for enteral natriuretic peptide (NPPA) and alpha-adducin (ADDI) may be feeding. Clin Nutr 2013;32:162–71. involved. The risk of gastroschisis appears higher in children with 25. Helmrath MA, Shin CE, Fox JW, et al. Adaptation after small bowel resection is attenuated by sialoadenectomy: the role for endogenous ICAM1 and NOS3 single-nucleotide polymorphisms with mothers epidermal growth factor. Surgery 1998;124:848–54. who smoked in pregnancy. It has been hypothesised that tobacco 26. Olieman JF, Penning C, Ijsselstijn H, et al. Enteral nutrition in children impairs VEGF-NOS3 and ICAM1 signalling leading to defective with short-bowel syndrome: current evidence and recommendations for angiogenesis and vascular remodelling. the clinician. J Am Diet Assoc 2010;110:420–6. 27. Cummins AG, Thompson FM. Effect of breast milk and weaning on epithelial growth of the small intestine in humans. Gut 2002;51: REFERENCES 748–54. 1. Wilmore DW, Dudrick SJ. Growth and development of an infant 28. Ksiazyk J, Piena M, Kierkus J, et al. Hydrolyzed versus nonhydrolyzed receiving nearly all nutrients entirely by vein. JAMA 1968;20:860–4. protein diet in short bowel syndrome in children. J Pediatr Gastro- 2. Rickham PP. Massive small intestinal resection in newborn infants. enterol Nutr 2002;35:615–8. Hunterian Lecture delivered at the Royal College of Surgeons of 29. Diamanti A, Fiocchi AG, Capriati T, et al. Cow’s milk allergy and England on 13th April 1967. Ann R Coll Surg Engl 1967;41:480–92. neonatal short bowel syndrome: comorbidity or true association? Eur J 3. Rickham PP, Irving I, Shmerling DH. Long-term results following Clin Nutr 2015;69:102–6. extensive small intestinal resection in the neonatal period. Prog Pediatr 30. Bines J, Francis D, Hill D. Reducing parenteral requirement in children Surg 1977;10:65–75. with short bowel syndrome: impact of an amino acidbased complete 4. Hughes CA, Bates T, Dowling RH. Cholecystokinin and secretin infant formula. J Pediatr Gastroenterol Nutr 1998;26:123–8. prevent the intestinal mucosal hypoplasia of total parenteral nutrition 31. De Greef E, Mahler T, Janssen A, et al. The influence of neocate in in the dog. Gastroenterology 1978;75:34–41. paediatric short bowel syndrome on PN weaning. J Nutr Metab 5. Ricour C. Continuous infusion technique in short bowel syndrome. J 2010;2010:pii: 297575. Pediatr 1976;88:1072–3. 32. D’Antiga L, Goulet O. Intestinal failure in children: the European view. 6. Christie DL, Ament ME. Dilute elemental diet and continuous infusion J Pediatr Gastroenterol Nutr 2013;56:118–26. technique for management of short bowel syndrome. J Pediatr 1975;87: 33. Lacaille F, Gupte G, Colomb V, et al. Intestinal failure associated liver 705–8. disease. A position paper by the ESPGHAN Working Group of In- 7. Lentze MJ. Intestinal adaptation in short-bowel syndrome. Eur J Pediatr testinal Failure and Intestinal Transplantation. J Pediatr Gastroenterol 1989;148:294–9. Nutr 2015;60:272–83. www.jpgn.org S75 Supplement JPGN  Volume 66, Supplement 1, April 2018

34. Goulet O, Colomb-Jung V, Joly F. Role of the colon in short bowel 50. Charbit-Henrion F, Chardot C, Ruemmele F, et al. Anastomotic ulcera- syndrome and intestinal transplantation. J Pediatr Gastroenterol Nutr tions after intestinal resection in infancy. J Pediatr Gastroenterol Nutr 2009;48(suppl 2):S66–71. 2014;59:531–6. 35. Tappenden KA, Thomson AB, Wild GE, et al. Short-chain fatty 51. Fre´mond ML, Viala J, Tre´ton X, et al. Digestive perianastomotic acid-supplemented total parenteral nutrition enhances functional adap- ulcerations and Crohn’s disease. J Crohns Colitis 2014;8:1624–31. tation to intestinal resection in rats. Gastroenterology 1997;112: 52. Bianchi A. Intestinal loop lengthening—a technique for increasing 792–802. small intestinal length. J Pediatr Surg 1980;15:145–51. 36. Bartholome AL, Albin DM, Baker DH, et al. Supplementation of total 53. Kim HB, Lee PW, Garza J, et al. Serial transverse enteroplasty for short parenteral nutrition with butyrate acutely increases structural aspects of bowel syndrome: a case report. J Pediatr Surg 2003;38:881–5. intestinal adaptation after an 80% jejunoileal resection in neonatal 54. Sudan D, Thompson J, Botha J, et al. Comparison of intestinal length- piglets. JPEN J Parenter Enteral Nutr 2004;28:210–22. ening procedures for patients with short bowel syndrome. Ann Surg 37. Finkel Y, Brown G, Smith HL, et al. The effects of a pectin-supple- 2007;246:593–601. mented elemental diet in a boy with short gut syndrome. Acta Paediatr 55. Puntis JW, Sugarman ID. Autologous intestinal reconstructive surgery Scand 1990;79:983–6. to reduce bowel dilatation improves intestinal adaptation in SBS. J 38. Dahhak S, Uhlen S, Mention K, et al. D-Lactic acidosis in a child with Pediatr Gastroenterol Nutr 2014;58:e11–12. short bowel syndrome. Arch Pediatr 2008;15:145–8. 56. Crenn P, Coudray-Lucas C, Thuillier F, et al. Postabsorptive plasma 39. Wales PW, de Silva N, Kim J, et al. Neonatal short bowel syndrome: citrulline concentration is a marker of absorptive enterocyte mass and population-based estimates of incidence and mortality rates. J Pediatr intestinal failure in humans. Gastroenterology 2000;119:1496–505. Surg 2004;39:690–5. 57. Bailly-Botuha C, Colomb V, Thioulouse E, et al. Plasma citrulline 40. Husebye E. The patterns of small bowel motility: physiology and concentration reflects enterocyte mass in children with short bowel implications in organic disease and functional disorders. Neurogas- syndrome. Pediatr Res 2009;65:559–63. troenterol Motil 1999;11:141–61. 58. Oliveira C, de Silva N, Wales PW. Five-year outcomes after serial 41. Hukkinen M, Kivisaari R, Merras-Salmio L, et al. Small bowel dilata- transverse enteroplasty in children with short bowel syndrome. J Pediatr tion predicts prolonged parenteral nutrition and decreased survival in Surg 2012;47:931–7. pediatric short bowel syndrome. Ann Surg 2017;266:369–75. 59. Goulet O, Dabbas-Tyan M, Talbotec C, et al. Effect of recombinant 42. Lilja HE, Finkel Y, Paulsson M, et al. Prevention and reversal of human growth hormone on intestinal absorption and body composition intestinal failure-associated liver disease in premature infants with short in children with short bowel syndrome. JPEN J Parent Enter Nutr bowel syndrome using intravenous fish oil in combination with omega- 2010;34:513–20. 6/9 lipid emulsions. J Pediatr Surg 2011;46:1361–7. 60. Peretti N, Loras-Duclaux I, Kassai B, et al. Growth hormone to improve 43. Angsten G, Finkel Y, Lucas S, et al. Improved outcome in neonatal short short bowel syndrome intestinal autonomy: a pediatric randomized bowel syndrome using parenteral fish oil in combination with (-6/9 lipid open-label clinical trial. J Parenter Enteral Nutr 2011;35:723–31. emulsions. JPEN J Parenter Enteral Nutr 2012;36:587–95. 61. Jeppesen PB, Sanguinetti EL, Buchman A, et al. Teduglutide (ALX- 44. Goulet OJ. Intestinal failure-associated liver disease and the use of fish 0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2 oil-based lipid emulsions. World Rev Nutr Diet 2015;112:90–114. analogue, improves intestinal function in short bowel syndrome pa- 45. Hojsak I, Colomb V, Braegger C, et al. ESPGHAN Committee on tients. Gut 2005;54:1224–31. Nutrition. ESPGHAN Committee on Nutrition Position Paper. Intrave- 62. Carter BA, Cohran VC, Cole CR, et al. Outcomes from a 12-week, open- nous lipid emulsions and risk of hepatotoxicity in infants and children: a label, multicenter clinical trial of teduglutide in pediatric short bowel systematic review and meta-analysis. J Pediatr Gastroenterol Nutr syndrome. J Pediatr 2017;181:102–11. 2016;62:776–92. 63. Sukhotnik I, Mogilner J, Shamir R, et al. Effect of subcutaneous insulin 46. Khan FA, Squires RH, Litman HJ, et al., Pediatric Intestinal Failure on intestinal adaptation in a rat model of short bowel syndrome. Pediatr Consortium. Predictors of enteral autonomy in children with intestinal Surg Int 2005;21:132–7. failure: a multicenter cohort study. J Pediatr 2015;167:29–34. 64. Shamir R, Kolacek S, Koletzko S, et al. Oral insulin supplementation in 47. Joly F, Mayeur C, Bruneau A, et al. Drastic changes in fecal and paediatric short bowel syndrome: a pilot observational study. J Pediatr mucosa-associated microbiota in adult patients with short bowel syn- Gastroenterol Nutr 2009;49:108–11. drome. Biochimie 2010;92:753–61. 65. Puntis J, Jenkins HR. Intestinal failure. Arch Dis Child 2009;94:919–20. 48. Engstrand Lilja H, Wefer H, Nystro¨m N, et al. Intestinal dysbiosis in 66. Olieman JF, Poley MJ, Gischler SJ, et al. Interdisciplinary management children with short bowel syndrome is associated with impaired out- of infantile short bowel syndrome: resource consumption, growth, and come. Microbiome 2015;3:18. nutrition. J Pediatr Surg 2010;45:490–8. 49. Davidovics ZH, Carter BA, Luna RA, et al. The fecal microbiome in 67. Dauve V, McLin VA. Recent advances in the molecular and genetic pediatric patients with short bowel syndrome. JPEN J Parenter Enteral understanding of congenital gastrointestinal malformations. J Pediatr Nutr 2016;40:1106–13. Gastroenterol Nutr 2013;57:4–13.

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Chapter 5.2.2. From the Syndrome of Intractable Diarrhoea of Infancy to Molecular Analysis and Cell Biology: 50 Years of Evolution

Olivier Goulet and Alan Phillips

n the year of ESPGHAN’s birth, Avery et al described a groups of IDI have been separated. The first one included autoim- ‘‘syndrome of intractable diarrhoea of infancy’’ defined as a mune enteropathies first described by Unsworth and Walker-Smith diarrhoeaI occurring in a newborn younger than 3 months of age and from London, UK (9) and immune-mediated enteropathies. The lasting more than 2 weeks with 3 or more negative stool cultures for second group includes early onset of severe intractable diarrhoea bacterial pathogens (1). Most cases were managed in hospital using with various degree of villous atrophy with low or without mononu- intravenous fluids while the diarrhoea was persistent and ‘‘intrac- clear cell infiltration of the lamina propria, but specific histological table.’’ The mortality rate from infection or malnutrition was high abnormalities involving the epithelium. These diseases are related to and no specific diagnosis was performed in most patients who defects in enterocytes differentiation and polarisation (Table 1). More survived or died (2). Paediatricians and new specialists, who are recently, with Roberto Berni Canini, we proposed a classification of nowadays known as ‘‘paediatric gastroenterologists,’’ developed congenital diarrhoeal disorders (CDDs) in 4 groups of CDDs accord- digestive and nutritional management, including continuous enteral ing to the main pathogenetic mechanism (10): defects in absorption feeding using protein hydrolysates, already available at that time. and transport of nutrients and electrolytes; defects in enterocyte Parenteral nutrition (PN) became available in the early 1970s and differentiation and polarisation; defects in enteroendocrine cell dif- dramatically changed the outcome of this syndrome (3,4). Such ferentiation; and defects in intestinal immune-related homeostasis. severe protracted diarrhoea resulted from associated factors, includ- Many ESPGHAN members contributed to highlight the setting of ing increased intestinal permeability, food antigen sensitisation, CDDs including defects in absorption and transport of nutrients and bacterial overgrowth, infection and malnutrition, thereby leading to electrolytes (Table 2). In this paper, we will focus on defects in a vicious circle. Distinguished ESPGHAN members, Guarino et al enterocyte differentiation and polarisation. (5) and Catassi et al (6) proposed the term ‘‘severe diarrhoea requiring PN.’’ Two major subtypes can be differentiated within THE LEADING DEFECT IN ENTEROCYTE this group. The first includes patients with ‘‘protracted diarrhoea of infancy’’ (PDI), which resumes despite its initial severity. PDI can DIFFERENTIATION result from a specific immune deficiency or a sensitisation to a In 1978 Davidson et al from Australia reported 5 infants with common food protein (eg, cow’s milk or gluten), it can be secondary severe, persistent diarrhoea beginning in the newborn period (11). to a severe infection of the digestive tract (postenteritis syndrome). Light microscopy revealed crypt hypoplastic villus atrophy while The second group is characterised by ‘‘intractable diarrhoea of electron microscopic examination showing severe brush-border infancy’’ (IDI), based on the clinical observation of abundant abnormalities and increased liposome-like bodies and intracytoplas- diarrhoea (>100 mL/kg and day) starting within the first days or mic cysts made up of brush border (Fig. 1). Further children were weeks of life, persistent despite bowel rest along with an abnormal reported with these characteristic cytoplasmic inclusions of the brush- intestinal mucosa. Diarrhoea rapidly becomes life threatening border membrane and were well described by Alan Phillips abnor- requires long-term PN and persists for years despite prolonged malities by using electron microscopy (12). This ‘‘new’’ disease was bowel resting and various therapeutic trials. called microvillus inclusion disease (MVID) or microvillous atrophy. A. Phillips (London, UK) and J. Schmitz (Paris, France) reported an ESPGHAN survey of 23 cases (13). The group of Necker Paris, PROGRESSES IN ESPGHAN CLASSIFICATION OF reported a single centre survey of 24 patients (14) in which some CONGENITAL DIARRHOEAL DISORDERS children have successfully received an intestinal allograft (15). Clinically, diagnosis of IDI may be easy according to the date Many hypotheses have been designed for explaining the very of symptom onset, clinical presentation and associated disorders. specific histological pictures observed: a defect in the membrane Many cases are associated with affected siblings and consanguinity trafficking of immature and/or differentiating enterocytes, or a among families. Histopathological analysis is required for perform- disorder of the enterocytes’ cytoskeleton, which produces an abnor- ing or orienting the diagnosis. An attempt to classify IDI according mal assembly of microvilli. Studies have suggested that the direct to villous atrophy was proposed by the Paris group, on the basis of and indirect constitutive pathways are intact in this disorder and immunohistological criteria emphasising the role of activated T speculated that the abnormal staining pattern reflects accumulation cells in the intestinal mucosa (7). An ESPGHAN multicentre survey of glycocalyx-related material (16). Finally, European collaboration leaded by O. Goulet, collected cases of IDI and villous atrophy with involving ESPGHAN members allowed to identify the MYO5B precisely defined light microscopic characteristics, thereby allow- mutation responsible for MVID (17). Several genotypes have been ing several types of IDI to be categorised (8). Two clearly different identified by the Robert Debre´ Paris groups (18). Girard et al (19) from Paris-Necker reported that MVID patients are at risk of Received January 27, 2018; accepted January 29, 2018. developing a PFIC-like liver disease. Whole-exome sequencing Copyright # 2018 by European Society for Pediatric Gastroenterology, of DNA from MVID patients, with milder clinical phenotypes Hepatology, and Nutrition and North American Society for Pediatric permitting partial or complete weaning from total parenteral nutri- Gastroenterology, Hepatology, and Nutrition tion, showed homozygous truncating mutations in syntaxin 3 DOI: 10.1097/MPG.0000000000001915 (STX3) an apical receptor involved in membrane fusion of apical

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TABLE 1. Defects in enterocyte differentiation and polarization

Gene

Disease Name OMIM number Position Protein Inheritance and incidence

Microvillous inclusion disease MYO5B 606540 18q21.1 Myosin B AR; rare; highest frequency among Navajo Congenital tufting enteropathy EPCAM 185535 2p21 Protein for cell-cell interaction AR; 1:50–100,000; higher among Arabians SPINT2 605124 19q13.2 Serine protease inhibitor <1/1 000 000 Trichohepatoenteric syndrome TTC37 614589 5q15 Component of the SKI complex AR; <1/1,000,000 (Syndromic diarrhoea) SKIV2L 600478 6p21.33 Component of the SKI complex AR; <1/1,000,000

Congenital tufting enteropathy associated to EPCAM mutation is characterised by only intestinal involvement, while mutation in SPINT2 lead to a syndromic form with extra-intestinal abnormalities. vesicles in enterocyte (20). Loss of STX3 function causes variant ANOTHER STRANGE EPITHELIAL PICTURE MVID Interestingly, another ESPGHAN member by using a new- generation sequencing approach, identified MYO5B mutations in In 1994 Reifen et al in Toronto, Canada (25) and in 1995 patients with progressive familial intrahepatic cholestasis-like phe- Goulet et al in Paris, France (26), reported cases of neonatal severe notype with normal serum gamma-glutamyl transferase activity diarrhoea with abnormal epithelial pictures, which were clearly without intestinal disease (21). different from MVID (Fig. 2). Studies performed in these patients Cell biology is nowadays an approach for understanding both by the Necker-Paris group, allowed the identification of IED as a the pathophysiology of MVID and the development and organisa- constitutive epithelial disorder involving both the small intestine tion of intestinal epithelial cells and mucosa (22,23). According to and colon (26,27). Congenital intestinal epithelial dysplasia (CIED) the initial outcome before the 1980s, PN now allows most infants is frequent in patients of Arabic origin and in Middle East or North and children to survive. However, chronic water-electrolytes imbal- Africa as well as Malte Island (28). A main characteristic of this ance and PN-related complications do limit the long-term survival. disease is its clinical and histological heterogenicity and its associ- Thus, intestinal transplantation has become the only definitive ation with malformation or other epithelial diseases such as keratitis treatment of this rare intestinal disease (24). and choanal atresia for the most frequent (29,30).

TABLE 2. Defects in absorption and transport of nutrients and electrolytes

Gene

Disease Name OMIM number Position Protein Inheritance and incidence

Congenital chloride diarrhoea SLC26A3 126650 7q31.1 Cl-/base exchanger AR, sporadic; common in some ethnic groups Congenital sodium diarrhoea SLC9A; 616868; 5p15.33; Naþ-Hþ exchanger AR, <1:1,000,000 GUCY2C 270420 12p12.3 Congenital lactase deficiency LCT 603202 2q21.3 Lactase-phlorizin hydrolase AR, 1:60,000 in Finland; lower in other ethnic groups Sucrase-isomaltase deficiency SI 609845 3q26.1 Isomaltase-sucrase AR, 1:5000; higher in Greenland, Alaska and Canada Maltase-glucoamylase deficiency MGAM 154360 7q34 Maltase-glucoamylase Only few cases described Glucose-galactose malabsorption SLC5A1 182380 22q13.1 Naþ/glucose AR, a few hundred cases described Fructose malabsorption SLC2A5 138230 1p36.23 Fructose transporter More than 40% Fanconi-Bickel syndrome SLC2A2 138160 3q26.2 Basolateral AR, rare Acrodermatitis enteropathica SLC39A4 607059 8q24.3 Zn2þ transporter AR, 1:500.000 Lysinuric protein intolerance SLC7A7 603593 14q11.2 Cationic amino acid transporter AR, approximately 1:60,000 in Finland and Japan; rare in other ethnic groups Primary bile acid diarrhoea SLC10A2 601295 13q33.1 Ileal Naþ/bile salt transporter AR FGF-19 603891 11q13.3 Bile acids negative feedback Only few cases described Enterokinase deficiency TMPRSS15 606635 21q21.1 Proenterokinase AR Abetalipoproteinemia MTTP 157147 4q23 Microsomal triglyceride AR, about 100 cases described; transfer protein higher frequency among Ashkenazi Hypobetalipoproteinemia Apo B 107730 2p24.1 Apolipoprotein B 100/48 Autosomal co-dominant Familial diarrhoea syndrome GUCY2C 601330 12p13.1-p12.3 Receptor for heat-stable Described in 32 members of a enterotoxins Norwegian family Diarrhoea associated DGAT1 DGAT1 604900 8q24.3 Diacylglycerol acyltransferases One family has been reported mutation

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FIGURE 1. PAS/Alcian blue stained human small intestinal mucosa. Dark blue ¼ acidic mucus, magenta ¼ neutral glyco-substances. (A). Normal, showing neutral stain in brush border and acidic mucus in goblet cells, on the brush border and in the lumen. (B). MVID, acidic goblet cells and mucus adhering to the brush border and the absence of brush border neutral stain with its accumulation within apical cytoplasm.

EPCAM gene mutation has been shown by Sivagnanam et al vice versa in case of absence may contribute to the inflammatory from San Diego, California (31). EPCAM belongs to cell adhesion reaction observed in the CIED as reported by Simon Murch (32). A receptors, which in addition to structural functions, play a role in second group of CIED individuals is characterised by mutations in signalling, migration, proliferation and cellular differentiation SPINT2 (33). SPINT2, like EPCAM, is a transmembrane protein (31). By mediating homotypic interactions between intraepithelial also called hepatocyte growth factor activator inhibitor type 2 (34). lymphocytes and intestinal epithelial cells, EPCAM contributes to This potent serine protease inhibitor is involved in epithelial form an immunological barrier against mucosal infections, and regeneration, as well as in the NF-kBandTGF-b signalling pathways. The Paris-Necker group showed that SPINT2 patients present with a syndromic form associated with superficial punctate keratitis and choanal atresia in half of the cases, as well as other sporadic abnormalities, suggesting a syndromic form of CIED (34). Taken together, these findings establish SPINT2 as a second gene associated with CIED. The different but overlapping enterocyte abnormalities suggest that the 2 CIED-associated genes belong to distinct pathways both regulating cell adhesion the most recent and cytoskeleton dynamics leading to CIED phenotype (34). Recently, inspired by the characterisation of cellular defects in EpCAM-related CIED, Julie Salomon and Delphine Delacour (Institut Jacques Monod, Paris, France) reported that these unusual cell organisation and intestinal tissue defects are driven by the loss of actomyosin network homoeostasis and contractile activity clustering at tricellular contacts, reversed by myosin-II inhibitor treatment (35). This might open the door to targeted new therapies, since EpCAM modulation protects against epithelial dysplasia and stabilises human tissue architecture.

WHEN LIVER AND INTESTINE MEET The so-called ‘‘phenotypic diarrhoea’’ or ‘‘syndromatic diar- rhoea’’ was described by the Paris-Necker group as diarrhoea starting within the first 6 months of life without histological specific abnormalities but with several associated features, including small for gestational age (SGA), facial dysmorphism and a distinct abnormality of hair with tricorrhexis nodose (36). The reported patients had defective antibody responses despite normal serum immunoglobulin levels and defective antigen-specific skin tests despite positive proliferative responses in vitro. The reported prognosis was poor, most patients died between 2 and 5 years of age, most with early onset of liver disease (37). FIGURE 2. On haematoxylin-eosin staining, it is a typical aspect of tufts, From a cohort of patients with early onset unknown liver dilated glands and branching that characterise congenital tufting disease associated with diarrhoea and abnormal hairs, the Birming- enteropathy (CTE) or congenital intestinal epithelial dysplasia (CIED). ham group identified a mutation of the gene TTC37 (38). From www.jpgn.org S79 Supplement JPGN Volume 66, Supplement 1, April 2018

Clinical approach of early onset severe diarrhea

Onset day 1-30

Persists at bowel rest Reduced at bowel rest Disappears at bowel rest

Family history Family history Feeding testing Hydramnios / prematurity Extra-digestive disease: Lactose, glucose, Watery diarrhea lymphopenia, anemia, skin rash galactose, fructose Biological presentation Protein losing enteropathy Familiy history Glucose-galactose Consanguinity Chloride diarrhea CDG syndrome Malabsorption (SLC5A1) Abundant watery SLC26A3 Mitochondrial disease diarrhea Primary lactase deficiency (LCT) Sodium diarrhea Neurogenin 3 deficiency Defects in enterocyte SPINT2, GLUCY2C, differentiation and polarization Lymphangiectasia Enterokinase deficiency (TMPRSS15) Microvillous atrophy Consanguinity MYO5B, STX3, SGA birth Bile salts malabsorption SLC10-A2 A-beta UNC 45A Facial dysmorphy lipoproteinemia Hair abnormalities HSPG deficiency (MTTP) Epithelial dysplasia Liver disease EpCam / SPINT2 Early IPEX /and AIE*/ Other Defects in absorption and transport Syndromic diarrhea VEOIBD * THE syndrome Other « new » *AIE: autoimmune enteropathy; VEOIBD: very early onset - IBD diseases/mutations Mutations : TTC37, SKIV2L And other candidate genes to be founded CMPA and IPEX as well as sucrase deficiency From O.Goulet are rarely of early neonatal onset

FIGURE 3. Proposed algorythm for the clinical approach of early onset severe diarrhoea.

Phenotypic or Syndromatic diarrhoea to the so-called tricho-hepato- perspectives. The research that enabled these advances in knowl- enteric syndrome (THES). The gene TTC37 encodes a hypothetical edge to be made occurred for most, in European centres of protein known as Thespin, which Fabre et al from Marseille paediatric gastroenterology. The partnership between clinicians (France) showed the existence in many tissues (vascular endothe- and scientists has been of key importance in these developments. lium, lymph, pituitary stalk, lung and intestine), but is not, contrary The recent ESPGHAN paper leaded by Roberto Berni Canini and to what the clinic might suggest, expressed in the live (39). TTC37 Olivier Goulet, entitled ‘‘Congenital Diarrheal Disorders: an evolv- is reported as being the ortholog of yeast SKI3, which encodes a key ing web of inherited enteropathies,’’ summarised the current component of the SKI complex, a multiprotein complex required for knowledge in that evolving disease setting (10). For the clinician exosome-mediated RNA surveillance (40). Subsequently, muta- facing to early onset intractable diarrhoea of infancy, gene panel tions in SKIV2L in a group of 6 individuals affected by typical analysis, as it has been developed in some European centres such as SD/THE syndrome, but negative for TTC37 mutations, have been Necker-Imagine (Paris, France) by the group of Nadine Cerf- described by Fabre et al (41). The mutation types suggest that the Bensussan or the European Laboratory for the Investigation of disease mechanism is loss of function SKIV2L a cytoplasmic- Food Induced Diseases, University of Naples, Federico II, Naples, exosome cofactor involved in various mRNA decay pathways Italy, diagnosis has become easier especially in case of atypical and required for normal cell growth (42). The mechanism by which presentation. Molecular analysis has changed the diagnostic sce- mRNA-surveillance defects lead to various clinical symptoms, such nario in CDDs, and led to a reduction in invasive and expensive as severe diarrhoea, hair abnormalities, or immunodeficiency, procedures. Moreover, this approach may make possible the diag- needs further investigations (43). nosis of especially rare digestive disease as reported by other In conclusion, CDDs represent a group of challenging clini- ESPGHAN members, such as heparan-sulfate (44) or neurogenin3 cal conditions for paediatricians because of the severity of the deficiency (45). presentation and the broad range of possible differential diagnoses. With the onset of adequate nutritional support, the so-called CDDs arise from alterations in the transport of nutrients and ‘‘intractable diarrhoea of infancy’’ has moved from a mysterious electrolytes across the intestinal mucosa, from enterocyte and syndrome with a high mortality and morbidity to specific diseases, enteroendocrine cell differentiation and/or polarisation defects, genetic in origin. However, behind this apparent easiness, manage- and from the modulation of the intestinal immune response. The ment raises many important questions, including ethical issues and number of well-characterised disorders attributed to CDDs has therapeutic choices. Infants with IDI remain dependent on PN for gradually increased over the past several years, and many new months, years and, for most, forever because of the permanent genes have been identified, opening new diagnostic and therapeutic intestinal malabsorption and a high rate of digestive losses. Because

S80 www.jpgn.org JPGN Volume 66, Supplement 1, April 2018 Supplement of complications of long-term PN and/or poor quality of life, 22. Ruemmele FM, Mu¨ller T, Schiefermeier N, et al. Loss-of-function of alternative treatments, such as intestinal transplantation, have been MYO5B is the main cause of microvillus inclusion disease: 15 considered (24). novel mutations and a CaCo-2 RNAi cell model. Hum Mutat 2010;31: 544–51. 23. Michaux G, Massey-Harroche D, Nicolle O, et al. The localisation of the REFERENCES apical Par/Cdc42 polarity module is specifically affected in microvillus 1. Avery GB, Villacivencio O, Lilly JR, et al. Intractable diarrhea in early inclusion disease. Biol Cell 2016;108:19–28. infancy. Pediatrics 1968;41:712–22. 24. Lacaille F, Irtan S, Dupic L, et al. Twenty-eight years of intestinal 2. Ricour C, Navarro J, Frederich A, et al. La diarrhe´e grave rebelle transplantation in Paris: experience of the oldest European center. du nourrisson (a` propos de 84 observations). Arch Fr Pediatr Transpl Int 2017;30:178–86. 1977;34:44–59. 25. Reifen RM, Cutz E, Griffiths AM, et al. Tufting enteropathy: a newly 3. Ricour C, Nihoul-Fekete C, Pellerin D, et al. Technique and indications recognized clinicopathological entity associated with refractory diar- of long term parenteral nutrition in the child. Acta Gastroenterol Belg rhea in infants. J Pediatr Gastroenterol Nutr 1994;18:379–85. 1973;36:67–77. 26. Goulet O, Kedinger M, Brousse N, et al. Intractable diarrhea of infancy: 4. Walker-Smith J. Diarrheal disease: current concepts and future chal- a new entity with epithelial and basement membrane abnormalities. J lenges. Malnutrition and infection. Trans R Soc Trop Med Hyg Pediatr 1995;127:212–9. 1993;87(suppl 3):13–5. 27. Patey N, Scoazec JY,Cuenod-Jabri B, et al. Distribution of cell adhesion 5. Guarino A, Spagnuolo MI, Russo S, et al. Etiology and risk factors of molecules in infants with intestinal epithelial dysplasia (tufting entero- severe and protracted diarrhea. J Pediatr Gastroenterol Nutr pathy). Gastroenterology 1997;113:833–43. 1995;20:173–8. 28. Salomon J, Espinosa-Parrilla Y, Goulet O, et al. A founder effect at the 6. Catassi C, Fabiani E, Spagnuolo MI, et al. Severe and protracted EPCAM locus in Congenital Tufting Enteropathy in the Arabic Gulf. diarrhea: results of the 3-year SIGEP multicenter survey. J Pediatr Eur J Med Genet 2011;54:319–22. Gastroenterol Nutr 1999;29:63–8. 29. Goulet O, Salomon J, Ruemmele F, et al. Intestinal epithelial dysplasia 7. Cuenod B, Brousse N, Goulet O, et al. Classification of intractable (tufting enteropathy). Orphanet J Rare Dis 2007;2:20. diarrhea in infancy using clinical and immunohistological criteria. 30. Roche O, Putterman M, Salomon J, et al. Superficial punctate keratitis Gastroenterology 1990;99:1037–43. and conjunctival erosions associated with congenital tufting enteropa- 8. Goulet O, Brousse N, Canioni D, et al. Syndrome of intractable thy. Am J Ophthalmol 2010;150:116–21. diarrhoea with persistent villus atrophy in early childhood: a clinico- 31. Sivagnanam M, Mueller JL, Lee H, et al. Identification of EpCAM as the pathological survey of 47 cases. J Pediatr Gastroenterol Nutr gene for congenital tufting enteropathy. Gastroenterology 2008;135: 1998;26:151–61. 429–37. 9. Unsworth DJ, Walker-Smith JA. Auto-immunity in diarrheal disease. J 32. Murch SH. The molecular basis of intractable diarrhoea of infancy. Pediatr Gastroenterol Nutr 1985;4:375–80. Baillieres Clin Gastroenterol 1997;11:413–40. 10. Canani RB, Castaldo G, Bacchetta R, et al. Congenital diarrhoeal 33. Heinz-Erian P, Mu¨ller T, Krabichler B, et al. Mutations in SPINT2 cause disorders: advances in this evolving web of inherited enteropathies. a syndromic form of congenital sodium diarrhea. Am J Hum Genet Nat Rev Gastroenterol Hepatol 2015;12:293–302. 2009;84:188–96. 11. Davidson GP, Cuiz E, Hamilton JR, et al. Familial enteropathy: a 34. Salomon J, Goulet O, Canioni D, et al. Genetic characterization of syndrome of protracted diarrhea from birth, failure to thrive, and congenital tufting enteropathy: epcam associated phenotype and in- hypoplastic villus atrophy. Gastroenterology 1978;75:783–90. volvement of SPINT2 in the syndromic form. Hum Genet 12. Phillips AD, Jenkins P, Raafat F, et al. Congenital microvillus atrophy: 2014;133:299–310. specific diagnostic features. Arch Dis Child 1985;60:135–40. 35. Salomon J, Gaston C, Magescas J, et al. Contractile forces at tricellular 13. Phillips AD, Schmitz J. Familial microvillus atrophy: a clinicopatho- contacts modulate epithelial organization and monolayer integrity. Nat logical survey of 23 cases. J Pediatr Gastroenterol Nutr 1992;14: Commun 2017;8:13998. 380–96. 36. Giraut D, Goulet O, Ledeist F, et al. Intractable diarrhea syndrome 14. Halac U, Lacaille F, Joly F, et al. Microvillous inclusion disease: how to associated with phenotypic abnormalities and immune deficiency. improve the prognosis of a severe congenital enterocyte disorder. J J Pediatr 1994;125:36–42. Pediatr Gastroenterol Nutr 2011;52:460–5. 37. Goulet O, Vinson C, Roquelaure B, et al. Syndromic (phenotypic) 15. Ruemmele FM, Jan D, Lacaille F, et al. New perspectives for children diarrhea in early infancy. Orphanet J Rare Dis 2008;3:6. with microvillous inclusion disease: early small bowel transplantation. 38. Hartley JL, Zachos NC, Dawood B, et al. Mutations in TTC37 cause Transplantation 2004;77:1024–8. trichohepatoenteric syndrome (phenotypic diarrhea of infancy). Gastro- 16. Phillips AD, Brown A, Hicks S, et al. Acetylated sialic acid residues and enterology 2010;138:2388–98. blood group antigens localise within the epithelium in microvillous 39. Fabre A, Roquelaure B, Lacoste C, et al. Exclusion of EGFR, HRAS, atrophy indicating internal accumulation of the glycocalyx. Gut DSP, JUP, CTNNB1, PLEC1, and EPPK1 as functional candidate genes 2004;53:1764–71. in 7 families with syndromic diarrhoea. J Pediatr Gastroenterol Nutr 17. Mu¨ller T, Hess MW, Schiefermeier N, et al. MYO5B mutations cause 2009;48:501–3. microvillus inclusion disease and disrupt epithelial cell polarity. Nat 40. Fabre A, Martinez-Vinson C, Roquelaure B, et al. Novel mutations in Genet 2008;40:163–5. TTC37 associated with tricho-hepato-enteric syndrome. Hum Mutat 18. Perry A, Bensallah H, Martinez-Vinson C, et al. Microvillous 2011;32:277–81. atrophy: atypical presentations. J Pediatr Gastroenterol Nutr 2014; 41. Fabre A, Charroux B, Martinez-Vinson C, et al. SKIV2L mutations 59:779–85. cause syndromic diarrhea, or trichohepatoenteric syndrome. Am J Hum 19. Girard M, Lacaille F, Verkarre V, et al. MYO5B and bile salt export Genet 2012;90:689–92. pump contribute to cholestatic liver disorder in microvillous inclusion 42. Fabre A, Martinez-Vinson C, Goulet O, et al. Syndromic diarrhea/ disease. Hepatology 2014;60:301–10. Tricho-hepato-enteric syndrome. Orphanet J Rare Dis 2013;8:5. 20. Wiegerinck CL, Janecke AR, Schneeberger K, et al. Loss of syntaxin 3 43. Fabre A, Breton A, Coste ME, et al. Syndromic diarrhoea of infancy/ causes variant microvillus inclusion disease. Gastroenterology tricho-hepato-enteric syndrome. Arch Dis Child 2014;99:35–8. 2014;147:65–8. 44. Murch SH, Winyard PJ, Koletzko S, et al. Congenital enterocyte 21. Gonzales E, Taylor SA, Davit-Spraul A, et al. MYO5B mutations cause heparan sulphate deficiency with massive albumin loss, secretory cholestasis with normal serum gamma-glutamyl transferase activity in diarrhoea, and malnutrition. Lancet 1996;347:1299–301. children without microvillous inclusion disease. Hepatology 45. Mutant Wang J, Cortina G, WU, SV, et al. Mutant neurogenin-3 in 2017;65:164–73. congenital malabsorptive diarrhea. N Engl J Med 2006;355:270–80.

www.jpgn.org S81 SUPPLEMENT

Chapter 5.2.3. Parenteral Nutrition and Home Parenteral Nutrition Changed the Face of Paediatric Gastroenterology

Antonella Diamanti, John Puntis, Sanja Kolacek, Susan Hill, and Olivier Goulet

he history of parenteral therapy extends back to at least the newborns, infants, and children, but also helped the concept of IF to 17th century, following William Harvey’s publication in 1628 be developed, and aided the identification of many of its underlying Tof his treatise (‘‘De Motu Cordis’’) describing the circulation of the causes. This was especially the case for so called ‘‘intractable blood (1). William Courteen, at the University of Montpellier in diarrhoea of early onset’’ (see Chapter 5.2.2), and transformed the France, in 1678 injected warm olive oil to dogs, which died within a outcome in short bowel syndrome (see Chapter 5.2.1). As a complex few minutes from fat embolism. A few years later Christopher Wren new therapy requiring multiprofessional and interdisciplinary man- and Robert Boyle experimented with infusing wine, ale and opium agement in addition to careful monitoring, PN can be regarded as into a dog using a goose quill as a venous cannula. The Scottish one of the most important stimuli for the development of paediatric physician Thomas Latta used an infusion of hypotonic saline to treat gastroenterology as a clinical specialty. Moreover, by sustaining victims of the 1831/32 cholera pandemic, and later in the 19th century life PN made it possible to undertake metabolic studies, in both there were trials of subcutaneous injection of nutrients to malnour- stable and unstable conditions, using indirect calorimetry, stable ished patients. By the 1940s, hydrolysed proteins and glucose were isotope infusions and body composition measurements, generating being given to adult surgical patients, and in Europe in 1944 the first improved knowledge of the physiology of PN. Much of this clinical protein hydrolysate was marketed, developed by Arvid Wretlind in research was carried out in North America (mainly in Canada by the Sweden. Such products were later superseded by solutions of crys- group associated with Paul Pencharz), and in Europe with the group talline amino acids, first used in Germany in 1964. Wretlind went on of Claude Ricour (6–15). to develop a more balanced amino acid solution (Vamine), as well as Over time PN has become safer through experience and an effective and ‘‘non-toxic’’ soybean oil based lipid emulsion learning, multidisciplinary nutritional team working, research, and (Intralipid) introduced in 1961, permitting a dual energy supply development of novel feeding products. Amino acid solutions have during parenteral nutrition (PN). For all these innovations he is been adapted for particular age groups, lipid emulsions have remembered as the ‘‘father of complete parenteral nutrition’’ (1). evolved to become more physiological, and additive products have In the USA in 1968 (incidentally coinciding with the foundation of been refined. ESPGHAN members have contributed to this progress ESPGHAN), Wilmore and Dudrick reported a landmark case of long by performing randomised double-blind clinical trials (RCTs) term PN in a child with short bowel syndrome (SBS) (2). Introduction supporting new generations of intravenous lipid emulsion (ILE) of PN into wider clinical practice soon followed, with it becoming a (16–19). Deficiency states from taurine and selenium have been standard intervention in the care of premature newborn as well as recognised (retinal abnormalities; skeletal and cardiac myopathy), proving life-saving support for children with intestinal failure (IF). and the hazards of oversupply of chromium (renal damage), man- From the early 1970s, complete PN feeding regimens for children ganese (neurotoxicity, Parkinson’s like state) and aluminium (bone were described by Grotte et al in Sweden, Børreson and Knutrud in disease, neurotoxicity, liver disease) identified – all leading to Norway, Jurgens et al in Germany (3), Harries in the UK (4) and changes in clinical practice. Knowledge, protocols and suggestions Ricour in France (5). Continuous advances have been made in the for research priorities have been shared, most notably in the provision of effective and safe nutritional support, with a transformed ESPGHAN/ESPEN joint guideline on PN published in 2005 at outcome for children with chronic IF (CIF). Many of these can now be the initiative of Berthold Koletzko, Raanan Shamir and Olivier discharged on home-parenteral nutrition (HPN) as a viable alternative Goulet (20) and further revised and updated to be published in 2018. to both long term hospitalisation and intestinal transplantation. In his 1971 ‘‘personal practice’’ paper reviewing the state of Together with our colleagues across the world, ESPGHAN members PN, John Harries (4) listed some of the important complications and their teams have made a very significant contribution to this including sepsis, metabolic acidosis, phlebitis/venous thrombosis, process. This short history paper focuses mostly on long-term use of catheter displacement, hypoglycaemia, and heart failure. To this list PN and home-PN related to chronic intestinal failure (CIF). can be added intestinal failure associated liver disease (IFALD), the term proposed for encompassing the effects of both PN and IF (21). ESPGHAN AND THE ADVANCEMENT OF After decades of advances, some of these complications continue to PARENTERAL NUTRITION present challenges. While ESPGHAN strongly endorsed the use of enteral tube feeding whenever possible, this form of nutritional support was FROM INTESTINAL FAILURE TO clearly unsuitable for managing patients with severe and/or pro- ‘‘NUTRITIONAL FAILURE’’ tracted IF. PN not only contributed to saving the lives of many Catheter-related Bloodstream Infections Received January 27, 2018; accepted January 29, 2018. (CRBSIs) and Venous Thrombosis Copyright # 2018 by European Society for Pediatric Gastroenterology, The central venous catheter (CVC) is an essential device for Hepatology, and Nutrition and North American Society for Pediatric delivering long-term PN. CRBSIs are the most frequent complica- Gastroenterology, Hepatology, and Nutrition tions during PN whatever its indication and duration. These com- DOI: 10.1097/MPG.0000000000001915 plications have been studied in large cohorts, and have contributed

S82 JPGN  Volume 66, Supplement 1, April 2018 JPGN  Volume 66, Supplement 1, April 2018 Supplement significantly to morbidity, mortality and health care costs in patients only 15% to 30% of nonprotein calories (33). Intravenous lipids on long-term PN (22–24). Hermans, with the Paris-Necker group, have been thought to cause cholestatic liver disease (35,36). The has shown a clear link between CRSBIs and IFALD (25). Contam- new generation of composite intravenous fat emulsion containing inated devices and hands of health care providers are the common- fish oil has shown beneficial effects in reversing or preventing est sources of infection in tunnelled CVC. Microbes migrating from cholestasis (37,38). However, recommendations for using this new the skin surrounding the insertion site have the same role in the generation of ILE remain strongly debated by ESPGHAN experts short-term catheters, while a contaminated PN solution and bacte- contributing to the new guidelines. Interestingly, ILE is the main rial translocation from the patients’ gastrointestinal tract are sub- field in which rRCTs are available at least for the short- and mid- stantially less frequent causes. Numerous studies clearly showed term use. Although it is considered that obtaining long term safety that the treatment approach to infected CVC in children on long- data based on RCTs will remain almost impossible, this should not term PN did not change significantly. Broad spectrum antibiotics Æ impede the use of the last generation that provide the advantages of antimycotic agents are recommended in all febrile children with the containing less potentially detrimental (excess n-6 fatty acids) or CVC ‘‘in situ’’ who do not have a clear source of infection, toxic components (phytosterols) and more beneficial components switching if necessary to the most appropriate antibiotics once such as antioxidant agents (alpha-tocopherol) or n-3 fatty acids the cause of sepsis is culture-confirmed. The success of this including EPA and DHA (39). treatment approach certainly contributed to a decrease in mortality and morbidity of patients on long-term PN. However, it is the Metabolic Bone Disease improvement in preventive strategies that resulted in the decreasing frequency of CVC related bacteremia. ESPGHAN guidelines pub- PN related metabolic bone disease (MBD) in children can lished in 2005, summarized the evidence and provided detailed result in permanent bone damage or reduced bone mineralisation recommendations on how to achieve an aseptic approach on inser- and increased fracture risk (40). Several causes of BMD have been tion and for all subsequent contacts during CVC manipulations, and highlighted by ESPGHAN member pioneers in PN and include have certainly helped in achieving this downward trend (20). In the aluminum exposure from PN, imbalanced parenteral calcium and last 10 years, the addition of ethanol (26) in the US or taurolidine phosphorus intake, variable parathyroid hormone concentrations, line-locks in Europe (27) and introduction of multimodal protocols and vitamin D toxicity (41,42). (bundles) into clinical practice (28) resulted in even more effective With the development of dual-energy x-ray absorptiometry prevention of CRBSI. Lambe et al, from the Paris-Necker group, (DXA), assessment of bone mineral density (BMD) can be easily reported beneficial results of using taurolidine locks in a home-PN achieved while a high-risk population may be defined. A cross cohort achieving an incidence of 0.8/1000 PN days (29). sectional study from the Great Ormond Street Hospital in London, CRBSIs promote venous thrombosis that can be seen in up to reported that approximately 50% of children were short with height 40% of patients with a CVC in situ and is sometimes symptomatic SDSs less than À2 at baseline, and one-third of children had low (eg, superior vena cava obstruction; pulmonary embolus). Loss of BMD. Children with enteropathy or intestinal mucosal inflamma- venous access through thrombosis in individual patients over the tion are at greatest risk of growth failure (43). Two more recent years became an indication for intestinal transplantation (ITx), and studies from France showed similar results (44,45). The issue of as discussed by d’Antiga and Goulet can be considered one of the BMD remains important as shown by the ESPGHAN Guidelines elements of so-called ‘‘nutritional failure’’ (30). Limiting CVC debate recommending optimal calcium and phosphorus intake for insertion to experienced operators, planned replacement during long term PN (PN Guidelines to be published in Clinical Nutrition daytime hours and the involvement of interventional radiologists 2018). as part of the nutritional support team are likely to be important in Finally, paediatric PN achieved tremendous progress from its protecting veins, as is minimising the risk of CRBSI. Novel onset 50 years ago. Several ESPGHAN members have been pio- approaches such as stereotactic passage of a guidewire and stenting neers in the field and ESPGHAN provided the first Guidelines in can facilitate reinsertion of a CVC in a patient with venous 2005 (to be updated in 2018). Their aim is to ‘‘guide’’ the thrombosis. physicians in clinical practice and recommendations are supported by evidence based on RCTs and meta-analysis whenever possible. However, sufficient evidence based data will never be available Intestinal Failure Associated Liver Disease because paediatrics ranges from neonatalogy to post-adolescence, populations to be studied are limited, and clinical research has Cholestasis was an early recognised and common complica- become ethically difficult to perform. In the absence of ‘‘traditional tion of PN, particularly in preterm infants. It was initially thought to evidence’’ we have to rely on recommendations based on physiol- be due to a toxic effect of PN components on the liver, giving rise to ogy, toxicology, experience, real life, and common sense. In the terms such as ‘‘PN related cholestasis,’’ and ‘‘PN associated liver absence of RCTs, the practice of long term PN and home-PN are disease.’’ Subsequently, lack of enteral nutrition, immaturity of mostly based on cohort surveys and experience of expert centres. liver function, small intestinal bacterial overgrowth (SIBO) (see Chapter 5.2.1) and CRBSIs have been identified as major risk factors for what is now recognised as a multifactorial disorder. This HOME PARENTERAL NUTRITION topic has recently been comprehensively reviewed by an ESP- In 1973 Jeejeebhjoy et al (46) reported provision of PN at GHAN working group and individual authors (31–34). A study home for an adult patient over nearly 2 years. Such complex care from London, involving 87 infants requiring PN for at least 28 days, and management provided at home would have been inconceivable reported IFALD in 29 infants (33%) (32). In a Paris study of 302 at the time PN first started to be used for hospitalised children. children receiving long term home PN from 1980–1999, 23% However, the development of cyclical PN and of ‘‘All-In-One’’ developed IFALD, 2% died of liver failure and 2% underwent systems simplified the prospect of HPN for some patients and liver-small bowel transplantation (31). Out of 251 children, the families. Claude Ricour in France and Peter Milla in UK have been same group reported a similar incidence (20%) between 2000 and the main promoters of pediatric HPN in Europe (47,48). Drivers for 2013. The ESPGHAN working group pointed to lipid intake as an home care have mainly been based on cost, but there are clear important factor and suggested restriction of fat intake to provide advantages to the child and family in being at home, including www.jpgn.org S83 Supplement JPGN  Volume 66, Supplement 1, April 2018 decreased risk of CRBSI and improved psychosocial development is very beneficial for the children but can be difficult for the parents and quality of life (49,50). A prerequisite in most European and siblings to accept especially in the absence of an alternative countries for home PN to be established has been the growth of strategy other than intestinal transplantation (60). Social and famil- home care companies to undertake compounding of feeds, and their ial environment should always be carefully assessed and monitored home delivery together with supplies of consumables and equip- to ensure not only safety but familial harmony and function. Today, ment. Companies also provide an element of nursing support, ‘‘transition’’ has become an important issue because of an increas- including continuation of training for carers following hospital ing number of adolescents needing to be referred to adult intestinal discharge when necessary. The overall clinical condition of the rehabilitation centres. Very few data are available on the outcome child needs to be stable, but with careful planning and ongoing after ‘‘transition’’. Interestingly, a recent paper from France telephone support from expert nurses and dieticians in the nutrition reported successful pregnancy in young women on long-term home support team, even those with additional requirements such as PN for CIF (61). enteral tube feeding or high stoma losses can often be cared for out of hospital. Long-term follow-up studies from Paris-Necker (33) showed that outcome was good, with survival at 2, 5, 10, and CONCLUSIONS AND PERSPECTIVES 15 years of 97%, 89%, 81%, and 72%, respectively. Children with Commenting on intravenous therapy for cholera patients in intractable diarrhoea had the highest mortality (25%) and the 1831, a Dr Lewins promised that ‘‘this ‘astonishing method of highest incidence of IFALD (48%). More recent results from the medication’ will lead to wonderful improvements in the practice of same group show continuous improvements in survival and inci- medicine’’ (62). The history of PN over the last 50 years proves him dence of CRBSIs and IFALD (34). Other groups in Europe, from to have been prescient. However, problems as well as controversies Croatia (23), Sweden (51), Poland (52), Czech Republic (53), UK still manifest when attempting to establish recommendations and (54), Italy (55–57), or France (58), reported encouraging results. guidelines. There are difficulties in reaching a consensus in defining Moreover, Loris Pironi from Bologna designed an ESPEN and duration of PN as short-, mid- or long-term PN together with very ESPGHAN collaboration providing an important European survey different groups of children from newborns and premature babies to on Home-PN in Europe (59). pre-adolescents and adolescents. Controversies emerged recently While neonatal SBS accounts for the majority, the number of regarding the appropriateness of using PN in critically ill children as patients receiving HPN continues to rise, in part through an increase illustrated by the so-called ‘‘PEPaNIC Trial’’ (63) and commented in the prevalence of certain conditions such as congenital entero- by ESPGHAN members (64,65). pathies, chronic intestinal pseudo-obstruction syndrome or extreme Fortunately, continual advances have been made in the and/or complex SBS. Even children with less than 10 cm small provision of effective and safe nutritional support, with a trans- bowel (ultra-SBS) can do very well on long-term HPN (54), formed outcome for children with IF. PN is a well-recognized life- avoiding life-threatening complications and enjoying a good quality saving therapy, while long-term home-PN has become a viable of life despite the severe handicap from SBS. The aim of nutritional alternative to both long-term hospitalisation and intestinal trans- management is the weaning from PN and HPN, but when this plantation. Together with our colleagues across the world, ESP- cannot be achieved the future presents significant challenges. HPN GHAN members and their teams have made a very significant

FIGURE 1. View of extremely malnourished children in the early 1970’s. Parenteral nutrition made them surviving and recovering from severe protein-energy malnutrition. (Photos by courtesy of Claude Ricour).

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FIGURE 2. From medical prescription to home delivery. It illustrates how the multi-professional approach makes Home-PN possible. contributiontothisprocess.Management of children requiring 9. Van Aerde JE, Sauer PJ, Pencharz PB, et al. Effect of replacing glucose HPN should be undertaken only in specific centres by multidisci- with lipid on the energy metabolism of newborn infants. Clin Sci (Lond) plinary teams, including physicians (neonatologists, gastroenter- 1989;76:581–8. ologists and surgeons), pharmacists, nurses, dieticians, social 10. Salas J, Girardet JP, De Potter S, et al. Glucose versus glucose-fat workers and psychologists. The Network for Intestinal Transplan- mixture in the course of total parenteral nutrition: effects on substrate tation in Europe (NITE) provided a recent overview of the organi- utilisation and energy metabolism in malnourished children. Clin Nutr 1991;10:272–8. sation and current practice of specialised paediatric IF teams across 11. Bresson JL, Bader B, Rocchiccioli F, et al. Protein-metabolism kinetics Europe (66) and compared these results to the ESPGHAN/ESPEN and energy-substrate utilization in infants fed parenteral solutions with guideline (20). Most practices have a low-level evidence base, different glucose-fat ratios. Am J Clin Nutr 1991;54:370–6. being mostly conducted on the basis of expert opinion. Harmoni- 12. Salas JS, Dozio E, Goulet OJ, et al. Energy expenditure and substrate sation and optimisation of clinical guidelines for managing long- utilization in the course of renutrition of malnourished children. JPEN J term PN in IF patients is a goal that we should aim to achieve in the Parenter Enteral Nutr 1991;15:288–93. future (Fig. 2). 13. Goulet O, DePotter S, Salas J, et al. Leucine metabolism at graded amino acid intakes in children receiving parenteral nutrition. Am J Physiol 1993;265 (4 pt 1):E540–6. REFERENCES 14. Van Aerde JE, Sauer PJ, Pencharz PB, et al. Metabolic consequences of 1. Vinnars E, Wilmore D. History of parenteral nutrition. JPEN J Parenter increasing energy intake by adding lipid to parenteral nutrition in full- Enteral Nutr 2003;27:225–31. term infants. Am J Clin Nutr 1994;59:659–62. 2. Wilmore DW, Dudrick SJ. Growth and development of an infant 15. Jones MO, Pierro A, Garlick PJ, et al. Protein metabolism kinetics in receiving nearly all nutrients entirely be vein. JAMA 1968;20:860–4. neonates: effect of intravenous carbohydrate and fat. J Pediatr Surg 3. Vassilyadi F, Panteliadou AK, Panteliadis C. Hallmarks in the history of 1995;30:458–62. enteral and parenteral nutrition: from antiquity to the 20th century. Nutr 16. Abi Nader E, Lambe C, Dong L, et al. A New Concept to Achieve Clin Pract 2013;28:209–17. Optimal Weight Gain in Malnourished Infants on Total Parenteral 4. Harries JT. Intravenous feeding in infants. Arch Dis Child 1971;46: Nutrition. JPEN J Parenter Enteral Nutr 2018;42:78–86http://onlineli- 855–63. brary.wiley.com/store/10.1002/jpen.1014/asset/jpen1014.pdf. 5. Ricour C, Nihoul-Fe´ke´te´ C, Bertin P, et al. Continuous parenteral 17. Goulet O, De Potter S, Antebi H, et al. Long-term efficacy and safety of feeding by intracaval catheter in children. Ann Chir Infant a new olive oil-based intravenous fat emulsion in pediatric patients: a 1972;13:7–16. double-blind randomized study. Am J Clin Nutr 1999;70:338–45. 6. Sauer PJ, Van Aerde JE, Pencharz PB, et al. Glucose oxidation rates in 18. Tomsits E, Pataki M, Tolgyesi A, et al. Safety and efficacy of a lipid newborn infants measured with indirect calorimetry and [U-13C] emulsion containing a mixture of soybean oil, medium-chain triglycer- glucose. Clin Sci (Lond) 1986;70:587–93. ides, olive oil, and fish oil: a randomised, double-blind clinical trial in 7. Pencharz P, Beesley J, Sauer P, et al. Total-body protein turnover premature infants requiring parenteral nutrition. J Pediatr Gastroenterol in parenterally fed neonates: effects of energy source studied by Nutr 2010;51:514–21. using [15N] glycine and [1-13C] leucine. Am J Clin Nutr 1989;50: 19. Goulet O, Antebi H, Wolf C, et al. A new intravenous fat emulsion 1395–400. containing soybean oil, medium-chain triglycerides, olive oil, and fish 8. Bresson JL, Narcy P, Putet G, et al. Energy substrate utilization in oil: a single-center, double-blind randomized study on efficacy and infants receiving total parenteral nutrition with different glucose to fat safety in pediatric patients receiving home parenteral nutrition. JPEN J ratios. Pediatr Res 1989;25:645–8. Parenter Enteral Nutr 2010;34:485–95. www.jpgn.org S85 Supplement JPGN  Volume 66, Supplement 1, April 2018

20. Rayyan M, Devlieger H, Jochum F, et al. Short-term use of parenteral 41. Larchet M, Chaumont P, Galliot M, et al. Aluminium loading in children nutrition with a lipid emulsion containing a mixture of soybean oil, olive receiving long-term parenteral nutrition. Clin Nutr 1990;9:79–83. oil, medium-chain triglycerides, and fish oil: a randomized double- 42. Larchet M, Garabe´dian M, Bourdeau A, et al. Calcium metabolism in blind study in preterm infants. JPEN J Parenter Enteral Nutr 2012; children during long-term total parenteral nutrition: the influence of 36:81S–94S. calcium, phosphorus, and vitamin D intakes. J Pediatr Gastroenterol 21. Koletzko B, Goulet O, Hunt J, et al. Guidelines on Paediatric Parenteral Nutr 1991;13:367–75. Nutrition of the European Society of Paediatric Gastroenterology, 43. Pichler J, Chomtho S, Fewtrell M, et al. Growth and bone health in Hepatology and Nutrition (ESPGHAN) and the European Society for pediatric intestinal failure patients receiving long-term parenteral nu- Clinical Nutrition and Metabolism (ESPEN), Supported by the Eur- trition. Am J Clin Nutr 2013;97:1260–9. opean Society of Paediatric Research (ESPR). J Pediatr Gastroenterol 44. Poinsot P, Geoffroy P, Braillon P, et al. Longitudinal bone mineralization Nutr 2005;41(suppl 2):S1–87. assessment in children treated with long-term parenteral nutrition for 22. Goulet O, Joly F, Corriol O, et al. Some new insights in intestinal failure- severe intestinal failure. JPEN J Parenter Enteral Nutr 2017Mar associated liver disease. Curr Opin Organ Transplant 2009;14:256–61. 1:148607117701399. doi: 10.1177/0148607117701399. [Epub ahead 23. Goulet O, Larchet M, Gaillard JL, et al. Catheter related sepsis during of print]. long-term parenteral nutrition in paediatric gastroenterology patients: 45. Abi Nader E, Lambe C, Ce´cile Talbotec C, et al. Metabolic bone disease a study of 185 consecutive central venous catheters. Clin Nutr in children with intestinal failure is not related to parenteral nutrition 1990;9:73–8. dependency. Metabolic Bone Disease in Children with Intestinal Failure 24. Hojsak I, Strizic´ H, Misˇak Z, et al. Central venous catheter related sepsis Is Not Associated to Parenteral Nutrition Dependency Index. Clin Nutr in children on parenteral nutrition: a 21-year single-center experience. 2018; in press. Clin Nutr 2012;31:672–5. 46. Jeejeebhjoy KN, Zohrab WJ, Langer B, et al. Total parenteral nutrition 25. Colomb V, Fabeiro M, Dabbas M, et al. Central venous catheter-related at home for 23 months, without complications, and with good rehabi- infections in children on long-term home parenteral nutrition: incidence litation. Gastroenterology 1973;65:811–20. and risk factors. Clin Nutr 2000;19:355–9. 47. Ricour C, Gorski AM, Goulet O, et al. Home parenteral nutrition in 26. Hermans D, Talbotec C, Lacaille F, et al. Early central catheter infec- children: 8 years of experience with 112 patients. Clin Nutr 1990;9: tions may contribute to hepatic fibrosis in children receiving long-term 65–71. parenteral nutrition. J Pediatr Gastroenterol Nutr 2007;44:459–63. 48. Bisset WM, Stapleford P, Long S, et al. Home parenteral nutrition in 27. Oliveira C, Nasr A, Brindle M, et al. Ethanol locks to prevent catheter- chronic intestinal failure. Arch Dis Child 1992;67:109–14. related bloodstream infections in parenteral nutrition: a meta-analysis. 49. Gottrand F, Staszewski P, Colomb V, et al. Satisfaction in different life Pediatrics 2012;129:318–29. domains in children receiving home parenteral nutrition and their 28. Handrup MM, Moller JK, Schroder H. Central venous catheters and families. J Pediatr 2005;146:793–7. catheter locks in children with cancer: a prospective randomized trial of 50. Engstro¨m I, Bjo¨rnestam B, Finkel Y. Psychological distress associated taurolidine versus heparin. Pediatr Blood Cancer 2013;60:1292–8. with home parenteral nutrition in Swedish children, adolescents, and 29. Miller MR, Niedner MF, Huskins WC, et al. Reducing PICU central their parents: preliminary results. J Pediatr Gastroenterol Nutr line-associated bloodstream infections: 3-year results. Pediatrics 2003;37:246–50. 2011;128:e1077–1083. 51. Friedman-Gruszczyn´ska J, Ossolin´ska M, Popin´ska K, et al. Parenteral 30. Lambe C, Poisson C, Talbotec C, et al. Strategies to reduce catheter- nutrition mixtures prepared at home by trained parents are as safe as related bloodstream infections in pediatric patients on home parenteral -made mixtures: a 3-y prospective study. Nutrition 2013; nutrition: the efficacy of taurolidine-citrate prophylactic locking. JPEN 29:988–92. J Parenter Enteral Nutr 2018. doi: 10.1002/jpen.1043. [Epub ahead of 52. Sty´blova´ J, Kalousova´ J, Adamcova´ M, et al. Czech Home PN Group of print]. the Society of Clinical Nutrition and Intensive Metabolic Care. Pae- 31. D’Antiga L, Goulet O. Intestinal failure in children: the European view. diatric home parenteral nutrition in the czech republic and its devel- J Pediatr Gastroenterol Nutr 2013;56:118–26. opment: multicentre retrospective study 1995–2011. Ann Nutr Metab 32. Lacaille F, Gupte G, Colomb V, et al., ESPGHAN Working Group of 2017;71:99–106. Intestinal Failure and Intestinal Transplantation. Intestinal Failure-As- 53. Barclay A, Henderson P, Gowen H, et al. The continued rise of sociated Liver Disease: a position paper of the ESPGHAN working paediatric home parenteral nutrition use: implications for service and group of intestinal failure and intestinal transplantation. J Pediatr the improvement of longitudinal data collection. Clin Nutr 2015; Gastroenterol Nutr 2015;60:272–83. 34:1128–32. 33. Bishay M, Pichler J, Horn V, et al. Intestinal failure-associated liver 54. Diamanti A, Conforti A, Panetta F, et al. Long-term outcome of home disease in surgical infants requiring long-term parenteral nutrition. J parenteral nutrition in patients with ultra-short bowel syndrome. J Pediatr Surg 2012;47:359–62. Pediatr Gastroenterol Nutr 2014;58:438–42. 34. Colomb V, Dabbas-Tyan M, Taupin P, et al. Long-term outcome of 55. Diamanti A, Gambarara M, Knafelz D, et al. Prevalence of liver children receiving home parenteral nutrition: a 20-year single-center complications in pediatric patients on home parenteral nutrition: in- experience in 302 patients. J Pediatr Gastroenterol Nutr 2007;44: dications for intestinal or combined liver-intestinal transplantation. 347–53. Transplant Proc 2003;35:3047–9. 35. Abi Nader E, Lambe C, Talbotec C, et al. Outcome of home parenteral 56. Gandullia P, Lugani F, Costabello L, et al. Long-term home parenteral nutrition in 251 children over a 14-y period: report of a single center. Am nutrition in children with chronic intestinal failure: A 15-year experi- J Clin Nutr 2016;103:1327–36. ence at a single Italian centre. Dig Liver Dis 2011;43:28–33. 36. Colomb V, Jobert-Giraud A, Lacaille F, et al. Role of lipid emulsions in 57. Peyret B, Collardeau S, Touzet S, et al. Prevalence of liver complica- cholestasis associated with long-term parenteral nutrition in children. tions in children receiving long-term parenteral nutrition. Eur J Clin JPEN J Parenter Enteral Nutr 2000;24:345–50. Nutr 2011;65:743–9. 37. Petit LM, Girard D, Ganousse-Mazeron S, et al. Weaning off prognosis 58. Pironi L, Joly F, Forbes A, et al. Home Artificial Nutrition & Chronic factors of home parenteral nutrition for children with primary digestive Intestinal Failure Working Group of the European Society for Clinical disease. J Pediatr Gastroenterol Nutr 2016;62:462–8. Nutrition and Metabolism (ESPEN). Long-term follow-up of patients on 38. Goulet O, Lambe C. Intravenous lipid emulsions in pediatric patients home PN in Europe: implications for intestinal transplantation. Gut with intestinal failure. Curr Opin Organ Transplant 2017;22:142–8. 2011;60:17–25. 39. Hojsak I, Colomb V, Braegger C, et al. ESPGHAN Committee on 59. Lacaille F, Irtan S, Dupic L, et al. Twenty-eight years of intestinal Nutrition Position Paper. Intravenous Lipid Emulsions and Risk of transplantation in Paris: experience of the oldest European center. Hepatotoxicity in Infants and Children: a Systematic Review and Transpl Int 2017;30:178–86. Meta-analysis. J Pediatr Gastroenterol Nutr 2016;62:776–92. 60. Billiauws L, Armengol Debeir L, Poullenot F, et al. Pregnancy is 40. Diamanti A, Bizzarri C, Basso MS, et al. How does long-term parenteral possible on long-term home parenteral nutrition in patients with chronic nutrition impact the bone mineral status of children with intestinal intestinal failure: results of a long-term retrospective observational failure? J Bone Miner Metab 2010;28:351–8. study. Clin Nutr 2017;36:1165–9.

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61. Cosnett JE. The origins of intravenous fluid therapy. Lancet 64. Koletzko B, Goulet O, Jochum F, et al. Use of parenteral nutrition in the 1989;1:768–71. pediatric ICU: should we panic because of PEPaNIC? Curr Opin Clin 62. Fivez T, Kerklaan D, Mesotten D, et al. Early versus late parenteral Nutr Metab Care 2017;20:201–3. nutrition in critically ill children. N Engl J Med 2016;374:1111–22. 65. Neelis E, de Koning B, van Winckel M, et al. Wide variation in 63. Goulet O, Jochum F, Koletzko B. Early or late parenteral nutrition in organisation and clinical practice of paediatric intestinal failure teams: critically ill children: practical implications of the PEPaNIC trial. Ann an international survey. Clin Nutr 2017Nov 22. pii: S0261-5614(17) Nutr Metab 2017;70:34–8. 31406-1. doi: 10.1016/j.clnu.2017.11.008. [Epub ahead of print].

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Chapter 5.2.4. Intestinal Transplantation: On a Long and Uneven Road From the Past to the Future

Florence Lacaille, Girish Gupte, and Olivier Goulet

he first ever reported organ transplantation was reported to be cellular (16). Today it is well established that humoral around 250 AD by 2 Greek physicians, Cosmas and Damia- rejection may be predominant. The diagnosis and management Tnos, who implanted a leg from a dead to a living man, with of humoral rejection benefited from the donor specific antibody immunosuppression based on Holy Water (1). The experience then (DSA) knowledge and technology as well as the availability of new faded away, until the second half of the 20th century. Following the generations of monoclonal antibodies (17). The risk of rejection is success of kidney then liver transplantation, and after extensive higher in the first months, but late acute rejection and chronic experimental work, 1 of the first intestinal transplantations (ITx) in rejection remain important causes of late graft (9). Medium- and the world was performed in 1987 on a baby with short bowel long-term follow-up showed a significant rate of late graft loss as syndrome (SBS), using cyclosporine, in the institution of several well as severe complications, either from the or the eminent members of ESPGHAN, Necker-Enfants Malades in Paris psychological burden of a chronic condition often present from (Fig. 1) (2–4). The first attempt with cyclosporine as the immuno- birth (9). suppressive agent failed until tacrolimus has been available in Parallel to the slow increase in numbers of ITx, the manage- Europe, restarting ITx in Paris in 1994. This institution not only ment of children with IF improved, due to the establishment of pioneered the development ITx, but had the foresight to develop specialized centres in many European countries, called ‘‘Intestinal integrated care of children with intestinal failure (IF) as promoted Rehabilitation Centres’’ (IRC) associated for most with home- by Olivier Goulet (5), thus establishing the pathway for intestinal parenteral nutrition programmes (HPN) (18). The scientific socie- rehabilitation (IR) centres (6–8). In 2015, the international Intesti- ties, in first place ESPGHAN, were instrumental in getting physi- nal Transplant Registry reported on 3067 patients, including 1697 cians together and creating networks for such a rare condition as IF children: 1621 only (822 children) of them were still alive, even (19). A network, called NITE for ‘‘Network for Intestinal Trans- fewer off parenteral nutrition (9). The 10-year graft survival was plantation in Europe,’’ was created under the umbrella of ESP- 40% to 60%, with a consistent improvement in the survival of GHAN, to strengthen the cooperation for clinical work and children transplanted within the last 10 years. The relatively small research, both in IF and transplantation. number, as compared to other solid organ transplantation, highlights the difficulties of this rare and demanding procedure, whose long- term results are far from satisfactory. We must acknowledge the INDICATIONS FOR INTESTINAL crucial role of Thomas Starzl and his Pittsburgh team in promoting TRANSPLANTATION: A DEBATED QUESTION ITx (Fig. 2). Building up experience is difficult, when only a few Intestinal transplantation is indicated in children with irre- centres in the world have transplanted more than 100 patients in 20 versible IF, highly dependent on PN (receiving over 100% of their years. The 3 large European paediatric centres are, Necker-Enfants resting energy expenditure requirements through PN) with associ- Malades in Paris (Fig. 3) (10), Birmingham Children’s Hospital ated life-threatening complications. It was confirmed by the work- (Fig. 4) (11), and La Paz in Madrid (12). The world champion of ing group on IF and ITx, including clinical nutrition in the 28 World long-term survivor following intestinal transplantation is a French Congress of Pediatric Gastroenterology, Hepatology, and Nutrition child transplanted in March 1989 with cyclosporine-based immu- (Paris 2004) (20). The medium-term mortality of children on HPN nosuppression (13). However, ITx numbers increased in the 1990s is nowadays nearly zero (21), and uncontrollable complications of after the introduction of tacrolimus. The first Intestinal Transplant long term PN only are an indication for ITx (22). A proportion of Registry report, published in demonstrated the leadership of US patients eventually develop life-threatening complications such as transplant group that remains until now (14). severe septic episodes, fluid and electrolytes imbalance, loss of venous access for PN, and end-stage liver disease. The term WHAT ARE THE SPECIFICITIES OF INTESTINAL ‘‘nutritional failure’’ was proposed by d’Antiga and Goulet as TRANSPLANTATION? the incapacity to continue PN on the long-term because of such The intestine harbours 80% of the body’s immune cells and is life-threatening complications (22). IF is a rare condition that certainly not sterile, conditions that make its transplantation chal- should be managed in experienced centres or in close collaboration lenging. In addition, it is a bacteria-hosting organ, suffering from with such centres offering an interdisciplinary management to ischaemia-reperfusion, and denervation (Fig. 5). Many improve- facilitate an early referral rather than a referral at the terminal ments have been achieved in the last 25 years in the selection of stage of a life-threatening complication (23). The waiting times for patients, surgical technique, immunosuppression, anti-infection ITx are usually long, and the child should remain on PN in pre- and therapy and follow-up, with a marked increase in short-term post-intestinal transplant period until nutritional rehabilitation can survival (15). At the early phase, acute rejection has been thought be established. The Birmingham group reported improvements in long-term survival of children referred for ITx they attributed to earlier referral and innovative surgical strategies (24). Received January 27, 2018; accepted January 29, 2018. The irreversibility of IF is obvious if the child has a very short Copyright # 2018 by European Society for Pediatric Gastroenterology, gut, microvillous inclusion disease, long segment Hirschsprung Hepatology, and Nutrition and North American Society for Pediatric disease, severe form of chronic intestinal pseudo-obstruction syn- Gastroenterology, Hepatology, and Nutrition drome. Successful transplantations have been reported by the Paris- DOI: 10.1097/MPG.0000000000001915 Necker group in infants and children suffering microvillous

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FIGURE 1. After the first intestinal transplantation at Necker-Enfants malades March 1987. From the right: Claude Ricour, Denys Pellerin, Yann Re´villon and Olivier Goulet.

inclusion disease (25), long segment Hirschsprung disease (26). ITx may be an option in the most severe form of chronic intestinal pseudo-obstruction syndrome (27). The Birmingham ITx unit reported encouraging results in chronic intestinal pseudo-obstruc- tion syndrome patients (28). In dubious situations, HPN should be optimised so as to allow for a successful ITx in the future. With the improvement of HPN management, the availability of non-trans- plant surgery (29) and the perspective of using GLP-2 analogues (30), SBS should become a rare indication (see Chapter 5.2.1). One rare indication for ITx may be when a child with irreversible IF is long-term resident in the hospital for social or medical reasons. This does raise ethical issues requiring to be discussed in the IRC by the multi-professional (psychologists, social workers, physiotherapists) and inter-disciplinary (paediatric gastroenterologist and nutritionist, paediatric surgeons) group (31). Psychological intolerance to HPN is a difficult situation, where the patient «who feels like a dog on the leash», does not realize that the leash will not disappear after ITx but only become transparent, but can develop non-compliance and new complications related to ITx (32).

THE MANY FACES OF INTESTINAL TRANSPLANTATION Due to stereometry, the graft usually comes from a size- matched child, which explains the long waiting time. The Birming- ham group promoted techniques of tissue expansion to facilitate liver and small bowel transplant in young children with contracted abdominal cavities (33) or staged abdominal closure techniques (34). The small bowel can be transplanted alone, together with the right colon when the disease also involves the colon (congenital enteropathies, motility disorders), together with the liver in case of IFALD, or together with the whole intestinal tract (from stomach to colon, and the liver) in motility disorders or severe portal hyper- tension. The Paris group was the first to report successful right colon transplantation (35). During the last decade, the Birmingham group promoted the indication for isolated liver Tx in SBS children with end-stage IFALD and a bowel length estimated sufficient for PN weaning (36,37). Taha et al reported a group of children with SBS and IFALD who have the potential for adaptation in the residual bowel underwent isolated LTx (38). The prognosis remains poor FIGURE 2. Thomas Starzl (died 2016) has been the pioneer in organ after this procedure, with 8 survivors out of 14 children undergoing transplantation. ITx (38). This indication can be avoided in the first place by www.jpgn.org S89 Supplement JPGN Volume 66, Supplement 1, April 2018

FIGURE 3. The complexity of the transplanted intestine. preventing IFALD in infants. With changes in clinical management own immunosuppression protocol, showing that none of the of SBS and the onset of fish oil based lipid emulsions, IFALD protocols are superior than the others. Inclusion of the liver in incidence has decreased and this option can be progressively the graft is probably protective on the long-term, and immuno- abandoned. suppression should not be too minimized for isolated intestinal Improved outcome has been reported in animal models when transplants. intestinal allograft is transplanted with the liver (39–41). The advantages in human were reported by several centres and the intestinal transplant Registry but remain debated (8,42,43). A stoma IS THE TRANSPLANTED INTESTINE is created on the terminal ileum, in order to follow-up the function FUNCTIONAL? of the transplanted organ (making stool) and to perform biopsies. Depending on ITx related complications and on the tolerance The stoma is usually closed several weeks or months after transplant of enteral feeding, PN can be discontinued after a few weeks (45). surgery in the absence of surgical complications following the Protocols for diet are as diverse as for immunosuppression, both transplant procedure (44). highlighting the many uncertainties of ITx (46). A normal diet is The immunosuppressive therapy is based on usual drugs, but possible in long-term, especially when there are no associated at higher doses than for the liver or the kidney. Every centre has its feeding disorders. Adapting the caloric intake to the intestinal

FIGURE 4. Transplantation group at Birmingham Children’s Hospital. From the left: Girish Gupte, Deidre Kelly and Sue Beath.

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FIGURE 5. The Necker transplantation group in 2017.

function, with supplemental enteral feeding as needed, allows a Therefore, it was suggested that ITx should be used only as a normal growth in most patients (47). There are very few reports in life-saving procedure. Although experienced North-American the literature about the function of the transplanted intestine. Stool transplantation centres have suggested that the role of ITx should balance analysis, routinely used by the Paris group, is a very be expanded to a pre-emptive/rehabilitative procedure applicable precious tool for assessing, both in a short and long term, intestinal to all patients with irreversible IF, the recent findings have shown absorption capacity after ITx (45,47). that home PN is the treatment of choice for IF in adults as well as In the short to medium and long-term follow-up, the patients in children (49). An early referral to a multi-disciplinary IR remain exquisitely sensitive to acute diarrhoea and dehydration, programs is essential to optimise the long-term management of which is poorly tolerated by the transplanted bowel. Diarrhoea may IF (23,24). be a confusing symptom as it can be the first manifestation of acute Advances in the knowledge of factors implicated with PN rejection or of viral gastroenteritis, the treatment of which is and IF complications and improvements in the medical and surgical diametrically opposite. Digestive symptoms should always ring a management of SBS result in better outcomes. Isolated liver Tx for bell for a possible rejection, and prompt further investigations. SBS patients who have the potential of bowel adaptation should be Early clinical suspicion and early diagnosis along with rapid no longer required. Interestingly, the most recent International treatment is a key to reversion of a late acute rejection. Close Intestinal Transplantation Registry reported in New York in June follow-up of growth is a key issue. Stunting without any obvious 2017, showed evidence of a worldwide trend of reduction in the endocrine cause should alert the clinician to a possibility of chronic number of paediatric ITx since 2007. This might be explained by graft rejection. There are no clear well established international several factors: consensus criteria for diagnosis of chronic rejection and more research is needed to understand about the treatment and timing 1. the provision of guidelines and training of reversibility of chronic rejection. 2. the development of IR centres with increasing IF expertise As an example, among the 103 patients, transplanted in 3. the enlarged use of nontransplant surgery Necker from 1994 under tacrolimus, 20 have nowadays a functional 4. the better prevention of IFALD, with fish oil based lipid small bowel graft for more than 10 years (15 more than 15 years), 3 emulsions playing a role among them with a second ITx procedure; one more, ‘‘the world 5. the improved prevention of catheter related sepsis by using champion’’ was transplanted in 1989 (48). taurolidine or ethanol locks.

HOME-PN VERSUS INTESTINAL FUTURE AND RESEARCH TRANSPLANTATION: IS IT A DILEMMA? After 25 years, intestinal transplantation (ITx) remains a There is probably a different threshold for ITx on both challenging procedure, where optimism and realism should travel sides of the Atlantic Ocean. The European approach inclines to together. Collaborative working within various intestinal trans- support long-term home PN, which is cost-effective and provides plant centres is needed especially as the patients with long-term an acceptable quality of life (see Chapter 5.2.3). Pironi et al have functioning grafts expose us to new challenges. The results of performed a 3-year prospective study including both adults and ITx can improve if there is understanding of the complex children on long-term PN for IF (49). The results showed that interplay between the immune system and gut microbiota. Future only patients with nutritional failure due to IFALD or major areas of research should concentrate on the intestinal microbiome catheter complications had an increased risk of death on home after ITx and its relationship with immunological and infectious PN, thus supporting its use as the primary treatment for IF. events, the changes of innate and adaptive immunity in the host www.jpgn.org S91 Supplement JPGN Volume 66, Supplement 1, April 2018 and organ. The network, called NITE for ‘‘Network for Intestinal 20. Kocoshis SA, Beath SV, Booth IW, et al. ??? J Pediatr Gastroenterol Transplantation in Europe’’ can be a useful platform within Nutr 2004;39:S655–61. Europe to promote clinical exchanges and collaborative research 21. Abi Nader E, Lambe C, Talbotec C, et al. Outcome of home parenteral (19). Major efforts are needed to improve the outcome of ITx nutrition in 251 children over a 14-y period: report of a single center. Am that will likely remain part of the armamentarium required to J Clin Nutr 2016;103:1327–36. prolong the survival of children with life-threatening IF complica- 22. D’Antiga L, Goulet O. Intestinal failure in children: the European view. J Pediatr Gastroenterol Nutr 2013;56:118–26. tions (50). When outcome of ITx and long-term PN are compared, it is 23. Ganousse-Mazeron S, Lacaille F, Colomb-Jung V, et al. Assessment and clear that PN outcome is better than after ITx (51). In the future, we do outcome of children with IF referred for intestinal transplantation. Clin hope that improvements of ITx will make us able to propose ITx over Nutr 2015;34:428–35. long-term PN, in patients with chronic IF for a better quality of life 24. Gupte GL, Beath SV, Protheroe S, et al. Improved outcome of referrals and for transmitting life (52). for intestinal transplantation in the UK. Arch Dis Child 2007;92: 147–52. 25. Ruemmele FM, Jan D, Lacaille F, et al. New perspectives for children with microvillous inclusion disease: early small bowel transplantation. REFERENCES Transplantation 2004;77:1024–8. 1. https://fr.wikipedia.org/wiki/La_Le´gende_dore´e Accessed 9 January 26. Sauvat F, Grimaldi C, Lacaille F, et al. Intestinal transplantation for total 2018. intestinal aganglionosis: a series of 12 consecutive children. J Pediatr 2. Ricour C, Revillon Y, Pletyncx M, et al. Hypothermic conservation and Surg 2008;43:1833–8. autotransplantation of small intestine in piglets. Gastroenterol Clin Biol 27. Goulet O, Sauvat F, Jan D. Surgery for pediatric patients with chronic 1981;5:977–86. intestinal pseudo-obstruction syndrome. J Pediatr Gastroenterol Nutr 3. Revillon Y, Jan D, Goulet O, et al. Small bowel transplantation in seven 2005;41:S66–8. children: preservation technique. Transplant Proc 1991;23:2350–1. 28. Millar AJ, Gupte G, Sharif K. Intestinal transplantation for motility 4. Schroeder P, Goulet O, Lear PA. Small-bowel transplantation: European disorders. Semin Pediatr Surg 2009;18:258–62. experience. Lancet 1990;336:110–1. 29. Kim HB, Lee PW, Garza J, et al. Serial transverse enteroplasty 5. Goulet O. Intestinal failure in children. Transplant Proc 1998;30: for short bowel syndrome: a case report. J Pediatr Surg 2003; 2523–5. 38:881–5. 6. Goulet O, Re´villon Y, Jan D, et al. Which patients need small bowel 30. Carter BA, Cohran VC, Cole CR, et al. Outcomes from a 12-week, open- transplantation for neonatal short bowel syndrome? Transplant Proc label, multicenter clinical trial of teduglutide in pediatric short bowel 1992;24:1058–9. syndrome. J Pediatr 2017;181:102–11. 7. Revillon Y, Jan D, Sarnacki S, et al. Intestinal transplantation in 31. Zamvar V, Puntis JW, Gupte G, et al, Social circumstances and medical the child: experimental and clinical studies. J Pediatr Surg complications in children with intestinal failure. Arch Dis Child 2014; 1993;28:292–8. 99:336-41. 8. Goulet O, Lacaille F, Jan D, et al. Intestinal transplantation: 32. Zamvar V, Lazonby G, Puntis JW. Recurrent life-threatening sepsis in indications, results and strategy. Curr Opin Clin Nutr Metab Care intestinal failure: transplantation or foster care? Arch Dis Child 2000;3:329–38. 2013;98:556–7. 9. Grant D, Abu-Elmagd K, Mazariegos G, et al. Intestinal transplant 33. Vidyadharan R, van Bommel AC, Kuti K, et al. Use of tissue registry report: global activity and trends. Am J Transplant expansion to facilitate liver and small bowel transplant in young 2015;15:210–9. children with contracted abdominal cavities. Pediatr Transplant 10. Lacaille F, Irtan S, Dupic L, et al. Twenty-eight years of intestinal 2013;17:646–52. transplantation in Paris: experience of the oldest European center. 34. Sheth J, Sharif K, Lloyd C, et al. Staged abdominal closure after Transpl Int 2017;30:178–86. small bowel or multivisceral transplantation. Pediatr Transplant 11. Dopazo C, Gupte GL, Sharif K, et al. Combined liver-intestine grafts 2012;16:36–40. compared with isolated intestinal transplantation in children: a single- 35. Goulet O, Auber F, Fourcade L, et al. Intestinal transplantation including center experience. Transplantation 2012;94:859–65. the colon in children. Transplant Proc 2002;34:1885–6. 12. Dore M, Junco PT, Moreno AA, et al. Ultrashort bowel syndrome 36. Olio DD, Gupte G, Sharif K, et al. Immunosuppression in infants with outcome in children treated in a multidisciplinary intestinal rehabilita- short bowel syndrome undergoing isolated liver transplantation. Pediatr tion unit. Eur J Pediatr Surg 2017;27:116–20. Transplant 2006;10:677–81. 13. Ruemmele FM, Sauvat F, Colomb V, et al. Seventeen years after 37. Dell-Olio D, Beath SV, de Ville de Goyet J, et al. Isolated liver successful small bowel transplantation: long term graft acceptance transplant in infants with short bowel syndrome: insights into without immune tolerance. Gut 2006;55:903–4. outcomes and prognostic factors. J Pediatr Gastroenterol Nutr 2009; 14. Grant D, Abu-Elmagd K, Reyes J, et al. 2003 report of the 48:334–40. intestine transplant registry: a new era has dawned. Ann Surg 2005; 38. Taha AM, Sharif K, Johnson T, et al. Long-term outcomes of 241:607–13. isolated liver transplantation for short bowel syndrome and intestinal 15. Fishbein TM. Intestinal transplantation. N Engl J Med 2009;361: failure-associated liver disease. J Pediatr Gastroenterol Nutr 2012;54: 998–1008. 547–51. 16. Cerf-Bensussan N, Brousse N, Jarry A, et al. Role of in vivo activated T 39. Sarnacki S, Revillon Y, Cerf-Bensussan N, et al. Long term small bowel cells in the mechanisms of villous atrophy in humans: study of allograft graft survival induced by spontaneously tolerated liver allograft in rejection. Digestion 1990;46(suppl 2):297–301. inbred rat strains. Transplantation 1992;54:383–5. 17. Rabant M, Racape´ M, Petit LM, et al. Antibody-mediated rejection in 40. Jugie M, Canioni D, Le Bihan C, et al. Study of the impact of liver pediatric small bowel transplantation: Capillaritis is a major determi- transplantation on the outcome of intestinal grafts in children. Trans- nant of C4d positivity in intestinal transplant biopsies. Am J Transplant plantation 2006;81:992–7. 2018. doi: 10.1111/ajt.14685. [Epub ahead of print]. 41. Jugie M, Badoual C, Le Bihan C, et al. CD4þCD25þ T cells play a 18. Beath S, Pironi L, Gabe S, et al. Collaborative strategies to reduce complex role in the pediatric combined liver-intestinal graft acceptance. mortality and morbidity in patients with chronic IF including those who Transplantation 2010;90:95–7. are referred for small bowel transplantation. Transplantation 2008; 42. Goulet O, Jan D, Lacaille F, et al. Intestinal transplantation in children: 85:1378-84. preliminary experience in Paris. JPEN J Parenter Enteral Nutr 19. Neelis E, de Koning B, van Winckel M, et al. Wide variation in 1999;23:S121–5. organisation and clinical practice of paediatric intestinal failure teams: 43. Abu-Elmagd KM, Kosmach-Park B, Costa G, et al. Long-term survival, an international survey. Clin Nutr 2017. pii: S0261-5614(17)31406-1. nutritional autonomy, and quality of life after intestinal and multi- doi 10.1016/j.clnu.2017.11.008. [Epub ahead of print]. visceral transplantation. Ann Surg 2012;256:494–508.

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44. Gupte GL, Haghighi KS, Sharif K, et al. Surgical complications after 49. Pironi L, Goulet O, Buchman A, et al. Outcome on home parenteral intestinal transplantation in infants and children–UK experience. nutrition for benign intestinal failure: a review of the literature and J Pediatr Surg 2010;45:1473–8. benchmarking with the European prospective survey of ESPEN. Clin 45. Ordonez F, Barbot-Trystram L, Lacaille F, et al. Intestinal absorption Nutr 2012;31:831–45. rate in children after small intestinal transplantation. Am J Clin Nutr 50. Gupte GL, Beath SV. Update on intestinal rehabilitation after intestinal 2013;97:743–9. transplantation. Curr Opin Organ Transplant 2009;14:267–73. 46. Colomb V, Goulet O. Nutrition support after intestinal transplantation: 51. Norsa L, Artru S, Lambe C, et al. Long term outcomes of intestinal how important is enteral feeding? Curr Opin Clin Nutr Metab Care rehabilitation in children with neonatal very short bowel syndrome: 2009;12:186–9. Parenteral nutrition or intestinal transplantation. Clin Nutr 2018 Feb 15. 47. Lacaille F, Vass N, Sauvat F, et al. Long-term outcome, growth and pii: S0261-5614 (18)30067-0. doi: 10.1016/j.clnu.2018.02.004. [Epub digestive function in children 2 to 18 years after intestinal transplanta- ahead of print]. tion. Gut 2008;57:455–61. 52. Srivastava R, Clarke S, Gupte GL, et al. Successful pregnancy outcome 48. Goulet O, Revillon Y, Brousse N, et al. Successful small bowel trans- following triple organ transplantation (small intestine, liver and pan- plantation in an infant. Transplantation 1992;53:940–3. creas). Eur J Obstet Gynecol Reprod Biol 2012;163:238–9.

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Chapter 5.3.1. ESPGHAN History of Gastrointestinal Paediatric Endoscopy

Samy Cadranel, Jean-Franc¸ois Mougenot, and Mike Thomson

ttempts to inspect the internal cavities of the in years; Mike Thomson, the youngest colleague of this trio has vivo are probably as ancient as medicine itself. A challenge accepted to write about the very important topic of training Awas to find a safe source of light that would not generate heat that in endoscopy. could damage tissues. Following the adaptation of fiberoptics for medical instruments, endoscopy of the GI tract became a popular tool in gastroenterology units, to such an extent that adaptation of FROM CONVENTIONAL FIBERSCOPES TO fiberoptics to gastrointestinal endoscopy has been considered the VIDEOENDOSCOPY major advance in gastroenterology in the last 70 years (1). Diag- Today the fiberoptic endoscope has largely been replaced by nostic investigations of digestive diseases in children were formerly the electronic video endoscope, first introduced in the 1980s. The based on contrast radiology, although a few children would occa- objective lens at the tip of the video endoscope forms an image of sionally be treated in such units, mainly for retrieval of foreign the object in view on the distal face of the electronic image sensor. bodies. The possibility to directly observe the GI tract and take The image is captured by a charge-coupled device (CCD), or by a guided biopsies represents a major progress in paediatric gastroen- complementarity metal-oxide semiconductor sensor (CMOS), terology. It contributes not only to the solution of some diagnostic transmitted electronically, and displayed on a video monitor. There mysteries but also to the treatment of diseases that before were is substantial additional cost associated with the video endoscope reserved to invasive surgery. and its required accessories. However, in contrast to older instru- ments in which the endoscopist viewed the image through a FROM CONVENTIONAL FIBERSCOPES TO proximal eyepiece, the image display on a monitor is more com- PAEDIATRIC ENDOSCOPES fortable for the endoscopist and allows shared simultaneous view- ing by trainees and assistants. In the early 1970s only first-generation conventional fiber- In pediatric practice an important consideration is the choice scopes were available and, due to their large diameter, only a few of an appropriate endoscope suitable for the patient’s age or size. older children could be investigated using them. During the 1972 Companies including Fujinon, Olympus, and Pentax now produce a annual meeting of ESPGA in Hamburg we paid a visit to the comprehensive range of endoscopes. However, light sources, pro- European branch of Olympus and convinced their engineers to cessors, video endoscopes, and some accessories are not inter- adapt a slim ‘‘industrial’’ fiberscope into a medical instrument changeable. Smaller endoscopes (4.9–6.0 mm) are preferred for suitable for children. This prototype allowed safe GI endoscopies in neonates and infants. These smaller instruments have disadvantages children and can be considered the first step of the development of in relation to image resolution, biopsy size, and durability. More- paediatric GI endoscopy (2). At the very first ESPGHAN workshop, over, only instruments with sufficiently large operating channels are held in Bern in 1981, we were able to gather the few paediatric suited for therapeutic endoscopy. endoscopists who presented their findings and technical expertise. It Pediatric single-channel colonoscopes have been developed was an opportunity to discuss with instrument makers our require- with the following characteristics: length: 133 to 150 cm; diameter: ments for the manufacture of slim instruments adapted to our 9.5 to 11.5 mm (insertion tube diameter); accessory channel: diverse needs (Figures 1–4). 3.2 mm. They have a narrow tip deflection radius and short bending Thanks to the reduction in instrument diameter, further section, adapted for paediatric use. Since there is no colonoscope technical improvements and progress in sedation and anaesthetics, designed specifically for infants, tiny gastroduodenoscopes must be examinations of the GI tract in children have become easier and used despite their asymmetrical distal bending and excessive stiff- safer. Publications highlighted the importance of pediatric endos- ness. In patients older than 7 years, colonoscopes with an accessory copy, its diagnostic and therapeutic value and contribution to our channel of 3.7 or 3.8 mm are preferable. knowledge of many GI diseases in infants and children (3–10). Less than 10 years after its introduction in paediatric gastroenterology, endoscopy was the subject of several books in Spanish, German, NEW TECHNOLOGY FOR ENDOSCOPIC and English (11–14). Jean Franc¸ois Mougenot, one of the very first paediatric DIAGNOSIS endoscopists who actively contributed to the advancement of these In adult patients, dyeless virtual chromoendoscopy is a instruments, has been invited to write about the progressive innova- valuable technique, assisting in the characterization of lesions, such tions and the passage from fiberendoscopy to videoendosopy. as polyps, and predicting the histological findings. Contrast Through ESPGHAN the 3 authors of this historical chapter have enhancement is based on the phenomenon that the penetration of been training a great number of fellows over a period of almost 50 light into the mucosa varies according to the wavelengths: 400 to 500 nm are ideal for analysing surface structures whereas, because of the absorption properties of haemoglobin, longer wavelengths of Received January 27, 2018; accepted January 29, 2018. about 550 nm are more effective for visualization of blood vessels Copyright # 2018 by European Society for Pediatric Gastroenterology, (15). In Narrow Band Imaging (NBI) developed by Olympus a Hepatology, and Nutrition and North American Society for Pediatric rotating optical interference filter is interposed after the white light Gastroenterology, Hepatology, and Nutrition source to restrict the incident light into 2 narrow bands of different DOI: 10.1097/MPG.0000000000001915 wavelengths. The blue at 415 nm image channel analyses the fine

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FIGURE 2. The slim 2-directional Olympus GIF-P compared to the FIGURE 1. Literature on very early endoscopes was available only in softer 4-directional GIF P2. Japanese.

surface architecture of the mucosa and the superficial capillary lesions to a much wider development than what was expected network. The green at 540 nm image channel analyses the deeper from fiberendoscopy. collecting vessels. After colour adjustment by the processor that further enhances the contrast by reassessing the colour channels, the superficial and deep details are superimposed in a single final mixed ENDOSCOPY TRAINING AND RECENT NBI image. Although the image is significantly darker than with ADVANCES IN PAEDIATRICS normal white light, enhanced visualization of fine morphology of It has become increasingly apparent in recent years that the the mucosal layer and especially of the capillary pattern is provided landscape of paediatric endoscopy training varies widely, not only by combining the NBI system with a magnifying endoscope (16). between differing health systems and countries, which in principle Flexible spectral Imaging Color Enhancement (FICE), manufac- may aspire to identical standards of training excellence, but even tured by Fujinon, is a technology based on digital image processing between apparently comparable endoscopy units who are ostensibly that performs spectral estimation processing of a real-time endo- seen to be ‘training’ units for our next generation of trainees in this scopic image to produce spectral images, selects images of given procedural specialty, unique in pediatric medicine. ESPGHAN and wavelengths, and assigns these to the Red Green Blue monitor input the JPGN have been pivotal in nurturing such views and in channels. With real-time electronic wavelength manipulation, an promoting such a philosophy. This has accelerated in recent years. infinite number of combinations can be used to create reconstructed As more senior endoscopy trainers, and as such representative of a images. Ten channels with different predefined absorption wave- generation who have had variable training ourselves, we have an lengths are available. FICE allows instantaneous switching between acute responsibility to get it right for the next generation of pediatric conventional white light and FICE-images, and between any of the endoscopists. 10 preset FICE-images in order to select the most suitable wave- How do we achieve the following unimpeachable impera- length for any particular examination. In children virtual chro- tives of paediatric endoscopy training? Namely: uniformity of moendoscopy is used in the follow-up of patients with polyposis excellence of training; uniformity of excellence of trainers; unifor- syndrome or identification of dysplasia lesions. The advent of mity of the best possible training environment; exposure early in numerical endoscopy has enhanced the diagnostic analysis possi- training to the correct principles and models of practice going bilities (confocal endoscopy, endosographic endoscopy, wireless forward; that these goals are achieved in a safe and paediatric- video capsule endoscopy (17) but also the treatment of GI tract specific environment. We suggest that a number of models have www.jpgn.org S95 Supplement JPGN  Volume 66, Supplement 1, April 2018

FIGURE 3. Caliber differences between conventional, paediatric and neonatal instruments. their merits but that, in principle, the following are basic building Paediatric endoscopy has had a golden era over the last blocks of such training structures and are now tried and trusted 20 years, and advances in diagnostic and therapeutic applications within the pediatric endoscopy sphere: have been nothing short of transformational for our capabilities, and in consequence with positive effects on children’s lives. Extending 1. Trained trainers who are competent not only in paediatric the capability anatomically to include a pan-enteric reach with the endoscopy themselves but, crucially, effective in imparting this advent of wireless capsule video-endoscopy is now standard in knowledge and skill base to their trainees in a constructive many units and the sister technology of enteroscopy without need manner; for surgical assistance has added a therapeutic arm to this approach. 2. Internet-based lesion recognition tools with examination It could not have entered the imagination of pediatric endoscopists sections, and web-based learning opportunities; in the 1970s or 1980s that such therapies as ileal polypectomy, 3. Hands-on small number participating courses at the inception of argon plasma ablation of blue rubber blebs or percutaneous endo- training including virtual model training, animal models for scopic jejunostomies would be available within a few decades. So therapeutic work, and physical artificial models for diagnostic, many laparotomies have been prevented by minimally invasive with graduation to actual patients when appropriate; endoscopic approaches recently—or sometimes with the joint 4. National and International responsible bodies tasked with approach of laparoscopy and endoscopy combination. Examples the awarding of competency-based endoscopy-specific quali- of this include: endoscopic anti-reflux procedures; endoscopic fications in paediatric endoscopy at varying levels of pyloromyotomy; transgastric endoscopic pancreatic cyst drainage; competency; percutaneous endoscopic jejunostomy; duodenal stenosis endo- 5. Competency-based assessments which are both formative, at scopic division; Hemospray and other endoscopically delivered the beginning of training, and summative, prior to the award of treatments for acute GI bleeding; mid small bowel polypectomy; competency recognition; and mid small bowel variceal banding. These are a small example 6. Contemporaneous log book electronic records of experience in mix and represent the tip of the iceberg in terms of potential. The training; responsibility of those being trained at present is to stand on the 7. Regular Training Unit accreditation and assessment of ability shoulders of their trainers, the previous generation of pediatric and appropriateness of training environment. endoscopists and build on their progress, with a view to extending our ability along similar lines over the next 20 to 30 years. The only This approach may facilitate the ideal: that we may join as a limit is imagination—technology will catch up. An example of world community of like-minded individuals in order to attempt to imagination running ahead of technology is seen in Natural Orifice establish ground rules for how excellence in paediatric endoscopy Trans-Endoscopic Surgery (NOTES) which may be the future. It training may be achieved (18–21). has yet to show significant advantage over more established mini- mally invasive techniques such as those involving laparoscopy but it is very close to this. Surgical triangulation, sepsis and a viable endoscopic ‘‘tool-box’’ remain challenges in this area and it will be fascinating to observe the next paradigm shift from laparoscopic to NOTES and its velocity, compared to the previous generational change which occurred when laparotomy and ‘‘open’’ surgery gave way to laparoscopy. Pediatric endoscopy should remain at the front of the minds of those taking this forward in the next 10 to 20 years.

REFERENCES 1. Janowitz HD, Abittan CS, Fiedler IM. A gastroenterological list for the Millenium. J Clin Gastroenterol 1999;29:336–8. 2. Cremer M, Rodesch P, Cadranel S. Fiberendoscopy of the gastrointest- inal tract in children. Experience with newly designed fiberscopes. Endoscopy 1974;6:186–9. 3. Mougenot JF, Polonowski C. Apport de la fibroscopie a` la gastroente´r- ologie pe´diatrique Le Pediatre 1975;50:7–12. 4. Rodesch P, Cadranel S, Peeters JP, et al. Colonic endoscopy in children. FIGURE 4. Endoscopy is a very delicate maneuver in neonatalogy. Acta Paediatr Belg 1976;29:181–4.

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5. Mougenot JF, Montagne JP, Faure C. Gastrointestinal fibro-endoscopy 14. Cadranel S, Rodesch P. Fiberendoscopy of the upper gastrointestinal tract. in infants and children: radio-fibroscopic correlations. Ann Radiol In: Gans SL, ed. Pediatric Endoscopy. New York:Gru¨ne and Stratton; 1983. (Paris) 1976;19:23–34. 15. Williams CB, Cadranel S. Colonoscopy. In: Gans SL, ed. Pediatric 6. Forget PP, Meradji M. Contribution of fiberendoscopy to diagnosis and Endoscopy. New York: Gru¨ne and Stratton; 1983. management of children with gastroesophageal reflux. Arch Dis Child 16. Neumann H, Vieth M, Gu¨nther C, et al. Virtual chromoendoscopy for 1976;51:60–6. prediction of severity and disease extent in patients with inflammatory 7. Cadranel S, Rodesch P. Pediatric endoscopy in children: preparation and bowel disease: a randomized controlled study. Inflamm Bowel Dis sedation. Gastroenterology 1977;71:44–5. 2013;19:1935–42. 8. Cadranel S, Rodesch P, Peeters JP, et al. Fiberendoscopy of the gastro- 17. Kuznetsov K, Lambert R, Rey JF. Narrow-band imaging: potential and intestinal tract in children and infants: a series of 100 examinations. Am limitations. Endoscopy 2006;38:76–81. J Dis Child 1977;131:41–5. 18. Oliva S, Di Nardo G, Hassan C, et al. Second-generation colon capsule 9. Rumi G, Solt I, Kajtar P. Esophagogastroduodenoscopy in childhood. endoscopy vs. colonoscopy in pediatric ulcerative colitis: a pilot study. Acta Paediatr Acad Sci Hung 1978;19:315–8. Endoscopy 2014;46:485–92. 10. Isakova IuF, Stepanov EA, Geras’kin VI, et al. Fibroscopy in diagnosis 19. Thomson M, Heuschkel R, Donaldson N, et al. Acquisition of compe- of diseases of the upper digestive tract in children. Khirurgiia (Mosk) tence in paediatric ileocolonoscopy with virtual endoscopy training. J 1977;7:33–7. Pediatr Gastroenterol Nutr 2006;43:699–701. 11. Gershman GB, Bokser VO. Fibrogastroscopy in the diagnosis of 20. Haycock A, Koch AD, Familiari P, et al. Training and transfer of colono- gastritis in children. Vopr Okhr Materin Det 1979;24:25–30. scopy skills: a multinational, randomized, blinded, controlled trial of 12. Beltran S, Varea V, Vilar P. Fibroendoscopia en patologia digestiva simulator versus bedside training. Gastrointest Endosc 2010;71:298–307. infantile. Barcelona: Jims; 1980. 21. Obstein KL, Patil VD, Jayender J, et al. Evaluation of colonoscopy 13. Burdelski M, Huchzermeyer H. Gastrointestinale endoscopie im Kin- technical skill levels by use of an objective kinematic-based system. desalter. Berlin: Springer-Verlag; 1980. Gastrointest Endosc 2011;73:315–21.

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Chapter 5.3.2. Some Things Have Moved in the World of Motility

Marc Benninga, Annamaria Staiano, Peter Milla, and Nikhil Thapar

ommon upper and lower gastrointestinal (GI) motility dis- cells. Interstitial Cells of Cajal serve as these intermediaries and orders, such as gastro-oesophageal reflux disease and func- may also facilitate the propagation of electrical events along and tionalC constipation, but also relatively rare motility disorders, such around the gastrointestinal tract, and in doing so act as slow-wave as achalasia, Hirschsprung disease, and chronic intestinal pseudo- pacemaker generators for the muscle coats of the bowel. Smooth obstruction, have always been the core business of paediatric muscle cells, however, are inherently excitable and this is due to the gastroenterologists worldwide. Enormous strides have been made property of rhythmic variation of transmembrane potentials, which in the understanding of these motility disorders using novel tools to occurs even during complete motor quiescence. The cycle of investigate and treat them. This chapter briefly touches on what has depolarisation and repolarisation is the result of rhythmic changes happened in the last 50 years. in the activity of membrane ion pumps. Because of the increasing interest in (paediatric) motility The enteric nervous system coordinates activity of this disorders, particularly since the turn of the century, experts from all primary motor-effector to produce meaningful patterns of contrac- over the world met, and continue to meet, to discuss the latest tion throughout the whole organ. The structure and function and findings in the area of GI motility. These invaluable interactions neurochemistry of the enteric neurons are very similar to those of occurs within a number of collaborative initiatives such as regular the central nervous system and the neurons contained in ganglia are Pediatric GI Motility Meetings supported by ESPGHAN (the first in interconnected to function in a similar fashion with mechanisms for Capri 2001) as well as under the auspices of the dedicated ESP- integration and processing of information. GHAN Motility Special Interest Group. The motor neuron pool of the enteric nervous system consists of excitatory and inhibitory neurons. Excitatory motor THE RHYTHM OF THE GUT neurons release neurotransmitters (acetyl choline and substance A hundred years ago the rhythm of the gut was seen as simple P) that evoke muscle contraction and mucosal secretion. Inhibitory and straightforward. It was a tube, which moved the intraluminal motor neurons release neurotransmitters that suppress contractile contents by a peristaltic movement induced by distension. Studies activity of the musculature. Important examples are vasoactive over the last century have shown that it is much more complex than intestinal peptide and nitric oxide. The inhibitory motor neurons this and that the bowel contents are transferred from one specialised are of particular significance in the relationship of the excitable region of the gut to another by the co-ordinated contraction of nature of smooth muscle cells to the Interstitial Cells of Cajal. the smooth muscle coats. The pattern of motility is related to The activity state of these neurons determines when the and integrated with the function of particular regions of the omnipresent slow-waves will initiate contraction as well as the gastrointestinal tract. distance and direction of propagation once the contraction has Development of our understanding of basic smooth muscle begun. The circular muscle can only respond to the electrical physiology, of enteric neurons forming an enteric nervous system slow-wave when the inhibitory motor neurons in that segment of with higher levels of control, has revealed the beauty and sophisti- the intestine are switched off. Thus, loss of the intrinsic inhibitory cation of the rhythm of the gut. The musculature of the gut is the neurons will result in tonic contraction of that segment of intestinal motor-effector system, which is controlled by the enteric nervous circular muscle. system and the central nervous system. Control of the musculature While the signals to the enteric nervous system may come involves an integrated hierarchy of neural centres and pacemaker from the lumen of the bowel, its activity may also be altered by cells the Interstitial Cells of Cajal. Starting at the level of the gut humoral secretion of polypeptide hormones from entero-endocrine there is the enteric nervous system, which has local neural circuits cells and by the activity of the mucosal associated lymphoid tissue. for the integration of contraction. These local neural circuits can be There is now a large body of evidence, which shows that the motor modulated by higher levels of integration. The second level of and secretory responses in the gut to specific antigens are as a integration occurs in the prevertebral sympathetic ganglia where consequence of direct communication between the immune system peripheral reflex pathways are influenced by preganglionic sympa- and the enteric nervous system. This communication results in thetic fibres from the spinal cord. In the central nervous system, adaptive behaviour of the bowel in response to stimuli within there is sympathetic and parasympathetic outflow to the gut deter- the lumen. In addition to this local neuro-immune interaction there mined by reflexes with sensory fibres that travel with the autonomic is also evidence that mast cells are involved in the defence nerves. Higher brain centres supply descending signals, which mechanism apart from local antigen sensing and signalling to the integrate with the sympathetic and parasympathetic outflow of enteric nervous system. The brain to mast cell connection is a the gut. For effective contraction to take place intermediaries are mechanism that can link psycho-emotional events to the enteric required between enteric neurotransmission and the smooth muscle neuro-musculature. The journey in understanding the basic physiology of smooth muscle, enteric neurons and their higher levels of control, and the Received January 27, 2018; accepted January 29, 2018. enteric nervous system has been required to understand the whole Copyright # 2018 by European Society for Pediatric Gastroenterology, and increasing scope of neuro-gastroenterology. Much of this Hepatology, and Nutrition and North American Society for Pediatric journey was undertaken with simple tools such as this recording Gastroenterology, Hepatology, and Nutrition of the first small intestinal migrating motor complex in an infant DOI: 10.1097/MPG.0000000000001915 using home-made pressure catheters and a pen and ink recording

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FIGURE 1. Example of recording intestinal migrating motor complex in an infant using home-made pressure catheters and a pen and ink recording device. device (Fig. 1). Disturbance of these various elements is almost replaced conventional manometry and, as in adults, paediatricians certainly responsible for the gastrointestinal symptoms seen in a now use the Chicago classification to describe the different forms of wide variety of disease states, which affect the central nervous upper motility disorders such as achalasia (5,6). system, the immune system, and the gut itself. Moreover, oesophageal motility disorders also represent one of the main comorbidities in patients with neurological disabilities. In 1991 Staiano et al found that the oesophageal OESOPHAGEAL MOTILITY DISORDERS motility abnormalities identified in children with neurological The first papers on oesophageal motility disorders in children impairment persisted after the treatment of GOR, suggesting date back to the late 1940s and were mainly focused on ‘‘infantile that motility disorders in this subgroup of patients are directly cardiospasm’’ or achalasia. From that moment onwards numerous associated with neurological damage, rather than being a conse- studies started to investigate the pathogenesis of these disorders in quence of GOR (7). the paediatric age. The understanding of the mechanisms underly- ing the onset of oesophageal motility disturbances has always been ENTERIC NEUROPATHIES one of the main fields of interest for ESPGHAN. In fact, over the Submerged within the vast oceans of coeliac disease and past 50 years several ESPGHAN members have dedicated their inflammatory bowel disease that have bathed the society over the efforts to the identification of the conditions associated with altered last decades is a group of uncommon largely enigmatic conditions oesophageal function. termed ‘‘enteric neuropathies.’’ The literature is perhaps reflective From the outset, a key player in motility disorders has of this. In the 20 years before ESPGHAN was formed there were undoubtedly been gastro-oesophageal reflux (GOR). Already in 400 publications on Hirschsprung disease, 500 in the 20 years after, 1986, Cucchiara et al demonstrated the presence of oesophageal but more than 3500 in the 30 years since. The picture for chronic motor abnormalities in children with GOR (1). Thereafter numerous intestinal pseudo-obstruction in children, however, is very differ- other studies confirmed this association, and the close correlation ent—virtually undescribed before 1968 and only 500 publications between GOR and oesophageal motility. ESPGHAN attention to since. Yet ESPGHAN has been at the very heart of ‘‘neurogas- GOR has always been very high, leading in 2009 to the first troenterology and motility’’ the science dedicated to the study of combined ESPGHAN and NASPGHAN guidelines on GOR man- such disorders, and a branch of paediatric gastroenterology that is agement (2). These guidelines represent a milestone in ESP- seeing a surge of interest that will, undoubtedly, form a big focus for GHAN’s history, given that, from that point on, many other the society in the future. combined guidelines were produced. However, GOR is not the only condition associated with oesophageal dysmotility. For example, in 2009 Nurko et al identi- GASTROPARESIS fied the presence of ineffective peristalsis in children with eosino- Gastroparesis in children remains very poorly described or philic oesophagitis, a condition now recognised as one of the causes indeed understood with the majority of cases still considered of oesophageal motor dysfunction (3). idiopathic. In an elegant series of articles Peter Milla, together Since Cucchiara et al’s description in 1986 of the return of with the surgical pioneer Lewis Spitz and physiologist Paul peristalsis in a child with oesophageal achalasia, significant devel- Andrews, provided strong rationale for the careful consideration opments have been made in the measurement of pressures in the of fundoplication, especially in neurologically impaired children, oesophagus (4). High-resolution manometry, pioneered in historical given its effects on gastric emptying and post-operative complica- studies by Annamaria Staiano working with Ray Clouse, has tions (8). Cucchiara et al showed the potential use of medication in www.jpgn.org S99 Supplement JPGN  Volume 66, Supplement 1, April 2018

TABLE 1. Rome IV criteria for the diagnosis of functional gastrointestinal disorders of the neonates/toddlers

Infant regurgitation Infant colic Must include both of the following in otherwise healthy infants 3 weeks Must include all of the following: to 12 months of age: 1. An infant who is less than 5 months of age when the symptoms start and stop 1. Regurgitation 2 or more times per day for 3 or more weeks 2. Recurrent and prolonged periods of infant crying, fussing, or irritability 2. No retching, hematemesis, aspiration, apnea, failure to thrive, reported by caregivers that occur without obvious cause and cannot be feeding or swallowing difficulties, or abnormal posturing prevented or resolved by caregivers 3. No evidence of infant failure to thrive, fever, or illness Infant rumination syndrome Functional diarrhoea Must include all of the following: Must include both of the following in an infant less than 9 months of age: 1. Two or more periods of unremitting paroxysmal vomiting with or 1. At least 10 minutes of straining and crying before successful or unsuccessful without retching, lasting hours to days within a 6-month period passage of soft stools 2. Episodes are stereotypical in each patient 2. No other health problems 3. Episodes are separated by weeks to months with return to baseline health between episodes of vomiting Functional constipation Must include 1 month of at least 2 of the following in infants up to 4 years of age: 1. Two or fewer defecations per week 2. History of excessive stool retention 3. History of painful or hard bowel movements 4. History of large diameter stools 5. Presence of a large fecal mass in the rectum In toilet trained children, the following additional criteria may be used: 6. At least 1 episode/week of incontinence after the acquisition of toileting skills 7. History of large diameter stools which may obstruct the toilet Must include all of the folloing for at least 2 months: Must include all of the following: 1. Repetitive contractions of the abdominal muscles, diaphragm, and 1. Daily painless, recurrent passage of 4 or more large, unformed stools tongue 2. Symptoms last more than 4 weeks 2. Effortless regurgitation of gastric contents, which are either 3. Onset between 6 and 60 months of age expelled from the mouth or rechewed and reswallowed 4. No failure-to-thrive if caloric intake is adequate 3. Three or more of the following: a) Onset between 3 and 8 months; b) Does not respond to management for GERD and regurgitation; c) Unaccompanied by signs of distress; d) Does not occur during sleep and when the infant is interacting with individuals in the environment Cyclic vomiting syndrome Infant dyschezia

gastroparesis and that, akin to adults, diabetic children also dis- diseases such as total intestinal aganglionosis the work of ESP- played disturbances in gastric motility function, which appeared to GHAN intestinal transplant pioneers such as Olivier Goulet has correlate with glycaemic control (9). Milla’s group showed primary been critical (17). These poor outcomes, however, have driven disturbances in gastric function in intestinal pseudo-obstruction ESPGHAN to remain contemporary and futuristic with bold steps (10) and Staiano’s group, more recently, that gastric emptying is into regenerative medicine. Nikhil Thapar and colleagues have seen delayed in the presence of constipation confirming the exquisite considerable success with the potential of harvesting neural stem interplay between different regions of gastrointestinal tract (11). cells from patients themselves and developing novel stem cell replacements as curative for enteric neuropathies such as Hirsch- sprung disease (18,19). HIRSCHSPRUNG DISEASE AND CHRONIC Chronic intestinal pseudo-obstruction (CIPO), perhaps pre- INTESTINAL PSEUDO-OBSTRUCTION sents an even more challenging and devastating group of disorders Hirschsprung disease, the most commonly recognised enteric of the gastrointestinal tract and ESPGHAN experts have been at the neuropathy, has historically been the preserve of surgeons rather core (20). It is only the advent of parenteral nutrition around the than gastroenterologists. The last decades has seen much more of a birth of ESPGHAN in 1968 that children could now be kept alive joint effort between both these specialists together with basic (21). Surgical management of patients suffering CIPO remain very scientists to progress both our understanding and management of debated and challenging as reviewed by Goulet et al (22). One of the this condition. This collaboration is evident in early publications biggest challenges was the diagnosis. In the 1970s a significant from Peter Milla with Lewis Spitz (12). Milla also brought into proportion of intestinal physiology studies were still be carried out ESPGHAN much of the scientific understanding of the aetiopatho- in experimental animals such as dogs. It was Peter Milla and genesis of Hirschsprung disease gleaned through his interactions colleagues working in London in the early 1980s that made the with ENS developmental biologists and a keen self-interest (13,14). first recordings on small intestinal activity in children using proto- Together with the work of Alberto Aurrichio, A Ballabio and type catheters with triple lumens and 3 measuring ports placed in colleagues a number of genes involved in Hirschsprung and intes- the stomach and proximal duodenum, using somatostatin and tinal pseudo-obstruction have been described (15,16). For the worst cholecystokinin administered to patients during the studies in an

S100 www.jpgn.org JPGN  Volume 66, Supplement 1, April 2018 Supplement attempt to replicate body physiology (23,24). In the 1990s Salvatore Most recently they were part of the London Classification initiative Cucchiara together with Aurrichio and colleagues described mano- led by Charles Knowles that aims to make uniform and expert the metric characteristics of children with intestinal pseudo-obstruction application of histopathology to adult and paediatric motility dis- (25). Their work together with those of others in ESPGHAN and its orders (28). An ESPGHAN expert group led by Nikhil Thapar sister society NASPGHAN have contributed to establishing antro- together with neurogastroenterology and motility giants from ESP- duodenal manometry as a robust tool for diagnosing CIPO. Addi- GHAN (Annamaria Staiano, Marc Benninga, Yvan Vandenplas and tionally, Peter Milla together with Virpi Smith also brought to the Osvaldo Borrelli) as well as from NASPGHAN (Carlo Di Lorenzo field of intestinal pseudo-obstruction their deep knowledge of and Christophe Faure) now oversees the forward initiatives that aim histopathology of enteric neuropathies and myopathies (26,27). to tackle much need work in Intestinal pseudo-obstruction (now

TABLE 2. Rome IV criteria for the diagnosis of functional gastrointestinal disorders of the child/adolescent Functional nausea and vomiting disorders

Cyclic vomiting syndrome Rumination syndrome Must include all of the following: Must include all of the following: 1. Two or more periods of intense, unremitting nausea and paroxysmal 1. Repeated regurgitation and rechewing or expulsion of food that: vomiting, lasting hours to days within a 6-month period a. Begins soon after ingestion of a meal 2. Episodes are stereotypical in each patient b. Does not occur during sleep 3. Episodes are separated by weeks to months with return to baseline 2. Not preceded by retching health between episodes 3. After appropriate evaluation, the symptoms cannot be fully 4. After appropriate evaluation, the symptoms cannot be attributed to explained by another medical condition. An eating disorder must be another medical condition ruled out. Functional nausea Aerophagia Must include all of the followingÃ: Must include all of the followingÃ: 1. Bothersome nausea as the predominant symptom, occurring at least 1. Excessive air swallowing twice per week, and generally not related to meals 2. Abdominal distension due to intraluminal air which increases 2. Not consistently associated with vomiting during the day 3. After appropriate evaluation, the nausea cannot be fully explained 3. Repetitive belching and/or increased flatus by another medical condition 4. After appropriate evaluation, the symptoms cannot be fully explained by another medical condition Functional vomiting Must include all of the following (Criteria fulfilled for at least 2 months prior to diagnosis): 1. On average, one or more episodes of vomiting per week 2. Absence of self-induced vomiting or criteria for an eating disorder or rumination 3. After appropriate evaluation, the vomiting cannot be fully explained by another medical condition

Functional abdominal pain disorders

Functional dyspepsia1 Abdominal migraine Must include 1 or more of the following bothersome symptoms at least 4 Must include all of the following occurring at least twice (fulfilled for at least times a month for at least 2 months prior to diagnosis: 6 months prior to diagnosis) : 1. Postprandial fullness 1. Paroxysmal episodes of intense, acute periumbilical, midline or diffuse 2. Early satiation abdominal pain lasting 1 hour or more (should be the most severe and 3. Epigastric pain or burning not associated with defecation distressing symptom) 4. After appropriate evaluation, the symptoms cannot be fully 2. Episodes are separated by weeks to months explained by another medical condition 3. The pain is incapacitating and interferes with normal activities 4. Stereotypical pattern and symptoms in the individual patient 5. The pain is associated with 2 or more of the following : a) Anorexia ; b) Nausea ; c) Vomiting ; d) Headache ; e) Photophobia ; f) Pallor 6. After appropriate evaluation, the symptoms cannot be fully explained by another medical condition Irritable bowel syndrome Functional abdominal pain-not otherwise specified Must include all of the followingÃ: Must be fulfilled at least 4 times per month and include all of the followingÃ: 1. Abdominal pain at least 4 days per month associated with one or 1. Episodic or continuous abdominal pain that does not occur solely during more of the following: a) Related to defecation ; b) A change in physiologic events (e.g., eating, menses) frequency of stool ; c) A change in form (appearance) of stool 2. Insufficient criteria for irritable bowel syndrome, functional dyspepsia, or 2. In children with abdominal pain and constipation, the pain does not abdominal migraine resolve with resolution of the constipation (children in whom the pain 3. After appropriate evaluation, the abdominal pain cannot be fully explained resolves have functional constipation, not IBS) by another medical condition 3. After appropriate evaluation, the symptoms cannot be fully explained by another medical condition www.jpgn.org S101 Supplement JPGN  Volume 66, Supplement 1, April 2018

TABLE 2. Continued

Functional defecation disorders

Functional constipation Nonretentive faecal incontinence Must include 2 or more of the following occurring at least once per week Must include at least a 1-month history in a child with a developmental age older for a minimum of 1 month with insufficient criteria for a diagnosis of than 4 years of all of the following: IBS: 1. Defecation in places inappropriate to the sociocultural context 1. Two or fewer defecations in the toilet per week in a child of a 2. No evidence of fecal retention developmental age of at least 4 years 3. After appropriate evaluation, the fecal incontinence cannot be explained by 2. At least 1 episode of fecal incontinence per week another medical condition 3. History of retentive posturing or excessive volitional stool retention 4. History of painful or hard bowel movements 5. Presence of a large fecal mass in the rectum 6. History of large diameter stools which can obstruct the toilet After appropriate evaluation, the symptoms cannot be fully explained by another medical condition

ÃCriteria fulfilled for at least 2 months prior to diagnosis. 1Within FD the following subtypes are now adopted: (1) Postprandial distress syndrome (PDS) includes bothersome postprandial fullness or early satiation which prevents finishing a regular meal. Supportive features include upper abdominal bloating, postprandial nausea, or excessive belching. (2) Epigastric pain syndrome (EPS) which includes all of the following: bothersome (severe enough to interfere with normal activities) pain or burning localized to the epigastrium. The pain is not generalized or localized to other abdominal or chest regions and is not relieved by defecation or passage of flatus. Supportive criteria can include (a) burning quality of the pain but without a retrosternal component; (b) commonly induced or relieved by ingestion of a meal but may occur while fasting.

coined ‘‘Paediatric Intestinal Pseudo-obstruction’’ or ‘‘PIPO’’) and abnormalities in colonic motility patterns in children with slow related disorders. transit constipation (40–43). The group of Great Ormond street recently showed that HR colonic manometry even accurately predicts colonic neuromuscular pathological phenotype in paedi- FUNCTIONAL DEFECATION DISORDERS atric slow transit constipation (44). In the past 2 decades, in a joint effort, ESPGHAN and The treatment of children with functional constipation is a NASPGHAN members played an important role in defining func- challenge and in many children long-lasting. In 2014, a combined tional gastrointestinal disorders in children of all age groups, ESPGHAN and NASPGHAN guideline on functional constipation including infant dyschezia, functional diarrhoea, functional consti- extensively described the different treatment options (45). pation and functional nonretentive faecal incontinence (29,30). In 1994, Benninga et al, described a group of children, ESPGHAN Members, such as Peter Milla, Anna Maria Staiano, mainly boys, presenting with faecal incontinence without any other Jan Taminiau and Marc Benninga, played prominent roles in symptom of constipation; functional nonretentive faecal inconti- updating the Rome Criteria (29,30). The updated Rome IV Criteria nence (FNRFI) (46). As in constipation, the underlying mechanism are summarised in Tables 1 and 2. of FNRFI is still largely unknown. Colonic transit studies using Functional diarrhoea (FD) or non-specific chronic diarrhoea radio-opaque markers clearly showed normal transit through all is considered the most frequent cause of chronic diarrhoea without colonic segments (47). Whereas anorectal manometry and rectal failure to thrive in toddlers. Although the pathophysiology of FD is barostat studies also failed to identify abnormalities in children with not well understood, Peter Milla in 1983 had already suggested that FNRFI (36). Current treatment options are disappointing with food may fail to interrupt the migrating motor complex (31). Hans success rates after 2 years of intensive follow up of only 29% Hoekstra and Frank Kneepkens, suggested that in fruit juices, the (48). Loperamide has shown to be an alternative treatment in these increased presence of nonabsorbable sugars is an important etio- children (49). In summary, there has been a considerable historical logical factor in FD (32). Despite the high worldwide prevalence and ongoing contribution to the field of functional defecation and large interest in functional constipation the pathophysiology is disorders in children from ESPGHAN. still not fully understood. Pioneers in functional testing in children with functional constipation, Meunier and Loening-Baucke, REFERENCES showed that hyposensitivity of the rectum is a relevant factor in 1. Cucchiara S, Staiano A, Di Lorenzo C, et al. Esophageal motor the aetiology of chronic constipation (33,34). Benninga and Di abnormalities in children with gastroesophageal reflux and peptic Lorenzo however showed that rather than impaired sensitivity, esophagitis. J Pediatr 1986;108:907–10. increased rectal compliance is of major importance in these 2. Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroeso- children (35,36). Furthermore, abnormal defecation dynamics phageal reflux clinical practice guidelines: joint recommendations of the have been described as a major factor involved in the development North American Society for Pediatric Gastroenterology, Hepatology, and persistence of childhood constipation. It was again Loening- and Nutrition (NASPGHAN) and the European Society for Pediatric Baucke and later Benninga, more than 30 years ago, that showed Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr that more than half of the children with functional constipation, Gastroenterol Nutr 2009;49:498–547. 3. Nurko S, Rosen R, Furuta GT. Esophageal dysmotility in children with indeed contract rather than relax their sphincter complex during a eosinophilic esophagitis: a study using prolonged esophageal mano- defecation attempt (37,38). Inconsistent data have been published metry. Am J Gastroenterol 2009;104:3050–7. about the efficacy of biofeedback/pelvic physiotherapy in these 4. Cucchiara S, Staiano A, Di Lorenzo C, et al. Return of peristalsis in a children (38,39). In recent years several groups, using child with esophageal achalasia treated by Heller’s myotomy. J Pediatr either conventional or HRM colonic manometry, have shown Gastroenterol Nutr 1986;5:150–2.

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5. Bredenoord AJ, Fox M, Kahrilas PJ, et al. Chicago classification 28. Knowles CH, De Giorgio R, Kapur RP, et al. The London Classification criteria of esophageal motility disorders defined in high resolution of gastrointestinal neuromuscular pathology: report on behalf of the esophageal pressure topography. Neurogastroenterol Motil 2012; Gastro 2009 International Working Group. Gut 2010;59:882–7. 14:57–65. 29. Benninga MA, Faure C, Hyman PE, et al. Childhood functional 6. Singendonk MM1, Smits MJ, Heijting IE, et al. Inter- and intrarater gastrointestinal disorders: neonate/toddler. Gastroenterology 2016; reliability of the Chicago Classification in pediatric high-resolution 150:1443–55. esophageal manometry recordings. Neurogastroenterol Motil 2015; 30. Hyams JS, Di Lorenzo C, Saps M, et al. Functional disorders: children 27:269–76. and adolescents. Gastroenterology 2016;150:1456–68. 7. Staiano A, Cucchiara S, Del Giudice E, et al. Disorders of oesophageal 31. Fenton TR, Harries JT, Milla PJ. Disordered small intestinal motility: a motility in children with psychomotor retardation and gastro-oesopha- rational basis for toddlers’ diarrhoea. Gut 1983;24:897–903. geal reflux. Eur J Pediatr 1991;150:638–41. 32. Hoekstra JH, van den Aker JH, Ghoos YF, et al. Fluid intake and 8. Spitz L, Roth K, Kiely EM, et al. Operation for gastro-oesophageal industrial processing in apple juice induced chronic non-specific diar- reflux associated with severe mental retardation. Arch Dis Child rhoea. Arch Dis Child 1995;73:126–30. 1993;68:347–51. 33. Meunier P, Marechal JM, de Beaujeu MJ, et al. Rectoanal pressures and 9. Cucchiara S, Franzese A, Salvia G, et al. Gastric emptying delay and rectal sensitivity studies in chronic childhood constipation. Gastroen- gastric electrical derangement in IDDM. Diabetes Care 1998;21: terology 1979;77:330–6. 438–43. 34. Loening-Baucke VA. Sensitivity of the sigmoid colon and rectum in 10. Devane SP, Ravelli AM, Bisset WM, et al. Gastric antral dysrhythmias children treated for chronic constipation. J Pediatr Gastroenterol Nutr in children with chronic idiopathic intestinal pseudoobstruction. Gut 1984;3:454–9. 1992;33:1477–81. 35. van den Berg MM, Voskuijl WP, Boeckxstaens GE, et al. Rectal 11. Boccia G, Buonavolonta` R, Coccorullo P, et al. ??? Clin Gastroenterol compliance and rectal sensation in constipated adolescents, recovered Hepatol 2008;6:556–60. adolescents and healthy volunteers. Gut 2008;57:599–603. 12. Heath AL, Spitz L, Milla PJ. The absorptive function of colonic 36. Voskuijl WP, Ginkel van R, Benninga MA, et al. New insight into rectal aganglionic intestine: are the Duhamel and Martin procedures rational? function in pediatric defecation disorders: disturbed rectal compliance is J Pediatr Surg 1985;20:34–6. an essential mechanism in pediatric constipation. J Pediatr 2006; 13. Milla PJ. Endothelins, pseudo-obstruction and Hirschsprung’s disease. 148:62–7. Gut 1999;44:148–9. 37. Loening-Baucke VA, Cruikshank BM. Abnormal defecation dynamics 14. Kapur RP, Gershon MD, Milla PJ, et al. The influence of Hox genes and in chronically constipated children with encopresis. J Pediatr 1986; three intercellular signalling pathways on enteric neuromuscular devel- 108:562–6. opment. Neurogastroenterol Motil 2004;16(suppl 1):8–13. 38. van der Plas RN, Benninga MA, Bu¨ller HA, et al. Biofeedback training 15. Auricchio A, Griseri P, Carpentieri ML, et al. Double heterozygosity in treatment of childhood constipation: a randomised controlled study. for a RET substitution interfering with splicing and an EDNRB mis- Lancet 1996;348:776–80. sense mutation in Hirschsprung disease. Am J Hum Genet 1999; 39. van Engelenburg-van Lonkhuyzen ML, Bols EM, Benninga MA, et al. 64:1216–21. Effectiveness of pelvic physiotherapy in children with functional con- 16. Auricchio A. Genetic aspects of neurocristopathies. J Pediatr Gastro- stipation compared with standard medical care. Gastroenterology enterol Nutr 1997;25(suppl 1):S28–9. 2017;152:82–91. 17. Ganousse-Mazeron S, Lacaille F, Colomb-Jung V, et al. Assessment and 40. Di Lorenzo C, Flores AF, Reddy SN, et al. Use of colonic manometry to outcome of children with intestinal failure referred for intestinal trans- differentiate causes of intractable constipation in children. J Pediatr plantation. Clin Nutr 2015;34:428–35. 1992;120:690–5. 18. Burns AJ, Goldstein AM, Newgreen DF, et al. White paper on guide- 41. King SK, Catto-Smith AG, Stanton MP, et al. 24-Hour colonic mano- lines concerning enteric nervous system stem cell therapy for enteric metry in pediatric slow transit constipation shows significant reductions neuropathies. Dev Biol 2016;417:229–51. in antegrade propagation. Am J Gastroenterol 2008;103:2083–91. 19. McCann CJ, Cooper JE, Natarajan D, et al. Transplantation of enteric 42. Giorgio V, Borrelli O, Smith VV, et al. High-resolution colonic mano- nervous system stem cells rescues nitric oxide synthase deficient mouse metry accurately predicts colonic neuromuscular pathological pheno- colon. Nat Commun 2017;8:15937. type in pediatric slow transit constipation. Neurogastroenterol Motil 20. Faure C, Goulet O, Ategbo S, et al. Chronic intestinal pseudoobstruction 2013;25:70–8. syndrome: clinical analysis, outcome, and prognosis in 105 children. 43. Wessel S, Koppen IJ, Wiklendt L, et al. Characterizing colonic motility French-Speaking Group of Pediatric Gastroenterology. Dig Dis Sci in children with chronic intractable constipation: a look beyond high- 1999;44:953–9. amplitude propagating sequences. Neurogastroenterol Motil 2016;28: 21. Goulet O, Talbotec C, Jan D, et al. Nutritional management of pediatric 743–57. patients with chronic intestinal pseudo-obstruction syndrome. J Pediatr 44. Giorgio V, Borrelli O, Smith VV. High-resolution colonic manometry Gastroenterol Nutr 2001;32(suppl 1):S44–7. accurately predicts colonic neuromuscular pathological phenotype in 22. Goulet O, Sauvat F, Jan D. Surgery for pediatric patients with chronic pediatric slow transit constipation. Neurogastroenterol Motil 2013;25: intestinal pseudo-obstruction syndrome. J Pediatr Gastroenterol Nutr 70–8. 2005;41:S66–8. 45. Tabbers MM, DiLorenzo C, Berger MY, et al. Evaluation and treatment 23. Milla PJ, Fenton TR. Small intestinal motility patterns in the perinatal of functional constipation in infants and children: evidence-based period. J Pediatr Gastroenterol Nutr 1983;2(suppl 1):S141–4. recommendations from ESPGHAN and NASPGHAN. J Pediatr Gas- 24. Bisset WM, Watt JB, Rivers RP, et al. Ontogeny of fasting small troenterol Nutr 2014;58:258–74. intestinal motor activity in the human infant. Gut 1988;29:483–8. 46. Benninga MA, Bu¨ller HA, Heymans HS, et al. Is encopresis always the 25. Cucchiara S, Minella R, Scoppa A, et al. Antroduodenal motor effects of result of constipation? Arch Dis Child 1994;71:186–93. intravenous erythromycin in children with abnormalities of gastroin- 47. Benninga MA, Voskuijl WP, Akkerhuis GW, et al. Colonic transit times testinal motility. J Pediatr Gastroenterol Nutr 1997;24:411–8. and behavior profiles in children with defecation disorders. Arch Dis 26. Smith VV, Scha¨ppi MG, Bisset WM, et al. Lymphocytic leiomyositis Child 2004;89:13–6. and myenteric ganglionitis are intrinsic features ofcystic fibrosis: studies 48. Voskuijl WP, Reitsma JB, van Ginkel R, et al. Longitudinal follow-up in distal intestinal obstruction syndrome and meconium ileus. J Pediatr of children with functional nonretentive fecal incontinence. Clin Gas- Gastroenterol Nutr 2009;49:42–51. troenterol Hepatol 2006;4:67–72. 27. Smith VV, Milla PJ. Histological phenotypes of enteric smooth muscle 49. Voskuijl WP, van Ginkel R, Taminiau JA, et al. Loperamide supposi- disease causing functional intestinal obstruction in childhood. Histo- tories in an adolescent with childhood-onset functional non-retentive pathology 1997;31:112–22. fecal soiling. J Pediatr Gastroenterol Nutr 2003;37:198–200.

www.jpgn.org S103 SUPPLEMENT

Chapter 5.3.3. The Story of Gastro-oesophageal Reflux That Became a Disease

Gigi Veereman, Yvan Vandenplas, and Peter Milla

nfants have been spiting up since Adam and Eve, but it took the integrate with the sympathetic and parasympathetic outflow of critical look of Yvan Vandenplas and colleagues in distant the gut. For effective contraction to take place intermediaries are countriesI to describe, register and analyse all burps and spits some required between enteric neurotransmission and the smooth muscle 30 years ago (1–4). Curiosity and technical developments enabled cells. Interstitial cells of Cajal serve as these intermediaries and may researchers to register esophageal acidity and intestinal motility and also facilitate the propagation of electrical events along and around helped to establish a large body of knowledge on the development the gastrointestinal tract, and in doing so act as slow-wave pace- of gastrointestinal motility and gastro-oesophageal reflux. The maker generators for the muscle coats of the bowel. Smooth muscle focus has been on discriminating between physiological and path- cells, however, are inherently excitable and this is due to the ological states, pathophysiology, associated conditions and under- property of rhythmic variation of transmembrane potentials which lying conditions such as inflammation. The purpose of this paper is occurs even during complete motor quiescence. The cycle of to walk through the major developments in intestinal motility and depolarisation and repolarisation is the result of rhythmic changes gastro-oesophageal reflux (disease) GOR(D), with a focus on work in the activity of membrane ion pumps. The movement of potas- published by ESPGHAN members, but not to provide a compre- sium, particularly, across the plasma membrane of the smooth hensive scientific overview. Therefore we apologize for any omis- muscle cell results in depolarisation of the cell membrane and sions of important work by other colleagues and for lack of the voltage change opens voltage sensitive calcium channels in the scientific rigour. sarcoplasmic reticulum which then allows calcium to gain access to First of all ... the basics—A FEELING FOR GUT the contractile proteins of the smooth muscle cell which results RHYTHM in contraction. A hundred years ago the rhythm of the gut seemed straight- The enteric nervous system co-ordinates activity of this forward. It was a simple tube which moved the intraluminal primary motor-effector to produce meaningful patterns of contrac- contents by a peristaltic movement induced by distension. Studies tion throughout the whole organ. The enteric nervous system is a over the last century have shown that it is much more complex than local mini-brain within which is stored a library of programmes for this and that the bowel contents are moved from 1 specialised region different patterns of gut contraction and each programme can be of the gut to another by the co-ordinated contraction of the smooth called up from the programme library either by commands from the muscle coats. The pattern of motility is related to and integrated brain or by local sensory detection of events in the lumen of the with the function of particular regions of the gastrointestinal tract. bowel. The structure and function and neurochemistry of the enteric Thus, the oesophagus is a propulsive conduit for the ingestion of neurons are very similar to those of the central nervous system and food, the stomach initiates digestion, transit through the small the neurons contained in ganglia are interconnected to function in a intestine is related to the digestion and absorption of nutrients similar fashion with mechanisms for integration and processing and the colon an organ of conservation of water, electrolytes of information. and calories. This is the rhythm of the gut in early 20th century The motor neuron pool of the enteric nervous system terms. consists of excitatory and inhibitory neurons. Excitatory motor Development of an understanding of basic smooth muscle neurons release neurotransmitters (acetyl choline and substance physiology, of enteric neurons forming an enteric nervous system P) that evoke muscle contraction and mucosal secretion. Inhibitory with higher levels of control, has revealed the beauty and sophisti- motor neurons release neurotransmitters that suppress contractile cation of the rhythm of the gut as it really is. The musculature of the activity of the musculature. Important examples are vasoactive gut is the motor-effector system which is controlled by the enteric intestinal peptide and nitric oxide. The inhibitory motor neurons nervous system and the central nervous system. Control of the are of particular significance in the relationship of the excitable musculature involves an integrated hierarchy of neural centres and nature of smooth muscle cells to the interstitial cells of Cajal. pacemaker cells the interstitial cells of Cajal. Starting at the level of The activity state of these neurons determines when the the gut there is the enteric nervous system which has local neural omnipresent slow-waves will initiate contraction as well as the circuits for the integration of contraction. These local neural circuits distance and direction of propagation once the contraction has can be modulated by higher levels of integration. The second level begun. The circular muscle can only respond to the electrical of integration occurs in the prevertebral sympathetic ganglia where slow-wave when the inhibitory motor neurons in that segment of peripheral reflex pathways are influenced by preganglionic sympa- the intestine are switched off. Thus, loss of the intrinsic inhibitory thetic fibres from the spinal cord. In the central nervous system, neurons will result in tonic contraction of that segment of intestinal there is sympathetic and parasympathetic outflow to the gut deter- circular muscle. mined by reflexes with sensory fibres that travel with the autonomic Whilst the signals to the enteric nervous system may come nerves. Higher brain centres supply descending signals which from the lumen of the bowel its activity may also be altered by humoral secretion of polypeptide hormones from enteroendocrine Received January 27, 2018; accepted January 29, 2018. cells and by the activity of the mucosal associated lymphoid tissue. Copyright # 2018 by European Society for Pediatric Gastroenterology, There is now a large body of evidence, which shows that the motor Hepatology, and Nutrition and North American Society for Pediatric and secretory responses in the gut to specific antigens are as a Gastroenterology, Hepatology, and Nutrition consequence of direct communication between the immune system DOI: 10.1097/MPG.0000000000001915 and the enteric nervous system. This communication results in

S104 JPGN  Volume 66, Supplement 1, April 2018 JPGN  Volume 66, Supplement 1, April 2018 Supplement adaptive behaviour of the bowel in response to stimuli within the 1980s (Fig. 2A–D). Therefore, ESPGHAN-consensus papers were lumen. In addition to this local neuroimmune interaction there is published proposing some standardization to avoid too much dis- also evidence that mast cells are involved in the defence mechanism crepancy in published results because of differences in methodology. apart from local antigen sensing and signalling to the enteric During the same years, the combat against sudden infant death nervous system. Ultrastructural and light microscopic studies syndrome (SIDS) became a priority and Belgium had chosen to suggest that enteric mast cells are always in association with nerves invest in risk-screening with polysomnography. The (still unan- in the mucosa of the bowel and that these nerves may be both swered) question whether reflux may cause apnoea or respiratory projections from the central nervous system and intrinsic irregularities dates from that period. Because of the wide screening primary afferent neurons. The brain to mast cell connection is a program for SIDS-risk, pH-metry was performed in healthy infants as mechanism that can link psychoemotional events to the enteric part of the polysomnography. But the dilemma was: what is a normal neuromusculature. infant? Is it an infant that does not regurgitate (probably too selective), Our understanding the basic physiology of smooth muscle, or is it an infant that is not treated for reflux-disease (probably enteric neurons and their higher levels of control, and the including infants that should be treated). No-one ever evaluated if enteric nervous system, has been required to understand the whole pH 4.0 was an appropriate cut-off in infants and children. It was and increasing scope of neurogastroenterology. Disturbance of simply taken over from the adults, in whom it was shown that pH 4.0 these elements is almost certainly responsible for the gastrointesti- was the best cut-off in patients with noncardiac thoracic pain caused nal symptoms seen in a wide variety of disease states which by acid reflux. affect both the central nervous system, the immune system Cisapride was launched in the same period. Because pH- and the gut itself. A long and tortuous journey from a simple metry was gaining popularity during the same period, many tube responding to distension to a complex sophisticated system clinical trials were started, suggesting that pH-metry was needed with greater computing power to control it than many modern to diagnose reflux, and that cisapride was needed in every regurgi- computers. tating infant. But then cisapride disappeared because of safety And then facing the spitting ...GASTRO OESOPHAGEAL issues. Next, impedance was developed, to measure nonacid reflux REFLUX DISEASE UNMASKED as well acid reflux. However, measuring nonacid reflux lacks When the beautiful downstream motion of food is inversed, it clinical impact since there is no medical treatment for nonacid is called ‘reflux’. Reflux of gastric contents into the oesophagus of reflux. neonates and spitting up of ingested food has long been naively A group of ESPGHAN members interested by the indica- accepted as normal ...but no longer so when it was understood that tions, methodology and interpretation of pH-metry published mul- acid regurgitation may cause pain and esophageal inflammation tiple consensus papers. Other papers focused on treatment. These (Fig. 1). publications can be considered position papers or guidelines avant Measuring the acid ...pH-METRY...AND IMPEDANCE la lettre. In 2005 (6), the NASPGHAN published recommendations In the early 1980s the first pH-metry devices were commer- for the diagnosis and management of reflux. In 2009, a combined cialised. The first device registered during 17 hours 1 pH per minute ESPGHAN and NASPGHAN guideline on GER was published, in memory, exactly storing 1020 items of data in memory and printing which has been cited by 92 Pubmed articles (7). An updated version them on a curve. That was it. But it was revolutionary at that time. For has been published in 2018 (8). the first time it became possible to detect reflux outside a postprandial Fighting the acid...not the cause—PATHOPHYSIOLOGY period. Technical possibilities changed continuously during the AND TREATMENT

FIGURE 1. pH probes glass and antimony. www.jpgn.org S105 Supplement JPGN  Volume 66, Supplement 1, April 2018

FIGURE 2. A–D, Sweet memories of acid recorders.

The desire to unveil the pathophysiology of GORD went left side or prone to diminish GOR but the battle was won by the viral and it is ‘‘down under’’ that the inappropriate LES relaxations SIDS risk group establishing that supine is the safest position. The were revealed and incriminated. Now we are back to the basics: GORD rescue team then proposed supine but elevated (Fig. 3), motility. Although this knowledge could have led to pharmacolog- which as a side effect may have prevented any occurrence of vertigo ical intervention, there is still no satisfactory etiological treatment to later in life (no studies available). Paediatricians are still awaiting help physicians tackle the frequent manifestations of GORD. We the safe compound that will move things in the right direction. are left with treating the consequences of GORD with proton pump inhibitors after installing conservative measures such as thickening Acknowledgments: Mrs Kris Vandemaele was dedicated in the feeds and positional treatment. As a consequence, the market developing the motility lab at UZBrussels and protected the proposes a broad selection of thickened formulas and paediatricians collection of pH monitoring devices and probes over the years. are never left without another option. Babies were positioned on the We are indebted to her for the pictures that bring up memories from industrious years.

REFERENCES 1. Vandenplas Y, Belli D, Boige N, et al. A standardized protocol for the methodology of esophageal pH monitoring and interpretation of the data for the diagnosis of gastroesophageal reflux. (ESPGAN society state- ment). J Pediatr Gastroenterol Nutr 1992;14:467–71. 2. Vandenplas Y,Ashkenazi A, Belli D, et al. A proposition for the diagnosis and treatment of gastro-oesophageal reflux disease in children: a report from a working group on gastro-oesophageal reflux disease. Eur J Pediatr 1993;152:704–11. 3. Vandenplas Y, Ashkenazi A, Belli D, et al. Reflux oesophagitis in infants and children. J Pediatr Gastroenterol Nutr 1994;18:413–22. 4. Vandenplas Y, Belli D, Benhamou PH, et al. Current concepts and issues in the management of regurgitation of infants: a reappraisal. Acta Paediatr 1996;85:531–4. 5. Rudolph CD, Mazur LJ, Liptak GS, et al. Guidelines for evaluation and treatment of gastroesophageal reflux in infants and children: recommendations of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr 2001; 32(suppl 2):S1–31. 6. Omari T. Gastro-oesophageal reflux disease in infants and children: new insights, developments and old chestnuts. J Pediatr Gastroenterol Nutr FIGURE 3. Anti-GORD position. 2005;41(suppl 1):S21–3.

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7. Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroeso- 8. Rosen R, Vandenplas Y, Singendonk M, et al. Pediatric Gastroesophageal phageal reflux clinical practice guidelines: joint recommendations of the Reflux Clinical Practice Guidelines: Joint Recommendations of the North North American Society for Pediatric Gastroenterology, Hepatology, and American Society for Pediatric Gastroenterology, Hepatology, and Nu- Nutrition (NASPGHAN) and the European Society for Pediatric Gastro- trition (NASPGHAN) and the European Society for Pediatric Gastro- enterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastro- enterology, Hepatology, and Nutrition (ESPGHAN) J Pediatr Gastrol enterol Nutr 2009;49:498–547. Nutr 2018. Epub ahead of print.

www.jpgn.org S107 SUPPLEMENT

Chapter 5.4.1. Acute Diarrhoea

Alfredo Guarino, Hania Szajewska, Jehan-Franc¸ois Desjeux, and Yvan Vandenplas

cute gastroenteritis has always been a topic of major interest BOX within ESPGHAN and parallels the development of the ASociety. In the 1960s acute gastroenteritis was a major cause of From Biophysics to Public Health; the Discovery infantile death throughout the world, including Europe, much more of Oral Rehydration Therapy than what is now. However, the reader may be surprised to learn that (by Jehan-Francois Desjeux) even now in Europe not less than 500 children die every year Oral Rehydration Therapy (ORT) is a major medical because of acute gastroenteritis (1). achievement of the second part of the last century. It is not the discovery of 1 person; rather it involved many people from a wide THE EARLY YEARS: BASIC RESEARCH diversity of expertise. Here, I will try to simply present how that discovery was closely linked with my professional life, as paedia- When ESPGHAN was founded most agents of gastroenteritis trician gastroenterologist. In 1967, during my military duties, I was were unknown. Rotavirus was first to be described in 1973, by Ruth sent to Tunis, as resident in Paediatrics. My main activity was to Bishop, and most other viruses were discovered afterwards (2). In take care of children with severe dehydration and malnutrition. the early years of ESPGHAN several members were actively Unfortunately, many children died whatever my frantic activity. I involved in basic research, which was then regarded as the top- rushed to the medical library, but could not find good answers level science compared to clinical research (many people are still dealing with the care of those children. At that time diarrhoea was convinced of that). Three groups were highly active and provided treated with antibiotics, severe malnutrition with high protein diet substantial novel information on the mechanisms of diarrhoea. Alan and dehydration with complex IV therapy. This is how I decided to Phillips was working as a PhD student with John Walker-Smith and try to solve that issue. It rapidly became obvious to me that I needed then with Peter Milla (later on, they became JPGN Editor 1995 to to understand the mechanism of diarrhoea (7). In 1970, I joined the 2000 and the President of ESPGHAN, respectively 2001 to 2004) department of Biophysics at Yale University. Based on irreversible and he was an outstanding expert of enterocyte morphology, using thermodynamic concepts, the mechanism of water movement electron microscopy and immunofluorescence. Alan Phillips across the epithelium was linked to sodium and an experimental (before becoming ESPGHAN Treasurer) published several papers model of diarrhoea (cholera) was validated on rabbit. Thus, I including some with—at that time—spectacular images of the learned that cholera toxin caused water and electrolyte secretion enterocyte-enteropathogenic Escherichia coli interaction (3). and glucose could stimulate water and electrolyte absorption. When The other major research group was guided by Stefano I came back as resident in paediatrics in Paris, I was called by the Guandalini (Fig. 1), who later became the president of ESPGHAN World Health Organization (WHO) to be a Scientific Adviser for (1998–2001). Guandalini, who had been trained in Italy and then in the just starting Control of Diarrhoeal Disease Programme. This is the United States by Michael Field, was an expert of in vitro studies where I met with Dilip Mahalanabis, just hired as Secretary of the in intestinal ion transport. In turn, he trained several young scien- group of 7 people. He is the paediatrician who discovered in 1973 tists, including Alfredo Guarino (JPGN Editor-in-Chief, 2005 to the beneficial effect of oral rehydration solution in severely dehy- 2009), Alessio Fasano (currently Chair of Pediatrics at Harvard drated children escaping the war of Bangladesh (8). He told me: Medical School), and Carlo Di Lorenzo (NASPGHAN President, ‘‘Within two or three weeks, we realized that it was working and 2014 to 2016), before going back to USA where is presently leading that it seemed to be all right in the hands of untrained people...We the Celiac Center in Chicago. Another outstanding ESPGHAN were just happy that it worked there and that we could help these investigator was Jean-Francois Desjeux, who was actively involved people.’’ The aim of the programme was to implement ORT in in top-level research on diarrhoeal mechanisms and rehydration children at the global scale. At that time, in the late seventies, more (see BOX). than 5 million children were dying of diarrhoea every year, many The Ussing chamber system allowed the discovery of bacte- with severe malnutrition. Although the scientific basis was solid and rial and viral toxins as well as antidiarrheal drugs active on the first clinical trials encouraging, there were many questions to be intestinal transport (4–6) (Fig. 2A and B). It was an in vitro model solved before implementing a global programme. I was now on 2 to investigate the transepithelial fluxes of charged electrolytes seats: a scientific one to further understand the mechanisms of (chloride, sodium, potassium, and bicarbonate). The Ussing cham- diarrhoea using a biophysical approach, essentially based on con- ber model was based on Ohms law, and allowed to monitor the cepts developed by Hans Ussing in 1951 (9). We started by showing passage of each electrolyte across the intestinal epithelial layer. that the child intestine reacted to infectious agents and glucose like This system played a crucial role in the understanding of glucose- the rabbit’s. The other seat was clinical. We needed firm results of sodium co-transport as well as the development of Oral Rehydration standardized clinical trials in different regions of the globe to make Solution (ORS). effective recommendations. We thus trained clinicians all over the world and wrote WHO recommendations (10). ORT is now used Received January 27, 2018; accepted January 29, 2018. globally. The global mortality is probably less than 1 million per Copyright # 2018 by European Society for Pediatric Gastroenterology, year. In addition, in Dhaka, Bangladesh, we could recently show Hepatology, and Nutrition and North American Society for Pediatric that with a combination of IV and oral rehydration, no children Gastroenterology, Hepatology, and Nutrition with severe dehydration and malnutrition died (11). Nowadays, to DOI: 10.1097/MPG.0000000000001915 further improve and sustain ORT expertise also needs to involve

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FIGURE 2. A and B. Modern multiple Ussing chambers (Physiologic Instruments, Inc. San Diego, CA). Photo kindly provided by Dr. V. Buccigrossi.

Some papers focused on smectite (14) and racecadotril (15) and FIGURE 1. A young Dr Stefano Guandalini working with the Ussing other drugs, but most focused on probiotics (16–18) (Table 1). Chamber system. Many of those papers were published in JPGN and provided the main source for meta-analyses and guidelines that brought ESP- GHAN to the EBM era. , , and its marketing together with paediatric gastroenterology. From Clinical Studies to Guidelines and Implementation Science

Translation of Basic Science to Children: The The first ‘‘modern’’ ESPGHAN guidelines on acute gastro- Era of Clinical Trials enteritis were developed by a combined working group of ESP- GHAN and the European Society of Pediatric Infectious Diseases The composition of ORS was an issue since it had been (ESPID) that discussed trials and meta-analyses in meetings hold in developed for adults with cholera. A group of investigators worked various European airports (at that time this was a stress-free and to adapt the solute content to the conditions and etiologic agents of feasible option). The drafts were circulated and discussed by emails children of Europe (12). A low sodium low osmolality solution was with a progressive tailoring of the text until the final paper was developed and a subsequent paper reported a reduced need of obtained. This helped to minimize the costs. For the guidelines on intravenous rehydration, lower stool volume and less vomiting in management of gastroenteritis, thousands of papers were screened children (largely in developing countries) compared to those receiv- ing standard WHO ORS (13). Administration of ESPGHAN ORS was implemented with spectacular results. Subsequently it became clear that active intervention could reduce symptoms duration and TABLE 1. Active interventions – in adjunct to oral rehydration- for intensity when used in adjunct to oral rehydration (which remains reducing duration and intensity of acute gastroenteritis according to the key step in the management of diarrhoea). ESPGHAN guidelines Starting in the early 1990s, several groups within ESPGHAN started to conduct clinical trials in the attempt to investigate the Strains Study Evidence Recommendations effects of various therapies to reduce the duration and severity of Lactobacillus GG 15 RCTs Strong In adjunct to ORS acute gastroenteritis. Erika Isolauri, Alfredo Guarino, Hania Sza- S.boulardii 13 RCTs Strong In adjunct to ORS jewska, Yvan Vandenplas, and others, produced data that brought to L.reuteri 2 RCTs Weak In adjunct to ORS the concept that in acute gastroenteritis the best option was ‘‘to do Smectite 11 RCTs Weak In adjunct to ORS little, but do well.’’ The main role of basic research was progres- Racecadotril 9 RCTs Weak In adjunct to ORS sively replaced by well-conducted clinical research including trials. www.jpgn.org S109 Supplement JPGN  Volume 66, Supplement 1, April 2018

FIGURE 3. A ‘‘family picture’’ taken at the 2012 World Congress in Taiwan. by title, many abstracts were carefully read and the entire text with needed to manage a case’’ by each physician (measured before and results of hundreds of data were carefully reviewed in order to after the course). Being gastroenteritis such a common problem, this develop evidence based recommendations. To support the accuracy approach is likely to provide a substantial improvement in the and rigor of the recommendations, the guidelines included the management of diarrhoea (20). tables of evidence that showed the real data on which the guidelines A further initiative consisted in the development of an app for had been constructed. In this manner, the reader and interested mobile phones on the management of acute gastroenteritis (21). parties may check the data included in the analysis, evaluate This was part of a larger project for the management of common eventual missing paper or reasons for exclusion. The guidelines gastrointestinal problems in children. The app is possibly suitable underwent a severe peer-review process and approval by ESP- for improving the management of gastroenteritis also developing GHAN council before publication. They were published in open countries. This leads us back to the role of ESPGHAN in the access in 2008 (19). management of gastroenteritis outside Europe, closely linked The guidelines on management of acute gastroenteritis were to FISPGHAN. the first guidelines to be freely accessible in JPGN. This contributed to the spreading of such documents toward the medical and scientific community. The application of the guidelines was moni- A Global View From ESPGHAN to FISPGHAN tored and was fairly accurate and widespread. The guidelines on management of gastroenteritis of children of Europe were published ESPGHAN has always played a major role in the manage- in a revised update edition (1), which largely confirmed the previ- ment of acute diarrhoea at the global level with an impact on ous recommendations. Afterwards many other similar documents policies and practices well outside the continental borders. A major were produced by several institutions and agencies with very breakthrough was achieved with the series of the World Con- similar recommendations. gresses of Pediatric Gastroenterology, Hepatology and Nutrition. The subsequent step brought research from a clinical This was a major development from the joint meeting between approach to implementation science. The TEEN-AGE (Tutorial ESPGHAN and NASPGHAN in 1986 in New York. Subsequently, Electronic European Network on Acute Gastroenteritis), an ESP- a giant enterprise was undertaken in order to promote common GHAN project led by Alfredo Guarino, was awarded a grant upon initiatives by the 4 continental societies in Europe (ESPGHAN), competitive application by the United European Gastroenterology North America (NASPGHAN), Latin America (LASPGHAN) and Federation (UEG). The project was based on the concept of the Asian Pan Pacific (APPSPGHAN) to merge in the Federation of spreading ESPGHAN guidelines through e-learning and evaluate the Continental Society of Pediatric Gastroenterology Hepatology their effect. This specific strategy was explored in a population of and Nutrition (FISPGHAN). The Commonwealth Association physicians from 11 European Countries, who completed an e- (CAPGAN) joined FISPGHAN as an affiliate Society and more learning specific course encompassing 6 modules available on recently the Pan Arab Society of Pediatric Gastroenterology ESPGHAN website. The course resulted in increased application Hepatology and Nutrition (PASPGHAN) also joined FISPGHAN of recommendations, and also in a reduction of the ‘‘average time (Fig. 3).

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TABLE 2. The series of World Congresses of Pediatric Gastro- oral rehydration within the proposed ‘‘medical interventions’’ enterology and the Presidents of FISPGHAN and education of physicians, social workers and using social media (23). Location Presidents The Working Groups that worked from 2012 to 2016, actively carried on a collaborative activity which resulted in 2000 – Boston Massachusetts, Stefano Guandalini (2000–2004) practical achievements as follows: Starting from a joint ESPID/ USA – Chair, Harland Winter ESPGHAN medical position papers recommending the worldwide 2004 – Paris, France – Chair, Geoff Cleghorn (2004–2008) implementation of Rotavirus immunization (24) a survey was Olivier Goulet published on Rotavirus immunization, which includes the barriers 2008 – Iguassu Falls, Brazil – Mei-Hwei Chang (2008–2012) that at local level hamper the effective spreading of immunization Chair, Ulysses Fagundes-Neto (25). A collaborative paper was published comparing the guidelines 2012 – Taipei, Taiwan – Chair, Kathy Schwarz (2012–2016) for management of gastroenteritis in the world, showing that the Yen-Hsuan Ni indications are largely similar (26). As a result, the group is carrying 2016- Montreal, Canada – Chair Bert Koletzko (2016–2020) on an initiative to produce the ‘‘Universal guidelines’’ for the Kathy Schwarz management of gastroenteritis (26). Finally a group of ESPGHAN Trainees won a competitive application for producing a video to promote good management of gastroenteritis directed to physicians, social women and mothers of at risk areas as an educational tool FISPGHAN mission was to promote a global strategy of (Fig. 4). cooperation for health care, research and education among paediatric FISPGHAN goals should be considered in a timeframe of a gastroenterologists mainly through the World Congress of Pediatric quarter of a century and they have been at least partially achieved. Gastroenterology, Hepatology and Nutrition (WCPGHAN). This is Not all the working groups that operated in the various editions held every 4 years and is now in its second round 20 years after the developed an active collaboration and, in some cases, their report first edition (Table 2). were limited to a well written document consisting in a more or less Because FISPGHAN has a worldwide perspective, a major comprehensive state of the art review. However, in many cases, an interest is directed toward geopolitical areas in need of help and active cooperation developed that brought to important collabora- implementation, that is, the so-called developing countries. tions, examples of which are the translation of the ESPGHAN An organizing model to achieve FISPGHAN mission are the guidelines on gastroenteritis in China and in Russia. The World so-called FISPGHAN Working Groups that have a double purpose. Congress is not only a large paediatric gastroenterology, haepatol- First, to provide indications of what needs to be done to promote ogy, and nutrition scientific meeting, it also provides an opportunity research, medical interventions and educational activities in order for sharing ideas between physicians and scientists of rich and less to improve the health of the digestive system of children of the rich countries. world. The other aim is to promote cooperation among scientists Overall, ESPGHAN has deeply affected the fight against and physicians from all over the word. Accordingly, most of the acute gastroenteritis in several ways and had a major role in the reports of the working groups have focused on devastating diseases successful development of effective strategies to prevent and in developing countries (22). The list of working group progres- counteract this disease at the world level. Several members of sively moved from 18 in 2000 and 2004 to only 4 and 3 in 2012 and the society in those 50 years of history provided major contributes 2016, respectively, including hepatitis B, malnutrition and and many are still actively working facing the new challenges such acute gastroenteritis. as Clostridium difficile and other conditions such as trying to find The priorities in research, medical interventions and educa- effective strategies to counteract diarrhoea where it is most dan- tion indicated in Working group report in 2012 are reported below gerous. Today, the focus is directed at malnourished children in as an example of FISPGHAN vision (Table 3) and include the Africa. ‘‘ESPGHAN goes Africa’’ is a recent initiative that aims at implementation of Rotavirus immunization the spreading of bringing solid support to counteract gastroenteritis as well as

TABLE 3. The priorities indicated in the acute diarrhea Working group report in 2012

Priotities Medical Interventions Education Research

1 Rotavirus immunization Hygiene procedures focused on 3 issues: Understand the pertubations of the intestinal (target coverage >80%) with soap/access to safe water/toilet microbiome and the metabolome during episodes construction of acute gastroenteritis Family education and promotion of ORS provided during well-being visits Implementation of breast feeding 2 Promote early use of Dissemination and implementation of guidelines for Investigate environmental and host factors, such as optimal composition management of acute gastroenteritis. Education of immune function, that may affect outcomes in ORS women improves child health children with acute gastroenteritis 3 Reduce inappropiate e-Learning programs for a worldwide education on Apply systems biology methodology integrating host, medical interventions acute gastroenteritis with an emphasis on education microbial, immunologic, genetic, and epigenetic of girls and women factors to identify novel metabolic pathways, which will lead to the discovery of new therapeutic interventions and more effective ORS www.jpgn.org S111 Supplement JPGN  Volume 66, Supplement 1, April 2018

FIGURE 4. The opening slide of the video clip on acute gastroenteritis produced by ESPGHAN trainees (Ilse Broekaert, Nathalie Rock, Andrea Lo Vecchio, Corina Pienar, Adriana Lozinsky, Alfredo Guarino) in 2017. building effective cooperation between people living in the various 13. Hahn S, Kim Y, Garner P. Reduced osmolarity oral rehydration solution parts of the world. for treating dehydration due to diarrhea in children: systematic review. BMJ 2001;323:81–5. REFERENCES 14. Guarino A, Bisceglia M, Castellucci G, et al. Smectite in the treatment 1. Guarino A, Ashkenazi S, Gendrel D, et al. European Society for of acute diarrhea: a nationwide randomized controlled study of the Pediatric Infectious Diseases. European Society for Pediatric Gastro- Italian Society of Pediatric Gastroenterology and Hepatology (SIGEP). enterology, Hepatology, and Nutrition/European Society for Pediatric J Pediatr Gastroenterol Nutr 2001;32:71–5. Infectious Diseases evidence-based guidelines for the management of 15. Guarino A, Buccigrossi V, Armellino C. Colon in acute intestinal acute gastroenteritis in children in Europe: update 2014. J Pediatr infection. J Pediatr Gastroenterol Nutr 2009;48(Suppl 2):S58–62. Gastroenterol Nutr 2014;59:132–52. 16. Guarino A, Canani RB, Spagnuolo MI, et al. Oral bacterial therapy 2. Bishop RF, Davidson GP, Holmes IH, et al. Virus particles in epithelial reduces the duration of symptoms and of viral excretion in children with cells of duodenal mucosa from children with acute non-bacterial mild diarrhea. J Pediatr Gastroenterol Nutr 1997;25:516–9. gastroenteritis. Lancet 1973;2:1281–3. 17. Szajewska H, Mrukowicz JZ. Probiotics in the treatment and prevention 3. Phillips AD. Enteropathogenetic Escherichia coli: from inpatient to of acute infectious diarrhea in infants and children: a systematic review intimin. J Pediatr Gastroenterol Nutr 2002;34(Suppl 1):S57–61. of published randomized, double-blind, placebo-controlled trials. J 4. Fasano A. Cellular microbiology: how enteric pathogens socialize with Pediatr Gastroenterol Nutr 2001;33(Suppl 2):S17–25. their intestinal host. J Pediatr Gastroenterol Nutr 1998;26:520–32. 18. Loeb H, Vandenplas Y, Wu¨rsch P, et al. Tannin-rich carob pod for the 5. Guandalini S, Fasano A, Rao MC, et al. Effects of loperamide on treatment of acute-onset diarrhea. J Pediatr Gastroenterol Nutr intestinal ion transport. J Pediatr Gastroenterol Nutr 1984;3:593–601. 1989;8:480–5. 6. Guarino A, Berni Canani R, Pozio E, et al. Enterotoxic effect of stool 19. Guarino A, Albano F, Ashkenazi S, et al. Evidence-Based Guidelines for supernatant of Cryptosporidium infected calves on human jejunum. the Management of Acute Gastroenteritis in Children in Europe Expert Gastroenterology 1994;106:28–34. Working Group. J Pediatr Gastroenterol Nutr 2008;46:619–21. 7. Desjeux JF, Sandler L, Sassier P, et al. Acquired and congenital 20. Nicastro E, Lo Vecchio A, Liguoro I, et al. The Impact of E-Learning on disorders of intestinal transport of D. glucose in children. Rev Eur Etud Adherence to Guidelines for Acute Gastroenteritis: A Single-Arm Clin Biol 1971;16:364–6. Intervention Study. PLoS One 2015;10:e0132213. 8. Mahalanabis D, Choudhuri AB, Bagchi NG, et al. Oral fluid therapy of 21. Lo Vecchio A, Vandenplas Y, Benninga M, et al. An international cholera among Bangladesh refugees. Johns Hopkins Med J consensus report on a new algorithm for the management of infant 1973;132:197–205. diarrhoea. Acta Paediatr 2016;105:e384–9. 9. Ussing HH, Zerahn K. Active transport of sodium as the source of 22. Guarino A, Sibal A. Introduction to the FISPGHAN Working Group electric current in the short-circuited isolated frog skin. Acta Physiol reports. J Pediatr Gastroenterol Nutr 2012;55:619–21. Scand 1951;23:110–27. 23. Guarino A, Winter H, Sandhu B, et al. Acute gastroenteritis disease: 10. World Health Organization. The management of acute diarrhea in Report of the FISPGHAN Working Group. J Pediatr Gastroenterol Nutr children: a manual for physicians and other senior health workers. 1981. 2012;55:621–6. 11. Alam NH, Islam S, Sattar S, et al. Safety of rapid intravenous rehydra- 24. Vesikari T. Evidence-based recommendations for rotavirus vaccination tion and comparative efficacy of 3 oral rehydration solutions in the in Europe. Pediatr Gastroenterol Nutr 2008;46(Suppl 2):v–vi. treatment of severely malnourished children with dehydrating cholera. J 25. Lo Vecchio A, Liguoro I, Dias JA, et al. Rotavirus immunization: Global Pediatr Gastroenterol Nutr 2009;48:318–27. coverage and local barriers for implementation. Vaccine 2017;35:1637–44. 12. Booth I, Cunha Ferreira R, Desjeux J-F. Recommendations for compo- 26. Lo Vecchio A, Dias JA, Berkley JA, et al. Comparison of Recommen- sition of oral rehydration solutions for the children of Europe. J Pediatr dations in Clinical Practice Guidelines for Acute Gastroenteritis in Gastroenterol Nutr 1972;14:113–5. Children. J Pediatr Gastroenterol Nutr 2016;63:226–35.

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Chapter 5.4.2. ESPGHAN Made the Gastrointestinal Microbiota Grow

Yvan Vandenplas, Hania Szajewska, and Alfredo Guarino

apid progress in the field of probiotics and prebiotics is linked supplementation of a term infant’s formula with a mixture of to the interest in the microbiota (1). Humans have 10 times galacto- and fructooligosaccharides had a dose-dependent stimu- Rmore microbial cells than human cells, with the highest concentra- lating effect on the growth of Bifidobacteria and Lactobacilli in the tion of microorganisms located within the gut, specifically in the intestine (12). colon. Many of these microbes maintain health, while others are potential pathogens and can cause illness. Consequently, microbiota THE JOURNAL OF PEDIATRIC and its modifications have become the focus of active research of many scientists, including members of ESPGHAN. GASTROENTEROLOGY AND NUTRITION (JPGN) JPGN published its first ‘‘probiotic’’ papers in the mid-to- SHORT HISTORY late 1990s (13,14). A 1997 JPGN paper documented the results of a An interest in probiotics started in the 1950s, with papers randomized controlled trial in which the administration of lyophi- published on their use in combination with antibiotics in the lized Lactobacillus GG reduced the duration of diarrhea and the rate treatment of whooping cough and tuberculosis. In 1965, the first of rotavirus-positive stools in a population of 100 children with paper to claim that probiotics have an effect on the growth of other acute gastroenteritis (14). Since then, an increasing number of microorganisms was published in Science (2). In 1984 Wadstro¨m papers have presented evidence in favour of using microbes to showed for the first time that probiotics can prevent acute gastro- fight microbes. enteritis (3). Still, in the 1980s, the probiotic literature focused mostly on the indications and applications of probiotics in veteri- nary medicine. In 1990, Reid et al. returned the focus of attention to FIRST PROBIOTIC TRIAL UNDER THE the use of probiotics in humans while in 1992, Hekmat and UMBRELLA OF ESPGHAN McMahon published on different vehicles for administering pro- One of the first probiotic randomized controlled trials, biotics (1,5). The authors showed that the bacteria can be grown to published under the umbrella of ESPGHAN, was a multicentre high numbers in an ice cream mix and remain viable during frozen randomized controlled trial evaluating the effectiveness of Lacto- storage (5). In 1991 Isolauri et al. reported that Lactobacillus GG in bacillus GG administered in oral rehydration solution to children the form of fermented milk or freeze-dried powder is effective in with acute diarrhea (15). By now, this ESPGHAN paper, written by shortening the course of acute diarrhea (6). The first 2 papers on the Guandalini et al and published in JPGN in 2000, has been cited use of probiotics in preterm infants date from 1993, showing that more than 700 times! Lactobacillus GG was well tolerated and did colonize the bowels of premature infants (7,8). However, there was no evidence that such FIRST ESPGHAN META-ANALYSIS ON colonization had any positive clinical benefit. In addition to pro- biotics, prebiotics are also an area of interest. The first paper on the PROBIOTICS presence of oligosaccharides in breast milk was published in 1957 A meta-analytical approach was introduced within ESP- (7). While Gibson and Roberfroid, regarded as pioneers in the field, GHAN by the JPGN publication in 2001 of the first meta-analysis published their paper almost 40 years later (10). of the effectiveness of probiotics in the treatment and prevention of acute infectious diarrhea in infants and children (16). By now, it has been cited more than 500 times. FIRST PEDIATRIC PROBIOTIC PAPERS The paper regarded as the take-off point for the explosion of paediatric literature on probiotics is the Lancet paper by Saavedra et ESPGHAN OPINION LEADERS ON PROBIOTICS/ al published in 1994. In this randomized controlled trial, the authors PREBIOTICS showed that 8 (31%) of the 26 patients who received the control It became increasingly obvious that probiotics and prebiotics formula compared with only 2 (7%) of the 29 who received the were going to play an important role in paediatric nutrition and formula supplemented with B bifidum & Str thermophilus devel- health care, for both prevention and treatment. In a paper published oped diarrhea during the course of the study (P ¼ 0.035) (11). in 2002, ESPGHAN opinion leaders stated: ‘‘In today’s attempt to improve infant and follow-up formulas, probiotics or prebiotics FIRST PEDIATRIC PREBIOTIC PAPER supplementation represents a fascinating concept and the presently It took until the early 2000s before the first paper on the use available scientific knowledge justifies from now on the consump- of prebiotics in infant formula was published, indicating that tion of some of these products by infants. However, despite recent important advances, the data available actually remain, in many cases, preliminary. Ongoing and upcoming research will certainly Received January 27, 2018; accepted January 29, 2018. bring, in the near future, new and convincing data to answer the Copyright # 2018 by European Society for Pediatric Gastroenterology, main questions. In any case, there is a need for a rigorous scientific Hepatology, and Nutrition and North American Society for Pediatric evaluation of all products marketed to insure their safety and Gastroenterology, Hepatology, and Nutrition efficacy. For this reason, intervention studies are absolutely neces- DOI: 10.1097/MPG.0000000000001915 sary to evaluate the immediate and long-term benefits and the

JPGN Volume 66, Supplement 1, April 2018 S113 Supplement JPGN Volume 66, Supplement 1, April 2018 absence of harmful consequences of any new formula. This evalua- PROBIOTICS AND ESPGHAN GUIDELINES tion must be part of a program of public and not only Initially, the approach used to include the full representation performed by industry’’ (17). of the original data on which the recommendations are based was innovative. However, subsequently, this rigorous approach was COMMITTEE ON NUTRITION adopted for the development of ESPGHAN guidelines. First, for ESPGHAN has the merit of being a Society that regards those related to the management of acute gastroenteritis (led by scientific evidence as a priority. In 2011, the ESPGHAN Committee Alfredo Guarino) (25,26) and then for those on the use of probiotics on Nutrition published a paper in JPGN stating that ‘‘scientific data to manage antibiotic associated diarrhoea (23). Currently, all suggest that the administration of currently evaluated probiotic- ESPGHAN guidelines undergo a rigorous peer review process and/or prebiotic-supplemented formula to healthy infants does not and are published in JPGN in an open access mode. Many of these raise safety concerns with regard to growth and adverse effects. The guidelines are the result of a series of consecutive meetings held at safety and clinical effects of one product should not be extrapolated international airports to minimize costs. to other products. At present, there is insufficient data to recommend the routine use of probiotic- and/or prebiotic-supplemented formu- ACTIVITIES ENDORSED BY ESPGHAN lae. The Committee considers that the supplementation of formula The development of ideas and trends on how to exploit the with probiotics and/or prebiotics is an important field of research. clinical applications of probiotics and prebiotics has been at least, in There is a need in this field for well-designed and carefully part, driven by the discussions developed within a series of Rome conducted randomized controlled trials, with relevant inclusion/ meetings on ‘‘Probiotics, Prebiotics and New Foods’’ which has exclusion criteria and adequate sample sizes. These studies should brought together the most active members of ESPGHAN every 2 use validated clinical outcome measures to assess the effects of years since 1997 (26). More recently, a novel forum was developed probiotic and/or prebiotic supplementation of formulae. Such trials called ‘‘Probiotics and Prebiotics in Paediatrics’’ (or PPP). The should also define the optimal doses and intake durations, as well as Rome meetings provide expert overviews of data in order to provide more information about the long-term safety of probiotics facilitate inclusion of probiotics in algorithms and clinical guide- and/or prebiotics. Because most of the trials were company funded, lines and also in the design of new directions for in vitro and in vivo independent trials, preferentially financed jointly by national/gov- research. The PPP is more oriented toward the presentation and ernmental/European Union bodies and other international orga- discussion of clinical data, again with ESPGHAN playing a major nizations, would be desirable’’ (18). The latter statement is a cause role. of major concern for many nutritional studies conducted in infants and children: it is quite difficult, although not impossible, to obtain governmental money for this kind of study. THE CURRENT SCENARIO In 2011 the Consensus Group on Outcome Measures Made in It is now clear that on the one side ‘‘there is some efficacy of Paediatric Enteral Nutrition Clinical Trials (COMMENT) initiative probiotics in selected childhood diseases‘‘. On the other hand, there was launched, involving the ESPGHAN Committee on Nutrition, is a major interest of commercial companies in developing, mar- with the aim of developing common outcome measures for nutri- keting, and promoting this novel class of products that is positioned tional interventions in clinical trials. Five working groups were between a drug and food supplement. As a matter of fact, customers formed with the mandate to provide indications on definitions and do like the concept of probiotics, because of the ‘‘natural’’ approach key outcomes for evaluating functional nutrients in trials on growth, as opposed to the more aggressive and hostile perceptions linked acute diarrhea, atopic dermatitis and cows’ milk protein allergy, with chemical medications. Moreover, probiotics are devoid of respiratory infections and ’gut comfort’ (19). The COMMENT adverse effects, have a relative low cost and good palatability, and initiative is expected to provide guidance in the design of trials create the perspective of being ‘‘tailored to the problem,’’ that is, on functional nutrients, thereby overcoming differences in defini- offer a gentle approach to actively fighting a disturbing, although tions and key outcome measures to make the results of different not severe, clinical condition. trials suitable for comparative evaluation and meta-analysis. Key Progressively, probiotics are becoming part of the standard outcomes for acute gastroenteritis and for respiratory infections management of several conditions, either for prevention such as in have already been published (20,21), and others are in preparation the case of antibiotic-associated diarrhea (23) or as an additional within the COMMENT initiative. intervention or main treatment as in the case of intestinal and extra- intestinal inflammatory conditions. Probiotics also have become an ESPGHAN WORKING GROUP FOR PROBIOTICS important part of the management of conditions such as steatohe- patitis (27). The role of probiotics in the prevention of narcotising AND PREBIOTICS enterocolitis in preterm infants is still being debated (28). The Working Group, established in 2000, has been consis- tently active in promoting collaborative work and in discussing data and future directions. The main impact of the group has been in the FUTURE DIRECTIONS development of algorithms and guidelines. The group developed The option of targeting the intestinal microbiome is in its guidelines for the management of acute gastroenteritis (22) and the early stages of development and is profoundly affected by meth- prevention of antibiotic-associated diarrhea (23). A manuscript on odological issues. However, active research is ongoing with the aim the quality of probiotic food supplements has been published and of investigating the long-term effects of nutritional interventions indicated that there is an urgent need for a more stringent quality that include use of probiotics and prebiotics in newborns, both term control process (24). Several other papers on the indications of and preterm, and infants. The reason to target this age group is probiotics are in preparation. The group would like to do active obvious, as if there exists a ‘‘window of opportunity’’ to skew the clinical research; however, it struggles to find funding, as the group immune system in a health-promoting direction, it is situated in does not want to conduct clinical trials ‘‘for’’ industry, and industry early life. The effects of such interventions in children are somehow is not interested in financing trials that are not of direct interest to easier to investigate than those in adults, because of the ‘‘naı¨ve’’ them. At this stage, various governments and the European Union nature of the child to previous interventions as well as the limited seem to have other priorities. exposure to confounding variables including lifestyle features that

S114 www.jpgn.org JPGN Volume 66, Supplement 1, April 2018 Supplement are common in adults. Interventions in infants and young children 15. Guandalini S, Pensabene L, Zikri MA, et al. Lactobacillus GG may offer unique opportunities to exploit immunological windows administered in oral rehydration solution to children with acute diar- and decrease the risk of chronic inflammatory/allergic diseases. rhea: a multicenter European trial. J Pediatr Gastroenterol Nutr 2000;30:54–60. 16. Szajewska H, Mrukowicz JZ. Probiotics in the treatment and prevention CONCLUDING REMARKS of acute infectious diarrhea in infants and children: a systematic Overall, it can be said with some pride (supported by review of published randomized, double-blind, placebo-controlled evidence) that the work by pediatricians within ESPGHAN has trials. J Pediatr Gastroenterol Nutr 2001;33(suppl 2):S17–25. been productive and successful in ensuring an effective use of 17. Ghisolfi J, Roberfroid M, Rigo J, et al. Infant formula supplemented probiotics and prebiotics for clinical purposes. The rigor and with probiotics or prebiotics: never, now, or some day? J Pediatr Gastroenterol Nutr 2002;35:467–8. scientific solidity have led to major progress in the inclusion of 18. Braegger C, Chmielewska A, Decsi T, et al. Supplementation of infant these strategies in clinical protocols to the advantage of children. formula with probiotics and/or prebiotics: a systematic review and Yet, after more than 25 years of work, the feeling is that we are still comment by the ESPGHAN Committee on Nutrition. J Pediatr Gastro- in the initial stage of application of these strategies. Future devel- enterol Nutr 2011;52:238–50. opments are already focusing on areas in which we have been 19. Koletzko B, Szajewska H, Ashwell M. Early Nutrition Academy and fighting microbes for decades such as cancer and premature birth. European Society for Paediatric Gastroenterology, Hepatology and However, recent data suggest that adding microbes (the good ones!) Nutrition Committee on Nutrition – Consensus Group on Outcome may, in fact, be a better option than fighting them. Measures Made in Paediatric Enteral Nutrition Clinical Trials. Doc- umentation of functional and clinical effects of infant nutrition: setting the scene for COMMENT. Ann Nutr Metab 2012;60:222–32. REFERENCES 20. Karas J, Ashkenazi S, Guarino A, et al. Consensus Group on Outcome 1. Tamburini S, Shen N, Wu HC, et al. The microbiome in early life: Measures Made in Paediatric Enteral Nutrition Clinical Trials (COM- implications for health outcomes. Nat Med 2016;22:713–22. MENT). A core outcome set for clinical trials in acute diarrhoea. Arch 2. Lllly DM, Still Well RH. Probiotics: growth-promoting factors pro- Dis Child 2015;100:359–63. duced by microorganisms. Science 1965;147:747–8. 21. Guarino A, Bruzzese E, Lo Vecchio A, et al. Definitions and outcomes 3. Wadstro¨m T. Streptococcus faecium M 74 in control of diarrhoea of nutritional interventions in children with respiratory infections: induced by a human enterotoxigenic Escherichia coli strain in an the approach of the COMMENT initiative. Ann Nutr Metab 2013;63: infant rabbit model. Zentralbl Bakteriol Mikrobiol Hyg A 1984;257: 248–55. 357–63. 22. Szajewska H, Guarino A, Hojsak I, et al. Use of probiotics for manage- 4. Reid G, Bruce AW, McGroarty JA, et al. Is there a role for lactobacilli in ment of acute gastroenteritis: a position paper by the ESPGHAN prevention of urogenital and intestinal infections? Clin Microbiol Rev Working Group for Probiotics and Prebiotics. J Pediatr Gastroenterol 1990;3:335–44. Nutr 2014;58:531–9. 5. Hekmat S, McMahon DJ. Survival of Lactobacillus acidophilus and 23. Szajewska H, Canani RB, Guarino A, et al., ESPGHAN Working Group Bifidobacterium bifidum in ice cream for use as a probiotic food. J Dairy for Probiotics. Probiotics for the prevention of antibiotic-associated Sci 1992;75:1415–22. diarrhea in children. J Pediatr Gastroenterol Nutr 2016;62:495–506. 6. Isolauri E, Juntunen M, Rautanen T, et al. A human Lactobacillus strain 24. Kolacˇek S, Hojsak I, Berni Canani R, et al., ESPGHAN Working Group (Lactobacillus casei sp strain GG) promotes recovery from acute for Probiotics and Prebiotics. Commercial Probiotic Products: A Call for diarrhea in children. Pediatrics 1991;88:90–7. Improved Quality Control. A position paper by the ESPGHAN working 7. Stansbridge EM, Walker V, Hall MA, et al. Effects of feeding premature group for probiotics and prebiotics. J Pediatr Gastroenterol Nutr infants with Lactobacillus GG on gut fermentation. Arch Dis Child 2017;65:117–24. 1993;69 (5 Spec No):488–92. 25. Guarino A, Ashkenazi S, Gendrel D, et al., European Society for 8. Millar MR, Bacon C, Smith SL, et al. Enteral feeding of premature infants Pediatric Gastroenterology, Hepatology, and Nutrition; European with Lactobacillus GG. Arch Dis Child 1993;69 (5 Spec No):483–7. Society for Pediatric Infectious Diseases. European Society for Pedia- 9. Malpress FH, Hytten FE. Oligosaccharides of human milk. Nature tric Gastroenterology, Hepatology, and Nutrition/European Society 1957;180:1201. for Pediatric Infectious Diseases evidence-based guidelines for the 10. Gibson GR, Roberfroid MB. Dietary modulation of the human colonic management of acute gastroenteritis in children in Europe: update microbiota: introducing the concept of prebiotics. JNutr1995;125:1401–12. 2014. J Pediatr Gastroenterol Nutr 2014;59:132–52. 11. Saavedra JM, Bauman NA, Oung I, et al. Feeding of Bifidobacterium 26. Kolacˇek S, Hojsak I, Berni Canani R, et al., ESPGHAN Working Group bifidum and Streptococcus thermophilus to infants in hospital for for Probiotics and Prebiotics. Commercial probiotic products: a call for prevention of diarrhoea and shedding of rotavirus. Lancet 1994;344: improved quality control. A position paper by the ESPGHAN Working 1046–9. Group for Probiotics and Prebiotics. J Pediatr Gastroenterol Nutr 12. Moro G, Minoli I, Mosca M, et al. Dosage-related bifidogenic effects of 2017;65:117–24. galacto- and fructooligosaccharides in formula-fed term infants. J 27. Boursier J, Diehl AM. Nonalcoholic fatty liver disease and the gut Pediatr Gastroenterol Nutr 2002;34:291–5. microbiome. Clin Liver Dis 2016;20:263–75. 13. Majamaa H, Isolauri E, Saxelin M, et al. Lactic acid bacteria in the 28. Ivan den Akker CHP, van Goudoever JB, Szajewska H, et al., treatment of acute rotavirus gastroenteritis. J Pediatr Gastroenterol Nutr ESPGHAN Working Group for Probiotics, Prebiotics & Committee 1995;20:333–8. on Nutrition. Probiotics for preterm infants: a strain specific 14. Guarino A, Canani RB, Spagnuolo MI, et al. Oral bacterial therapy systematic review and network meta-analysis. J Pediatr Gastroenterol reduces the duration of symptoms and of viral excretion in children with Nutr 2018. doi: 10.1097/MPG.0000000000001897. [Epub ahead of mild diarrhea. J Pediatr Gastroenterol Nutr 1997;25:516–9. print].

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Chapter 6. ESPGHAN’s Contributions to Paediatric Hepatology

Martin Burdelski, yEtienne Sokal, zPilar Nannini, §Anil Dhawan, §Giorgina Mieli-Vergani, ôDiego Vergani, #Nedim Hadzic, Giussepe Maggiore, yyPietro Vajro, zzGiulia Paolella, §§Giovanna Alfano, jjjjRoderick Houwen, and ôôDeirdre Kelly

List of Chapter 6 Cystic Fibrosis, and Defects; Manuscript: 3075 words; Chapter 6.0—History of Paediatric Hepatology in ESPGHAN; References: 65. Manuscript: 302 words; Abstract: 179; Figures: 4; Tables: 2. Chapter 6.4—Diagnostic Progress in Cholestasis; Manuscript: 1884 Chapter 6.1—Pediatric Chronic Hepatitis B and C: 30 Years of words; References: 20; Figures: 2. ESPGHAN Clinical Research and Recommendations; Manuscript: Chapter 6.5—Pediatric Liver Transplantation; Manuscript: 2048 1861 words; Abstract: 143 words; References: 36 words; References: 15; Chapter 6.2—Immune Function-related Liver Disease and Figures: 5. ESPGHAN’s Contribution to the Advancement of Science in Chapter 6.6—The Role of ESPGHAN in Developing Effective the Last Three Decades; Manuscript: 4635; References: 60; Immunosuppression Following Paediatric Liver Transplantation; Figures: 1. Manuscript: 724 words; References: 12. Chapter 6.3—Studies on Hepatic Metabolic Disorders Driven by ESPGHAN Members: The Case of Alpha1-Antitrypsin Deficiency,

Received January 28, 2018; accepted January 29, 2018. From the University Hospital Hamburg, Eppendorf, Germany, the yCliniques Universitaires Saint Luc, Gastroenterologie et Hepatologie Pe´diatrique, the zUniversite´ Catholique de Louvain, Cliniques Univer- sitaires St Luc, 1Service de Gastroente´rologie et He´patologie Pe´diatri- que, Brussels, Belgium, the §Paediatric Liver, GI and Nutrition Centre and Mowat Labs, Kings’ College Hospital, London, UK, the ôInstitute of Liver Studies, MowatLabs, King’s College Hospital, London, UK, the #????, the Department of Medical Sciences, Paediatric Section, University of Ferrara, Italy, the yyDepartment of Medicine and Surgery, Pediatric Section, University of Salerno, Baronissi (Salerno), Italy, the zzPediatric Intermediate Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy, the §§Department of Pediatrics, Hoˆpital Fribourgeois (HFR), Fribourg, Switzerland, the jjjjDepartment of Pediatric Gastroenterology, Wilhel- mina Children’s Hospital and University Medical Center, Utrecht, The Netherlands, and the ôôUniversity of Birmingham and The Liver Unit, Birmingham Women’s & Children’s Hospital, Birmingham, UK. Address correspondence and reprint requests to Martin Burdelski, MD, Professor of Pediatric Hepatology, University Hospital Hamburg, Am Wuesten Bleek 10, D-37520 Osterode a.H., Eppendorf, Germany (e-mail: [email protected]). Copyright # 2018 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000001916

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Chapter 6.0. History of Paediatric Hepatology in ESPGHAN

Martin Burdelski

ABSTRACT Right from the beginning of ESPGAN hepatology played an Hepatology played an important role in ESPGAN from the beginning. In important role in this Society. ESPGAN members such as Alec 1989, the Hepatology Committee was started. In the early 1990s H for Mowat, Birgitta Strandvik, Daniel Alagille, later Giorgina Mieli- hepatology was included in ESPGHAN. Hepatology Summer schools were Vergani, Deirdre Kelly, Carla Colombo, Etienne Sokal, and Martin held from 1995 and later monothematic conferences met the needs of many Burdelski contributed significant presentations and papers to young ESPGHAN members. The role of ESPGHAN members in the ESPGAN meetings and to the official journal of the Society, the progress of diagnostic and therapeutic measures in hepatitis B and C will Journal of Pediatric Gastroenterology and Nutrition. In 1989 the be elucidated (Chapter 6.1) as well as the role of other ESPGHAN members Hepatology Committee of ESPGAN was founded and started to in the understanding of immunological hepatic disorders of childhood attract young members of the Society and those who wanted to (Chapter 6.2). During childhood, many metabolic hepatic disorders threaten attend regular sessions at the biannual meetings of ESPGHAN. the life and health of children making orchestrated measures in diagnostic To attract even more young scientists to develop an interest and therapeutic efforts necessary (Chapter 6.3). The pathophysiology of in paediatric hepatology Hepatological Summer Schools were cholestasis was cleared by the detection of bile salt transporters, which were initiated, the first being that in the Lueneburg heather in Wilsede, identified by ESPGHAN members in the Netherlands, France, United Germany. A list of all hepatological summer schools held so far is Kingdom and Germany (Chapter 6.4). Finally liver transplantation for acute shown in Tables 1 and 2. fulminant and chronic end stage liver disease was established as a mean- In the 1990s, the importance of hepatology in ESPGAN had while standard treatment option (Chapter 6.5). Immunosupression in liver grown to such an extent, that Hepatology was added to the title of transplantation was improved and standardized through the cooperation of this Society, which was then renamed ESPGHAN. Having in mind many ESPGHAN member driven studies (Chapter 6.6). that there was only a minority of studies performed on behalf of (JPGN 2018;66: S117–S118) ESPGHAN, most of the studies reported here concerning paediatric hepatology were done by members of the society and were pre- sented in the meetings (Figs. 2–4). F igure 1

TABLE 1. List of all hepatological summer schools held as of year end of 2017

Date Place Organizer

1995 Wilsede, Germany D. Kelly, M. Burdelski 1999 Ischia, Italy A. Vegnente 2001 Kokke-le Zout, Belgium E. Sokal 2003 Azores, Portugal I. Goncalves 2006 Balatonfuered, Hungaria A. Nemeth, L. Szonyi 2008 Venice, Italy L. d’Antiga 2010 Cracow, Poland P. Socha 2014 Salerno, Italy P. Vajro

TABLE 2. Time, location, and organizer of monothematic ESPGHAN FIGURE 1. Martin Burdelski. conferences Cell Genes and Molecules 2009 United A. Dhawan Monothematic Conference Kingdom Received January 28, 2018; accepted January 29, 2018. Liver Transplant Monothematik 2013 Hanover, U. Baumann, # Copyright 2018 by European Society for Pediatric Gastroenterology, Conference Germany McLin B. Fischler Hepatology, and Nutrition and North American Society for Pediatric First Liver Transplant 2015 Rovinj, D. Hadzic, Gastroenterology, Hepatology, and Nutrition School Croatia L. d’Antiga DOI: 10.1097/MPG.0000000000001916

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FIGURE 4. Eleven years later: Faculty and students at the Balaton ESPGHAN Hepatology Summer School in 2006. FIGURE 2. The Main Players in Wilsede: Bill Balistreri, Martin Bur- delski, and Deirdre Kelly.

In the following pages, the most important issues in paediat- ric hepatology and their relation to ESPGHAN will be discussed. These are Chapter 6.1. Viral hepatitis in paediatrics by Etienne Sokal and Pilar Nannini. Chapter 6.2. Immunological disorders in paediatric hepatology by Anil Dhawan, Giorgina Mieli-Vergani, Diego Vergani, Nedim Hadzic, and Giuessepe Maggiore. Chapter 6.3. Hepatic metabolic disorders by Pietro Vajro, Giulia Paolella, and Giovanna Alfano. Chapter 6.4. Development of understanding of cholestasis by Roderick Houwen. Chapter 6.5. Liver transplantation in children by Martin Burdelski. Chapter 6.6. Development of immunosuppression in liver transplantation by Deirdre Kelly. FIGURE 3. Faculty and students of the first ESPGHAN Hepatology Summer School in Wilsede, 1995.

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Chapter 6.1. Pediatric Chronic Hepatitis B and C: 30 Years of ESPGHAN Clinical Research and Recommendations

Etienne M. Sokal and Pilar Nannini

ABSTRACT risk of developing CHB, and 25% will die from chronic liver The expression of hepatitis B and C virus infections in children differs from disease during adulthood. that in adults and requires specific paediatric expertise. The European Society of Pediatric Gastroenterology, Hepatology, and Nutrition (ESP- GHAN) has been a pioneer in this field, having stressed the need for straightforward recommendations since the mid-1980s. Following much Treatment observation, surveillance, and research, a panel of ESPGHAN experts was Since the mid-1980s, the ESPGHAN society has been push- able to develop such recommendations on hepatitis B infection in children in ing for straightforward recommendations to clarify who needs to be 2009, which was then followed in June 2013 by proper guidelines. In the treated and when to start the treatment. Management proposals were field of Chronic Hepatitis C, in 2011 ESPGHAN experts published also the published by an expert group in 2009 (9), with proper guidelines Guidance for Clinical Trials for Children and Adolescents, and approved in published in 2013 by a panel of ESPGHAN experts (10) who 2012 the NASPGHAN guidelines for treatment. The ESPGHAN Society is developed a treatment algorithm to assist practitioners in their to be commended for its pioneering work in furthering our understanding of decision-making process. Antiviral treatment should be considered chronic hepatitis B and C disease presentations in infants, children, and for children with high ALT levels for at least 6 months, an indirect adolescents. marker of ongoing liver injury, in order to avoid treating patients Key Words: Chronic Hepatitis B, Chronic Hepatitis C, children, undergoing spontaneous HBeAg seronconversion. Since the upper recommendations limit of normal (ULN) for ALT in children has not been established, ESPGHAN guidelines recommend those patients to be considered (JPGN 2018;66: S119–S121) for antivirals if ALT levels exceed 1.5 times the laboratory ULN. In the presence of high ALT levels, the assessment of serum HBV DNA is required, with high HBV DNA values warranting antivirals, HEPATITIS B whereas low levels require further investigations to exclude other causes for liver injury. Other factors must be considered prior to Epidemiology and Natural History initiating therapy: liver histology, family HCC history, coexisting liver diseases, and prior treatments (10). Antivirals are indicated in epatitis B virus (HBV)–related chronic hepatitis (CHB), children undergoing liver transplantation, while prophylactic defined as positive HBsAg for 6 months, is typically administration is recommended for HBsAg-positive patients due Hasymptomatic in childhood. Nevertheless, 25% of all HBV chronic to receive immunosuppressive or cytotoxic therapy (11,12). The carriers worldwide exhibit a life-long risk of developing hepatocel- Food and Drug Administration (FDA) has approved 6 medications lular carcinoma (HCC), with an incidence of cirrhosis of 2% to 3% for treating CHB in children: interferon-alfa (IFNa) and pegylated per year (1). HBV is transmitted through exposure to infectious interferon-alfa (PEG-IFNa), lamivudine, adefovir, entecavir, and blood, semen, vaginal secretions, and saliva (2). The infection tenofovir, with all these drugs tested in children in multicenter prevalence has been declining worldwide since 1991, when the ESPGHAN-NASPGHAN (North American Society for Pediatric World Health Organization (WHO) called for all countries to Gastroenterology, Hepatology and Nutrition) trials. incorporate HBV in national immunization programs IFNa, the first drug approved for CHB in children, is (3,4). Additionally, strict blood-donor and pregnant women screen- associated with a virological response (VR: undetectable HBV ings have been instrumental in decreasing the prevalence. Ten HBV DNA and HBeAg clearance) in 26% of IFNa-treated children after genotypes (A–J) have been reported, with genotype A predominant 24 weeks versus 11% of untreated controls (12). This response rate in Europe, while genotypes B, C, D, and F are more common in increases to 35% when only patients with elevated ALT levels are high/intermediate HBV prevalence countries (5–7). In Western considered. HBsAg clearance is noted in 10% of treated children countries the vertical transmission is prevalent (8). Vertical- versus 1.2% of controls. Response probability is shown to be infected infants become immunotolerant to the virus and develop associated with low baseline HBV DNA, younger age (<5 years a lasting asymptomatic infection, characterized by high viral repli- old), and female gender (13). In early years, IFNa was presumed to cation yet no liver injury. Nevertheless, these infants exhibit a 90% accelerate HBeAg seroconversion, and it was confirmed by 3 studies, though with similar long-term HBeAg clearance rates Received January 28, 2018; accepted January 29, 2018. between treated and untreated patients (14–16). Despite having Copyright # 2018 by European Society for Pediatric Gastroenterology, no long-term consequences, IFNa therapy is shown to cause Hepatology, and Nutrition and North American Society for Pediatric transient impairment of growth. Today IFNa administration is Gastroenterology, Hepatology, and Nutrition recommended in HBeAg-positive children aged 2 years, with DOI: 10.1097/MPG.0000000000001916 abnormal ALT and low-intermediate HBV DNA levels. Several

JPGN Volume 66, Supplement 1, April 2018 S119 Supplement JPGN Volume 66, Supplement 1, April 2018 trials were implemented by ESPGHAN–NASPGHAN members in countries, while in developing countries contamination through order to assess nucleotide/nucleoside analogues in CHB children transfusion or health care procedures is still common. The prevalence with multiple European and US centres involved. Lamivudine was of HCV infection in children in developed countries ranges between the first nucleoside analogue to be FDA-approved for CHB treat- 0.1% and 0.4%, while it is lower in high-income countries (0.05%– ment in children aged 3 years. VR is achieved in 23% of patients, 0.36%) (23–25). The rate of perinatal transmission from an infected in 34% if considering patients with elevated ALT levels (17,18). mother to her child ranges from 2% to 5%. Among vertically infected Lamivudine’s essential limitation is the risk of developing lami- children, HCV infection is shown to chronicize in 80% (26–27). vudine-resistant mutations in the tyrosine-methionine-aspartate- Children with HCV infection differ from adults in several ways aspartate (YMDD) viral locus. Combination of lamivudine and including modes of transmission, rates of clearance, progression of IFNa in immunotolerant patients is shown to achieve 17% rate of fibrosis, and the duration of potential chronic infection when acquired complete viral control (HbsAg loss) (19). Adefovir dipivoxil, a at birth. Infected children are usually asymptomatic, with a low risk of purine analogue, was FDA-approved in 2010 for treating CHB progression of the disease, but almost 5% of them develop significant children aged 12 years. VR is achieved in 23% of patients aged 12 liver disease in childhood. to 17 years. Compared to lamividune, adefovir offers a major The incubation period for HCV infection can range from advantage of proving effective against all hepatitis B viruses, 2 weeks to 6 months. More than three-quarters of HCV-infected including lamivudine-resistant strains, and in the long run adefovir children and adolescents are asymptomatic, with normal or only resistance rates are lower (20). Moreover, adefovir appears to be mildly increased serum ALT levels. Nonspecific signs and symp- effective in HBeAg-negative hepatitis. Entecavir, a carbocyclic toms (hepatomegaly, hyperpyrexia, lethargy, anorexia, nausea, analogue of 20-deoxyguanosine, is active on both lamivudine- vomiting, abdominal colic, deep-coloured urine, light-coloured resistant and adefovir-resistant strains. It is approved by FDA for faeces, arthralgia, and yellowish discoloration of skin and sclera) children 2 years old, and it is effective in inhibiting viral replica- can occur in approximately 15% of paediatric population. tion, but only patients with HBeAg seroconversion are likely able to discontinue treatment without relapse, thus this may require several Treatment years of treatment. VR is reported in 24% of patients after 48 weeks (21), significantly associated with lower DNA (<8 log10), trans- In 2012 ESPGHAN/NASPGHAN guidelines on ‘‘Diagnosis aminase levels >2 ULN, and genotype A/C. Based on these data, and Management of Hepatitis C Infection in Infants, Children, and ESPGHAN now recommends to carefully select candidates eligible Adolescents’’ suggested to start treating children with hepatitis C for treatment. Tenofovir, a nucleotide analogue similar in structure who demonstrate persistently elevated serum aminotransferases or to adefovir but less nephrotoxic, is among the first-line treatments those with progressive disease (ie, fibrosis on liver histology). Peg- for adult CHB, along with PegIFN and entecavir. Like entecavir, IFN and ribavirin were approved by the FDA (2008) and the EMA tenofovir has proven to be effective against lamivudine-resistant (2009) for children aged more than 3 years. The rate of SVR is lower mutations. Tenofovir was investigated in children aged 12 to in case of genotype 1, the most prevalent HCV genotype globally, 18 years old, with 89% of them achieving VR. However, after which 48 weeks-treatment results in a sustained virologic response 72 weeks of therapy, HBeAg-Ab seroconversion rate was not higher (SVR) in <50% of children (28). In the case of genotype 4 SVR rate in the treated patients as compared to placebo (22). Telbivudine, a is achieved in 40% to 69% of children after 48 weeks of therapy L-nucleoside analogue, was approved by FDA in 2006 for children (29). ESPGHAN/NASPGHAN guidelines recommend treatment of 16 years. In comparison with adefovir and entecavir, resistance patients with genotype 1 and 4 for 48 weeks, patients with genotype rates for telbivudine have proved to be higher, increasing with the 2 and 3 for 24 weeks. However, this regimen is burdened with duration of treatment. consistent adverse effects: pyrexia, headache, gastrointestinal New antiviral approaches that target various steps and com- symptoms, depression, neutropenia and haemolytic anaemia, ponents of the HBV lifecycle are being investigated, with the hope including deleterious effects on growth (30–33). Furthermore, of a complete viral eradication. These approaches include HBV the use of IFN for the treatment of HCV has been traditionally entry inhibitors, such as Myrcludex B, a lipo-myristolated peptide contraindicated in decompensated cirrhosis, leaving these patients mimicking the pre-S1 domain that competes with HBV particles to at even greater risk for the development of end-stage liver disease. bind to the sodium taurocholate co-transporting polypeptide Given these assumptions, additional treatment options are still (NTCP). Studies on the drug’s safety carried out on healthy adults needed to eradicate the infection, with better SVR, especially for showed modest and transient elevations of amylase and lipase, genotype 1, and less adverse effects. For this purpose, in 2011 an without clinical relevance in a low percentage of patients (18). ESPGHAN committee published the ‘‘Guidance for Clinical Trials Studies on paediatric population could be crucial on eradicating for Children and Adolescents with Chronic Hepatitis C’’ (28). HBV infection in children. Modern direct antiviral agents (DAA) have revolutionized therapy of HCV infection and are now preferred for treatment in HEPATITIS C adults. The combination multiple classes of HCV antivirals is shown to reduce the development of viral resistance and improves Epidemiology and Natural History SVR rates. The fixed dose once-daily-single-tablet- regimen of With the availability of HCV treatments in the early 1990s, the sofosbuvir (an inhibitor of the NS5B RNA-dependent RNA poly- incidence rate of HCV infection has significantly decreased in the last merase) and ledipasvir (an inhibitor of the NS5A protein) has been 2 decades, nevertheless the number of deaths per year due to HCV approved for the treatment of chronic HCV genotype 1 in patients liver disease (cirrhosis, hepatocellular carcinoma and liver failure) is aged >18 years in December 2013. This combination is shown to constantly increasing. Eleven million of infected people are younger lead to SVR rates of >95% in HCV-genotype 1–infected patients, than 15 years of age, of whom 5 million are viremic. Up to now, 7 not only treatment naive but also with prior treatment experience. genotypes (1–7) have been reported, with genotype 1 the most Phase II and III trials of combination DAAs, including the fixed- prevalent worldwide (46.2%, 83.4 million), counting for the majority dose combination sofosbuvir and ledipasvir, for children aged 3 to of HCV infections in developed countries. After the universal 17 years with chronic HCV is currently ongoing (34). Safety results screening of blood products, vertical transmission is the most com- have shown comparable pharmacokinetics parameters and safety mon route of acquiring HCV in infants and children in developed profiles between adult and adolescent populations with HCV

S120 www.jpgn.org JPGN Volume 66, Supplement 1, April 2018 Supplement infection, and first patients treated confirm similar pharmacokinet- 16. Bortolotti F, Jara P, Barbera C, et al. Long-term effect of alpha interferon ics and efficacy before and after paediatric liver transplantation in children with chronic hepatitis B. Gut 2000;46:715–8. (35). Mild and inconstant adverse effects are reported in adults, not 17. Jonas MM, Kelly DA, Mizerski J, et al. Clinical trial of lamivudine affecting the final outcome (36). in children with chronic hepatitis B. N Engl J Med 2002;346: 1706–13. 18. Sokal EM, Kelly DA, Mizerski J, et al. Long-term lamivudine therapy CONCLUSIONS for children with HBeAg-positive chronic hepatitis B. Hepatology HBV and HCV infections are still a major issue worldwide. 2006;43:225–32. Current treatments available for paediatric population are partially 19. D’Antiga L, Aw M, Atkins M, et al. Combined lamivudine/interferon- efficient in curing the diseases and burdened with several adverse alpha treatment in ‘‘immunotolerant’’ children perinatally infected with effects. New treatment options, such as new drugs blocking viral hepatitis B: a pilot study. J Pediatr 2006;148:228–33. entry via the NTCP receptor and modern DAA need to be designed 20. Marcellin P, Chang TT, Lim SGL, et al. Long-term efficacy and safety of for HBV for HCV-infected children respectively. Long-term studies adefovir diplovoxil for the treatment of hepatitis B e antigen-positive remain a must to better apprehend the natural history of these chronic hepatitis. Hepatology 2008;48:750–8. 21. Jonas MM, Chang MW, Sokal EM, et al. Randomized, controlled trial of infections, along with the treatments’ impact. entecavir versus placebo in children with hepatitis B envelope antigen- positive chronic hepatitis B. Hepatology 2016;63:377–87. REFERENCES 22. Murray KF, Szenborn L, Wysocki J, et al. Randomized, placebo- 1. McMahon BJ. The natural history of chronic hepatitis B virus infection controlled trial of tenofovir disoproxil fumarate in adolescents with in children. Hepatology 2009;49:545–55. chronic hepatitis B. Hepatology 2012;56:2018–26. 2. Kidd-Ljunggren K, Holmberg A, Bla¨ckberg J, et al. High levels of 23. Ades AE, Parker S, Walker J, et al. HCV prevalence in pregnant women hepatitis B virus DNA in body fluids from chronic carriers. J Hosp Infect in the UK. Epidemiol Infect 2000;125:399–405. 2006;64:352–7. 24. Gerner P, Wirth S, Wintermeyer P, et al. Prevalence of hepatitis C virus 3. Liang X, Bi S, Yang W, et al. Epidemiological serosurvey of hepatitis B infection in children admitted to an urban hospital. J Infect in China-declining HBV prevalence due to hepatitis B vaccination. 2006;52:305–8. Vaccine 2009;27:65550–7. 25. Hepatitis C virus infection. American Academy of Pediatrics. Commit- 4. Ni Y-H, Huang LM, Chang MH, et al. Two decades of universal hepatitis tee on Infectious Diseases. Pediatrics 1998;101 (3 pt 1):481–5. B vaccination in Taiwan: impact and implications for future strategies. 26. Iorio R, Giannattasio A, Sepe A, et al. Chronic hepatitis C in childhood: Gastroenterology 2007;132:1287–93. an 18-year experience. Clin Infect Dis 2005;41:1431–7. 5. Liu HF, Sokal E, Goubau P. Wide variety of genotypes and geographic 27. Jara P, Resti M, Hierro L, et al. Chronic hepatitis C virus infection in origins of hepatitis B virus in Belgian children. J Pediatr Gastroenterol childhood: clinical patterns and evolution in 224 white children. Clin Nutr 2001;32:274–7. Infect Dis 2003;36:275–80. 6. Ni YH, Chang MH, Wang KJ, et al. Clinical relevance of hepatitis B 28. Wirth S. Current treatment options and response rates in children with virus genotype in children with chronic infection and hepatocellular chronic hepatitis C. World J Gastroenterol 2012;18:99–104. carcinoma. Gastroenterology 2004;127:1733–8. 29. Abdel-Ghaffar TY, Sira MM, El Naghi S. Hepatitis C genotype 4: the 7. Lin CL, Kao JH. The clinical implications of hepatitis B virus genotype: past, present, and future. World J Hepatol 2015;7:2792–810. recent advances. J Gastroenterol Hepatol 2011;26(suppl 1):123–30. 30. El Naghi S, Abdel-Ghaffar TY, El-Karaksy H, et al. Safety and efficacy 8. Margolis HS, Alter MJ, Hadler SC. hepatitis B: evolving epidemiology of Hansenula-derived PEGylated-interfer- on alpha-2a and ribavirin and implications for control. Semin Liver Dis 1991:84–92. combination in chronic hep- atitis C Egyptian children. World J 9. Shah U, Kelly D, Chang MH, et al. Management of chronic hepatitis in Gastroenterol 2014;20:4681–91. children. J Pediatr Gastroenterol Nutr 2009;48:399–404. 31. Yee HS, Currie SL, Darling JM, et al. Management and treatment of 10. Sokal EM, Paganelli M, Wirth S, et al. Management of chronic hepatitis hepatitis C viral infection: recommendations from the Department of in childhood: ESPGHAN clinical practice guidelines - Consensus of an Veterans Affairs Hepatitis C. Resource Center program and the National expert panel on behalf of the European Society of Pediatric Gastro- Hepatitis C Program office. Am J Gastroenterol 2006;101:2360–78. enterology, Hepatology and Nutrition. J Hepatol 2013;59:814–29. 32. Kamal SM. Hepatitis C genotype 4 therapy: increasing options and 11. Shapira R, Mor E, Bar-Nathan N, et al. Efficacy of lamivudine for the improving outcomes. Liver Int 2009;29s1:39–48. treatment of hepatitis B virus infection after liver transplantation in 33. Varghese R, Al-Khaldi J, Asker H, et al. Treatment of chronic hepatitis children. Transplantation 2001;72:333–6. C genotype 4 with peginterferon alpha-2a plus ribavirin. Hepatogas- 12. Sokal EM, Conjeevaram HS, Roberts EA, et al. Interferon alfa therapy troenterology 2009;56:218–22. for chronic hepatitis B in children: a multinational randomized con- 34. Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed Dose trolled trial. Gastroenterology 1998;114:988–95. Combination þ/ Ribavirin in Adolescents and Children With Chronic 13. Kobak GE, MacKenzie T, Sokol RJ, et al. Interferon treatment for HCV-Infection. ClinicalTrials.gov Identifier NCT02249182 https://clin- chronic hepatitis B: enhanced response in children 5 years old or icaltrials.gov/ct2/show/NCT02249182. Accessed May 20, 2017. younger. J Pediatr 2004;46:715–8. 35. Huysentruyt K, Stephenne X, Varma S, et al. Sofosbuvir/ledipasvir and 14. Iorio R, Giannattasio A, Cirillo FD, et al. Long-term outcome in ribavirin tolerability and efficacy in pediatrics liver transplant recipients. children with chronic hepatitis B: a 24-year observation period. Clin Liver Transpl 2017;23:552–3. Infect Dis 2007;45:943–9. 36. Alqahtani SA, Afdhal N, Zeuzem S, et al. Safety and tolerability of 15. Marx C, Martin SR, Chicoine JF, et al. Long-term follow-up of chronic ledipasvir/sofosbuvir with and without ribavirin in patients with chronic hepatitis B virus infection in children of different ethnic origins. J Infect hepatitis C virus genotype 1 infection: analysis of phase III ION trials. Dis 2002;186:295–301. Hepatology 2015;62:25–30.

www.jpgn.org S121 SUPPLEMENT

Chapter 6.2. Immune Function–related Liver Disease and ESPGHAN’s Contribution to the Advancement of Science in the Last 3 Decades

Anil Dhawan, Giorgina Mieli-Vergani, Diego Vergani, Nedim Hadzic, and Giuseppe Maggiore

ver the last 3 decades ESPGHAN has been at forefront of 3. Shah T, Cale C, Hadzic N, Jones A. Dedicator of cytokinesis 8 clinical research in liver disease of immune dysregulation deficiency: a predisposition to sclerosing cholangitis. Clin andO also immune phenomena developing in children with liver Immunol 2014;155(1):71-73. disease, including post-transplant complications. Several ESP- 4. McLauchlin J, Amar CFL, Pedraza-Diaz S, Mieli-Vergani G, GHAN members (Prof Giorgina Mieli-Vergani, Prof Diego Ver- Hadzic N, Davies EG. Polymerase chain reaction-based gani, Prof Nedim Hadzic, Prof Giuessepe Maggiore) have been diagnosis of infection with Cryptosporidium in children with world leaders. The following document highlights some of theirs primary immunodeficiencies. Pediatr Inf Dis J 2003;22:329-34. and ESPGHAN’s achievements. 5. Amrolia P, Gaspar HB, Hassan A, Webb D, Jones A, Sturt N, Mieli-Vergani G, Pagliuca A, Mufti G, Hadzic N, Davies G, LIVER DISEASE IN PRIMARY Veys P. Nonmyeloablative stem cell transplantation for IMMUNODEFICIENCIES (PROF HADZIC) congenital immunodeficiencies. Blood 2000;96:1239-46. 6. Gaspar HB. Amrolia P, Hassan A, Webb D, Jones A, Sturt N, For a long time liver disease in primary immune deficiencies Vergani G, Pagliuca A, Mufti G, Hadzic N, Davies G, Veys P. (PIDs) has been underdiagnosed with significant impact on mor- Non-myeloablative stem cell transplantation for congenital tality and success of haematopoietic stem cell transplantation immunodeficiencies. Recent Results Cancer Res 2002;159: (HSCT). We have been first to report that liver transplantation 134-42. (LT) is possible in children with primary immune deficiencies with 7. Hadzic N, Pagliuca A, Rela M, Portmann B, Jones A, Veys P, a good outcome (1). We have also noted that around 20% of Heaton ND, Mufti GJ, Mieli-Vergani G. Correction of the children with PIDs develop liver disease (2), often in the form hyper-IgM syndrome after liver and bone marrow transplanta- of chronic cholangiopathy (3) associated with Cryptosporidium tion. N Engl J Med 2000;342:320-4. parvum (4). Our group has suggested that these patients need to 8. Taylor RM, Cheeseman P, Davenport M, Tizzard SA, Goldblatt be considered for an early haematopoietic stem cell transplantation D, Mieli-Vergani G, Hadzic N. Humoral immunity in children (HSCT) if the liver disease is not too advanced (5,6). We have with biliary atresia splenic malformation syndrome. Eur J established that peri- and early post-HSCT complications are Pediatr 2003;162(7-8):539-40. proportional to degree of underlying liver damage. Furthermore, 9. Hadzic N, Portmann B, Lewis I, and Mieli-Vergani G. Giant cell we have demonstrated that if the liver disease is severe a novel Coombs positive autoimmune hepatitis: a new feature of Evans concept of sequential liver and HSCT could potentially be curative syndrome (letter). Arch Dis Child 1998;78:397-8. (7). Transplanted liver can tolerate conditioning and hepatotoxic drugs required post-HSCT (7). In addition, we have published novel observations on humoral immunity in children with syndromic form of biliary atresia, where abnormal spleen is unable to mount IMMUNE-MEDIATED PHENOMENA AFTER adequate responses relevant for prevention of cholangitis, which LIVER TRANSPLANTATION is the commonest early complication in management of biliary King’s College Hospital has international reputation for man- atresia (8). We have described treatment of giant cell Coombs agement of acute liver failure (ALF). We have described diagnostic positive hepatitis of infancy and its overlapping features with some approach and management of one of the commonest post-ALF other autoimmune conditions (9). complications—aplastic anaemia (10–12). This condition is life- threatening, but our clinical experience showed successful evolution 1. Hadzic N, Heaton ND, Baker AJ, Saxena R, Mowat AP, and from complete immune ablation in absence of haploidentical donor Mieli-Vergani G. Successful orthotopic liver transplantation for to effective HSCT in the presence of one. Furthermore, we have fulminant liver failure in a child with autosomal recessive reported other immune mediated post-LT complications, including chronic granulomatous disease. Transplantation 1995;60: de novo autoimmune hepatitis (13,14), post-transplant lymphopro- 1185-6. liferative disease (15–17), immune-mediated glomerulonephritis 2. Rodrigues F, Davies ED, Harrison P, Portmann B, Karani J, (18) and suboptimal immune responses to immunisation after LT McLaughlin J, Jones A, Veys P, Mieli-Vergani G, Hadzic N. (19). For post-transplant lymphoproliferative disease (PTLD) we Liver disease in primary immunodeficiencies. J Pediatr 2004; have been able to gather a massive clinical experience, which 145:333-9. provided a bulk of the UK national data on diagnosis and manage- ment of this potentially fatal condition.

Received January 28, 2018; accepted January 29, 2018. 10. Hadzic N, Layton M, Heaton ND, Rela M, Baker AJ, and Copyright # 2018 by European Society for Pediatric Gastroenterology, Mieli-Vergani G. Anti-thymocyte globulin, cyclosporin A and Hepatology, and Nutrition and North American Society for Pediatric granulocyte colony-stimulating factor for severe aplastic Gastroenterology, Hepatology, and Nutrition anaemia complicating paediatric liver transplantation. Eur J DOI: 10.1097/MPG.0000000000001916 Pediatr 1998;157:107-8.

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11. Tung J. Hadzic N, Layton M, Baker AJ, Dhawan A, Rela M, 20. Dignan FL, Wynn RF, Hadzic N, Karani J, Quaglia A, Heaton ND, Mieli-Vergani G. Bone marrow failure in children Pagliuca A, Veys P, Potter MN. BCSH/BSBMT guideline: with acute liver failure. J Pediatr Gastroenterology Nutr diagnosis and management of veno-occlusive disease (sinu- 2000;31:557-61. soidal obstruction syndrome) following haematopoietic stem 12. Hadzic N, Height S, Ball S, Rela M, Heaton ND, Veys P, cell transplantation. Br J Haematol 2013;163:444-57. Mieli-Vergani G. Evolution in the management of acute liver failure-associated aplastic anaemia in children: a single centre experience. J Hepatol 2008;48:68-73. LANGERHANS CELL HISTIOCYTOSIS 13. Pinkerton CR, Hann I, Weston CL, Mapp T, Wotherspoon A, Hobson, Kelly DA, Mieli-Vergani G, Hadzic N. Rees L, Burke About one third of children with Langerhans cell histiocy- M, Thomas AJ. Immunodeficiency-related lymphoprolifera- tosis (LCH) develop hepatic complications of this rare systemic tive disorders: prospective data from the disease, previously known as histiocytosis X. Typically, these Children’s Cancer Study Group Registry. Br J Haematol children develop progressive cholangiopathy, which occasionally 2002;118:456-61. can respond to chemotherapy. Ensuing portal hypertension can be severe, requiring repeated upper gastrointestinal endoscopies and 14. Messahel B, Taj MM, Hobson R, Hadzic N, Ramsay A, Hann I, Pinkerton R. Single agent efficacy of rituximab in childhood management of oesophageal varices. The most severe forms require immunosuppression related lymphoproliferative disease: a LT on the basis of progressive cholangiopathy and biliary cirrhosis. United Kingdom Children’s Cancer Study Group (UKCCSG) However, this procedure could only be effective in the absence of retrospective review. Leuk Lymphoma 2006;47:2584-9. signs of ongoing LCH activity. Additional immunosuppression required may facilitate potentially fatal opportunistic infections. 15. Taj M, Hadzic N, Height S, Wotherspoon A, Burke M, Hobson R, Viskaduraki M, Pinkerton R. Long term outcome for Interestingly, these children remain at high risk of developing immune suppression and immune related lymphoproliferative PTLD after LT. We have reviewed King’s experience (23), includ- disorder: prospective data from the UK CCLG registry 1994- ing a seminal observation that the condition could recur in liver 2004. Leuk Lymphoma 2012;53:842-8. grafts after LT, when re-LT may be required (24). 16. Indolfi G, Waller S, Horsfield C, Hadzic N. Poststreptococcal 21. Kyrana S, Puppi J, Brock P, Hadzic N. Hepatic involvement in Acute Glomerulonephritis and Dense Deposit Disease After Langerhans cell histiocytosis, Hepatology 2013, 58:820A. Pediatric Liver Transplantation. Transplantation 2011;91(6): 22. Hadzic N, Pritchard J, Portmann B, Heaton N, Rela M, Webb e44-e46. D, Dhawan A, Baker A, Mieli-Vergani G. Recurrence of 17. Donati M, Zuckerman M, Dhawan A, Hadzic N, Heaton N, Langerhans cell histiocytosis in the grafts after liver North-Lewis P, Mieli-Vergani G. Response to varicella transplantation. Transplantation 2000;70:815-9. immunisation in pediatric liver transplant recipients. Trans- plantation 2000;70:1401-4. JUVENILE AUTOIMMUNE LIVER DISEASE HEPATIC COMPLICATIONS AFTER (GIORGINA MIELI-VERGANI, DIEGO VERGANI) Autoimmune liver disorders are inflammatory liver diseases HAEMATOPOIETIC STEM CELL characterized histologically by a dense mononuclear cell infiltrate TRANSPLANTATION in the portal tract that invades the surrounding parenchyma (inter- For a number of years our centre has been providing support face hepatitis), biochemically by increased levels of transaminases, in managing children after HSCT developing complications such as and serologically by the presence of circulating autoantibodies and graft-versus-host-disease, sinusoidal obstructive syndrome and high levels of immunoglobulin G (IgG), in the absence of a known drug hepatotoxicity. Given our extensive experience we have been aetiology. If left untreated the prognosis of these disorders is severe, asked to join a national panel to develop guidelines for management while they generally respond well to immunosuppression, which of hepatic complications. This UK national activity has resulted in should be instituted as soon as the diagnosis is made, because best several frequently cited publications helping prevention and man- results are obtained with early treatment. These conditions can agement of these life-threatening conditions. Some of these children present insidiously or with a picture of acute hepatitis. The juvenile have been referred for consideration of LT, which have been forms of autoimmune liver disease, whose prototype is autoimmune successful in some, but not in all children (20–22). hepatitis (AIH), have a more aggressive course than their adult counterparts. Pathogenic and clinical aspects of juvenile autoim- 18. Dignan FL, Clark A, Amrolia P, Cornish J, Jackson G, Mahendra P, Scarisbrick JJ, Taylor PC, Hadzic N, Shaw BE, mune liver disease have been the focus of intense research by 2 Potter MN; on behalf of the Haemato- Task Force of groups within the ESPGHAN society: the French group at the the British Committee for Standards in Haematology and the Hoˆpital Le Kremlin-Biceˆtre in Paris and the British group at King’s British Society for Blood and Marrow Transplantation. College Hospital in London. Both groups have published seminal Diagnosis and management of acute graft-versus-host disease. papers on the presentation, management and outcome of juvenile Br J Haematol 2012;158:30-45. autoimmune liver disease (1–6). A close collaboration between clinicians and basic scientists within tertiary paediatric hepatology 19. Dignan FL, Scarisbrick JJ, Cornish J, Clark A, Amrolia P, Jackson G, Mahendra P, Taylor PC, Shah P, Lightman S, centres has led to the elucidation of immune mechanisms involved Fortune F, Kibbler C, Andreyev J, Albanese A, Hadzic N, in the pathogenesis of autoimmune liver disease and in the discov- Potter MN, Shaw BE; on behalf of the Haemato-oncology ery of novel disease entities. The results of the past 4-decade Task Force of the British Committee for Standards in research in this field are summarised below. Haematology and the British Society for Blood and Marrow Transplantation. Organ-specific management and supportive AUTOIMMUNE HEPATITIS care in chronic graft-versus-host disease. Br J Haematol Two forms of AIH are recognized according to the type of 2012;158:62-78. autoantibody present in the serum. Type 1 AIH (AIH-1) is www.jpgn.org S123 Supplement JPGN Volume 66, Supplement 1, April 2018 seropositive for smooth muscle antibody (SMA) and/or antinuclear be promoting the formation of the massive inflammatory cell antibody (ANA) (7,8), while type 2 AIH (AIH-2) for liver/kidney infiltrate present at diagnosis. Whatever the initial trigger, it is microsomal type 1 (anti LKM-1) (9) and/or anti liver type 1 most probable that such a high number of activated inflammatory (anti-LC-1) (10) antibody. Both AIH types affect mainly females. cells cause liver damage. The different possible pathways that an AIH-1 accounts for two-thirds of the cases and presents often immune attack can follow to inflict damage on the hepatocyte are around puberty, whereas AIH-2 tends to present at a younger summarised in Figure 1. Over the past 4 decades, different aspects age, also during infancy, and more acutely than AIH-1. of this pathogenic scenario have been the focus of intense investi- gation by the King’s group. An impairment of immunoregulatory mechanisms has been described in AIH. Both children and young Pathogenic Mechanisms adults with this condition have low levels of T cells expressing the CD8 marker, and impaired suppressor cell function (12) which The typical histologic picture of AIH, characterized by a segregates with the possession of the HLA haplotype B08/ dense mononuclear cell infiltrate eroding the limiting plate and DRB103 (formerly B8/DR3), and can be corrected by therapeutic invading the parenchyma (interface hepatitis), first suggested that doses of corticosteroids (13). Furthermore, patients with AIH have auto-aggressive cellular immunity might be involved in its causa- been reported to have a specific defect in a subpopulation of T cells tion. Immuno-cytochemical studies have identified the phenotype controlling the immune response to liver-specific membrane anti- of the infiltrating cells. T lymphocytes mounting the alpha/beta T- gens (14). Further evidence for an impairment of immunoregulatory cell receptor predominate. Among the T cells, a majority are function in AIH has been obtained in the last decade (15–17). positive for the CD4 helper/inducer phenotype, and a sizable Amongst T cell subsets with potential immunosuppression function, minority are positive for the CD8 cytotoxic phenotype. Lympho- CD4þ T cells constitutively expressing the interleukin 2 receptor cytes of non–T-cell lineage are fewer and include (in decreasing (IL-2R) alpha chain (CD25) (regulatory T cells, T-regs) have order of frequency) natural killer cells (CD16/CD56 positive), emerged as the dominant immunoregulatory population (18). These macrophages, and B lymphocytes (11). A powerful stimulus must cells, which represent 5% to 10% of the total population of

FIGURE 1. Autoimmune attack to the hepatocyte. An autoantigen is presented to uncommitted T helper (Th0) lymphocytes within the HLA class II molecule of an antigen-presenting cell (APC) either in the regional lymph nodes or within the liver itself. Activated Th0 cells differentiate into TH1or TH2 cells in the presence of interleukin (IL)-12 or IL-4, respectively, and according to the nature of the antigen. This triggers a series of immune reactions determined by the cytokines they produce. TH1 cells secrete IL-2 and interferon (IFN)-g, which are cytokines that stimulate cytotoxic T lymphocytes (CTL), enhance expression of class I HLA molecules, induce expression of class II HLA molecules on the liver cells and activate macrophages. Macrophages (M) release IL-1 and tumor necrosis factor (TNF). TH2 cells secrete mainly IL-4, IL-10 and IL-13, and stimulate autoantibody production by B lymphocytes. Regulatory T cells (Treg) are derived from Th0 in the presence of transforming growth factor (TGF)-b. In the presence of defective Treg, hepatocyte destruction ensues from the engagement of damaging effector mechanisms, including CTL, cytokines released by TH1 and by activated macrophages, complement activation, or adhesion of natural killer (NK) cells to autoantibody-coated hepatocytes through their Fc receptors. TH17 cells produce the inflammatory cytokine IL-17 and derive from Th0 cells in the presence of TGF-b and IL-6. They are the focus of current investigations.

S124 www.jpgn.org JPGN Volume 66, Supplement 1, April 2018 Supplement peripheral CD4þ T lymphocytes, control the innate and the adap- (28,29). It is therefore conceivable that an as yet unknown virus tive immune responses by preventing the proliferation and effector infection may be at the origin of the autoimmune attack in AIH. function of autoreactive T cells. Their mechanism of action Titres of antibodies to liver-specific lipoprotein, a macro- involves mainly a direct contact with the target cells, and to a molecular complex present on the hepatocyte membrane, and to its lesser extent the release of immunoregulatory cytokines, such as well-characterized component asialoglycoprotein receptor, corre- interleukin 10 and tissue growth factor beta 1. late with the biochemical and histological severity of AIH (30,31). A numerical Treg impairment affects both children and Antibodies to alcohol dehydrogenase, a second well-defined com- adults with AIH. This defect is more evident at diagnosis than ponent of liver-specific lipoprotein, have been described in patients during drug-induced remission, although even then circulating with AIH (32). Immunofluorescence studies on monodispersed Treg frequencies fail to reach the levels seen in health suspensions of liver cells obtained from patients with AIH showed (15,19,20). The percentage of T-regs inversely correlates with that these cells are coated with antibodies in vivo (33). A pathogenic biomarkers of disease severity, suggesting that a reduction in role for these autoantibodies has been indicated by cytotoxicity regulatory T-cells favours autoimmune liver disease. Importantly, assays showing that autoantibody-coated hepatocytes from patients several studies from King’s show that Tregs from AIH patients at with AIH are killed when incubated with autologous (34) lympho- diagnosis are impaired in their ability to control the proliferation of cytes. The effector cell was identified as an Fc receptor–positive CD4 and CD8 effector cells compared to Tregs isolated from AIH mononuclear cell (34). T-cell clones obtained from liver biopsies of patients at remission or from healthy subjects (19). What causes children with AIH and expressing the gamma/delta T-cell receptor Treg impairment in AIH remains unclear. The King’s group has have been shown to be cytotoxic to a variety of targets but to recently observed that Tregs in AIH are defective in the expression preferentially kill liver-derived cells as opposed to cell lines derived of CD39, an ectonucleotidase that initiates an ATP/ADP hydrolysis from other organs (35). cascade culminating with the generation of immunosuppressive The establishment of cell lines and clones has shown that the adenosine. CD39þ Tregs from AIH patients are therefore defective majority of T-cell clones obtained from the peripheral blood and a in their ectoenzymatic activity and inhibition of TH17-cell pro- proportion of those from the liver of patients with AIH are CD4 inflammatory function. CD39pos Tregs from AIH patients are also positive and use the conventional alpha/beta T-cell receptor (35– unstable upon pro-inflammatory challenge (21), suggesting that 38). Some of these CD4-positive clones were further characterized defective immuno-regulation in AIH might result not only from and were found to react with partially purified antigens, such as reduced Treg number and function, but also from increased con- crude preparations of liver cell membrane or liver-specific lipopro- version of Tregs into effector cells. tein (36), and with purified asialoglycoprotein receptor (36,39) or The same group have also reported that effector CD4 T-cells recombinant CYP2D6 (37) and to be restricted by HLA class II isolated from patients with AIH are less susceptible to the regula- molecules in their response. Because CD4 is the phenotype of Th tory control exerted by Tregs. This defect is linked to reduced cells, T cell clones were investigated for their ability to help expression of the inhibitory receptor T-cell-immunoglobulin-and- autologous B-lymphocytes in the production of immunoglobulin mucin-domain-containing-molecule-3 (Tim-3), which upon liga- in vitro (36,39). Indeed, their co-culture with B-lymphocytes tion of galectin-9 expressed by Tregs, induces effector cell death resulted in a dramatic increase in autoantibody production. (22). Hepatocytes from patients with AIH, in contrast to normal The possible role of TH17 cells in the pathogenesis of AIH is hepatocytes, express HLA class II molecules (23), and, although under investigation. TH17 cells contribute to autoimmunity by lacking the antigen-processing machinery typical of APCs, they producing the proinflammatory cytokines IL-17, IL-22, and may present peptides through a bystander mechanism. Given the TNF-a, and inducing hepatocytes to secrete IL-6, which further impaired regulatory function and the inappropriate expression of enhances TH17 activation. TH17 cells have been shown to be HLA class II antigens on the hepatocytes, it is conceivable that an elevated in the circulation and liver of patients with AIH (40). autoantigenic peptide is presented to the helper/inducer cells, leading to their activation. Although there is no direct evidence as yet that an autoantigenic peptide is presented and recognized, Animal Model activation of helper cells has been documented in AIH (11,24). Animal models of human disorders help in the understanding These activated cells possess the CD4 phenotype, and their numbers of mechanisms of disease and in devising novel modes of treatment. are highest when the disease is most active. Though several models of AIH have been published, none of them Most advances in the study of T cells have occurred in AIH- recapitulates faithfully the human disease. The King’s group, in 2, since the knowledge that cytochrome P4502D6 (CYP2D6) is the collaboration with groups in Yale and Montreal, have recently main autoantigen (25) has enabled the characterization of both CD4 developed a model based on the HLA-DR3 transgenic mouse by and CD8 T-cells targeting this cytochrome. One study has shown immunization with a DNA plasmid coding for human CYP2D6/ that CD4 T cells from patients with AIH-2 positive for the predis- FTCD fusion protein. FTCD (formiminotransferase cyclodeami- posing HLA allele DRB10701 recognize 7 regions of CYP2D6 nase) is the target antigen of anti-LC1 antibody in AIH-2 (41). (26), 5 of which have later been shown to be also recognized by Importantly, immunization with CYP2D6/FTCD fusion protein CD8 T cells (27). A high number of interferon-gamma producing leads to increased transaminase levels, development of autoanti- CD4 T cells and CD8 T cells is associated with biochemical bodies and to a histological picture mimicking the human disease— evidence of liver damage, suggesting a combined cellular immune including interface hepatitis and fibrosis—more closely than other attack. What triggers the immune system to react to an autoantigen published models, supporting a strong association between HLA is unknown. A lesson may be learned by the study of humoral and AIH (42). autoimmune responses during viral infections. Thus, studies aimed at determining the specificity of the LKM-1 antibody, present in both the juvenile form of AIH and in some patients with chronic NOVEL DISEASE ENTITIES HCV infection, have shown a high amino acid sequence homology The exposure to unique clinical material in tertiary Paediatric between the HCV polyprotein and CYP2D6, the molecular target of Liver Centres, together with a keen interest in trying to unravel anti-LKM-1, thus implicating a mechanism of molecular mimicry the immunopathogenesis of liver disease, has led to the description as a trigger for the production of anti LKM-1 in HCV infection of 3 novel entities: autoimmune sclerosing cholangitis, de novo www.jpgn.org S125 Supplement JPGN Volume 66, Supplement 1, April 2018 autoimmune hepatitis after liver transplantation and giant cell colonoscopy, should be part of the evaluation of all children with hepatitis with Coombs’ positive haemolytic anaemia. liver disease associated with autoimmune features to be able to distinguish ASC from AIH. Children with ASC respond usually well to the same immu- Autoimmune Sclerosing Cholangitis nosuppressive treatment used in AIH, that is, prednisolone induc- tion, followed by prednisolone and azathioprine maintenance (5), Sclerosing cholangitis is an uncommon disorder, character- with resolution of liver test abnormalities within a few months in ized by chronic inflammation and fibrosis of the intrahepatic and/or most patients. Ursodeoxycholic acid is usually added at a dose of 15 extrahepatic bile ducts. In childhood, sclerosing cholangitis may to 20 mg/kg per day. However, the medium- to long-term prognosis occur as an individual disease or may develop in association with a of ASC is worse than that of AIH because of progression of bile duct wide variety of disorders, including Langerhans’ cells histiocytosis, disease despite treatment in some 50% of patients, with 20% of immunodeficiency, psoriasis, cystic fibrosis, and chronic inflam- them eventually requiring liver transplantation (5,45). Reactivation matory bowel disease. In a retrospective study of paediatric scle- of the liver disease often follows flares of the intestinal disease in rosing cholangitis in the 1980s the King’s group observed that 40% ASC patients with IBD. It is therefore essential to control the bowel of the patients had initially been diagnosed as having AIH because pathology to avoid progression of liver disease. they had clinical, biochemical, immunologic, and histologic fea- tures indistinguishable from AIH (43). In these patients cholangi- De-novo Autoimmune Hepatitis After Liver ography was performed during follow up because of the appearance of biochemical and/or histological changes of cholestasis/bile duct Transplantation disease. The sequence of diagnoses was then interpreted as an In the late 1990s, the King’s group observed that AIH can evolution from AIH to sclerosing cholangitis, when, in fact, the arise de novo after liver transplantation in children who had not concurrence of these diseases had not been excluded by cholangio- been transplanted for autoimmune liver disease (46). Characteristic graphic studies performed at presentation. of this condition is a histological picture of interface hepatitis and In an attempt to assess the relative incidence of juvenile AIH multilobular collapse associated with increased IgG levels and and ASC, a prospective study was initiated at King’s College positive autoantibodies (46). These include ANA, SMA, and clas- Hospital in 1984 and patients enrolled over a period of 16 years sical anti-LKM-1, but also atypical anti-LKM-1, staining the renal (5). Interim results were published in 2001 and the patient cohort is tubules but not the liver. After the original report, de novo AIH being followed up to date. In this study, all children with increased following liver transplant has been confirmed by several studies transaminase levels, and associated serological (ie, positive auto- both in adult and paediatric patients (47,48) and has been reported to antibodies, high IgG levels) and histological (ie, interface hepatitis) be more frequent in steroid-free antirejection regimens (49,50). features of autoimmune liver disease underwent a cholangiogram at Importantly, treatment with prednisolone and azathioprine using the the time of presentation, independently from the presence of same schedule for classical AIH, concomitant with reduction of the biochemical or histological evidence of cholestasis. Surveillance calcineurin inhibitor dose, is highly effective in de novo AIH, enteroscopy to investigate for possible IBD was performed in all leading to excellent graft and patient survival. It is of interest that cases, independently from symptoms. Approximately 50% of the these patients do not respond satisfactorily to the standard anti- patients enrolled in this prospective study had alterations of the bile rejection treatment schedule, making it essential to reach an early ducts characteristic of sclerosing cholangitis, although they were diagnosis to avoid graft loss. generally less advanced than those observed in adult primary sclerosing cholangitis. These patients were diagnosed as having autoimmune sclerosing cholangitis (ASC). A quarter of the children Giant Cell Hepatitis With Coombs Positive with ASC, despite abnormal cholangiograms, had no histological Haemolytic Anaemia features that suggested bile duct involvement, and the diagnosis of sclerosing cholangitis was only possible because of the cholangio- In 1981, the French group reported for the first time a rare graphic studies. Virtually all ASC patients were seropositive for form of systemic autoimmunity characterised by giant cell hepatitis ANA and/or SMA. In contrast to AIH, which had a clear female and Coombs-positive haemolytic anaemia of the immunoglobulin preponderance, ASC was diagnosed in a similar proportion of boys G-positive C type (51). Of the original 4 children reported, 3 died of and girls. The mode of presentation of ASC was similar to that of liver failure, while one responded to immunosuppressive treatment AIH-1. IBD was present in 45% of children with ASC compared to with prednisone and azathioprine. Several case reports, totalling 18 20% of those with typical AIH, and 90% of children with ASC had patients, followed the original description. The disorder presents in greatly increased serum IgG levels. At the time of presentation, early childhood, usually between one month and 2 years of age, and standard liver function tests did not help in discriminating between affects both boys and girls. Liver histology is characterised by AIH and ASC, although the alkaline phosphatase/aspartate amino extensive giant cell transformation, while interface hepatitis is rare. transferase ratio was significantly higher in ASC. Peripheral anti- A family history of autoimmunity is present in 30% of cases and nuclear neutrophil antibody (pANNA), which are seen in adult some 20% of affected children have circulating autoantibodies primary sclerosing cholangitis and in inflammatory bowel disease, similar to those of classic AIH (52). were present in 74% of patients with ASC compared with 45% of The evolution of the haemolytic anaemia is often indepen- patients with AIH-1 and 11% of those with AIH-2. HLA studies dent of the evolution of the hepatitis. At times it is the presenting show that in the UK susceptibility to ASC is conferred by the symptom; at times it may not be clinically apparent during the possession of HLA DRB11301 (44). Evolution from AIH to ASC investigation of hepatitis; relapses of the anaemia may occur even was documented in one patient in the published prospective series when the hepatitis is under control. Occasionally autoimmune (5) and has been observed in 2 further patients during follow up thrombocytopenia complicates the clinical picture (52,53). Giant (45), suggesting that AIH and ASC are part of the same pathologic cell hepatitis with Coombs positive haemolytic anaemia has vari- process. Imaging of the biliary system by magnetic resonance able severity and variable response to immunosuppressive treat- cholangiopancreatography (MRCP), followed by endoscopic retro- ment. First line treatment consists of predniso(lo)ne and grade cholangiography if MRCP is not informative, as well as azathioprine, but a long period of high-dose steroids is necessary

S126 www.jpgn.org JPGN Volume 66, Supplement 1, April 2018 Supplement to achieve a response. Relapse during early steroid withdrawal is 13. Nouri-Aria KT, Donaldson PT, Hegarty JE, et al. HLA A1-B8-DR3 and very frequent. Cyclosporine and intravenous immunoglobulin G suppressor cell function in first-degree relatives of patients with auto- have been used to obtain a more rapid control of the disease (52). In immune chronic active hepatitis. J Hepatol 1985;1:235–41. refractory cases, anti-CD20 monoclonal antibody therapy has been 14. Vento S, Hegarty JE, Bottazzo G, et al. Antigen specific suppressor used with success (52,54). A particularly severe case, refractory to cell function in autoimmune chronic active hepatitis. Lancet 1984;1: all other modes of treatment, has shown complete resolution of the 1200–4. 15. Longhi MS, Ma Y, Bogdanos DP, et al. Impairment of CD4(þ)CD25(þ) disease with alemtuzumab therapy (55). The reported mortality/ regulatory T-cells in autoimmune liver disease. J Hepatol 2004;41: liver transplant rate is 39%. The disease can recur after liver 31–7. transplant (56). The largest long-term series published to date 16. Longhi MS, Meda F, Wang P, et al. Expansion and de novo generation of comes from the French group, and shows that after a median of potentially therapeutic regulatory T cells in patients with autoimmune 21 years of follow up, 12 of 16 patients were alive, one after liver hepatitis. Hepatology 2008;47:581–91. transplant, and 6 had successfully stopped immunosuppressive 17. Longhi MS, Hussain MJ, Mitry RR, et al. Functional study of treatment (52). CD4þCD25þ regulatory T cells in health and autoimmune hepatitis. J Immunol 2006;176:4484–91. 18. Shevach EM, McHugh RS, Piccirillo CA, et al. Control of T-cell CONCLUSIONS activation by CD4þ CD25þ suppressor T cells. Immunol Rev Over the past 4 decades, researchers within the ESPGHAN 2001;182:58–67. 19. Ferri S, Longhi MS, De Molo C, et al. A multifaceted imbalance of T community have elucidated several clinical and pathogenic aspects cells with regulatory function characterizes type 1 autoimmune hepa- of juvenile autoimmune liver disease, which have resulted in titis. Hepatology 2010;52:999–1007. improved disease recognition and management. They have played 20. Longhi MS, Ma Y, Mitry RR, et al. Effect of CD4þ CD25þ regulatory a major role in the establishment and running of the International T-cells on CD8 T-cell function in patients with autoimmune hepatitis. Autoimmune Hepatitis Group (IAIHG), which has established the J Autoimmun 2005;25:63–71. criteria for the diagnosis and management of AIH (57–59), and 21. Grant CR, Liberal R, Holder BS, et al. Dysfunctional CD39(POS) which meets twice a year during the major international European regulatory T cells and aberrant control of T-helper type 17 cells in and American conferences, where various aspects of autoimmune autoimmune hepatitis. Hepatology 2014;59:1007–15. liver disease in adults and children are discussed. The next task of 22. Liberal R, Grant CR, Holder BS, et al. The impaired immune regulation of autoimmune hepatitis is linked to a defective galectin-9/tim-3 path- the IAIHG is the creation of an international registry to collect way. Hepatology 2012;56:677–86. patient data from all centres willing to participate. Such registry will 23. Lobo-Yeo A, Senaldi G, Portmann B, et al. Class I and class II major foster a fruitful collaboration leading to a better definition and histocompatibility complex antigen expression on hepatocytes: a study management of the various forms of autoimmune liver disease and in children with liver disease. Hepatology 1990;12:224–32. to designing clinical trials in large patient cohorts. The registry will 24. Lobo-Yeo A, Alviggi L, Mieli-Vergani G, et al. Preferential activation of also provide a unique platform for research. helper/inducer T lymphocytes in autoimmune chronic active hepatitis. Clin Exp Immunol 1987;67:95–104. 25. Gueguen M, Meunier-Rotival M, Bernard O, et al. Anti-liver kidney REFERENCES microsome antibody recognizes a cytochrome P450 from the IID 1. Maggiore G, Bernard O, Homberg JC, et al. Liver disease associated subfamily. J Exp Med 1988;168:801–6. with anti-liver-kidney microsome antibody in children. J Pediatr 26. Ma Y, Bogdanos DP, Hussain MJ, et al. Polyclonal T-cell responses to 1986;108:399–404. cytochrome P450IID6 are associated with disease activity in autoim- 2. Codoner-Franch P, Bernard O, Maggiore G, et al. Clinical and im- mune hepatitis type 2. Gastroenterology 2006;130:868–82. munological heterogeneity of anti-liver-kidney microsome antibody- 27. Longhi MS, Hussain MJ, Bogdanos DP, et al. Cytochrome P450IID6- positive autoimmune hepatitis in children. J Pediatr Gastroenterol Nutr specific CD8 T cell immune responses mirror disease activity in 1989;9:436–40. autoimmune hepatitis type 2. Hepatology 2007;46:472–84. 3. Maggiore G, Porta G, Bernard O, et al. Autoimmune hepatitis with 28. Manns MP, Griffin KJ, Sullivan KF, et al. LKM-1 autoantibodies initial presentation as acute hepatic failure in young children. J Pediatr recognize a short linear sequence in P450IID6, a cytochrome P-450 1990;116:280–2. monooxygenase. J Clin Invest 1991;88:1370–8. 4. Gregorio GV, Portmann B, Reid F, et al. Autoimmune hepatitis in 29. Kerkar N, Choudhuri K, Ma Y, et al. Cytochrome P4502D6(193-212): a childhood: a 20-year experience. Hepatology 1997;25:541–7. new immunodominant epitope and target of virus/self cross-reactivity in 5. Gregorio GV, Portmann B, Karani J, et al. Autoimmune hepatitis/ liver kidney microsomal autoantibody type 1-positive liver disease. sclerosing cholangitis overlap syndrome in childhood: a 16-year pro- J Immunol 2003;170:1481–9. spective study Hepatology 2001;33:544–53. 30. Jensen DM, McFarlane IG, Portmann BS, et al. Detection of antibodies 6. Gregorio GV, Portmann B, Mowat AP, et al. A 12-year-old girl with directed against a liver-specific membrane lipoprotein in patients with antimitochondrial antibody-positive autoimmune hepatitis. J Hepatol acute and chronic active hepatitis. N Engl J Med 1978;299:1–7. 1997;27:751–4. 31. McFarlane BM, McSorley CG, Vergani D, et al. Serum autoantibodies 7. Mackay IR, Taft LI, Cowling DC. Lupoid hepatitis. Lancet 1956;27: reacting with the hepatic asialoglycoprotein receptor protein 1323–6. (hepatic lectin) in acute and chronic liver disorders. J Hepatol 1986; 8. Johnson GD, Holborow EJ, Glynn LE. Antibody to smooth muscle in 3:196–205. patients with liver disease. Lancet 1965;2:878–9. 32. Ma Y,Gaken J, McFarlane BM, et al. Alcohol dehydrogenase: a target of 9. Homberg JC, Abuaf N, Bernard O, et al. Chronic active hepatitis humoral autoimmune response in liver disease. Gastroenterology associated with antiliver/kidney microsome antibody type 1: a second 1997;112:483–92. type of autoimmune hepatitis. Hepatology 1987;7:1333–9. 33. Vergani D, Mieli-Vergani G, Mondelli M, et al. Immunoglobulin on 10. Bridoux-Henno L, Maggiore G, Johanet C, et al. Features and outcome the surface of isolated hepatocytes is associated with antibody- of autoimmune hepatitis type 2 presenting with isolated positivity for dependent cell-mediated cytotoxicity and liver damage. Liver 1987;7: anti-liver cytosol antibody. Clin Gastroenterol Hepatol 2004;2:825–30. 307–15. 11. Senaldi G, Portmann B, Mowat AP, et al. Immunohistochemical features 34. Mieli-Vergani G, Vergani D, Jenkins PJ, et al. Lymphocyte cytotoxicity of the portal tract mononuclear cell infiltrate in chronic aggressive to autologous hepatocytes in HBsAg-negative chronic active hepatitis. hepatitis. Arch Dis Child 1992;67:1447–53. Clin Exp Immunol 1979;38:16–21. 12. Nouri-Aria KT, Lobo-Yeo A, Vergani D, et al. T suppressor cell function 35. Wen L, Ma Y, Bogdanos DP, et al. Pediatric autoimmune liver diseases and number in children with liver disease. Clin Exp Immunol 1985;61: the molecular basis of humoral and cellular immunity. Curr Mol Med 283–9. 2001;1:379–89. www.jpgn.org S127 Supplement JPGN Volume 66, Supplement 1, April 2018

36. Wen L, Peakman M, Lobo-Yeo A, et al. T-cell-directed hepatocyte 48. Mieli-Vergani G, Vergani D. De novo autoimmune hepatitis after liver damage in autoimmune chronic active hepatitis. Lancet 1990;336: transplantation. J Hepatol 2004;40:3–7. 1527–30. 49. Venick RS, McDiarmid SV, Farmer DG, et al. Rejection and steroid 37. Lohr H, Manns M, Kyriatsoulis A, et al. Clonal analysis of liver- dependence: unique risk factors in the development of pediatric post- infiltrating T cells in patients with LKM-1 antibody-positive autoim- transplant de novo autoimmune hepatitis. Am J Transplant 2007;7: mune chronic active hepatitis. Clin Exp Immunol 1991;84:297–302. 955–63. 38. Lohr H, Treichel U, Poralla T, et al. Liver-infiltrating T helper cells in 50. Evans H. Progressive histological damage in liver allografts following autoimmune chronic active hepatitis stimulate the production of auto- pediatric liver transplantation. Hepatology 2006;43:1109–17. antibodies against the human asialoglycoprotein receptor in vitro. Clin 51. Bernard O, Hadchouel M, Scotto J, et al. Severe giant cell hepatitis with Exp Immunol 1992;88:45–9. autoimmune hemolytic anemia in early childhood. J Pediatr 1981;99: 39. Lohr H, Fleischer B, Michel G, et al. Hepatitis C virus antibody secretion 704–11. in vitro by peripheral blood lymphocytes. J Hepatol 1992; 14:112–7. 52. Maggiore G, Sciveres M, Fabre M, et al. Giant cell hepatitis with 40. Zhao L, Tang Y, You Z, et al. Interleukin-17 contributes to the autoimmune hemolytic anemia in early childhood: long-term outcome pathogenesis of autoimmune hepatitis through inducing hepatic inter- in 16 children. J Pediatr 2011;159:127–32e1. leukin-6 expression. PLoS One 2011;6:e18909. 53. Hadzic N, Portmann B, Lewis I, et al. Coombs positive giant cell 41. Lapierre P, Hajoui O, Homberg JC, et al. Formiminotransferase cyclo- hepatitis—a new feature of Evans’ syndrome. Arch Dis Child deaminase is an organ-specific autoantigen recognized by sera of 1998;78:397–8. patients with autoimmune hepatitis. Gastroenterology 1999;116:643–9. 54. Miloh T, Manwani D, Morotti R, et al. Giant cell hepatitis and auto- 42. Yuksel M, Wang Y, Tai N, et al. A novel ‘‘humanized mouse’’ model for immune hemolytic anemia successfully treated with rituximab. JPe- autoimmune hepatitis and the association of gut microbiota with liver diatr Gastroenterol Nutr 2007;44:634–6. inflammation. Hepatology 2015;62:1536–50. 55. Rovelli A, Corti P, Beretta C, et al. Alemtuzumab for giant cell hepatitis 43. el-Shabrawi M, Wilkinson ML, Portmann B, et al. Primary sclerosing with autoimmune hemolytic anemia. J Pediatr Gastroenterol Nutr cholangitis in childhood. Gastroenterology 1987;92 (5 pt 1):1226–35. 2007;45:596–9. 44. Underhill J, Ma Y, Bogdanos DP, et al. Different immunogenetic 56. Melendez HV, Rela M, Baker AJ, et al. Liver transplant for giant cell background in autoimmune hepatitis type 1, type and autoimmune hepatitis with autoimmune haemolytic anaemia. Arch Dis Child sclerosing cholangitis. J Hepatol 2002;36(suppl 1):156A. 1997;77:249–51. 45. Scalori A, Heneghan M, Hadzic N, et al. Outcome and survival in 57. Johnson PJ, McFarlane IG. Meeting report: International Autoimmune childhood onset autoimmune sclerosing cholangitis and autoimmune Hepatitis Group. Hepatology 1993;18:998–1005. hepatitis: a 13-year follow up study. Hepatology 2007;46S:555A. 58. Alvarez F, Berg PA, Bianchi FB, et al. International Autoimmune 46. Kerkar N, Hadzic N, Davies ET, et al. De-novo autoimmune hepatitis Hepatitis Group Report: review of criteria for diagnosis of autoimmune after liver transplantation. Lancet 1998;351:409–13. hepatitis. J Hepatol 1999;31:929–38. 47. Vergani D, Mieli-Vergani G. Autoimmunity after liver transplantation. 59. Hennes EM, Zeniya M, Czaja AJ, et al. Simplified criteria for the Hepatology 2002;36:271–6. diagnosis of autoimmune hepatitis. Hepatology 2008;48:169–76.

S128 www.jpgn.org SUPPLEMENT

Chapter 6.3. Studies on Hepatic Metabolic Disorders Driven by ESPGHAN Members: The Case of Alpha1-Antitrypsin Deficiency, Cystic Fibrosis, and Urea Cycle Defects

Giulia Paolella, Giovanna Alfano, and Pietro Vajro

ystic fibrosis (CF), alpha1-antitrypsin deficiency (A1ATD), these clinical premises, 3 recent studies, conducted on CFTR and urea cycle defects (UCD) are well known inborn meta- knockout Cftr/ mice and wild-type controls, shed light on the bolicC disorders characterized by specific abnormalities that may pathogenetic mechanisms of impaired biliary function in CF. severely affect one or more organ systems, including the liver. Dominique Debray demonstrated that Cftr/ and CftrDF508 mice Hepatic involvement may be and/or became the overriding problem have defects in gallbladder emptying that disrupt enterohepatic burdened by difficult management. As there are not completely circulation of biliary acids (BA) and create a cholecystohepatic effective medical therapies, it may require sooner or later liver shunt that restricts the amount of toxic secondary BA entering the transplantation. In the last 3 decades many efforts have been made liver (7); in 2 studies coauthored by Henkjan Verkade it has by ESPGHAN members in getting further insights and improved been shown that LD in Cftr/ mice is not related to increased clinical management of these rare hepatic metabolic disorders. bile hydrophobicity but probably to alterations in intestinal bacterial biotransformation of bile salts; smaller quantity of faecal CYSTIC FIBROSIS Bacteroides bacteria found in Cftr/ suggest Cftr dependent alterations in intestinal bacterial biotransformation of bile salts CF (OMIM #219700) is a genetic multiorgan disorder caused (8). Furthermore, prolonged cholate exposure did not induce by mutations in the CF conductance regulator gene (CFTR), located CF-LD in Cftr/ mice (9). Further studies in Cftr/ mice on chromosome 7. The identification of CF gene was published for authored by Dominique Debray have suggested that a high fat diet the first time in 1989. CF manifestations are related to the disruption has a critical impact, mainly via gut dysbiosis, on the emergence of of exocrine function of the pancreas, intestinal glands, biliary tree, CF-related bile duct injury (10). bronchial glands, and sweat glands; infertility occurs in males and Cirrhosis in CF patients has been shown to be significantly females (1). Biliary obstruction and progressive periportal fibrosis associated with either homozygous or compound heterozygous resulting from lack/dysfunction of the CFTR at the apical mem- mutations in the MBL2 gene encoding mannose-binding lectin brane of bile duct cells determine a focal biliary cirrhosis. Extension (11,12). In a 2-stage case-control multicentric study coauthored of the initially focal fibrogenic process may lead to multilobular by Carla Colombo, Dominique Debray and Florence Lacaille, it has biliary cirrhosis, portal hypertension and eventually liver failure. been shown that SERPINA1 Z allele is a risk factor (odds Why some patients develop liver disease (LD), sometimes with ratio ¼ approximately 5) for LD in CF with portal hypertension progressive outcome is currently still uncertain (2,3). (13), adding therefore an important piece of jigsaw by clarifying that a rare variant with large penetrance (such as the Z allele) may CF-related Liver Disease be more useful than a common variant with low penetrance in screening for genetic polymorphism. In a cohort of 241 CF children, Thierry Lamireau and colleagues showed that cystic fibrosis-related liver disease Diagnosis and Management of (CF-LD) occurred mainly in the first decade of life (prevalence 41% at age 12 years) (4). Although LD does not influence the Advanced CF-LD clinical course of CF, in some patients it may progress rapidly and In the last 25 years the paediatric hepatology research made require LT. In an Italian series of 177 CF patients without LD, Carla important progress in the evaluation and management of CF-LD. Colombo described during a 14-year follow-up, 48 patients (mainly An interesting collaborative study coauthored by several ESP- with history of meconium ileus, male sex, or severe genotype) that GHAN members (14) led to recommend an updated clinically developed subsequent LD, 5 with cirrhosis (5). In 1990, an Italian useful diagnostic workup (including the more recent fibroscan study coauthored by Pietro Vajro, demonstrated that the gallbladder assessment) and the therapeutic and surgical management of oeso- hypokinesia with impaired/slower emptying predisposes CF phageal varices, integrating previous guidelines (15). Surgical patients to gallstones even in early childhood (6). Based also on portosystemic shunting may be considered to relieve portal hyper- tension in CF-LD patients without progressive liver failure and severe lung disease as an alternative to LT (15). Received January 28, 2018; accepted January 29, 2018. Giulia Paolella and Giovanna Alfano are first two authors and contributed Pietro Vajro proved that correct diagnosis of cirrhosis in CF equally to the article. patients may be difficult unless liver biopsy is made under laparos- Copyright # 2018 by European Society for Pediatric Gastroenterology, copy control (16). Among serological markers of advanced CF-LD Hepatology, and Nutrition and North American Society for Pediatric persistently high GGT levels (17), and serum hyaluronic acid Gastroenterology, Hepatology, and Nutrition concentrations (18), have shown quite specific features of increased DOI: 10.1097/MPG.0000000000001916 risk of cirrhosis and/or hepatic fibrogenesis. These studies were

JPGN Volume 66, Supplement 1, April 2018 S129 Supplement JPGN Volume 66, Supplement 1, April 2018 coauthored by Henkjan Verkade (17), Anil Dhawan and Giorgina susceptibility (32). The role of rare allelic variants in chronic liver Mieli-Vergani (18), ESPGHAN members. disease is even less clear; heterozygous rare allelic variants may In a multicenter study coauthored by Carla Colombo, severe result in transient early onset hepatopathy as recently reported by LD was shown to significantly increase the risk of developing CF- Pietro Vajro (33). Deficiency state of another serine proteinase related diabetes thus representing a red flag for earlier diabetes inhibitor, namely alpha 1-antichymotrypsin, may predispose to screening to identify and possibly treat glucose intolerance (19). obstructive lung disease and influence the course of LD (34). As UDCA exerts in mice a choleretic effect and influences the an example, in a case control study coauthored by Nedim Hadzic an bile salt fractional turnover rate and profile with a more hydrophilic identified single nucleotide polymorphism conferred a significant bile salt pool independent of the presence of functional CFTR (20). risk for LD. This was the first description of a genetic modifier of Early UDCA treatment revealed beneficial in patients at risk of LD in homozygous ZZ children (35). developing CF-LD, eg, those with meconium ileus (21). Based on Miranda et al (Nedim Hadzic, coauthored this study) have results of a large double-blind multicenter trial conducted by Carla developed a conformation-specific monoclonal antibody (2C1) that Colombo, UDCA appeared to improve clinical and biochemical recognizes pathological polymers formed by A1AT and demon- parameters. Brigitta Strandvick group in Sweden demonstrated the strated that Z and shutter domain mutants of A1AT form polymers efficacy of 2 years UDCA treatment with liver biopsies and liver with a shared epitope likely having a similar structure (36). function tests in 10 CF-LD patients aged from 8 to 28 years. This In a retrospective study on 42 children with ZZ A1ATD study showed that UDCA modulates inflammation in CF-LD and coauthored by Alain Dabadie and Emmanuel Jacquemin, UDCA improves liver morphology (22). Three retrospective studies con- therapy improved clinical status and liver tests in some children ducted or coauthored by a number of ESPGHAN members (23–25) with LD but not in those with most severe liver involvement. revealed that the common indications for LT in CF patients are Elevated initial levels of GGT and total bilirubin have been shown hepatic failure and/or severe portal hypertension with well-pre- of prognostic value for therapy effectiveness (37). More recently, in served pulmonary function. In these conditions, LT is also associ- a study coauthored by Ulrich Baumann it has been shown a positive ated with long-term beneficial effects on the nutritional status and correlation between simple laboratory parameters (number of pla- seems to favour bone mineralisation. (26). Deirdre Kelly and Carla telets and common liver function tests) and LT and/or death (38). Colombo coauthored the first European large survey on LT in The presence of arteriovenous anastomoses in the lungs (ie, hepato- patients with advanced CF-LD. This study highlighted that liver pulmonary syndrome) can be assessed by scintiscanning as in other failure, hypersplenism, gastrointestinal bleeding and malnutrition chronic liver diseases (39). In a retrospective study (n ¼ 21 children; represented the major indications for LT and that most European 1 with A1ATD) co-authored by Piotr Socha no correlation was liver centres perform LT before the development of end-stage liver found between the severity of hepato-pulmonary syndrome and the disease or overt pulmonary or other clinical decompensation (27). aetiology and stage of the underlying disease (39). These combined Furthermore, en bloc liver-pancreas transplantation could be an series of useful information may considerably help the paediatrician appealing option since it concurrently restores exocrine function to take decisions during patients’ difficult follow-up. and prevents insuline-dependent diabetes (25). In January 2016 during the ESPGHAN CF monothematic conference in Paris it has Liver Transplantation in Alpha1-Antitrypsin been discussed the need for a universal consensus on the definition of CF-LD to clarify disease stage and to identify relevant biomark- Deficiency Children ers (eg, biomarkers of intestinal bile salt malabsorption) to assess LT in A1ATD patients with decompensated disease offers disease severity. Future medical treatment approaches have been good long-term outcome (33,40), also in small babies (41), with also evaluated. CF-LD drug candidates other than drug targeting the excellent results achievable provided the reduction of waiting time causative CFTR (ie, CFTR potentiator ivacaftor and combination list as reported by Anil Dhawan, Giorgina Mieli-Vergani and therapy with lumacaftor, a CFTR corrector) are: bile acid analo- Nedim Hadzic (42). In a tertiary care centre LT in A1ATD was gues, Farnesoid X receptor (FXR) agonists, fibroblast growth factor the second common indication to LT (8.1%), preceded by biliary 1, and vitamin D receptors (28). atresia (41.9%) (40). This study was coauthored by Loreto Hierro and Paloma Jara. Based on results of a large retrospective study at King’s College coauthored by Giorgina Mieli-Vergani and Nedim ALPHA1-ANTITRYPSIN DEFICIENCY Hadzic, LT resulted to have significantly improved the prognosis of A1ATD (OMIM #613490) is not a rare disease but a disease LD associated with PiZZ A1ATD. Duration of jaundice, severity of that is rarely diagnosed (29). It is an autosomal recessive disorder histological features and biochemical abnormalities predict out- characterised by both liver and lung injury. Pulmonary manifesta- come in early stage of the disease (43). In PiZZ patients with portal tions become evident in adults, whereas LD occurs already in hypertension, oesophageal varices, or deterioration of hepatic func- paediatric age. Mutation incidence is around 1:2500 live birth in tion, LT should not be delayed, as reported in a single centre Europe (1). In Sweden, the prevalence of A1ATD (PiZZ) is around retrospective study (n ¼ 59 children homozygous for A1ATD) 1:1600. This prevalence was established by a screening program of coauthored by Piotr Socha, ESPGHAN member (44). all 200,000 newborns during the period 1972–1974 (30). The pathogenesis of cholestatic LD remains to be largely clarified, although liver injury in ZZ genotype is due to thoroughly investi- UREA CYCLE DISORDERS gated toxic effects of the abnormal A1AT molecule accumulating UCDs result from several defects in the metabolism of waste within the endoplasmic reticulum of liver cells. nitrogen derived from the breakdown of protein and other nitrogen- In a Swedish series of neonatal cholestasis, Bjo¨rn Fischler containing molecules. Severe deficiency or total absence of activity showed that A1ATD together with progressive familial intrahepatic of any of the first 4 in urea cycle or the cofactor producer cholestasis was the second most common diagnosis after extrahe- results in the accumulation of ammonia and other precursor metab- patic biliary atresia, contrary to other countries where A1ATD is olites. The incidence of UCD is estimated to be at least 1:35,000 reported to be a rarer cause (31). Only 12% to 15% of individuals births; partial defects may make the figure much higher (45,46). with ZZ genotype develop LD due to the influence of other Hepatic involvement, for example, liver steatosis initially, is genetic and epigenetic/behavioural factors which determine this a frequent finding (47) with more frequent severe damage in

S130 www.jpgn.org JPGN Volume 66, Supplement 1, April 2018 Supplement (ASL) deficiency (48,49) and indication for LT, in all other UCD conditions the indication is transcarbamylase deficiency (OTCD). Episodes of hepatocellular based on the failure to maintain metabolic compensation with injury, liver dysfunction, and acute liver failure have been identified medical treatment as discussed in the article coauthored by Lorenzo in a high proportion of children with symptomatic OTCD. Two D’Antiga (54,55). Hepatocytes transplantation represents a more recent studies both coauthored by Etienne Sokal, described the and more promising therapeutic approach for patients with liver- initial presentation (48) and the evolving clinical phenotype (49) of based metabolic disorders. Anil Dhawan and Etienne Sokal have 343 UCD compared to 452 patients with Organic acidurias (OA). It pioneered in ESPGHAN the concept of hepatocyte transplantation was found that neurological impairment is common in OAD and as an alternative to LT in patients with liver-based metabolic UCD, whereas the involvement of other organs follows a disease- disorders, focusing on protocols (isolation of human hepatocytes specific pattern. Hepatic involvement was more frequent in UCD with collagenase perfusion, preparation in clean GMP conditions patients, in particular in ASL. with cells meeting criteria of function and lack of microbial Methyl malonic aminoacidemia and propionic acidemia are contamination, infusion of cells intraportally into the patient’s the 2 main Organic Acidurias which present also . liver) and on aetiologies of liver disease in which this technique Their clinical neonatal presentation is very similar, with neonatal has been used (including UCDs) (56). The Brussel’s cell transplant period onset, when feeds containing protein have been started. If not program has further demonstrated the long term engraftment of recognized and treated promptly, OA patients progress to severe hepatocytes with de novo enzyme activity following hepatocyte brain damage and death. Those presenting in the neonatal period transplantation (57), and has pioneered the second generation of cell have a worse prognosis. Immediate treatment is based on removal of therapy, using in vitro expanded liver derived stem cells as a new toxic metabolites. Long-term treatment is dietary protein restriction source of cells to treat patients with inborn errors of the urea cycle and essential amino acid supplementation. Hyperornithinaemia- (58,59). hyperammonaemia-homocitrullinuria syndrome (Mitochondrial Even if LT has an excellent survival rate this is not exempt Ornithine Transporter Deficiency) (OMIM #238970) is an autoso- from peri- and post-operative complications. Hepatocyte cell trans- mal recessive disorder caused by a defect in ornithine translocase. plantation instead avoids the risks of major surgery and can help The clinical presentation is variable, including episodic hyperam- bridge a patient to whole-organ transplantation or leave the option monaemia, chronic neurological manifestations and hepatic of gene therapy, if and when it becomes available in future. derangement which may appear as a fulminant hepatitis-like con- The ability to reproducibly generate a well-characterized dition. Its early recognition in the scenario of hepatic failure is source of engraftable and functional liver cells remains a challenge. important due to possible recovery without resorting to LT as In this regard, the use of metabolic profiling (NMR spectroscopy of reported by Pietro Vajro, in a case series of 3 children with urine and plasma) could be a promising method for evaluating the fulminant hepatitis (50). efficacy of cell infusions and the capability for the early detection of Neonatal intrahepatic cholestasis caused by deficiency response to therapy in real time. In 2009 it has been published the (NICCD) also known as Neonatal-onset type II citrullinemia first successful hepatocyte transplantation as a bridge to auxiliary (OMIM #605814), is caused by homozygous or compound hetero- partial orthotopic LT in a child antenatally diagnosed with severe zygous mutation in the SLC25A13 gene (1). Mutations have a ornithine transcarbamylase deficiency. In this single patient study carrier rate of 1:65 in Japan and China, whereas they are much coauthored by Anil Dhawan, NMR spectroscopic profiles of urine less frequent in the Western world. The same gene is involved also and plasma has been used for the first time for evaluating the in the adult-onset phenotype (citrullinemia 2, OMIM #603471) efficacy of cell infusions. NMR profiles indicated that the disrupted which is mainly characterized by fatty liver and late recurrent urea cycle could be normalized by hepatocyte cell infusion and this hyperammonemic neurological disturbance due to the decreased was confirmed using orthogonal partial least-squares-based chemo- associated liver-specific argininosuccinate synthetase (ASS) metrics (60). enzyme activity. The limited availability of donor tissue implies the search for NICCD typically presents as a self-limiting neonatal intra- new resources of liver tissue for isolation of high-quality hepato- hepatic cholestasis. Fatty liver, and increased serum citrulline may cytes. The group of King’s College with Anil Dhawan and Giorgina make it resembling an UCD. However, NICCD patients show a Mieli-Vergani suggested the use of segment IV with or without the unique carbohydrate aversion in contrast to protein dislike seen in caudate lobe obtained from split-liver procedures. Tissue-derived other UCD or in lysinuric protein intolerance. Fondness for proteins stem/progenitor cells and pluripotent stem cell-derived cells repre- and lipids should therefore not be discouraged (51,52). ESPGHAN sent now a new opportunity to remove/reduce challenges of hepa- members, Ulrich Baumann and Patrick McKiernan, reviewed this tocyte cells transplantation. (61). subject and reported 2 cases of NICCD children from UK, one Finally, cryopreserved cells have proved to allow short- to Caucasian and one of Pakistan origin. Both had typical clinical and medium-term metabolic control and urea synthesis while waiting biochemical changes with a diagnosis confirmed by previously for OLT (62). unreported mutations in the SLC25A13 gene. Citrin deficiency needs to be considered in the diagnosis of any neonate with an unexplained cholestasis independent from ethnic origin. MRI and CONCLUSIONS spectroscopy will probably become a powerful tool to measure the Several ESPGHAN members’ studies in this group of meta- effects of pharmacological neuroprotective approaches (53). bolic based liver diseases have substantially contributed to shed light on several disease-mechanisms, understanding why some Transplantation in Urea Cycle Defect affected patients develop a progressive outcome and other do not, and evaluating old and new medical therapies. In patients with severe types of UCD, LT also in case of For CF, A1ATD, and some UCD, LT has become an normal liver function remains the most effective means of prevent- accepted treatment capable of correcting totally or in part, the ing further hyperammonemic crises; it is associated with excellent metabolic defect while replacing the diseased organ, and sometimes survival rate if performed before irreversible brain damage. Auxil- may even improve pulmonary function (eg, in CF-LD). Correct iary partial orthotopic LT has shown encouraging results in UCD. timing for organ replacement has been an issue largely explored. In Apart from neonatal onset of OTC deficiency which is a clear UCD, and in some OA it may be more difficult in phenotypes with a www.jpgn.org S131 Supplement JPGN Volume 66, Supplement 1, April 2018

(still) little or even absent liver injury, and potential involvement of 21. Siano M, De Gregorio F, Boggia B, et al. Ursodeoxycholic acid other organ system. Ideally, LT should be considered as soon as treatment in patients with cystic fibrosis at risk for liver disease. Dig possible when dietary and medical treatments cannot reliably Liver Dis 2010;42:428–31. prevent metabolic decompensation and damage of severe extrahe- 22. Lindblad A, Glaumann H, Strandvik B. A two-year prospective study of patic organs (eg, CNS) (63–65). Auxiliary partial orthotopic LT, the effect of ursodeoxycholic acid on urinary bile acid excretion and and hepatocyte cells transplantation appear feasible alternatives. liver morphology in cystic fibrosis-associated liver disease. Hepatology 1998;27:166–74. 23. Milkiewicz P, Skiba G, Kelly D, et al. Transplantation for cystic fibrosis: Acknowledgments: We are indebted with Drs Debray, Colombo, outcome following early liver transplantation. J Gastroenterol Hepatol Fishler, Nemeth, Sokal, Dhawan for helpful discussion and reviewing 2002;17:208–13. the final draft of the Chapter. 24. Lamireau T, Martin S, Lallier M, et al. Liver transplantation for cirrhosis in cystic fibrosis. Can J Gastroenterol 2006;20:475–8. 25. Miguel M, Andres AM, Lopez-Santamaria M, et al. Liver transplanta- REFERENCES tion in children with cystic fibrosis: experience in our centre and 1 1. Online Mendelian Inheritance in Man An Online Catalog of Human preliminary results with a combined en bloc liver-pancreas graft. Eur Genes and Genetic Disorders Updated 17 May 2016. Availableat: http:// J Pediatr Surg 2012;22:60–6. www.omim.org/. 26. Colombo C, Costantini D, Rocchi A, et al. Effects of liver transplanta- 2. Colombo C. Liver disease in cystic fibrosis. Curr Opin Pulm Med tion on the nutritional status of patients with cystic fibrosis. Transpl Int 2007;13:529–36. 2005;18:246–55. 3. Colombo C, Battezzati PM. Hepatobiliarymanifestations of cystic 27. Melzi ML, Kelly DA, Colombo C, et al. Liver transplant in cystic fibrosis. Eur J Gastroenterol Hepatol 1996;8:748–54. fibrosis: a poll among European centers. A study from the European 4. Lamireau T, Monnereau S, Martin S, et al. Epidemiology of liver disease Liver Transplant Registry. Transpl Int 2006;19:726–31. in cystic fibrosis: a longitudinal study. J Hepatol 2004;41:920–5. 28. Debray D, Narkewicz MR, Bodewes FAJA, et al. Cystic fibrosis-related 5. Colombo C, Battezzati PM, Crosignani A, et al. Liver disease in cystic liver disease: research challenges and future perspectives. J Pediatr fibrosis: a prospective study on incidence, risk factors, and outcome. Gastroenterol Nutr 2017;65:443–8. Hepatology 2002;36:1374–82. 29. de Serres FJ. Alpha-1 antitrypsin deficiency is not a rare disease but a 6. Santamaria F, Vajro P, Oggero V, et al. Volume and emptying of the disease that is rarely diagnosed. Environ Health Perspect 2003;111: gallbladder in patients with cystic fibrosis. J Pediatr Gastroenterol Nutr 1851–4. 1990;10:303–6. 30. Sveger T. Liver disease in alpha1-antitrypsin deficiency detected by 7. Debray D, Rainteau D, Barbu V, et al. Defects in gallbladder emptying screening of 200,000 infants. N Engl J Med 1976;294:1316–21. and bile acid in mice with cystic fibrosis transmembrane conductance 31. Fischler B, Papadogiannakis N, Nemeth A. Aetiologicalfactors in regulator deficiencies. Gastroenterology 2012;142:1581–91. neonatalcholestasis. Acta Paediatr 2001;90:88–92. 8. Bodewes FA, Bijvelds MJ, de Vries W, et al. Cholic acid induces a Cftr 32. Hinds R, Hadchouel A, Shanmugham NP, et al. Variable degree dependent biliary secretion and liver growth response in mice. PLoS of liver involvement in siblings with PiZZ alpha-1-antitrypsin One 2015;10:e0117599. (Ref as Bodewes FA et al, 2015 B). deficiency-related liver disease. J Pediatr Gastroenterol Nutr 2006; 9. Bodewes FA, van der Wulp MY, Beharry S, et al. Altered intestinal bile 43:136–8. salt biotransformation in a cystic fibrosis (Cftr/) mouse model with 33. Mandato C, Poeta M, Petrillo P, et al. Early onset transient liver hepato-biliary pathology. J Cyst Fibros 2015;14:440–6. disease and rare allelic variants alpha-1 antitrypsin deficiency 10. Debray D, Brot L, El Mourabit H, et al. Impact of diet on gut microbiota (A1ATD). Plowell and Mheerlen Dig Liver Dis 2016;48(suppl 4):e254. and liver phenotype in cftr knockout mice. 47th ESPGHAN annual 34. Faber JP, Poller W, Olek K, et al. The molecular basis of alpha meeting. J Pediatr Gastroenterol Nutr 2014;58(suppl 1):92 (abstract). 1-antichymotrypsin deficiency in a heterozygote with liver and lung 11. Gabolde M, Hubert D, Guilloud-Bataille M, et al. The mannose binding disease. J Hepatol 1993;18:313–21. lectin gene influences the severity of chronic liver disease in cystic 35. Chappell S, Hadzic N, Stockley R, et al. A polymorphism of the alpha1- fibrosis. J Med Genet 2001;38:310–1. antitrypsin gene represents a risk factor for liver disease. Hepatology 12. Tomaiuolo R, Degiorgio D, Coviello DA, et al. An MBL2 haplotype and 2008;47:127–32. ABCB4 variants modulate the risk of liver disease in cystic fibrosis 36. Miranda E, Pe´rez J, Ekeowa UI, et al. A novel monoclonal antibody to patients: a multicentre study. Dig Liver Dis 2009;41:817–22. characterize pathogenic polymers in liver disease associated with 13. Bartlett JR, Friedman KJ, Ling SC, et al. Genetic modifiers of liver alpha1-antitrypsin deficiency. Hepatology 2010;52:1078–88. disease in cystic fibrosis. JAMA 2009;302:1076–83. 37. Lykavieris P, Ducot B, Lachaux A, et al. Liver disease associated with 14. Debray D, Kelly D, Houwen R, et al. Best practice guidance for the ZZ alpha1-antitrypsin deficiency and ursodeoxycholic acid therapy in diagnosis and management of cystic fibrosis-associated liver disease. children. J Pediatr Gastroenterol Nutr 2008;47:623–9. J Cyst Fibros 2011;10(Suppl 2):S29–36. 38. Pferdmenges DC, Baumann U, Mu¨ller-Heine A, et al. Prognostic 15. Debray D, Lykavieris P, Gauthier F, et al. Outcome of cystic fibrosis- marker for liver disease due to alpha1-antitrypsin deficiency. Klin associated liver cirrhosis: management of portal hypertension. J Hepatol Padiatr 2013;225:257–62. 1999;31:77–83. 39. Teisseyre M, Szymczak M, Swiatek-Rawa E, et al. Scintiscanning 16. Esposito C, Garipoli V, Vecchione R, et al. Laparoscopy-guided biopsy in diagnostics of hepatopulmonary syndrome. Med Sci Monit 2001; in diagnosis of liver disorders in children. Liver 1997;17:288–92. 7(suppl 1):255–61. 17. Bodewes FA, van der Doef HP, Houwen RH, et al. Increase of serum 40. Migliazza L, Lo´pez Santamarı´a M, Murcia J, et al. Long-term survival g-glutamyltransferase associated with development of cirrhotic cystic expectancy after liver transplantation in children. J Pediatr Surg fibrosis liver disease. J Pediatr Gastroenterol Nutr 2015;61:113–8. (Ref 2000;35:5–7. as Bodewes FA et al, 2015 A). 41. Va´zquez J, Ga´mez M, Santamarı´a ML, et al. Liver transplantation in 18. Wyatt HA, Dhawan A, Cheeseman P, et al. Serum hyaluronic acid small babies. J Pediatr Surg 1993;28:1051–3. concentrations are increased in cystic fibrosis patients with liver disease. 42. Prachalias AA, Kalife M, Francavilla R, et al. Liver transplantation Arch Dis Child 2002;86:190–3. for alpha-1-antitrypsin deficiency in children. Transpl Int 2000;13: 19. Minicucci L, Lorini R, Giannattasio A, et al. Liver disease as risk factor 207–10. for cystic fibrosis-related diabetes development. Acta Paediatr 2007; 43. Francavilla R, Castellaneta SP, Hadzic N, et al. Prognosis of alpha-1- 96:736–9. antitrypsin deficiency-related liver disease in the era of paediatric liver 20. Bodewes FA, Wouthuyzen-Bakker M, Bijvelds MJ, et al. Ursodeox- transplantation. J Hepatol 2000;32:986–92. ycholate modulates bile flow and bile salt pool independently from the 44. Bakula A, Socha P, Pawlowska J, et al. Good and bad prognosis of alpha- cystic fibrosis transmembrane regulator (Cftr) in mice. Am J Physiol 1-antitrypsin deficiency in children: when to list for liver transplanta- Gastrointest Liver Physiol 2012;302:G1035–42. tion. Transplant Proc 2007;39:3186–8.

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45. Batshaw ML, Tuchman M, Summar M, et al. A longitudinal study of 55. Darwish AA, McKiernan P, Chardot C. Paediatric liver transplantation urea cycle disorders. Mol Genet Metab 2014;113:127–30. for metabolic disorders. Part 2: Metabolic disorders with liver lesions. 46. Ah Mew N, Lanpher BC, Gropman A, et al. Urea cycle disorders Clin Res Hepatol Gastroenterol 2011;35:271–80. overview. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. 56. Dhawan A, Strom SC, Sokal E, et al. Human hepatocyte transplantation. GeneReviews1 [Internet]. Seattle, WA: University of Washington, Methods Mol Biol 2010;640:525–34. Seattle; 1993–2018. 57. Ste´phenne X, Najimi M, Sibille C, et al. Sustained engraftment and 47. Vajro P, Lenta S, Socha P, et al. Diagnosis of nonalcoholic fatty liver tissue enzyme activity after liver cell transplantation for argininosucci- disease in children and adolescents: position paper of the ESPGHAN nate lyase deficiency. Gastroenterology 2006;130:1317–23. Hepatology Committee. J Pediatr Gastroenterol Nutr 2012;54:700–13. 58. Sokal EM. Treating inborn errors of liver metabolism with stem 48. Ko¨lker S, Garcia-Cazorla A, Valayannopoulos V, et al. The phenotypic cells: current clinical development. J Inherit Metab Dis 2014;37: spectrum of organic acidurias and urea cycle disorders. Part 1: the initial 535–9. presentation. J Inherit MetabDis 2015;38:1041–57. Erratum in: J 59. Sokal EM, Ste´phenne X, Ottolenghi C, et al. Liver engraftment and Inherit Metab Dis 2015;38:1155-6. Cazorla, Angeles Garcia [corrected repopulation by in vitro expanded adult derived human liver stem cells to Garcia-Cazorla, Angeles]. in a child with ornithine carbamoyltransferase deficiency. JIMD Rep 49. Ko¨lker S, Valayannopoulos V, Burlina AB, et al. The phenotypic 2014;13:65–72. spectrum of organic acidurias and urea cycle disorders. Part 2: the 60. Legido-Quigley C, Cloarec O, Parker DA, et al. First example of evolving clinical phenotype. J Inherit Metab Dis 2015;38:1059–74. hepatocyte transplantation to alleviate ornithine transcarbamylase de- Erratum in: J Inherit Metab Dis 2015;38:1157-8. Garcia Cazorla, ficiency, monitored by NMR-based metabonomics. Bioanalysis 2009;1: Angeles [corrected to Garcia-Cazorla, Angeles]. 1527–35. 50. Fecarotta S, Parenti G, Vajro P, et al. HHH syndrome (hyperor- 61. Mitry RR, Dhawan A, Hughes RD, et al. One liver, three recipients: nithinaemia, hyperammonaemia, homocitrullinuria), with fulminant segment IV from split-liver procedures as a source of hepatocytes for hepatitis-like presentation. J Inherit Metab Dis 2006;29:186–9. cell transplantation. Transplantation 2004;77:1614–6. 51. Hutchin T, Preece MA, Hendriksz C, et al. Neonatal intrahepatic 62. Ste´phenne X, Najimi M, Smets F, et al. Cryopreserved liver cell cholestasis caused by citrin deficiency (NICCD) as a cause of liver transplantation controls ornithine transcarbamylase deficient disease in infants in the UK. J Inherit Metab Dis 2009;32(suppl 1): patient while awaiting liver transplantation. Am J Transplant 2005;5: S151–5. 2058–61. 52. Vajro P, Veropalumbo C. Citrin deficiency: learn more, and don’t forget 63. Vajro P, Strisciuglio P, Houssin D, et al. Correction of phenylketonuria to add it to the list of neonatal cholestasis and the NASH trash bin. after liver transplantation in a child with cirrhosis. N Engl J Med J Pediatr Gastroenterol Nutr 2010;50:578–9. 1993;329:63. 53. Braissant O, McLin VA, Cudalbu C. Ammonia toxicity to the brain. 64. Burdelski M. Liver transplantation in metabolic diseases: current status. J Inherit Metab Dis 2013;36:595–612. Pediatr Transplant 2002;6:361–3. 54. Fagiuoli S, Daina E, D’Antiga L, et al. Monogenic diseases that can be 65. Meyburg J, Hoffmann GF. Liver transplantation for inborn errors of cured by liver transplantation. J Hepatol 2013;59:595–612. metabolism. Transplantation 2005;80:S135–7.

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Chapter 6.4. Diagnostic Progress in Cholestasis

Roderick Houwen

he causes of neonatal cholestasis were largely an enigma in could be subdivided subsequently, initially into those with a high the 1960s. Of course it was clear that some infants presenting GGT and those with a low GGT. Peter Whitington then described Tin the neonatal period had an anatomical obstruction of the bile partial biliary diversion, a surgical procedure that delays or prevents ducts: (extrahepatic) biliary atresia. In most patients, however, a progression in some of the patients with low GGT PFIC (6). nonspecific histological picture was seen on liver biopsy: ‘‘neonatal Yet the pathogenesis of PFIC, and most of the other diseases hepatitis,’’ characterized by ballooning multinucleated hepatocytes mentioned, remained unclear. However in a large Dutch kindred and accumulation of bile pigment in hepatocytes and bile canaliculi with BRIC, biochemically characterized by low GGT cholestasis (Fig. 1). Some of these patients had a congenital infection, or a and clinically by episodes of severe itching, ESPGHAN member metabolic disorder like galactosemia or tyrosinaemia, but in most Roderick Houwen in Utrecht and Nelson Freimer in San Francisco no definitive diagnosis could be made. Similarly the differential demonstrated that all patients shared a stretch of DNA, originating diagnosis in older children presenting with cholestasis was limited from a common ancestor, on which the causative gene should reside to infectious agents, anatomical obstruction (eg, choledochal cyst), (7). With the human genome project in its early stages, the actual toxic agents or some diseases that were obviously genetic, like identification of the gene needed far more patients however. To this Wilson disease and Summerskill disease (benign recurrent intra- aim DNA of additional patients was collected in several countries, hepatic cholestasis, BRIC), while the cause in a large proportion of such as the remote Far Oer islands, where Niels Tygstrup had children remained unknown. Resolving this puzzle and improving described a cluster of patients with BRIC (8) (Fig. 2). Low GGT diagnosis was made possible by dedicated clinicians, many of them cholestasis was also a prominent feature in Byler disease, a form of ESPGHAN members, who were able to discern patterns amongst PFIC. Alex Knisely, then in Pittsburgh, had collected DNA of children with cholestasis, initially aided by histological techniques, several patients with Byler disease in the eponymous kindred. Using and towards the end of the millennium deploying more and more the these samples the—yet unknown—gene involved in Byler disease ever-increasing possibilities that genetics and cell biology had was shown to be allelic to the—yet unknown—gene causing BRIC to offer. in the patients from Holland (9); some years later the same group At the end of the 1960s it was already noted that some identified the causative gene, FIC1, now named ATP8B1 (10). The children with neonatal hepatitis had a deficiency of a1-antitrypsin actual function of its protein product is still not totally clear deficiency (1), a protein that at that time had only recently been however, but is probably necessary to stabilize the canalicular identified. Clumps of this glycoprotein could also be visualized with membrane of the hepatocyte. Bile canaliculi are ultrastructurally special staining techniques in the hepatocytes of these patients, remarkable in ATP8B1 deficiency: microvilli are missing and establishing a1-antitrypsin deficiency as a frequent cause of neo- coarsely granular material is observed in the canalicular lumen natal cholestasis. Daniel Alagille at the Hoˆpital Biceˆtre in Paris first (11). Not all patients with low GGT PFIC, however, shared this described hypoplasia of the intrahepatic bile ducts, in combination feature, and in some without it their disorder did not map to the with specific extrahepatic features that included pulmonary-artery ATP8B1 locus (11). Through genetic studies in patients with this lesions (2), followed by other descriptions of arteriohepatic dyspla- second form, ESPGHAN member Richard Thompson from King’s sia, now commonly known as ‘‘Alagille syndrome.’’ From this College in London, working with Laura Bull in San Francisco, same hospital ESPGHAN member Giuseppe Maggiore described a identified the locus and subsequently the gene involved, ABCB11, subgroup of patients with low GGT (Gamma Glutamyl Transferase) cholestasis, children who obviously did not have a good prognosis (3). Another cholestatic disease characterized by a low serum GGT and generally fatal in the first years of life was described amongst the Amish: Byler disease (4). Other rare diseases causing intrahe- patic cholestasis were also described or better defined in the first decades after the founding of ESPGHAN: Aagenaes disease, Greenland Eskimo childhood cholestasis, North American Indian childhood cirrhosis, renal tubular insufficiency combined with cholestasis and arthrogryposis (ARC syndrome), as well as others. The pathogenesis of these supposedly heterogeneic disorders remained a mystery. As many, but not all, of them had a fatal course, with unrelenting cholestasis, cirrhosis, and ultimately death, the need for better categorisation became pressing, especially in those patients that did not have distinguishing extrahepatic features. To this end the concept of progressive intrahepatic familial cholestasis (PFIC) was introduced (5), to describe this specific subset, which

Received January 28, 2018; accepted January 29, 2018. Copyright # 2018 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric FIGURE 1. Neonatal hepatitis in a patient with ABCB11 deficiency, Gastroenterology, Hepatology, and Nutrition with ballooning of multinucleated hepatocytes and orange-brown DOI: 10.1097/MPG.0000000000001916 bile pigment visible. Original magnification 200Â (HE).

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FIGURE 2. Left to right: Roderick Houwen, Jenneke Juijn (technician), Bjarni a Steig (local doctor) and Niels Tygstrup (hepatologist) at the Far Oer Islands for visiting BRIC patients. which turned out to encode BSEP, the long sought bile salt export but this should be avoided, as it is imprecise. It also overlaps with pump (12). Further work showed that both entities, ATP8B1 the more recent habit to label TJP2 deficiency as PFIC4, which deficiency and ABCB11 deficiency have severe progressive forms, should be avoided for the same reason. Over time the use of PFIC1, respectively PFIC type 1 and PFIC type 2, and mild, recurrent 2 and 3 will also be less common, as it will be replaced by ATP8B1 forms, respectively BRIC type 1 and BRIC type 2, with progression deficiency, ABCB11 deficiency and ABCB4 deficiency respec- from the mild to the more severe form being seen in some patients. tively. Given the long history of the term PFIC it is to be expected Solving the riddle of the high GGT variant of PFIC, that is, that this will take some time. type 3, was done by more old-fashioned techniques. Deficiency of Identification of the genetic background of many of these the mouse orthologue of multidrug resistance protein 3 (MDR3), defects and the elucidation of its pathophysiology has dramatically identified while researching resistance to cytotoxic drugs, was changed the diagnosis of cholestasis in neonates and older children. known to cause cholestasis, through insufficient phosphatidylcho- While diagnostic possibilities in neonatal cholestasis were very line transfer into the canalicular lumen. This disturbed the delicate limited 50 years ago, now the number of different diagnoses to be balance between phosphatidylcholine and bile salts, with noncha- considered in an infant with neonatal cholestasis can exceed 100. peroned bile salts causing damage to small bile ducts. ESPGHAN For older children the list is even longer. However by using clinical member Emanuel Jacquemin at Biceˆtre demonstrated the absence reasoning, based on the presence of extrahepatic features (eg, of MDR3 in the liver of some patients with high GGT cholestasis typical facies, renal or cardiac abnormalities, etc), some basic (13), and working with Ronald Oude Elferink in Amsterdam, biochemical results (eg, GGT, alpha-1-antitrypsin level, etc), serol- subsequently identified mutations in ABCB4, encoding MDR3, ogy for identifying common infectious agents and histopathologic in PFIC type 3 patients (14). findings in the liver, the number of diseases that should be consid- With the completion of the human genome project and the ered in a particular case can be reduced considerably. Using the development of automated sequencing, genetic techniques progres- tools that biochemistry presently has to offer an underlying meta- sively became more sophisticated and efficient. Using these oppor- bolic disease can generally be identified, although the diagnostic tunities it was increasingly simple to dissect the genetic background process can be long and cumbersome. Similarly a genetic diagnosis of specific cholestatic syndromes. While at the end of the millen- can be made by sequencing the genes that might be involved in a nium still hundreds of patients were necessary to identify ATP8B1 particular patient. To this aim, Sanger sequencing, which was ideal and ABCB11, described above, as well as Jag1, the gene mutated in when only 1 or 2 genes had to be considered, is gradually being most patient with Alagille syndrome, for identifying VPS33, the replaced by next generation sequencing (NGS) and whole exome gene mutated in ARC syndrome, 6 years later, only 29 patients were sequencing (WES). With these methods all genes, whether 5, 50, or necessary (15), and for the recent linking of TJP2 mutations to 150, that might cause cholestasis in a particular patient are being another form of low GGT cholestasis no more than twelve patients scrutinized for pathogenic mutations (18). As this technique is still were sufficient (16). relatively new its exact place with respect to metabolic investiga- Low GGT cholestasis can also be caused by defects in the tions in urine and/or blood has still to be defined. bile acid synthesis pathway (17). Each disorder is extremely rare For many of these diseases a diagnosis is mainly important with only a few cases published. For some time it was customary to for determining prognosis and genetic counselling, as available use the term PFIC4 for these defects, or for some of these defects, therapeutic options, apart from liver transplantation in end stage www.jpgn.org S135 Supplement JPGN  Volume 66, Supplement 1, April 2018 liver disease, are very few so far. For patients with low GGT PFIC a 3. Maggiore G, Bernard O, Riely CA, et al. Normal serum gamma- partial biliary diversion can be performed, with the better results glutamyl transpeptidase activity identifies groups of infants with idio- generally obtained in patients with mild mutations and thus some pathic cholestasis with poor prognosis. J Pediatr 1987;111:251–2. residual function of the canalicular transporter, either ATP8B1 or 4. Clayton RJ, Iber FL, Ruebner BH, et al. Byler disease: fatal familial ABCB11. Using an alternative pathway to excrete the toxic bile intrahepatic cholestasis in an Amish kindred. Am J Dis Child 1969; acids, by giving rifampicin, will reduce serum bile acid levels in 117:112–24. 5. Ballow M, Margolis CZ, Schatel B, et al. Progressive familial intrahe- some, while ursodeoxycholic acid (UDCA) may have a favourable patic cholestasis. Pediatrics 1973;51:998–1007. effect (19). UDCA also reduces liver damage in ABCB4 deficiency 6. Emond JC, Whitington PF. Selective surgical management of progres- by protecting the membranes of cholangiocytes against bile defi- sive familial intrahepatic cholestasis. J Pediatr Surg 1995;30:1635–41. cient in phosphatidylcholine. In these patients too the effect of 7. Houwen RHJ, Baharloo S, Blankenship K, et al. Genome screening by UDCA is more pronounced when some residual function of the searching for shared segments: mapping a gene for benign recurrent ABCB4 transporter is present (19). intrahepatic cholestasis. Nat Genet 1994;8:380–6. Additional therapeutic options for genetic diseases in which 8. Tygstrup N, Jensen B. Intermittent intrahepatic cholestasis of unknown single genes are mutated, and no structural damage to the liver is etiology in five young males form the Faroe islands. Acta Med Scand present, are likely to become available in the next decades, 1969;185:523–30. 9. Carlton VEH, Knisely AS, Freimer NB. Mapping of a locus for although it is impossible to predict which technique(s) will be progressive familial intrahepatic cholestasis (Byler disease) to 18q21- commonly used. Gene therapy for liver disease, using adeno- q22, the benign recurrent intrahepatic cholestasis region. Hum Mol associated virus vectors, is now possible for small genes like Genet 1995;4:1049–53. F9, encoding coagulation factor IX, while for other diseases human 10. Bull LN, van Eijk MJT, Pawlikowska L, et al. A gene encoding a P-type trials are being planned after successes in animal models. CRISPR- ATPase mutated in two forms of hereditary cholestasis. Nat Genet Cas gene editing technology, if proven safe in humans, might 1998;18:219–24. also be widely used. Small molecules (proteostasis regulators) 11. Bull LN, Carlton VEH, Stricker NL, et al. Genetic and morphological can often induce or enhance the level of functioning protein in findings in progressive familial intrahepatic cholestasis (Byler disease patients with missense mutations inaspecificgene,whileagents [PFIC-1] and Byler syndrome): evidence for heterogeneity. Hepatology 1997;26:155–64. also have been, or are being, developed to permit protein tran- 12. Strautnieks SS, Bull LN, Knisely AS, et al. A gene encoding a liver scription or translation in patients with stop or splice site mutations specific ABC transporter is mutated in progressive familial intrahepatic (20). Liver cell transplantation, now hampered by limited avail- cholestasis. Nat Genet 1998;20:233–8. ability of hepatocytes and rather low efficiency, might benefit 13. Deleuze J, Jacquemin E, Dubuisson C, et al. Defect of multidrug- from new techniques to obtain large numbers of hepatocytes, resistance 3 gene expression in a subtype of progressive familial either through induced pluripotent stem cells or through organoid intrahepatic cholestasis. Hepatology 1996;23:904–8. technology (20). 14. De Vree JM, Jacquemin E, Sturm E, et al. Mutations in the MDR3 gene In conclusion, the last 50 years have seen a tremendous cause progressive familial intrahepatic cholestasis. Proc Natl Acad Sci increase in knowledge regarding common and less common causes USA1998;95:282–7. 15. Gissen P, Johnson CA, Morgan NV, et al. Mutations in VPS33B, of cholestasis in infancy and in older children. ESPGHAN members encoding a regulator of SNARE-dependent membrane fusion cause have made important contributions to these developments. It is to be arthrogryposis-renal dysfunction cholestasis (ARC) syndrome. Nat expected that in the next 50 years this knowledge will be capitalized Genet 2004;36:400–4. into better therapy for these children. 16. Sambrotta M, Strautnieks S, Papouli E, et al. Mutations in TJP2 cause progressive cholestatic liver disease. Nat Genet 2014;46:326–8. 17. Bove KE, Heubi JE, Balistreri WF, et al. Bile acid synthesis defects Acknowledgments: Figure 1 was kindly supplied by Prof Dr A and liver disease: a comprehensive review. Pediatr Dev Pathol 2004; Mu¨ller (Bonn) and Dr A Knisely (Graz). Dr Knisely also reviewed 7:315–34. drafts of the manuscript. 18. Togawa T, Sugiura T, Ito K, et al. Molecular genetic dissection and neonatal/infantile intrahepatic cholestasis using targeted next genera- tion sequencing. J Pediatr 2016;171:171–7.e1–4. REFERENCES 19. Stapelbroek JM, van Erpecum KJ, Klomp LWJ, et al. Liver disease 1. Sharp HL, Bridges RA, Krivit W, et al. Cirrhosis associated with alpha- associated with canalicular transport defects: current and future thera- 1-antitrypsin deficiency: a previously unrecognized inherited disorder. pies. J Hepatol 2010;52:258–71. J Lab Clin Med 1969;73:934–9. 20. Van der Woerd WL, Houwen RHJ, van de Graaf SFJ. Current and future 2. Alagille D, Estrada A, Hadchouel M, et al. Syndromic paucity of therapies for inherited cholestatic liver diseases. World J Gastroenterol interlobular bile ducts. J Pediatr 1987;110:195–200. 2017;23:763–75.

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Chapter 6.5. Paediatric Liver Transplantation

Martin M. Burdelski

n the late 1960s there was a remarkably sad experience in adult Below the age of 2 years there is a predominance of cholestatic and paediatric hepatology. In acute and chronic end-stage liver diseases, whereas in older children cirrhosis, acute hepatic failure, diseaseI medical treatment was just palliation without any curative metabolic diseases and cancer have an increasing frequency effect. Despite every effort, these patients were bound to die very (Fig. 2). This development has been enabled by the use of technical soon from liver coma, variceal bleeding, septicaemia and multiorgan variants of liver transplantation, which are described in the next failure. In Denver an American surgeon with an Austrian back- section. Technical variants are used today in about 24% of all ground, Thomas Starzl, was the first to make a switch from medical transplants, in contrast to the late 80s, where only less than 5% were therapy to surgical cure. A liver disease, which did not respond to performed in this modification (5). medical therapy anymore, was treated by liver transplantation. In 1968 the first successful liver transplant was performed in a child Contraindications suffering from extrahepatic biliary atresia. This patient survived almost 1 year demonstrating a proof of principle (1). This experience Contraindications for liver transplantation have reduced could only be gathered by a surgeon, who dared to go beyond significantly. Today, only active bacterial or viral infections are established frontiers. Thomas Starzl was such a person. accepted contraindications. Vascular malformations, as seen in Some years later Sir Roy Calne in England, Henri Bismuth in syndromic extra hepatic biliary atresia with preduodenal portal France and Rudolph Pichlmayr in Germany, and later Jean Bernard vein, aplasia of the infradiaphragmatic vena cava, azygos or Otte in Belgium started liver transplantation in adults and in hemiazygos continuation, situs inversus and polysplenia syndrome children (2–4). The success rates in the seventies and early have been regarded as contraindication for liver transplantation 1980s of the last century were limited, due to lack of effective until the end of the 80s but now are accepted. Even systemic immunosuppression and only slow progress in surgical experience. disorders such as cystic fibrosis or mitochondrial disorders in some One must keep in mind that liver surgery in these days was not manifestation are indications today. But the extent of indications commonly performed. and disregard of many contraindications enhanced the lack of donor In 1985 Sir Roy Calne, Henri Bismuth, and Rudolph Pichl- organs. These developments have been made possible by the work mayr initiated a central registry for liver transplantation which has of many ESPGHAN and NASPGHAN members. collected so far information about more than 110.000 liver trans- plants in Europe in both adult and paediatric recipients. This registry provides us with actual numbers and results of TRANSPLANT TECHNIQUES liver transplantation gained in all Europe (5). There has been an exponential increase in numbers of children and adults undergoing Full Size Organs liver transplantation after the pioneering days in the early 1980s Using a full size liver was only possible if the size of the until 2008, thereafter the curve is flattening (Fig. 1). The reason for donor organ and the liver of the recipient was almost identical. The this rise is the steady extension of indications and the reduction of blood group had to be at least compatible. Progress reports from possible contraindications at the same time. The plateau is caused transplant centres in Cambridge/Kings College, Paris, Brussels, and by the increasing lack of suitable donor organs in the last 10 years. Hannover (2,4,6) showed slowly improving results which was With regard to paediatric liver transplantation there was always a mainly due to improved immunosuppression by Cyclosporin A. lack of suitable donor organs of appropriate size and blood group The ESPGHAN members involved in these activities were Alec stimulating transplant surgeons and the hepatologists to invent Mowat in Kings College, Daniel Alagille in Paris, Etienne Sokal in innovative techniques and strategies. Brussels, and Martin Burdelski in Hannover. In small patients, such as children below 10 kg body weight, there were almost no suitable donor organs available. The most INDICATIONS AND CONTRAINDICATIONS FOR frequent indication for liver transplantation in those days was LIVER TRANSPLANTATION IN CHILDREN biliary atresia. Without Kasai procedure, life expectancy of these children was almost below 1 year. By consequence, most of these Indications transplant candidates died before a transplantation could be per- Indications for liver transplantation in children nowadays are formed. Thus, mortality on the waiting list was up to 30% in almost heterogenous. At the beginning of transplantation it was only extra every European transplant centre. Since this was unacceptable, hepatic biliary atresia, but now almost 40 years later cholestatic, innovative surgery was needed. noncholestatic liver disorders, metabolic cirrhotic disorders or noncirrhotic ones are accepted. Due to the availability of organs even acute fulminant liver failure is an important indication. The Reduced Size Organs percentage of individual indications varies with the age of children: The concept of this technique aimed to reduce the size of the donor organ to fit the need of the recipient. This was made possible by Received January 28, 2018; accepted January 29, 2018. the improved knowledge of the surgical anatomy of the liver as Copyright # 2018 by European Society for Pediatric Gastroenterology, described by Couinod (7). The rest of the organ was discarded. Hepatology, and Nutrition and North American Society for Pediatric Surgeons actively working on reduced size liver transplantation were Gastroenterology, Hepatology, and Nutrition Henri Bismuth in Paris (8) Jean Bernard Otte in Brussels (4) and DOI: 10.1097/MPG.0000000000001916 Rudolph Pichlmayr in Hannover (6). Even in Australia, this type of

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of splitting 1 donor liver into 2 parts had to follow the module principle. Both parts should have hepatic artery, portal vein, hepatic vein and bile duct. This aim was achieved by dividing the liver into the left lateral segment (segments 2 and 3) and the right lobe plus segment 4. By doing this, 1 donor liver was used to provide 2 grafts, 1 for an adult and 1 for a child. Teams in Hannover and Paris were the first to publish the technique (10,11). Two years later, the Chicago team published an analysis of this innovative surgery of split liver grafting (12). This procedure was extremely demanding: because cold ischaemia time had to be kept below 12 hours, 2 surgical and 2 anaesthetic teams had to work in parallel using 2 operating rooms. Blood bank supply had to be organized. All this happened mostly during nighttime because of logistic reasons. Later, the split liver technique was modified and used even to provide 2 organs for 2 adult recipients. Using right and left lobe or extended right (segment 1, 4–8 and 2–3) according to the need of the corresponding recipient. Since the results of the adult recipient initially were worse compared to the paediatric ones, the idea of in situ splitting was initiated (13) which helped to improve the results FIGURE 1. Development of liver transplantation in Europe (from: of the adult recipient to the same level as in the recipient of the left ELTR report 2013). lateral segment. This technique then was used throughout the world. liver transplantation was performed (9). Shortly after, in USA Living Related Liver Transplantation reduced size liver transplantation was used by Christoph Broelsch, a pupil of Rudolph Pichlmayr. However, discarding the rest of the Despite the use of full size, reduced size and split liver donor organ induced a shortage of donor organs for adult recipients. transplantation the lack of donor organs forced transplant surgeons to extent the frontiers once again. By gaining experience in reduced- Split Liver size and split liver transplantation and in liver resection for benign and malignant liver disease, the idea of living related liver trans- The idea of split liver transplantation was born out of plantation was generated. The first surgeons to dare take this step experience with reduced-size liver transplantation. The technique were in Brazil and Australia, forced to do so in desperate situations.

FIGURE 2. Indications for liver transplantation in 2 paediatric age groups (from: ELTR report 2013).

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A first series after establishing an ethical approval and based on patients, respectively. The 10-year patient survival in children surgical experience was performed in Chicago by Christoph below and above 2 years are 78% and 77%. Broelsch, who was supported by Peter Whittington, a member of However, there is a significant influence of the underlying NASPGHAN and his coworkers. Two years later, Broelsch started a disease on survival in the paediatric transplant population. The living related paediatric liver transplantation program in Hamburg, 10-year transplant survival in metabolic and cholestatic disease is Germany where he was supported by an ESPGHAN member, with 82% excellent. Children with acute hepatic failure and non- Martin Burdelski (14). This living related liver transplantation in classified cirrhosis do less well and have a 10-year transplant Hamburg was the first to be done in Europe. In Japan, Tanaka and survival of only 68 and 70% respectively (Fig. 4). colleagues published the first series of living related liver trans- There is a trend towards better results in the 10 year survival plantation in 1991. for patients receiving living donated organs compared to all other Using all these technical variants in paediatric liver trans- technical variants: 60% versus 57%, 55%, and 54%. This analysis plantation world wide, acute and chronic end stage liver disease in includes both paediatric and adult recipients (Fig. 5). Death or children can be treated effectively. retransplantation is reported predominantly in the first 6 months after transplantation in both adult and paediatric patients. A second Results of Paediatric Liver Transplantation peak in mortality is observed in more than 5 years after transplan- tation, most probably caused by adult patients with either high-risk To acquire meaningful results of paediatric liver transplan- comorbidity or malignant disease. Since the prevalence of organ tation it makes sense to analyse statistics in large series rather than rejection has been significantly reduced by using improved immu- to look for results of individual centres. Such statistics are presented nosuppression protocols (see Chapter 6.6) it is infection under the by ELTR (European Liver Transplant Registry) in Europe and even current immunosuppression which is the major cause of morbidity better by SPLIT (Studies of Pediatric Liver Transplantation and even mortality in the first year after transplantation. This Research Group) in North America. Experienced single centres finding may indicate that the actual immunosuppression is still may have less complications and better results, but the efficacy too intense and that this policy has to be reconsidered. of a method such as liver transplantation has to remeasured in multicentre reports. Complications After Pediatric Liver Transplantation Survival There are surgical and medical complications encountered Factors which may determine the outcome of liver trans- after paediatric liver transplantation. Surgical complications and plantation are indication, age of the recipient, type of transplant, strategies to prevent them are mostly reported by surgical teams in cold ischaemic time and of course skills of the individual surgeon single centre reports. The use of intraoperative Doppler-ultrasound and experience of PICU und paediatric transplant team. examinations reduced the vascular and biliary tract complications With regard to the age of the paediatric recipient, there is no significantly. In contrast to North America, multicentre studies have difference to be observed in children below or above the age of been rarely performed in Europe (see SPLIT). The first multicentre 2 years (Fig. 3). The ELTR report shows no significant difference in trial in paediatric liver transplantation was initiated by ESPGHAN the 10-year survival rate for these age groups in 4270 and 5414 members (15).

FIGURE 3. Survival after pediatric liver transplantation in children 2 years of age according to different indications (from: ELTR report 2013). www.jpgn.org S139 Supplement JPGN  Volume 66, Supplement 1, April 2018

FIGURE 4. Patient and graft survival after paediatric liver transplantation according to different age groups (from: ELTR report 2013).

This study compared immunosuppression with tacrolimus infections and liver fibrosis. Of major concern is further the and steroids with Ciclosporin microemulsion in combination with transition time, where paediatric patients have to accept the steroids and azathioprine. There is still a great deficit with regard to different attitude of adult hepatologists when they have grown- these multicentre studies in ESPGHAN although only these studies up to young adults. During this time many patients start to be can give useful informations. non-compliant with medical advice and are at risk of damaging Apart from early complications the main interest today is the transplant. on the long-term outcome and quality of life after paediatric These complications are affecting the quality of life in liver transplantation. The complications causing trouble are cal- children after liver transplantation even after reaching adulthood. cineurin-inhibitor induced renal impairment, arterial hypertension, The importance of these complications makes it an ideal subject for malignancies, diabetes mellitus, bone disease, chronic viral ESPGHAN driven multicentre studies. It will be a major task of the

FIGURE 5. Survival after liver transplantation according to type of graft in both paediatric and adult liver transplantation (from: ELTR report 2013).

S140 www.jpgn.org JPGN  Volume 66, Supplement 1, April 2018 Supplement hepatology committee of ESPGHAN to inaugurate such studies in 9. Ong TH, Lynch SV, Baldierson GA, et al. Reduced-size liver trans- the near future. plantation in children: an experience with 7 cases. Transpl Proc 1989;21:2443–4. REFERENCES 10. Pichlmayr R, Ringe B, Gubernatis G, et al. Transplantation of a donor 1. Starzl TE, Koep LJ, Schro¨ter GP, et al. Liver replacement for pediatric liver to 2 recipients (Splitting transplantation) a new method in the patients. Pediatrics 1979;63:825–9. further development of segmental transplantation. Langenbeck’s Arch 2. Jamieson NV, Calne RY, Rolles K, et al. Results and problems in Chir 1988;373:127–30. pediatric liver transplantation in the Cambridge/Kings College Hospital 11. Morino M, Castaing D, Bismuth H. A new technique in liver transplant: series: 1968 to July 1986. Transplant Proc 1987;19:2447–8. a single donor for 2 receivers/partial grafting. Minerva Chir 3. Pichlmayr R, Bro¨lsch C, Wonigeit K, et al. Experiences with liver 1988;43:2021–8. transplantation in Hannover. Hepatology (suppl 1):1984:56S–60S. 12. Emond JC, Whitington PF, Thistlethwaite J, et al. Transplantation of 4. Otte JB, deVille de Goyet J, de Hemptinne B, et al. Liver transplantation two patients with one liver. Analysis of preliminary experience with in children: University of Louvain Medical School (Brussels). Experi- split-liver grafting. Ann Surg 1990;212:14–22. ences with the first 139 patients. Clin Transpl 1989:143–52. 13. Rogiers X, Malago M, Habib M, et al. In-situ Splitting of the liver in 5. ELTR report 2013. heart beating cadaveric organ donor for transplantation in two recipi- 6. Burdelski M, Pichlmayr R, Ringe B, et al. Pediatric liver transplanta- ents. Transplantation 1995;59:1081–3. tion—ten years experience in Hannover. Clin Transpl 1987:55–62. 14. Broelsch CE, Burdelski M, Rogiers X, et al. Living donor for liver 7. Couinoud C. Le foie, etudes anatomiques et surigcales. Paris: Masson; transplantation. Hepatology 1994;20:49S–55S. 1957. 15. Kelly D, Jara P, Rodeck B, et al. Tacrolimus and steroids versus 8. Alagille D, Laurent J, Roy CC. Is there still a place for Kasai-procedure ciclosporin microemulsion, steroids and azathioprin in children under- in the treatment of extra hepatic biliary atresia? J Pediatric Gastro- going liver transplantation: randomized European multicentre trial. enterol 1989;9:405–6. Lancet 2004;364:1054–61.

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Chapter 6.6. The Role of ESPGHAN in Developing Effective Immunosuppression Following Paediatric Liver Transplantation

Deirdre Kelly

iver transplantation has transformed the lives of many children The use of induction immunosuppression with monoclonal by providing treatment for patients with fatal acute or chronic antibodies (IL-2 inhibitors) such as daclizumab, a humanised organL failure. The success of liver transplantation is related to the antibody and basiliximab, a chimeric antibody has allowed reduc- development of innovative surgery, but also the discovery and tion of CNI doses in the first instance (6) while the use of development of immunosuppressive agents. ESPGHAN’s role in maintenance immunosuppression with renal sparing drugs such establishing safe and effective immunosuppression in children post as mycophenolate mofetil or (Rapamycin) may reduce transplant is as follows: long-term renal dysfunction (7,8). A more recent approach is the development of steroid free immunosuppressive regimens, which  Educational role in discussing and debating the risks and reduce hypertension, stunting and the cosmetic of benefits through numerous postgraduate courses and Hepa- steroid therapy (9). tology Summer Schools. In 2012, 7 major ESPGHAN paediatric liver transplant  Research and clinical trials led by ESPGHAN members. centres combined their scientific efforts and created the ChilSFree  Establishment of the Chilsfree network (through the study, which examines the functional degree of immunosuppression Hepatology Committee), which led to the network accredita- after paediatric liver transplantation. Immune monitoring data are tion EnPrema. correlated with clinical events, such as the occurrence of acute cellular rejection or infection. Data documentation is accomplished via a purpose-built web-based database, the creation of which was DEVELOPMENT OF IMMUNOSUPPRESSION supported by ESPGHAN (10). The ChilsFree study is now embedded in the framework of Early immunosuppression (1) consisted of a combination of the European Paediatric Liver Transplantation Network EPLTN. anti-thymic globulin (ATG), azathioprine (AZA) and prednisolone, This network of European specialist centres is dedicated to pro- but it was not until the discovery of cyclosporine (CsA) (2) that the moting both clinical and scientific excellence in paediatric hepa- modern era of paediatric liver transplantation (LTx) began (3). The tology. The EPLTN has been recognized by the European cyclophilin binding CsA was followed by the discovery of FKBP- Medicines Agency EMA as a member of Enpr-EMA, the European 12 binding tacrolimus (Tac) both inhibiting the calcium-mediated Network of Paediatric Research at the EMA. Besides the ChilSFree activation of lymphocytes via calcineurin. study, EPLTN facilitates a number of other studies including work on risk factors of cardiovascular disease after paediatric liver STANDARD IMMUNOSUPPRESSION transplantation, and on health-related quality of life after paediatric The 2 calcineurin Inhibitors (CNI), Tacrolimus and Cyclo- liver transplantation. sporin became the primary immunosuppressive agents for trans- The need to take immunosuppression long term presents a plantation of liver and other organs, with rejection-free rates in challenge in adolescents who have a high rate of anon- adherence Paediatric Liver transplant of 55% (Tac) and 40% (CsA) as partly related to teenage risk behaviour and partly due to the highlighted by the only prospective randomised clinical trial in cosmetic effects of immunosuppression (11). Identifying adequate paediatric immunosuppression (4) which was a collaboration strategies to resolve these issues urgently need identification. between 10 European centres, including Professor Kelly (Birming- Currently, it is thought that immunosuppression should be life long ham), Professor Burdelski (Hamburg) and Professor Jara (Madrid). as there have only been anecdotal accounts of safe withdrawal of This clinical trial established the standard immunosupression regi- therapy, although many ESPGHAN led units advise immunosup- men not just in Europe but internationally with Tacrolimus gradu- pression minimisation (prope tolerance) (12). A large prospective ally replacing Cyclosporin as first line therapy. In view of the long study of post-transplant withdrawal is in progress in The US and term side effects of immunosuppression which include: renal may provide valuable information. In the meantime, there are a host toxicity, infection, diabetes mellitus, hypertension and hypercho- of new biological agents whose clinical role is still being defined lesterolemia (5), the focus has changed to the use of induction (13) and ESPGHAN led units continue to work with the pharma- therapy, addition of combination therapy to reduce the dosage of ceutical industry to carry out safe trials of new therapy in children. the more toxic CNI inhibitors and the evaluation of steroid free The combination of surgical and pharmacological progress regimens. has made paediatric LTx the success story it is today, when patient 5 year survival rates for paediatric LTx recipients are from 73.0% to 89.4% in the US, depending on age at PLT. Received January 28, 2018; accepted January 29, 2018. Copyright # 2018 by European Society for Pediatric Gastroenterology, REFERENCES Hepatology, and Nutrition and North American Society for Pediatric 1. Marchioro TL, Rowlands DT Jr, Kirkpatrick CH, et al. Immunosup- Gastroenterology, Hepatology, and Nutrition pression after experimental and clinical homotransplantations of the DOI: 10.1097/MPG.0000000000001916 liver. Ann Surg 1964;160:411–39.

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2. Borel JF, Feurer C, Gubler HU, et al. Biological effects of cyclosporin 8. Watson CJ, Bradley JA. Sirolimus and everolimus: inhibitors of mam- A: a new antilymphocytic agent. Agents Actions 1976;6:468–75. malian target of rapamycin in liver transplantation. Transpl Rev 3. Furukawa H, Todo S. Evolution of immunosuppression in liver trans- 2006;20:104–14. plantation: contribution of cyclosporine. Transplant Proc 2004;36(2 9. Dell Olio D, Kelly DA. Immunosuppressants: what’s new? Curr Opin suppl):274S–84S. Organ Transplant 2010;15:594–600. 4. Kelly D, Jara P, Rodeck B, et al. Tacrolimus and steroids versus 10. Goldschmidt I, Debray D, D’Antiga L, et al. The combina- ciclosporin microemulsion, steroids, and azathioprine in children under- tion of lymphocyte subsets and plasma cytokine and chemo- going liver transplantation: randomised European multicentre trial. kine levels characterizes the adaptation of the immune system Lancet 2004;364:1054–61. after pediatric liver transplantation-first results of the EPLTN 5. Lloyd C, Aushat A, Jara P, et al. Long term follow-up of children network. J Pediatr Gastrol Nutr 2014;58(Abstract Suppl): receiving tacrolimus or cyclosporin A microemulsion post liver trans- 72. plantation. Pediatr Transpl 2017;21(Abstract Suppl 1): 75. 11. United Network for Organ Sharing Data. http://www.unos.org/donation/ 6. Arora N, McKiernan PJ, Beath SV, et al. Concomitant basiliximab with index. Accessed January 15, 2016. low-dose calcineurin inhibitors in children post-liver transplantation. 12. European Liver Transplant Registry. http://www.eltr.org/. Accessed Pediatr Transplant 2002;6:214–8. October 20, 2015. 7. Evans HM, McKiernan P, Kelly DA. Mycophenolate mofetil for renal 13. Chatenoud L. Biotherapies targeting T and B cells: from immune dysfunction after pediatric liver transplantation. Transplantation suppression to immune tolerance. Curr Opin Pharmacol 2015;23: 2005;79:575–80. 92–7.

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Chapter 7. The Contributions of the ESPGHAN Committees on Nutrition to Paediatric Nutrition Olle Hernell, yPeter Aggett, zMary Fewtrell, §Berthold Koletzko, and jjJean Rey

ABSTRACT interdependent entities and socio-economic improvements fostered The first Committee on Nutrition (CoN) was founded in 1974. Two years later better professional communications and international collabora- nutrition (N) was added to the society’s name, which then became ESPGAN. The tions to exploit and advance the knowledge base which underpinned Committee systematised compositional and quality criteria for breast milk clinical developments. In due course the professionals involved substitutes and food for special medical purposes, the first of many examples coalesced into international organisations which supported strategic on how recommendations and comments published by the Committees on research and the translation of new knowledge into diagnosis and Nutrition (CsoN) were adopted by the European Economic Community, later the management of disorders of paediatric nutrition. European Union and also influenced the World Health Organization/Food and Several new techniques including tissue (especially gastro- Agriculture Organization of the United Nations Codex standards. A second CoN intestinal) biopsies, the use of radioactive tracers, initially, and then focusing on preterm infants was established in 1979 and its recommendations of stable isotopes, developed our understanding of substrate and on nutrition of these infants were widely implemented. The third and standing nutrient metabolism and enhanced the quality of public health and CoN, established 1986, started to organise high-quality symposia at the annual clinical nutrition alike. This was a time when deficiencies of meetings appreciating the need to enhance the expertise in nutritional research. micronutrients, such as zinc and copper and of essential lipids were From 1991 the CoN has organised Summer Schools in paediatric nutrition for being recognised in preterm neonates and in children on parenteral young colleagues further emphasising its educational interest and more recently nutrition. In adult medicine, gastroenterology had developed into a an annual, more specialised Nutrition Masterclass. Successively the interest of separate specialty, and had enabled improvements in parenteral the CoN has expanded to other areas, such as highlighting dilemmas and nutrition in adult medicine and surgery, which served as exemplars uncertainties in the field of nutrition including the design, choice of outcomes for paediatric practice. In gastroenterology and nutrition for both and statistical analysis of trials in infant nutrition. The work of the CsoN have had age groups, there was a vast array of challenges, many of which great impact on paediatric nutrition and the committee will continue its important persist, particularly those concerning quantitative nutrient require- role by writing commentaries and systematic reviews and revising guidelines ments in the context of changing lifestyles and treating certain when required to inform and stimulate discussion among colleagues as well as diseases. It is significant that besides in the first 4 to 6 months there stimulate training in paediatric nutrition by organising workshops and scientific is still no harmonised international or intercultural approach to meetings, training courses, and other approaches, and by interaction with other feeding infants in general as well as those with specific needs, such expert groups. Key Words: children, feeding practice, infants, nutrition

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he 1960s and 1970s were burgeoning times in the internatio- nalisation of science and medicine which stimulated the Tformation of clinical subspecialties and interest groups, among which were ones in nutrition, such as substrate metabolism, inborn errors of metabolism, malnutrition in public health, and clinical care, especially hepatogastrointestinal disease. These were

Received January 24, 2018; accepted January 29, 2018. From the Department of Clinical Sciences/Pediatrics, Umea˚ University, Umea˚, Sweden, the yLancashire School of Health and Postgraduate Medicine, University of Central Lancashire, Preston, the zChildhood Nutrition Research Centre, UCL Great Ormond Street Institute of Child Health, London, UK, the §Division of Metabolic and Nutritional Medi- cine, Ludwig-Maximilians-Universita¨t Mu¨nchen, Dr. von Hauner Chil- dren’s Hospital, University of Munich Medical Center, Munich, Germany, and the jjHoˆpital Necker – Enfants Malades, University of Paris Descartes, Paris, France. Address correspondence and reprint requests to Olle Hernell, MD, PhD, Department of Clinical Sciences/Pediatrics, Umea˚ University, Umea˚, Sweden (e-mail: [email protected]). Copyright # 2018 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000001918 FIGURE 1. Olle Hernell.

S144 JPGN Volume 66, Supplement 1, April 2018 JPGN Volume 66, Supplement 1, April 2018 Supplement as the management of malnutrition affecting one or more essential discuss common problems as well as new scientific ideas of mutual nutrient, the infection malnutrition cycle, inborn errors of metabo- interest. Everyone with an interest in paediatric gastroenterology, lism and consensus on growth standards, encompassing not only clinical nutrition, or both (which was the rule rather than the linear and ponderal growth, but also body composition. exception at that time), was welcome to attend the annual meetings Advances in obstetrics and generated a need for of the Society, either as a member or as an invited observer. Thus, skilled nutritional support and management of preterm and, increas- all the initial 36 members of ESPGA had specific interests in ingly, low birthweight infants. Peculiar nutritional needs distinct to pediatric gastroenterology and nutrition with, between them, skills and dependent on the stages of development of preterm infants in inborn errors of metabolism, clinical biochemistry, developmen- fostered research on the maturation of the gastrointestinal tract tal physiology, substrate metabolism, and clinical nutrition as far as including hepatopancreatic function, impacting on the efficiency of it was needed to tackle nutritional problems prevalent at that time. digestion and absorption of macronutrients coupled with the func- One agreed mission, which has persisted over the years, was the tional role of breast milk, also beyond providing nutrition, as well as responsibility to disseminate knowledge within Europe, including on systemic effects of substrate metabolism on other organs, such as to those countries which were then behind the Iron Curtain. the kidney, body composition, and even psychomotor development. All this generated a unique and critical portfolio of information that THE BIRTH OF THE COMMITTEE OF needed to be systematised so that it could be used effectively to inform the development of appropriate enteral and parenteral NUTRITION 1974 nutritional regimens for preterm infants. Proper nutrition is still In 1974 Bertil Lindquist (Fig. 3) had identified the need for a one of the greatest, if not the greatest challenges in neonatology. CoN. Particularly pressing issues were the quality and standards of Techniques for parenteral nutrition developed, and simulta- infant formula composition, foods for specific medical purposes neously experience in creating formulas as breast milk substitutes or (FSMP), and diversification of the diet in early life. In 1974, at the for inborn errors of metabolism, was applied to enteral nutritional seventh annual meeting of the society in Verona, the ESPGA support. At the same time there was an increasing awareness that Council approved his proposal to establish a CoN. This importance adverse reactions to food and food components could be a serious of this new committee was highlighted in 1975 by the publication of problem for many infants and children. Interest in food allergies a paper addressing the need for ‘‘standards and indications for prompted research on mechanisms and management to achieve industrially produced infant formulas,’’ which catalogued the prin- immunotolerance and avoid immunosensitisation. Thus, nutrition cipal issues concerning the composition of infant formulas: that is, became a clinical subspecialty of its own, and the ESPGHAN characteristics relating to energy density, fat and individual fatty Committee on Nutrition has, in many ways, initiated and sustained acids, protein and amino acids, carbohydrate, and individual micro- this important paediatric discipline. nutrients (2). There was an obvious need to establish quality standards and, because this was a public health issue, there was a need to collaborate with industry, industrial associations, and EUROPEAN SOCIETY FOR PAEDIATRIC GASTROENTEROLOGY (ESPGA) 1968 The Committee of Nutrition (CoN) is the oldest, and a major committee within ESPGHAN (European Society for Pediatric Gastroenterology, Hepatology and Nutrition). Its origin can be traced back to Paris in 1968 with the founding of the European Society for Paediatric Gastroenterology (ESPGA) initiated by H.A. ‘‘Dolf’’ Weijers from Utrecht, The Netherlands, Bertil ‘‘Jotte’’ Lindquist from Lund, Sweden, and Jean Rey from Paris, France (Fig. 2) (1). The initial idea was not to create a large, formal scientific organisation but rather an informal platform where col- leagues from all over Europe could meet as friends to present and

FIGURE 2. Jean Rey (left) and Bertil Lindquist, the pioneers of the ESPG(H)AN Committee on Nutrition, at the 10th anniversary of FIGURE 3. Bertil Lindquist. Photo from the Information Center, Lund ESPGAN in Paris 1978 (from ref. (1)). University Hospital. www.jpgn.org S145 Supplement JPGN Volume 66, Supplement 1, April 2018

The struggle of the members to find the time for all their under- takings is symbolised by Beat Hadorn’s drawing (Fig. 4) (3). Initially the roles of the committee were seen simply as advising and commenting on (1) nutritional needs of infants and children; (2) guidelines on the feeding of infants and children; and (3) supporting education and research in nutrition during early life and childhood (1). At that time the Committee had no standing orders or defined constitutional status within the ESPGAN. It had no dedicated funding either. The first task of the CoN was to consider the need and composition for a single formula for healthy babies throughout infancy until 12 completed months. This concept had been endorsed in 1976 by the American Academy of Paediatrics FIGURE 4. Beat Hadorn was always busy, especially after he became (4). The recommended composition was then adopted by the Food Chairman in Graz. This was his drawing in a letter after he had to leave and Agriculture Organization of the United Nations (FAO)/World the CoN meeting prematurely to meet the Minister of Education. Jean Health Organization (WHO) Codex Alimentarius Committee with a Rey is the coachman and Otto Wolff standing in the ESPGAN carriage slight modification of the maximum acceptable protein content. The (from ref. (2)). discussions and debate engendered by these recommendations inspired the ESPGAN CoN to consider early life nutrition in the context of new insights on the maturation of infants’ physiology, regulatory and legislative authorities at national and international biochemistry, and substrate metabolism and the interaction of these levels. This set the framework for an important role of the CoN in with the compositional and functional characteristics of human the systemisation of compositional and quality criteria for breast breast-milk (eg, lipids and fatty acids, protein, amino acids and non- milk substitutes and for food-specific medical purposes. As is protein nitrogen, digestive enzymes, and hormones). The commit- mentioned later these criteria were taken up by the European tee developed an alternative concept of developing a formula Economic Community (EEC). suitable for the first 3 months or so of life, and another for the Subsequently, in 1976, when he was ESPGA President, latter part of infancy. Thus, Bertil Lindquist and the first CoN could Bertil Lindquist proposed including Nutrition in the name of the be credited for devising ‘‘adapted infant formulae’’ and ‘‘follow-up society. Thus, the European Society for Pediatric Gastroenterology formulae’’ (Fig. 5). and Nutrition (ESPGAN) was born, and the initially strong and These deliberations and guidelines were published in the first 3 continuously increasing impact of nutrition within the society was commentaries produced by ESPGAN CoN ((5–7) and Table 1) acknowledged (1). The first meeting of the CoN (Chairman Bertil between 1977 and 1982. The recommendations were well received, Lindquist, Secretary Jarmo Visakorpi, members: Beat Hadorn, and were acknowledged for the responsible use of available evidence, Sergio Nordio, Jean Rey, Otto Wolff and the 2 invited permanent and the effective synthesis of contemporary knowledge to achieve advisors June Lloyd and Eberhardt Schmidt) took place on June 29, reasoned recommendations which embraced evolving concepts and 1974 in Trieste. The following year Angel Ballabriga, Wolfgang practices in the countries of the participants. Collectively this series of Plenert and Eberhardt Schmidt became members of the CoN (3). reports established the reputation and authority of the ESPGAN CoN.

FIGURE 5. Members of the first CoN during a visit at the Research Institute for Child Nutrition in Dortmund 1977. From left to right: Bertil Lindquist, Eberhard Schmidt (in the back), Angel Ballabriga, Jarmo Visakorpi, Wolfgang Plenert, and W. Droese (Director of the Institute). Photo courtesy of Jean Rey.

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TABLE 1. Topics of position papers and comments published by the Committees on Nutrition and related subgroups

Guidelines on infant nutrition. I. Recommendations for the composition of an adapted formula (1977) Guidelines on infant nutrition. II. Recommendations for the composition of follow-up formula and Beikost (1981) Guidelines on infant nutrition. III. Recommendations for infant feeding (1982) Nutrition and feeding of preterm infants. Comment on the composition of cow’s milk based follow-up formulas (1990) Comment on the composition of soy protein based infant and follow-up formulas (1990) Comment on the content and composition of lipids in infant formulas (1991) Comment on antigen-reduced infant formulae (1993) Response to comments on antigen-reduced infant formulae (1993) Committee report: childhood diet and prevention of coronary heart disease (1994) ‘‘Recommended Dietary Allowances (RDAs), Recommended Dietary Intakes (RDIs), Recommended Nutrient Intakes (RNIs), and Population Reference Intakes (PRIs) are not ‘recommended intakes’’’ (1997) Comment on the vitamin E content in infant formulas, follow-on formulas, and formulas for low birth weight infants (1998) The nutritional and safety assessment of breast milk substitutes and other dietary products for infants (2001) Iron metabolism and requirements in early childhood: do we know enough? (2002) Antireflux or antiregurgitation milk products for infants and young children (2002) Nondigestible carbohydrates in the diets of infants and young children (2003) Core data for nutrition trials in infants: a discussion document (2003) Probiotic bacteria in dietetic products for infants (2004) Annotation: antireflux or antiregurgitation milk products for infants and young children (2004) Prebiotic oligosaccharides in dietetic products for infants 2004) Preparation and handling of powdered infant formula (2004) The need for nutrition support teams in paediatric units (2005) Soy protein infant formulae and follow-on formulae (2006) Feeding preterm infants after hospital discharge (2006) Fermented infant formulae without live bacteria (2007) Complementary feeding (2008) Breast-feeding (2009) Enteral nutrient supply for preterm infants (2010) Practical approach to paediatric enteral nutrition (2010) Supplementation of infant formula with probiotics and/or prebiotics: a systematic review and comment (2011) Role of dietary factors and food habits in the development of childhood obesity (2011) Supplementation of N-3 LCPUFA to the diet of children older than 2 years (2011) Vitamin D in the healthy European paediatric population (2013) Donor human milk for preterm infants: current evidence and research directions (2013) World Health Organization 2006 child growth standards and 2007 growth reference charts: a discussion paper (2013) Iron requirements of infants and toddlers (2014) Arsenic in rice: a cause for concern (2014) Intravenous lipid emulsions and risk of hepatotoxicity in infants and children: a systematic review and meta-analysis (2016) Prevention of vitamin K deficiency bleeding in newborn infants (2016) Complementary feeding: a position paper (2017) Sugar in paediatric nutrition (2017) Young child formula (2017) Working group and joint committee publications Dietary products used in infants for treatment and prevention of food allergy. Joint Statement of the European Society for Paediatric Allergology and Clinical Immunology (ESPACI) Committee on Hypoallergenic Formulas and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Committee on Nutrition (1999) Pesticides in dietary foods for infants and young children. Report of the working group on pesticides in baby foods of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) (1999) Global standard for the composition of infant formula: recommendations of an ESPGHAN coordinated international expert group (2005) Guidelines on paediatric parenteral nutrition of the European Society of Paediatric gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), supported by the European Society of Paediatric Research (ESPR) (2005) Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) (2009). Documentation of functional and clinical effects of infant nutrition: setting the scene for COMMENT (2012) Core data necessary for reporting clinical trials on nutrition in infancy. Consensus group on outcome measures made in paediatric enteral nutrition clinical trials (COMMENT); Early Nutrition Project (2015) Gluten introduction and the risk of coeliac disease: a position paper by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (2016). Attrition in long-term nutrition research studies: a commentary by the ESPGHAN Early Nutrition Research Working Group (2016).

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The guidelines on ‘‘Recommendations for the composition and to produce recommendations for good practice in feeding the of an adapted formula’’ influenced the WHO/FAO Codex CoN and preterm infant. The Committee’s report, produced in 1987, was Foods for Special Dietary Uses regulations during the late 1970s appreciated and acknowledged as an outstanding review of the and during the 1980s. There was a discernible concordance between topic, and its recommendations for the nutrition of low birth weight the ESPGAN CoN’s recommendations and the decisions of infants were widely implemented. The report, which was published CODEX. This was not that surprising: in fact, Bertil Lindquist, as a supplement of Acta Paediatrica Scandinavica (8) and as a Jean Rey, Eberhardt Schmidt, and Jarmo Visakorpi participated in stand-alone hardback book (9), still stands as a superb resource for the drafting panel for the ‘‘Codex Standard for Infant Formula’’ anyone who wishes to specialise in the nutrition of the low birth- (Codex Stan 72–1981). Several countries were convinced to adopt weight and preterm infant as well as infants in general. the concepts of follow-up, or follow-on, formulas as an alternative to cows’ milk, and the ‘‘Codex Standard for Follow-up Formula’’ THE THIRD AND STANDING COMMITTEE ON was adopted in 1987 (Codex Stand 156–1987). NUTRITION 1986 While the CoN of the Preterm Infant was deliberating, THE SECOND COMMITTEE ON NUTRITION Alexander (Sandy) McNeish, during his presidency (1983– 1979 1986), proposed the inception of a new standing CoN which was The next challenge was to address the nutritional needs of the convened during the subsequent presidency of Salvatore Auricchio preterm and low birthweight infant. By the end of the 1970s there (1986–1989). Initially the work of the ‘‘new’’ CoN (Chairman Jean was more insight, much of it acquired from research on animal Rey, secretary Peter Aggett, members, Ferdinand Haschke, Willi models in support of animal husbandry, into the maturation of the Heine, Olle Hernell, Kari Launiala, Armido Rubino, Gerhard hepatopancreatic system and the gastrointestinal tract, and of the Scho¨ch, Jacques Senterre, and Ramon Tormo), focused on issues subtle interactions between micronutrients and substrate metabo- concerning the composition of infant formulas and dietetic products lism, energy utilisation and body composition. Much of this work within the European Community. The latter had established its had been shared with paediatricians through the auspices of socie- Scientific Committee on Food (SCF) in 1974, and Jean Rey, Sergio ties dedicated to neonatology. Complementary expertise had also Nordio, Eberhart Schmidt, and Jacques Senterre participated in the become available from experience in the nutritional rehabilitation working group which prepared the European Commission’s SCF’s of malnourished children, particularly in the developing world. first report on the essential requirements of infant formulas and These skills were utilised when, in 1979, the ESPGAN CoN follow-up milks based on cow’s milk proteins in 1983. In 1989 the decided to establish a CoN of the Preterm Infant (Chairman: Brian EC produced a Directive (89/398/EEC) on the approximation of the Wharton (who had appreciable experience in East Africa with Member States’ various guidelines on food composition of Food- nutritional rehabilitation), members; Hans Bremer, Oliver Brooke, stuffs for Particular Nutritional Uses (PARNUTS) which included Marcello Orzalesi, Guy Putet, Niels Ra¨iha¨, Jacques Senterre, the standards, composition and use of formulas and dietetic pro- Jonathan Shaw (Fig. 6). After a preparatory meeting on ‘‘Nutrition ducts for infants and young children. This Directive, and improved of Low Birthweight Infants’’ organised in 1981 by Bertil Lindquist understanding of infant nutrition since 1983, was an opportunity for in Lund, this group started to systematise the available information the EC to update its guidance on Infant Formulae. The consequent

FIGURE 6. The Second CoN. Left to right: Oliver Brooke (London), Jacques Senterre (Liege). Guy Putet (Lyon), Marcello Orzalesi (Sassari, Sardinia), Brian Wharton (Birmingham), Hans Bremer (Dusseldorf), and Jonathan Shaw (London). Niels Ra¨iha¨ (Malmo¨) could not attend the meeting when the photo was taken. Photo courtesy of Brian Wharton.

S148 www.jpgn.org JPGN Volume 66, Supplement 1, April 2018 Supplement drafting and revision of European Directives on formulae and approaches to setting Dietary Reference Values at an International follow-on formulae (eg, 91/321/CEE) were both anticipated and level, particularly in the increasingly complex context of free trade strongly informed by the reports and commentaries of the earlier and world trade agreements (17). CoN and those of the ‘‘new’’ CoN on infant formulae on cows’ Other important aspects concerning the composition of milk-based follow-up formulas (10), soy protein-based infant and formulas and reference values were ambiguities and uncertainties follow-up formulas (11), lipids in infant formulas (12). in the definitions of lipids and fatty acids, and carbohydrates, and in The CoN also prepared a commentary on antigen reduced the assessment of children’s needs for these in general as well as infant formulae, including consideration of nomenclature, diagnosis, their specific components. Lipids were addressed relatively soon management, and prevention of allergy in infancy and later life after the commentaries on composition of infant formulae, as (13,14) topics for which scientifically based recommendations were mentioned above. This was followed by a comment, the first by largely absent at the time, particularly because of uncertainties about the CoN, addressing the impact of early nutrition on health in later the pathogeneses of allergic sensitisation. Many uncertainties remain, life, in the form of a report on the effect of childhood diet in the but the debate stimulated by this commentary contributed to the SCF’s reduction of the risk of coronary heart disease in adulthood (18). draft on this difficult topic, and additionally stimulated a collaborative The commentary on carbohydrates took longer, principally commentary with other specialist societies in Europe (15). because of the variability in their classification and analytical The experience of CoN members drafting guidelines for the quantification and the need to produce a succinct commentary composition of formulas, along with that of several, who, in the late on what remains a complex topic (19). Additionally, the CoN 80s and early 90s served on national (eg, Germany, France, UK) and prepared a critical review of the knowledge base and research international panels (FAO/WHO, DACH, Nordic Countries, and the needs relating to iron supply and the actual amounts that young SCF of the EEC) on setting and observing the use of ‘‘population children probably need. The reference values for iron were, and dietary reference values,’’ highlighted a number of problems. The probably still are, cautious (20). quality and quantity of data available for setting dietary or nutrient In the late 1990s, the CoN realised that, given the increasing reference values for adults and, particularly, for children beyond interest in early feeding and short- and long-term outcomes, it would infancy were limited. Furthermore, CoN members were disappointed be beneficial to have an agreed common approach to the nutritional that health practitioners, including paediatricians, treated the pub- and safety assessment of infant formulas. In particular the CoN lished values as definitive indices for diagnosis and therapy. Thus, emphasised the need for a rigorous approach to assessing the impact after the SCF Working Group had reported on ‘‘Population Reference and outcomes of dietary practice in infancy, and encouraged further Intakes’’ for the European Union (EU) population in 1993, the CoN constructive critical thinking in the practice of as decided to comment on the use, misuse, and misunderstanding of applied to infants and children as well as pregnant women (21). This Dietary Reference Values. This report ‘‘Recommended Dietary was followed by a proposal for the collection of core data in studies on Allowances, Recommended Dietary Intakes, Recommended Nutri- early life nutrition, so that data from individual studies would be ent Intakes, and Population Reference Intakes are not ‘recommended suitable for aggregation and review for long-term outcomes (22). This intakes’’’ was published in 1997 (16); it stimulated much discussion, is an ongoing topic within ESPGHAN (Fig. 7). and subsequently a United Nations University working group funded The status and authority of the ESPGHAN CoN was recog- by the FAO, WHO, and EC met to comment on ways to harmonise nised and internationally acknowledged in 2003 when it was

FIGURE 7. CoN meeting in Munich 2004. From left: John Puntis (Leeds), Dominique Turck (Lille), Irene Axelsson (Malmo¨), Carlo Agostoni (Milan), Olivier Goulet (Paris), Berthold Koletzko (Munich), Raanan Shamir (Tel Aviv), Hania Szajewska (Warsaw), Jacques Rigo (Liege), and Kim Michaelsen (Copenhagen). Photo courtesy of Mary Fewtrell. www.jpgn.org S149 Supplement JPGN Volume 66, Supplement 1, April 2018 granted formal observer status as an independent member in the formulas, complementary feeding and assessing health claims for Codex Alimentarius process and meetings. This led to the Codex nutritional products. While participation in the NDA Panel and CoN and Foods for Special Dietary Uses asking the ESPGHAN related working groups is by individual invitation, many current and CoN to initiate a consultation process with the international scien- former members of the CoN have participated or continue to tific community to provide a proposal on nutrient levels in infant participate in EFSA activities (Fig. 8). formulae, based on scientific analysis and taking into account Notwithstanding the changing regulatory climate, the CoN existing scientific reports on the subject. ESPGHAN accepted has maintained its high level of productivity, publishing 16 position the request and, in collaboration with its sister societies in the papers or comments on topics ranging from infant feeding to Federation of International Societies on Pediatric Gastroenterology, nutritional issues in older children, including obesity and clinical Hepatology and Nutrition formed an International Expert Group nutrition (Table 1). As in previous years, many of these papers have (IEG) to review the issues raised. The group, chaired by Berthold had a considerable impact on clinical practice and public health Koletzko, arrived at recommendations on the compositional across Europe and beyond. Indeed, 3 papers are categorised as requirements for a global infant formula standard. The report, ‘‘highly cited’’ by Web of Science (in the top 1% of papers in their which to a large extent was based on the ESPGHAN CoN’s field): vitamin D in the paediatric population (2013; 45 citations); publications and commentaries and the recent SCF report on enteral nutrient supply for preterm infants: commentary from the revision of Essential Requirements of Infant Formulae and Fol- European Society of Paediatric Gastroenterology, Hepatology and low-on Formulae (23) with Berthold Koletzko, Olle Hernell, and Nutrition Committee on Nutrition (2010; 254 citations); and Com- Dominique Turck as working group members (24), impacted plementary Feeding: a commentary by the ESPGHAN Committee substantially on the revised Codex standard that followed. on Nutrition (2008; 285 citations). The impact and influence of these papers is testament to the combination of a systematic approach to reviewing the literature with the collective knowledge THE ESPGHAN COMMITTEE ON NUTRITION and experience of CoN members, resulting in a scientifically FROM 2005 AND ONWARDS rigorous and yet pragmatic approach to each topic. This is particu- The CoN evolved in a number of ways from 2005. Whereas larly important since, as recognised by committee members in the in the early days, the Committee was instrumental in driving the late 1980s and early 1990s, for many areas of infant and child development of nutritional recommendations and setting composi- nutrition the evidence-base is still somewhat limited in quality and tional standards for infant formulas, these roles have been taken quantity. As discussed in the Committee’s 30th anniversary paper over by regulatory bodies such as the European (1), the format of Committee papers—specifically whether they Authority (EFSA). Set up in 2002, following a series of food crises should be narrative reviews or formal systematic reviews—is an in the late 1990s, EFSA was established under the EU General Food issue of ongoing discussion, which is particularly relevant since Law (Regulation 178/2002) which created a European food safety many topics in the field are not suitable for formal clinical guide- system in which responsibility for risk assessment (science) and for lines. The consensus of CoN members is that a combination of risk management (policy) are kept separate. EFSA is responsible for literature review using a systematic approach with narrative review the former area, and also has a duty to communicate its scientific and expert opinion remains appropriate for many topics. findings to the public. The EFSA Panel on Dietetic Products, The fact that the CoN no longer has a primary role in Nutrition & Allergies (NDA) is responsible for issues related to regulatory aspects of nutrition has enabled it to expand its focus infant and child nutrition, including providing scientific opinions on on other areas, such as highlighting ongoing dilemmas and uncer- nutritional requirements, the compositional requirements for infant tainties in the field including the design, choice of outcomes, and

FIGURE 8. CoN meeting in Pecs 2011. From left: Walter Mihatsch, Hans van Goudoever, Christian Braegger, Tamas Decsi, Dominique Turck, Raanan Shamir, Virginie Colomb, and Mary Fewtrell. Photo courtesy of Mary Fewtrell.

S150 www.jpgn.org JPGN Volume 66, Supplement 1, April 2018 Supplement statistical analysis of trials in infant nutrition with a recent position the opportunity to foster nutrition and metabolic research among paper on attrition in long-term follow-up studies (25). It also has young members and, for that matter, other members of ESPGHAN. increasing involvement in influencing the research agenda in Now the CoN designs the scientific programme for nutrition at the paediatric nutrition, including participation in EU platforms on annual ESPGHAN meetings; currently running 3 scientific symposia & Healthy Lifestyle; and Obesity. plus a keynote lecture and clinical practice session. The latter, Over the last 10 years, a number of nutrition working groups introduced at the 2014 annual meeting in Jerusalem, has proven and special interest groups have been established under the auspices extremely popular, providing a more practical approach to nutrition of the CoN which allow a wider group of ESPGHAN members to issues including breast-feeding, complementary feeding and feeding participate and to produce guidelines and position papers in specific disorders; and complementing the scientific sessions. areas. Current working groups cover Clinical Malnutrition; Infant In 1991 Peter Aggett and Ferdinand Haschke organised a Nutrition Research; Pre and Probiotics; Newborn Immunity, Gut Summer School on ‘‘Methodology in nutritional and metabolic and Brain (NEOMUNE); and, following on from the earlier com- research’’ at La Tour de Peilz, Switzerland. This was a valuable mentaries on Core Outcomes in Nutrition trials, COMMENT. The exercise in pre-competitive co-operation between industry, some objective of the latter working group is to identify and agree on core national government initiatives, and the society. Industry clearly outcome measures for use in infant nutrition research projects, with appreciated the potential benefits of having available in the com- the eventual aim of facilitating the pooling of trials in systematic munity of paediatricians, some who were well trained in nutritional reviews and meta-analyses. To date, 4 papers have been published science and in the essential skills of metabolic and nutritional by these working groups (Table 1). In addition, Committee mem- research. The course was a great success, largely thanks to the bers increasingly participate as representatives in working groups quality of the faculty; many of the participants established colla- under the auspices of other ESPGHAN Committees, producing joint borations with well-founded and internationally recognised papers on topics such as nutrition in children with cerebral palsy; research groups in North America and Europe, and have become updated guidelines for the introduction of gluten; and jejunal prominent investigators in their particular fields thereby raising the feeding. In collaboration with the European Society for Clinical standards of nutrition within the society. There followed a series of Nutrition and Metabolism (ESPEN) and European Society for Summer Schools, ‘‘Physiological and Metabolic Foundations of Paediatric Research (ESPR), the CoN has coordinated a revision Infant Feeding’’ (Warsaw, Poland 1992; Organizer Jerzy Socha), of the guidelines for parenteral nutrition in infants and children, ‘‘Lipid Metabolism and Nutrition’’ (Irsee/ Munich, Germany 1993; originally published in 2005. Organizers Berthold Koletzko, Olle Hernell, and Kim Michaelsen) to mention the first in a long series. The Nutrition Summer Schools now take place every 2 years. In addition to providing education on EDUCATION AFTER THE CREATION OF THE broad aspects of infants and child nutrition and related research, STANDING COMMITTEE ON NUTRITION IN these courses offer a unique opportunity for young colleagues to 1986 interact with Faculty; indeed many current CoN members were Immediately after its creation in 1986 the Committee Secretary students at one of the schools. Recent summer schools have taken started to organise high-quality symposia at annual meetings. The place in Ameland (The Netherlands, 2011), in Prague (2013), in committee appreciated that there was a need to enhance the expertise Cambridge (UK, 2015), and, most recently, in Bari, Italy (2017) in nutritional research both within the society and more widely. It took (Fig. 9). As a result of receiving support from the ESPGHAN EPP

FIGURE 9. CoN members at the Nutrition summer school in Bari, Italy, June 2017. From left: Christian Molgaard, Jirˇi Bronsky, Natasˇa Fidler Mis, Jessie Hulst, Iva Hojsak, Mary Fewtrell, Magnus Domello¨f, and Flavia Indrio. Photo courtesy of Mary Fewtrell. www.jpgn.org S151 Supplement JPGN Volume 66, Supplement 1, April 2018 and from UEG, the CoN was able to offer greatly subsidised fees for sponsorship and relationships with Industry. Further progress has attendance at the 2015 and 2017 schools, increasing the opportunity been made by the founding in 2015 of the Educational Partners for young trainees to attend from all over Europe and beyond and Programme (EPP), initiated by Berthold Koletzko as a result from greatly increasing the number of applicants. the ESPGHAN Code of Conduct, in which industry partners who The level of demand for educational activities in the field that wish to support the educational ventures of the Society contribute to is apparent, and the availability of funding from the EPP, has a central fund which is then administered by Council to support prompted plans to increase the number of such activities with selected activities. the aim to hold at least one more specialised Nutrition Masterclass annually; to date, topics have included Parenteral Nutrition in the PUBLIC AFFAIRS Intensive Care Unit and Clinical Trials in Paediatric Gastroenterol- This paper has outlined how the CoN historically had a major ogy, Hepatology & Nutrition. A further recent initiative instigated influence on infant and child nutrition practice and research via its by the CoN is to assist the development of nutrition research in societal papers, educational activities and by its presence at the Africa. Building on ESPGHAN-facilitated courses run 2012 to 2015 CODEX (described previously). All of these are ongoing. In addition, in South Africa with students attending from a variety of African with the formation of the ESPGHAN Public Affairs Committee in countries, the aim of the initiative is to provide basic training and 2014, there is greater emphasis on raising the profile of the Society, guidance in simple research methods with initial work focussing on especially in terms of lobbying for greater European Investment in complementary feeding. research in the fields of paediatric gastroenterology, haepatology, and nutrition. This initiative has some urgency given the low priority COMMITTEE GOVERNANCE AND TERMS OF given to paediatric research in the EU Horizon 2020 programme to REFERENCE date. The Committee is also represented on EU platforms (eg, Diet, Improved governance of the society and the need to rejuve- Physical activity and Health Lifestyle), offering further opportunities nate the CoN as well as the other standing committees of the Society to provide input to EU policy and funding decisions. has become increasingly important especially given the global move towards greater transparency. In the late 1990s, in part at THE FUTURE the instigation of the CoN, and as a result of the formation of other Training in paediatric nutrition is still lacking in many Standing Committees and Working Groups, ESPGHAN Council settings. This is an important issue for CoN given its reliance on started to formalise the accountability and governance of its work- a supply of suitably trained and experienced colleagues, ideally ing groups and committees. ESPGHAN set specific rules for the covering a range of disciplines (not all gastroenterologists or Terms of Reference, skill portfolio, and duration of committee neonatologists, for example). One arm of this undertaking should membership, including that of the Chair and Secretary. This also be to develop standard curriculums and clinical guidelines across provided an opportunity to review the achievements and challenges Europe and to continue to promote the building of nutritional that the CoN had experienced since its inception in 1986. support teams. A second aim is to promote increased funding for The standing CoN specified its terms of reference or mission infant and child nutrition research within the EU. Appropriate statement as promoting child health through good nutrition by: interaction with Industry will continue to be an important issue, both in terms of the exchange of scientific information and Industry Writing and publishing authoritative commentaries of clinical and scientific relevance on pertinent questions in the area of support for ESPGHAN’s educational activities. paediatric nutrition in health and disease, Although progress has been made in many areas of paediatric nutrition, there are still important gaps and issues, for example, Providing advice on matters related to paediatric nutrition to ESPGHAN and other scientific societies, regulatory bodies, relating to lipids, proteins, amino acids, micronutrients (especially non-governmental organisations, industry and other inter- iodine) requirements, and nutrient and risk assess- ested parties, ments. Thus, the CoN will continue its important role in writing commentaries and systematic reviews and revising guidelines when Contributing to the exchange of scientific information in promoting high-quality research and training in paediatric required to inform and stimulate discussion among colleagues. nutrition by organising workshops and scientific meetings, training courses, and other suitable approaches, and REFERENCES Providing guidance on teaching in paediatric nutrition, the 1. Rey J, Aggett P, Koletzko B. Thirty Years of the ESPGAN/ESPGHAN organisation of nutritional care and education, practical Committee on nutrition. J Pediatr Gastroenterol Nutr 2004;39:474–9. approaches to nutrition, the quality of nutritional products and 2. Lindquist B. Standards and indications for industrially produced infant their use and other questions of relevance. formulas. Some principles. Acta Paediatr Scand 1975;64:677–83. 3. Visakorpi JK. Memories on the history of ESPGHAN. In: Strandvik B, ed. ESPGHAN, the European Society for Paedatric Gastroenterology Producing high-quality position papers and comments relies and Nutrition. 25 Years Memories 1968–1992. Go¨teborg, Sweden: on the ability of the Committee to attract suitably experienced and ESPGHAN; 1993:18–25. enthusiastic colleagues. Members can now serve for a maximum of 4. American Academy of Pediatrics, Committee on Nutrition. Commen- 3 years, renewable once, to ensure a supply of new ideas and tary on breast-feeding and infant formulas, including proposed stan- perspectives. The need to provide a future supply of suitably trained dards for formulas.Pediatrics 1976;57:278–85. colleagues who value the work of the Committee and who wish to 5. ESPGAN Committee on Nutrition. Guidelines on infant nutrition. I. participate links to another essential component of the Committee’s Recommendations for the composition of an adapted formula.Acta work—educational activities. Paediatr Scand Suppl 1977;262:1–20. 6. ESPGAN Committee on Nutrition. Guidelines on infant nutrition. II. The potentially wide impact of Committee papers necessi- Recommendations for the composition of follow-up formula and Bei- tates a rigorous and transparent approach in the conduct of the kost.Acta Paediatr Scand Suppl 1981;287:1–25. committee’s affairs. This has been aided by the agreement in 2014 7. ESPGAN Committee on Nutrition. Guidelines on infant nutrition. III. of the new ESPGHAN Code of Conduct, which provides specific Recommendations for infant feeding.Acta Paediatr Scand Suppl guidance to both members and committees, especially regarding 1982;302:1–27.

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8. Bremer HJ, Brooke OC, Orzalesi M, et al. Nutrition and feeding of 18. Aggett PJ, Haschke F, Heine, et al. Committee report: childhood diet preterm infants. Acta Paediatr Scand Suppl 1987;336:1–14. and prevention of coronary heart disease. ESPGHAN Committe on 9. Wharton BA (ed). Nutrition and Feeding of Preterm Infants. Oxford: Nutrition. J Pediatr Gastroenterol Nutr 1994;19:261–9. Blackwell; 1987. pp. 1–248. 19. Aggett PJ, Agostoni C, Axelsson I, et al. Nondigestible carbohydrates in 10. Aggett PJ, Haschke F, Heine W, et al. Comment on the composition of the diets of infants and young children: a commentary by the ESPGHAN cow’s milk based follow-up formulas. ESPGAN Committee on Nutri- Committee on Nutrition. J Pediatr Gastroenterol Nutr 2003;36:329–37. tion. Acta Paediatr Scand 1990;79:250–4. 20. Aggett PJ, Agostoni C, Axelsson I, et al. Iron metabolism and require- 11. Aggett PJ, Haschke F, Heine W, et al. Comment on the composition of ments in early childhood: do we know enough?: a commentary by the soy protein based infant and follow-up formulas. ESPGAN Committee ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr on Nutrition. Acta Paediatr Scand 1990;79:1001–5. 2002;34:337–45. 12. Aggett PJ, Haschke F, Heine W, et al. Comment on the content and 21. Aggett PJ, Agostoni C, Goulet O, et al., European Society of Pediatric composition of lipids in infant formulas. ESPGAN Committee on Gastroenterology, Hepatology and Nutrition (ESPGHAN) Committee Nutrition. Acta Paediatr Scand 1991;80:887–96. on Nutrition. The nutritional and safety assessment of breast milk 13. Aggett PJ, Haschke F, Heine W, et al. Comment on antigen-reduced substitutes and other dietary products for infants: a commentary by infant formulae. ESPGAN Committee on Nutrition. Acta Paediatr the ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr 1993;82:314–9. 2001;32:256–8. 14. Antigen-reduced infant formulae. ESPGAN Committee on Nutrition. 22. Aggett P, Agostoni C, Axelsson I, et al., ESPGHAN Committee on Acta Paediatr 1993;82:1087–8. Nutrition. Core data for nutrition trials in infants: a discussion docu- 15. Høst A, Koletzko B, Dreborg S, et al. Dietary products used in infants ment—a commentary by the ESPGHAN Committee on Nutrition. J for treatment and prevention of food allergy. Joint Statement of the Pediatr Gastroenterol Nutr 2003;36:338–42. European Society for Paediatric Allergology and Clinical Immunol- 23. Scientific Committee on Food. Report of the Scientific Committee on ogy (ESPACI) Committee on Hypoallergenic Formulas and the Eur- Food on the Revision of Essential Requirements of Infant Formulae and opean Society for Paediatric Gastroenterology, Hepatology and Follow-on Formulae. Brussels, European Commission 2003. SCF/CS/ Nutrition (ESPGHAN) Committee on Nutrition. Arch Dis Child NUT/IF/65 Final 2003. 1999;81:80–4. 24. Koletzko B, Baker S, Cleghorn G. Global standard for the composition 16. Aggett PJ, Bresson J, Haschke F, et al. Recommended Dietary Allow- of infant formula: recommendations of an ESPGHAN coordinated ances (RDAs), Recommended Dietary Intakes (RDIs), Recommended international expert group. J Pediatr Gastroenterol Nutr 2005;41: Nutrient Intakes (RNIs), and Population Reference Intakes (PRIs) are 584–99. not ‘‘recommended intakes’’. J Pediatr Gastroenterol Nutr 1997; 25. Fewtrell MS, Domello¨f M, Hojsak J, et al. Attrition in long-term 25:236–41. nutrition research studies: a commentary by the European Society 17. King JC, Garza C, eds. International Harmonisation of Approaches for for Pediatric Gastroenterology, Hepatology and Nutrition. Early Nutri- Developing Nutrient-Based Dietary Standards. Food Nutr Bull 2007; 28 tion Research working group. J Pediatr Gastroenterol Nutr 2016;62: (suppl 1): S1–S153 180–2.

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Chapter 8. 50 Years of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN): Captivating Witness Reports of a Success Story

Salvatore Auricchio, ySamy Cadranel, zStefano Guandalini, §Deirdre Kelly, jjBerthold Koletzko, ôMichael J. Lentze, #Alexander S. McNeish, Peter J. Milla, yyJean Rey, yyJacques Schmitz, zzRaanan Shamir, §§Birgitta Strandvik, jjjjRiccardo Troncone, and ôôJarmo Visakorpi

ABSTRACT Raanan Shamir

Since the conception of an idea of a few paediatric gastroenterologists in urrent President (2016–2019) (Fig. 1). Europe to create a society for Paediatric Gastroenterology in 1967, and its C foundation in 1968, half a century has passed. The European Society for It gives me great honour and pleasure to write the introduc- Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) now tion to the ESPGHAN Presidents’ statements that are published as celebrates its 50th anniversary and its utmost success in combining clinical part of the 50th Anniversary celebrations of our organisation. and scientific expertise in the fields of paediatric gastroenterology, hae- This article provides an insight to the life of our Society from patology, and nutrition. To describe this success story 14 of the still living the days of its creation and carries with it the memories wishes and presidents of ESPGHAN recount their impressions of the steady growth of achievements of many individuals that worked with devoted teams ESPGHAN with all the historical facets from their own points of view. and a family of members to bring ESPGHAN to where it stands This historical view of ESPGHAN over the last 5 decades provides today. personal accounts of the development of all activities and creations of From ESPGA to ESPGAN and lastly ESPGHAN, we have this great European Society. The Society started as a small family of become a large organisation that encompasses full members, young/ experts in the field into a global working open society involved in a large trainee members, corresponding members, allied health profes- variety of activities within the subspecialties, becoming a leading organi- sional (AHP) members, emeritus members, and low-income coun- sation in Europe and beyond. This unique view gives also a wonderful tries members. Together, this group, reaching soon more than 900 insight into the famous clinicians and researchers from all over Europe members is part of a complex structure (Fig. 2) that not only who have helped in the growth and development of ESPGHAN. By represents paediatric gastroenterologists, nutritionists, liver experts describing all these activities and collaborations it becomes clear that and AHP in Europe, but also has active members worldwide with an this astonishing pan-European enterprise was achieved by people who put Annual meeting that, in 2016, brought together delegates from considerable effort and time into the development of this society. Their 103 countries. statements serve as a historical source and reference for future evaluation With so many functions and activities it is important to stop of the first 50 years of ESPGHAN. In depicting different time episodes, for a minute and reflect on our history. When reading through the and by assembling all the historical pieces of a puzzle together, the various reports one learns to appreciate the long road, we have taken statements help to illustrate how a highly structured society such as and the huge achievements of individuals, committees, groups, ESPGHAN has evolved over the last 50 years, for what it stands for networks, and the all ESPGHAN organisation over the years. This is nicely illustrated by the first report by Jean Rey who was the today and what is to be expected in the future. President from 1977–1980. It helps us meet the founding members Key Words: ESPGHAN, 50 year anniversary that created this society 50 years ago and how this all came to life at the first meeting in 1968. The pivotal role of celiac disease in (JPGN 2018;66: S154–S171) ESPGHAN returns in a few statements, reminding once again the importance of European scientists in establishing the role of gluten

Received January 25, 2018; accepted January 29, 2018. From the University of Naples Federico II, Naples, Italy, the yDepartment Bioscience and Nutrition, Karolinska Institutet, Novum, Stockholm, of Paediatric Gastroenterology, Queen Fabiola University Children’s Sweden, the jjjjDepartment of Medical Translational Sciences, Univer- Hospital, Bruxelles, Belgium, the zUniversity of Chicago, Chicago, sity of Naples Federico II, Naples, Italy, and the ôôDepartment Paediat- IL, the §Liver Unit, Birmingham Children’s Hospital and University rics, University of Tampere, Tampere, Finland. of Birmingham, Birmingham, UK, the jjDr. von Hauner Children’s Address correspondence and reprint requests to Michael J. Lentze, Emeritus Hospital, LMU-Ludwig-Maximilians-University, Munich, the ôDepart- Professor of Paediatrics, Department of Paediatrics, University Hospitals, ment Paediatrics, University Hospitals, Bonn, Germany, the #Institute of Adenauerallee 119, D-53113 Bonn, Germany Child Health, University of Birmingham, Birmingham, the UCL, (e-mail: [email protected]). Institute of Child Health, University College London, London, UK, Copyright # 2018 by European Society for Pediatric Gastroenterology, the yyHoˆpital Necker Enfants Malades-University Paris Descartes, Hepatology, and Nutrition and North American Society for Pediatric France, the zzInstitute for Gastroenterology, Nutrition and Liver Dis- Gastroenterology, Hepatology, and Nutrition eases, Schneider Children’s Medical Center, Sackler Faculty of Medi- DOI: 10.1097/MPG.0000000000001919 cine, Tel-Aviv University, Tel-Aviv, Israel, the §§Department of

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in causing celiac disease when American journals found it impos- sible to believe that bread is related to celiac disease, leading to multiple European publications and to the first paediatric diag- nostic criteria (the 1969 Interlaken Criteria). Reading through we realise how important ESPGHAN was and is in establishing nutri- tion guidelines and reinforces our position as the representative body of Paediatric Gastroenterology, Hepatology and Nutrition (PGHAN). Currently ESPGHAN has an Executive Committee (Presi- dent, Secretary, and Treasurer), a council (Executive Committee, Past president for 1 year or President Elect, Education Secretary, International Affairs Representative, Scientific Secretary, Chairs of the 3 Committees, Gastroenterology, Hepatology, and Nutrition), Chair of the Local Organizing Committee of the next Annual Meeting, Chair of the Young ESPGHAN Committee and the Chair of the AHP), and multiple active working groups. Some Commit- tees (International Affairs, AHP, and Young ESPGHAN) are represented in Council and some (Ethic, Finance, History, National Societies, Public Affairs, and Publication Committees) report to Council and we are all in debt to the huge voluntary work of all individuals. Now that we have an active website (www.espgha- n.org) all individuals working for ESPGHAN can be found there including their specific role. Finally, in addition to a European Editor and Editorial Board for our Journal, we have an e-learning editor and growing e-learning activities. As the current president, most of the actions that brought us to where we are now can be found in the various reports. This history brought us to be a Society with more than 900 members, FIGURE 1. Raanan Shamir. having more than 20 very active working groups and special interest

FIGURE 2. Structure of ESPGHAN 2018. www.jpgn.org S155 Supplement JPGN Volume 66, Supplement 1, April 2018 groups and our vivid Society continue to have the largest disease. He invited me in Utrecht to discuss the methods we had Annual meeting in PGHAN and in the last Annual meeting developed in Paris to study and treat these children, methods largely (Prague 2017) we had a record attendance of 4770 delegates from inspired from Weijers and Van de Kamer papers. We spent 2 or 96 countries. 3 days examining several of my cases and discussing the interest of I would like to add that our vision is to reinforce ESPGHAN’s intestinal biopsy they had not yet used. Weijers’s conclusion was position as the leading organisation for clinicians, educators, scien- ‘‘You may come as much as you wish in our laboratory and consider tists, and health care professionals in Europe and beyond. In parallel, which methods you would like to use in Paris.’’ That year I spent a we are committed to continue and assist ESPGHAN committees, week in his home and later on I returned to Utrecht every year, alone working groups, and individuals in achieving their goals, while or with my wife Franc¸oise. maintaining the family spirit of our organisation. As you know it is Dolf Weijers, who in the 50s with Jan van ESPGHAN should continue to be a worldwide leader in the de Kamer, a pharmacist with a vast knowledge in musicology, had field of PGHAN, to increase the membership base and be the voice demonstrated the harmful effect of gluten in this disease. As an of all professionals in PGHAN in Europe and beyond and to help anecdote, I recall that the first paper submitted to an American our journal improve its scientific value and impact. paediatric journal was refused as it seemed unthinkable to the ESPGHAN will continue to strive for high-quality education reviewers that bread could be responsible for the disease. This is and dissemination of knowledge, setting the best clinical standards why all their later publications (except one 10 years later in and guidelines and promote high-quality paediatric research in the Paediatrics asked by this prestigious and faulty journal) were fields of gastroenterology, haepatology, and nutrition. This should published in Acta Paediatrica Scandinavica (1). include basic, translational, and clinical research. We should act Dolf used to take days off the hospital to guide us through with European Union scientific and regulatory bodies to set the Holland, to chat, to drink Sherry at 5 pm—‘‘its Sherry time’’ he research priorities and facilitate them. With the help of all members, used to say before having dinner with his wife Carla and their 2 we should continue to be the source for clinical guidelines and daughters. The family visited us in Paris at our home, in a hot month provide updated education material. We will work to ensure that of May. We spent together 2 or 3 days in Burgundy. During these anyone interested in having a voice, will be heard while structuring trips and meetings together he talked to me of his project of our guidelines. organising a yearly meeting of paediatricians interested in gastro- The main role of ESPGHAN is to improve the care of enterology from all over Europe. He had also submitted this plan to children with gastrointestinal, nutritional, and liver disorders. I Bertil Lindquist. Bertil was in charge of writing the Constitution of am proud of being an ESPGHAN member and humbly hope that this new Society, the European Society for Paediatric Gastroenter- I can steer this boat to even larger achievements in years to come ology (ESPGA). I had to organise the first meeting in Paris in and hope that ESPGHAN members and all paediatric gastroenter- October 1968. Nutrition and haepatology were out of the focus of ologists, nutritionists, and liver experts will find time to read and ESPGA, even though we had interests in these matters. reflect on this publication since history is the best guide for planning Bertil Lindquist insisted that paediatricians from Eastern the future. Europe—it was the time of cold war—should be invited at this first meeting, and colleagues from Hungary and German Demo- Jean Rey, France 1977–1980 cratic Republic could attend. I will always remember Kerpel Fronius from Budapest who recited in French large extracts from (Fig. 3) Anatole France to Franc¸oise before kissing the hollow of her elbow! The European Society for Paediatric Gastroenterology was The idea of the meetings was to exchange in the most informal way born in Utrecht in 1967 from a common initiative of Dolf Weijers possible, as Dolf and I did, and to try to make progresses in this new (Netherlands) and Bertil Lindquist (Sweden). I met Dolf in Paris in discipline. I went myself several times to Lund in Bertil and Anna- 1963 during a meeting where I was presenting a report on coeliac Britta’s family and he spent 2 weeks at our home to improve his French, but his progresses were limited to say ‘‘Monsieur Guillo- tin’’ (the French anatomist who invented the guillotine) every morning while cutting his boiled egg. ESPGA was the first European society of paediatric subspe- cialty to be founded, before the societies of nephrology, endocri- nology, and others. However, it had been preceded by the European Club of Paediatric Research, which later became the European Society for Paediatric Research (ESPR) founded by Pierre Royer (Paris), Ettore Rossi (Bern), Andreas Prader (Zurich), and other famous paediatricians. In fact, we had a first common meeting of ESPR and ESPGA in Interlaken in 1969. It is in Interlaken that the first diagnostic criteria of coeliac disease were worked out. Dolf Weijers was the President, Bertil Lindquist the Secre- tary and we used to meet in Holland at Dolf’s house with Charlotte Anderson (, then Birmingham) for the first meetings of the executive Committee of ESPGA. Dolf had insisted that the Society organise a session on paediatric gastroenterology during the coming meeting of the International Paediatrc Association (IPA) in Vienna in 1971. However, shortly after, Dolf Weijers had a severe myocardial infarction complicated by a few weeks long coma. He was slowly recovering and we had regular phone calls in English— he spoke French very well but used to say that conversation was easier in English for him. We had planned to meet in Utrecht in FIGURE 3. Jean Rey. early June 1972. The day before my departure I learned he had

S156 www.jpgn.org JPGN Volume 66, Supplement 1, April 2018 Supplement suddenly died while painting the door of his garden. I spent 3 days in papers increased even more. Therefore, the poster sessions were his family until his funeral. I was the only ESPGA member included in the meeting program in Madrid 1982 according to the attending the ceremony. model of joint meeting with ESPR in Berne in 1981. Reviewing the As President, I had the occasion to remember these memo- admitted papers for oral and poster presentations became more and ries during the ESPGAN meeting in Utrecht (our logo had been more difficult task for council members. Especially difficult was enriched by an N after the 1974 meeting when Bertil Lindquist this process when handling papers coming from eastern European founded the Nutrition Committee and proposed this new name). It countries, which we otherwise wanted support in research accord- was in 1979. Half of the audience had known Dolf and mourned ing to our objective of ‘‘missionary’’ function presented often during my talk recalling Dolf’s qualities, his intelligence and his strongly by Bertil Lindquist. understanding of others. At that time, we were a small group nearby My really strong memories on ESPGA, which was the Bertil Lindquist: Charlotte Anderson and Sandy McNeish, Salva- original name of society, are, however, bound to the early years, tore Auricchio and Armido Rubino, Jamo Visakorpi, Beat Hadorn, may be therefore that my own research activities with a group of Eberhard Schmidt, Ann Ferguson, and John Harries, who left us too young and active colleges, Kari Launiala, Pekka Kuitunen, and early. This group was in some way the soul of ESPGA, then Erkki Savilahti, all later ESPGA members, started in Helsinki at ESPGAN. about the same time during 1960s. We were studying malabsorptive The Nutrition Committee used to issue guidelines (1977– diseases, including coeliac disease, but we had no plans to develop a 1981), which still form the basis of European and international rules new subspecialty. I had also rather early 1 international contact: for infant food. We were all or nearly all able to discuss the various Bertil Lindquist, who became my mentor for whole my career and items during our early meetings. May be we knew nothing about close friend also at family level. He connected me also by many everything. Time passing, with increasing specialisation, only few ways to the activities of ESPGA. people still can take part in all discussions. In a certain way, young The main topic in the second annual meeting of ESGA in members know everything about nothing. Long life to ESPGHAN. 1969 in Interlaken, Switzerland, was panel discussion on coeliac disease and especially the diagnostic criteria of it. The idea of this Jarmo Visakorpi, Finland 1980–1983 program was launched by our first president Dolf Weyers, whose own research career was based as a member of the team of W.K. (Fig. 4) Dicke on study of this disease. He invited me to prepare this panel As the fourth president of ESPGHAN, in 1980–1983, I have discussion by conducting an international inquiry concerning the been invited to write my memories of the time of my presidency. topic of the planned discussion. The results of this inquiry showed However, my memories from that period are rather scanty partially clearly that some kind agreement on coeliac disease concerning therefore that my own academic interest on that time was quite both diagnosis and treatment was on that time really needed. The different than research and gastroenterology. conclusions of this panel meeting gained great popularity and they My main contributions to the society were acting as secretary become known as the ‘‘Interlaken Rules.’’ The knowledge of these 1971–1976 and secretary of the Nutrition Committee 1974–1981 rules spread also among the gastroenterologists for adults, for as well as organiser of 2 annual meetings, in Helsinki 1973 and in example, Sir Christopher Booth organised similar discussion at Tampere 1984. In these duties it was easy to learn to know the 2nd International Coeliac Symposium in Leyden at 1973. personally members of the society and even many invited guests Although Interlaken criteria were well accepted, the devel- working in the field especially from US sister organisation due to opment of research in this field has required continuous follow-up. joint meetings. Organising meetings by nonprofessional way with Therefore, several follow-up round-table discussions and commit- assistance of own team, which was possible on that time when the tees have been organised during the whole 50 years existent of number of participants was relatively limited, was challenging but ESPGA/ESPGHAN and will be certainly organised also in future. also interesting and gave familiar feelings to the meetings. There- The name of the society was changed at 1976 by adding the fore, networking of European paediatric gastroenterologists was word nutrition in the title. Thus, ESPGA became ESPGAN. This was very close from beginning, even without Facebook. strongly supported by Bertil Lindquist, the president on that time, During my presidency in the early 1980s the growth and who was also one of the main persons creating the society. By his development of the society were quite steady, since beginning the suggestion a committee on nutrition was established in 1974. I was number of members was doubled and the number of admitted invited to be secretary of this group obviously therefore that I had good connections to Bertil, although I did not have any scientific basis in nutrition. This became a real demanding task for next 7 years including 20 committee meetings mainly in central Europe and writing recommendations, which led to 3 supplement publications in Acta Paediatrica Scandinavica (2–4) on recommendations of compositions of different types of infant formulas and additional food as well as infant feeding in generally. After this committee a new one was appointed in 1981, during my presidency, for creating guidelines on enteral feeding of low-birth-weight babies. I think that ESPGA was established just in right time in late 1960s for supporting the establishment of paediatric gastroenterol- ogy in Europe. Earlier according to a common belief, GI diseases such as diarrhoeal disorders, including coeliac disease, prolonged vomiting, and the like were essential part of general paediatrics. Development of new methodology for clinical investigations such as small intestinal biopsy and fiberoptic endoscopies were the practical motives for establishment of a new subspecialty in the framework of paediatrics following the model of . FIGURE 4. Jarmo Visakorpi. This topic was not so much discussed during the first years in the www.jpgn.org S157 Supplement JPGN Volume 66, Supplement 1, April 2018

Society because all agreed that the main aim was to develop European in outlook; and should have the Society close to his or her research. Therefore also basic scientists were invited as full mem- heart. I know that I qualified on at least the last 2 points. I am writing bers of the society. But during these first years it became also this on the eve of the United Kingdom’s referendum on membership evident that paediatric gastroenterology is developing as its own of the European Union. The Society taught me to be a European subdiscipline, which will be a core substance of the Society. through good science, collaborations, food and wine, dancing, The plans for the program of the Society were already from laughter—but especially through the enduring friendships, which its beginning very ambitious. The routine to be a forum for scientific I have made. presentations and related discussions was not enough, but it was The English novelist L.P. Hartley has written: ‘‘The past is a wanted to see the impacts of scientific expertise in clinical gastro- foreign country. They do things differently there.’’ I agree with him enterology and clinical nutrition. The 2 examples, which I have [He was reflecting the thoughts of a man growing old. I shall resist described above, are good examples of this intention. The discus- the urge, common in those of advanced years, to state that ‘‘things sions and committee work around the coeliac disease have influ- were better then’’!]. How was our Society different then from now? enced much on the diagnosis and treatment of this disease and the Two features stand out, namely size, and scale of ambition. First, committee work on infant nutrition has contributed much on the size. The origin of most medical research societies was the wish, by nutrition of the children. As far I have been able to follow the likeminded people, who shared the same interest, to come together operations of the society the same line has been continued and and learn from each other. So it was for the European Society for strongly developed. Paediatric Gastroenterology (ESPGA, our original title) on its foundation in 1968. When I became a member in 1971, the Alexander S. McNeish (Sandy), United membership was small (less than 50) and grew only slowly over the next 15 years. Until the mid 1980s membership had been Kingdom 1983–1986 restricted to those who had obtained ‘‘a substantial career post (Fig. 5) in paediatric gastroenterology and nutrition.’’ Because of the period It was with great pride that I took over the Presidency from of specialist training varied in different European countries, the Jarmo Visakorpi at the end of the Graz meeting in 1983, on the very result was that some candidates were approaching middle age day of the 50th birthday of our host in Graz, Beat Hadorn. Now, before they were eventually eligible for membership. I recall with 33 years later, what do I remember? What are my thoughts and pleasure the decision by the Council in 1984, and adopted unani- feelings about what I continue to think of as ‘‘our dear Society’’? mously at the AGM in New York in 1985, to encourage positively It has always been an unwritten but generally known rule that the admission of younger members ‘‘of high achievement and candidates for our Presidency should be active in the science and potential,’’ under the age of 45 years. This was to include basic practice of paediatric gastroenterology, haepatology, and nutrition scientists in relevant disciplines. (haepatology was, rightly, added to the Society’s title after my The paper that was approved by the AGM hoped that the new time, through the effective lobbying of, among others, the late guidelines would allow the introduction of new blood, new ideas, Alex Mowat and Birgitta Strandvik); ‘‘young’’ but experienced; and new science, and would allow some young colleagues to mature as active members of the Society to the point where they were ready to assume responsibilities as Council members and officers when still young. In my view, these objectives have been met trium- phantly over the subsequent decades. The AGM paper did foresee certain possible disadvantages of the new approach, namely that ‘‘the membership could increase to a size which would cause the annual meeting to become impersonal.’’ This possibility could be minimised by ‘‘limiting the number of guests... [by a variety of means].’’ To the modern reader, these views may seem very old- fashioned and out of date, and with the ethos of an exclusive club. They were written in an era when our discipline was still young, and when members, while developing their own lines of research, retained an interest in each other’s progress within all aspects of PGHN. We thought of ourselves as pioneers. We were also ama- teurs, in the original sense of that word. I turn now to my second theme: scale of ambition. From the earliest years of our Society, there had been a wish to ‘‘spread the word’’ by reaching out to those countries in which, for one reason or another, paediatric gastroenterology had not yet had an opportunity to become established. Our great President, Bertil Lindquist, led the initiative into ‘‘Eastern Europe’’ mainly through personal contacts, and by inviting a small number of key individuals to become members of ESPGA, even though, in some cases, their formal qualifications in our discipline were modest. It was no accident that our 1976 [9th] Annual Meeting came to be held in Weimar, DDR. [Forty years later, my memories of that historic meeting are confined to watch towers at the border at Eisenach, and brass bands and grilled sausage on the castle terrace!] In 1990, with the prior approval of Council and based on my experiences of organising training courses with the late John Harries (see below), Peter Milla, Ian Booth, and I co-organised the first ESPGAN FIGURE 5. Alexander S. McNeish. Summer School, with the title, simply, ‘‘Gastroenterology.’’ It

S158 www.jpgn.org JPGN Volume 66, Supplement 1, April 2018 Supplement was held over 2 weeks in Birmingham, UK. Thirty-three delegates were selected from over 70 applicants. The feedback was positive, and Council embraced the concept of Summer Schools. [It is noteworthy that all the arrangements necessary to organise and present the course were made at the desk of my splendid secretary, Mrs Janet Garlick.] At the completion of our course, I thought naively that we in Birmingham may consider repeating the exercise in, perhaps, 3 years’ time. I completely underestimated the drive and ingenuity of future Presidents and Councils in steadily driving forward postgraduate education and training for health care pro- fessionals to the stage where, in 2015, the ambitious ESPGHAN Education Partner Programme has been launched, with multiple sponsorship. Again, I extend my congratulations to all concerned. With hindsight, the growth of ESPGHAN was predictable. The burgeoning of modern science, which cross cuts any organ, system, or clinically based definition of a subject, has made this inevitable. In addition, the exponential growth of our educational activities, franklyastonishingintheirscaletomyeyes,hasbeentruly remarkable. Our converts now number in thousands. This has meant, however, that the Annual Meeting has become more impersonal. The friendships within the Society that were, and are, so valued by members of my generation, are, I suspect, more difficult to make and retain—but seeking themwillbeasimportant as ever. I should like to add a few words about colleagues who were contemporaries, and who were, and are, ‘‘le vrais ESPGHAN’’ to me. I served as Secretary under 3 great Presidents: Bertil Lindquist, Jean Rey, and Jarmo Visakorpi. I learned so much from each of them-collectively they taught me to be a European. As some know, I also slept once with Jean Rey, but that is another story. Two Secretaries, Armido Rubino and Jacques Schmitz, supported me unsparingly and did not hesitate to tell me when I was wrong. FIGURE 6. Salvatore Auricchio. Council members Birgitta Strandvik and Samy Cadranel, deservedly progressed to lead our Society. I am fortunate to have retained their friendship. Salvatore Auricchio followed me as Salvatore Auricchio, Italy 1986–1989 President, but I have always thought of him as my senior—a great scientist and a true friend. (Fig. 6) This leaves 2 names, both dear friends, who never held office I would like to remember 2 activities of the ESPGHAN in our Society but who both influenced us all greatly before dying during the 1986–1889 periods: the Working Groups and the young (far too young): John Harries (1935–1983) and Anne ‘‘new’’ Nutrition Committee. At that time the Council, together Ferguson (1941–1998). I have written about John previously. A with the Nutrition Committee, was the only active groups of the young giant of paediatric gastroenterology, we remember his Society. Already excellent results were obtained when members science, his superb mentorship of trainees, his infectious friendship collaborated to provide standards (see for example the criteria for and his superb Welsh singing voice. With the death of Anne the diagnosis of coeliac disease) and guidelines (eg, for infant Ferguson at the tragically early age of 57, medicine lost a remark- nutrition). However, the Council considered necessary a real able intellect and a major star in clinical research in gastroenterol- participation of the members to the activities of the Society and ogy. A gut immunologist and adult gastroenterologist of a more active role in promoting research. By establishing within international distinction, she attracted research fellows from every the Society research teams on specific subjects, the working corner of the world. Her early animal studies in cell-mediated potentialities of different groups could be gathered and the results immunity proved that immune reactions in the gut could produce of such a cooperation discussed at the annual meeting. The creation severe enteric damage. In Edinburgh, Anne developed what was her of Working Groups was encouraged for multicentre studies on greatest professional skill, of investigating directly in her patients specific subjects, for elaboration of protocols on still debated the concepts generated by her basic research and using the results to clinical and diagnostic problems, to improve the knowledge on formulate new diagnostic methods and therapies for their benefit. rare diseases. She travelled widely, and was in constant demand for her lectures, In April 1987, Jacques Schmitz, as Secretary of the Society, which she delivered without notes and with a restless energy and sent to the 143 members outside the Council a letter asking their infectious enthusiasm. Somehow she found time to co-host with me opinion on such a project, also asking which working group they our (I believe successful) Annual Meeting in Edinburgh in 1986, would set up. We received 47 answers, 41 members were enthusi- She even arranged for the sun to shine throughout the Meeting in astic, showing that many people were ready to work together. At the what can be a grey city. Most of all, in the present context, Anne annual meeting in Lisbon in June 1987 the idea of having working loved ESPGHAN and we loved her. teams, created to realise few clinical research projects, was wel- In conclusion, I can only hope that the reader may detect in comed by all and many members suggested as topics to start with these few words the affection which I continue to feel for our dear (1) follow-up of coeliac patients on a gluten containing diet; (2) Society, and the wish that I have for its continued good fortune in liver diseases (natural history of hepatitis B and primary sclerosing the next 50 years. cholangitis, treatment of chronic active hepatitis, guidelines for www.jpgn.org S159 Supplement JPGN Volume 66, Supplement 1, April 2018 vaccination against hepatitis B, diagnosis of (neonatal) cholestasis, Chairman, Peter Aggett presented the members of the committee aspects of liver transplantation); and (3) diagnosis of food protein (Ferdinand Haschke, Willi Heine, Olle Hernell, Kari Launiala, sensitisation. Following this discussion, the Council decided to Armido Rubino, Gerhard Scho¨ch, Jacques Senterre, Ramon Tormo, promote collaborative work among members of the Society and to and Peter Aggett as Secretary). He described the role of the follow the numerous suggestions the members gave on this regard. Committee as follows: The final decision was taken at the AGM in Copenhagen in May 1988. Three Working Groups were established: (1) on coeliac - to give advices for future main topics in nutrition for annual disease, chaired by Jarmo Visakorpi; (2) on liver disease chaired meetings, by Alex Mowat; and (3) on food allergy chaired by Erki Savilahti. - to issue short ‘‘state of the art’’ papers or ‘‘editorials’’ that would The Working Groups started their work after the AGM in present the position of the Society on ‘‘hot topics’’ in Paediatric Copenhagen. That on coeliac disease prepared the revision of the nutrition, diagnostic criteria, discussing this topic in a workshop at the annual - to organise Summer School in nutrition, alternating them with meeting of ESPGHAN in Budapest 1989. In this workshop a special similar schools in gastroenterology. subcommittee was created to prepare the new diagnostic criteria. The subcommittee had 1 meeting in Paris in October 1989 orga- This program was effectively realised and the Committee nised by Jacques Schmitz and the revised criteria were published published various important reports. under the names of the Committee members, John Walker-Smith, As a matter of fact, the ESPGHAN birth was due to a series of Stefano Guandalini, Jacques Schmitz, David Shmerling, and Jarmo studies in the 1960s mainly on malabsorption syndromes, with the Visakorpi (Revised criteria for diagnosis of coeliac disease (5). identification of different forms of congenital and acquired defects After that the working group decided in a short meeting in connec- of the digestive and absorptive functions of the digestive system. tion with the 23rd annual meeting of ESPGHAN in Amsterdam in Our knowledge at that time on the molecular basis of these functions May 1990 to conduct a multicentre study on epidemiology of was quite scarce. That was a fruitful period, in which the clinical coeliac disease in Europe and in the Mediterranean Area. A studies paved the way to basic studies, increasing our knowledge in subcommittee composed of Jarmo Visakorpi, Luigi Greco, and this new field of gastroenterology. The ESPGHAN members were Markku Maki prepared an inquiry, which was conducted during the very close to each other thanks to common interests in research and Autumn and Winter 1990–1991. The preliminary results were to friendship: the ESPGHAN indeed, during the first years, with a discussed in a workshop at the 24th Annual Meeting of ESPGHAN limited number of members, was essentially a club of friends in London in June 1991. The final results were presented in a special sharing common scientific interests. meeting in Capri in October 1991 and were published in a book, The following developments of gastroenterology, and in Common Food Intolerance 1: Epidemiology of Coeliac Disease; particular the influence of the knowledge acquired thanks to the Karger, 1993. techniques of ‘‘adult’’ gastroenterology, together with the growing The Working Group for Food Allergy arranged a workshop number of members, led to the creation of a larger society of on food allergy in the joint meeting of ESPGHAN and NASPGHAN Paediatric Gastroenterology, a specialist branch of Paediatrics. in Amsterdam 1990. Recommendations for the diagnosis of food However, since the beginning, the importance that the promotion allergy were finalised by the working party in a 1-day meeting in of the research had in the society was very clear and it was the basis London in December 1990 and they were published (Erkki Savi- for the creation of the working groups. Anyway, I have to say that lahti, Martine Haymann, Jean Navarro, Martin Stern, Yvan Van- the ESPGHAN (and more generally Paediatric Gastroenterology) denplas, John Walker-Smith) in Diagnostic Criteria for Food has still a lot to do in this direction. More than 20 years ago, in a Allergy with Predominantly Intestinal Symptoms (6). booklet realised by the Society in occasion of its 25th Anniversary, I The Hepatology Working Group grew out of the need to recalled the attention on this: ‘‘Paediatric gastroenterology has not create a forum at which members could discuss their experiences enough contact with other areas of internal medicine and basic with liver transplantation. In Copenhagen 1989, a summary was research, in this respect behaving differently from other society presented of the current status of sclerosing cholangitis, with a view such as the American Gastroenterological Association. The biggest to encouraging cooperative work in different centres. From this, the challenge for the future of ESPGHAN is the role of the society in frequency of the condition in Europe was investigated and some promoting the research in Paediatric Gastroenterology and Nutri- minor collaborative projects emerged. At the same meeting, the role tion.’’ of hepatitis B immunisation was reviewed. In the 1990 meeting in Today, as it is well known, the problem has become much Amsterdam, there was a further discussion on projects in sclerosing more complex; in fact, basic and clinical research is able to produce cholangitis. The London meeting in 1991 provided an excellent an enormous amount of results, thanks to the new global approach session highlighting institutional problems in Paediatric liver dis- methods (omics) and to cellular and animal models, necessary to the ease and the importance of dietary management. In Brussels in comprehension of complex biological phenomena. At the same 1992, there was an excellent summary of the outcome of hepatitis B time, the work of the clinical scientist is becoming increasingly infection and the efficacy of interferon therapy. A major role of this difficult. In this context, ESPGHAN is called to give its contribution working group has been to provide a focus for those members of the to these epocal challenges. I am optimistic the Society will be able society who have a major interest in haepatology. to continue to play a significant role. The years 1986–1989 were also the years in which the ‘‘new’’ Nutrition Committee of ESPGHAN started its work. It was active under the chairmanship of Jean Rey and with invaluable Birgitta Strandvik, Sweden 1989–1992 contribution of the Secretary Peter Aggett. It contributed signifi- cantly to the organisation of the new ESPGHAN activities and to the (Fig. 7) atmosphere of warm and fruitful relationship between the ESP- I had the great honour to give my first presentation at ESPGA GHAN council members. This committee was officially established in Interlaken 1969. I remember it as a very small club and I was at the Edinburgh AGM in 1986, by A.S. McNeish, the then young and extremely nervous but very proud to have my paper ESPGHAN President. On that occasion Jean Rey was acclaimed accepted for oral presentation. I could then not attend for some years Chairman. At the 1988 AGM in Copenhagen on behalf of Jean Rey, because I had to be invited as a guest, since ESPGA was open for

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information by the development of new technology and thereby also the branching off of new subspecialties. We thus today have a great responsibility to be an umbrella organisation because many of these subspecialties are manifestations of a biological context, the human being. My memory of my time as President for ESPGAN was that it was a very busy period where I had to lead many discussions within the Society as well as with parts outside to extend the impact and importance of our Society. The decision to start a special journal related to ESPGAN has begun before my presidency and contained several problems. A delicate one was that starting a completely new journal would take long time to get indexed, and it had to compete with many other journals in gastroenterology and haepatology, and especially the Journal of Paediatric Gastroenterology and Nutri- tion, which Emanuel Lebenthal had started many years before. I had long discussion with Blackwell Publishers but at the end the Council, and finally the AGM, decided after some agony that it would be better to take over from Emi Lebenthal than start a competition—a decision that John Walker-Smith never has for- given me, as the acting President, because he absolutely wanted a new journal. The decision to take over the journal from Emi Lebenthal also strengthened the bond with NASPGAN, with which we had started to have common meetings during the leadership of Sandy McNeish. After electing editors for the western and eastern hemispheres to run the journal all contracts were signed and the cooperative work for the journal started officially in the beginning of 1991. Another important issue was to decide if we should join the United European Gastroenterological Federation (UEGF), which was just to be founded during these years. Gastroenterology had FIGURE 7. Birgitta Strandvik. developed rapidly and successfully in Europe and the goal was to start a corresponding federation to the American Gastroenterologi- cal Association, which ran the well-known AGA meetings. The idea members who at a meeting could bring only 1 guest, expected to was to have a yearly meeting comparable to the AGA week, called present research in the front of gastroenterology or nutrition. Since the UEGW (United European Gastroenterological Week). During 1973, I have probably attended all meetings, have served on the several meetings we discussed the format and gradually the UEGF Board, and 1989–1992 honourably acted as the first female Presi- emerged, the constitution being based on that of ESPGAN. The dent of ESPGAN. The late Charlotte Anderson was one of the ESPGAN Secretary during this time, Isabel Polanco from Madrid, founders of the Society but unfortunately it took decades until the and I had many meetings and I remember with great affection how glass roof was again broken through and yet after 50 years there nice our cooperation was in the struggle with all the men from the have only been 2 female Presidents of the Society. other societies. The first UEGW meeting was held in Athens in I have especially appreciated the club feeling during the first September 1992 with a small impact of ESPGAN. Unfortunately, decades which made the Society grow slowly so all knew each other this imbalance has persisted. I gave a presentation at the UEGW in well and the quality of the presentations as well as the activities was Oslo 1994 and the interest from the attendees representing adult the overwhelming goal; to gain the development of gastroenterol- gastroenterologists was great, which indicated that we probably ogy, including haepatology and pancreatology, and nutrition. Later would have an impact. However, in practice the UEGW has to also to extend science in Paediatric Hepatology motivated an H in compete with many other subspecialties, which probably has the acronym for the Society. A recent expanding interest in pan- contributed to relatively less visibility of ESPGHAN in the UEGW. creatology has made discussions how this can be included as well. To keep members informed I felt we needed a communica- During the latest 30 years working groups gathering about different tion forum and suggested that we should start a Newsletter, written subjects have grown and expanded, starting cooperation in science, by the President and the Secretary. This idea was approved by initiatives for summer schools and promoted friendships, and Council in February 1990. From the beginning it was decided that contributed to prevail the old club spirit. These activities have the Newsletter should not be delivered until JPGN was fully counter-balanced the impersonality the huge present annual meet- established as the voice of ESPGAN and then be included in each ings express. Personally I feel a little sad that the economic issue of the journal. However, the informal information was so struggles have open up the Society to everyone interested to join. much appreciated that the Newsletter is still living as a separated The thousands of attendees at the meetings have of course made it message to all members. possible to finance and extend the internal work of the Society, like The ESPGHAN annual meeting has always attracted working groups and educational programs which are of benefit for researchers from outside Europe and they could be elected members science, and education in a large part of the world. Still some claims on the basis of the same criteria as the Europeans but called are to be fulfilled for membership of ESPGHAN, but the increasing ‘‘corresponding’’ members without the right to vote. In 1988, a impact of general paediatric doctors and the industry at the meetings Pan Pacific Paediatric Society for Gastroenterology and Nutrition make them less personal and this has resulted in focused specialties was founded and that started the discussion of extending to triple making new groups with less interest to attend the big meetings. joint meetings, including ESPGAN, NASPGAN, and PPSGAN. It Probably that is natural to keep up with the great amount of new was suggested that the joint meeting with NASPGAN was to occur www.jpgn.org S161 Supplement JPGN Volume 66, Supplement 1, April 2018 every fourth year and the triple meeting was suggested to occur less historical first meeting of the Society in Paris in 1968. It was so frequently, and so it proceeds since many Asians in the field will exciting to get to know all the already famous individuals in continue to attend our meetings. addition to the 3 founding fathers: Charlotte Anderson, Salvatore I have been very proud to belong to ESPGHAN and happy to Auricchio, Beat Hadorn, who soon after would describe enteroki- see and to some extent have the possibility to contribute and take nase deficiency, Jarmo Visakorpi, Gunnar Meeuwisse, and others! part of the development of our Society. Despite my expression of This was my first encounter with ESPGA, when I got the virus. some nostalgia, this should mainly be taken as a sign of the joy and Then: first oral presentation in Interlaken, member in 1975 after friendship the Society stands for. I hope that the claim for quality returning from Robert Crane’s laboratory in Rutgers University will never be in question since the sign of quality will keep our (New Jersey), secretary from 1984 to 1988; my life in paediatric Society in the front line also for the future. gastroenterology was entirely shaped by ESPGAN. This deep involvement was also due to the extremely friendly atmosphere Jacques Schmitz, France 1992–1995 during these meetings. We were young and enthusiastic and it was not uncommon that a member stayed at another member’s home, as (Fig. 8) ‘‘the founding fathers’’ had done. «I had a farm in Africa...» Karen Blixen 1937 It seemed thus normal to me to wish to continue as President It was the time of balance studies so brilliantly used by to serve ESPGAN as I did with great interest and pleasure as Dicke, Weijers, and Van de Kamer to demonstrate the harmful Secretary of Sandy McNeish and Salvatore Auricchio. I presented effect of gliadin in coeliac disease and later by Weijers and my candidature to become President after Birgitta Strandvik at the colleagues to describe congenital sucrose-isomaltose intolerance; AGM during the Brussels meeting in 1992. However, that year it was the time of the spreading of intestinal biopsy, performed for Samy Cadranel and John Walker-Smith were also running for the first time in children in 1957, and of the elucidation of the President. ‘‘After careful consideration, the Council decided to structure and functions of the intestinal brush border, of the propose a democratic election instead of endorsing one particular emerging concept of glucose/sodium cotransport. Among the more candidate.’’ It was the first time that the Society elected its than 20 inborn errors of metabolism affecting the intestinal diges- President, usually proposed by the Council and accepted by the tion and absorption, 9 had been described between 1960 and 1964. It AGM. I was elected with a small majority, but democracy worked is in the context of this extraordinary blossoming of knowledge that very well later on. 3 of the main actors of these progresses—D. Weijers (coeliac When I took the presidency, ESPGAN was already a rather disease), B. Lindquist (glucose-galactose malabsorption), and J. large and well growing Society. Membership had grown from 39 in Rey (abetalipoproteinemia) decided in 1967 to found the European 1968 to 232 in 1993. Number of abstracts received had increased up Society for Paediatric Gastroenterology (ESPGA). to more than 250. Workshops introduced after 1982, working At that time, I just had joined Jean Rey’s laboratory groups after 1989 witnessed the vitality of the Society. My intention (INSERM U 12, J. Fre´zal, Director) and clinical unit as resident was to confirm or increase the scientific level and promotion of the working on dipeptidase activities, then a black box. Jean was Society without affecting his friendly atmosphere. friendly enough to invite me, and my wife Franc¸oise, to the With regard to promotion, the development of Summer Schools was impressive. After the success of the first ones in gastroenterology in Birmingham in 1990, and in Nutrition in Vevey in 1991, a Summer School was organised by Isabel Polanco, near Madrid in September 1993 with the project of ‘‘learning by doing.’’ A second Nutrition Summer School planned by Berthold Koletzko in 1994 had to be postponed to October 1995 because of funding problems. The first Hepatology Summer School was organised by Deirdre Kelly and Martin Burdelski, in Germany in 1995. Finally, facing the political upheavals of Europe, making Eastern Europe more accessible to us, I proposed to the Council in 1993 to organise Travelling Summer Courses in Eastern Europe to bring ESPGAN senior members close to a local audience. This proposal was enthusiastically received and in 1994 we (Deirdre Kelly, Erika Isolauri, Salvatore Cucchiara, Stefano Guandalini, Jan Taminiau, and I) went to Bialystok (Poland), thanks to the organising proac- tivity of Hania Szajewska, and to Budapest with the help of Hedvig Bodanski. In 1995, the Travelling Summer School welcomed by Pr Georgescu visited Bucharest but sadly had to cancel the Novi Sad course proposed by Tamara Vukavic because of the escalating and widening conflict in Yugoslavia. The kindness and enthusiasm of our audiences were our rewards. With regard to our scientific activity, the creation under the impulsion of Hans Bu¨ller and Deirdre Kelly of the Research Forum for young investigators was an excellent proposition. It was aimed at bringing together around 20 young researchers from all over Europe to present at length their ongoing work in the presence of Michael Lentze, the organisers and myself during the first Forum held in the Netherlands in June 1994. It was a great success both on the scientific level and for the friendly atmosphere. This Forum was repeated in January 1996 in the same place, organised by the same FIGURE 8. Jacques Schmitz. team, with the same success.

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These developments were made possible by the financial usually rewarding, sometimes disappointing but always the occasion support of the industry, MILUPA for the Travelling Course and of to meet colleagues who eventually become good friends. NUTRICIA for the research Forum. This support was visibly In the early years of our ESPGA (gastroenterology was consid- acknowledged as a response to the concern of some members ered wide enough to contain all aspects of our specialty) coeliac regarding our financial dependence on NESTLE for our Council disease, brush border membrane, mechanisms of diarrhoea were the Meetings in Vevey. running high profile subjects of our meetings. At the 1972 Hamburg The scientific quality of our Society was appreciated by adult meeting, we presented an original paper on Campylobacter jejuni, a gastroenterologists, who had welcomed ESPGAN into the United brand ‘‘new’’ intestinal infectious agent that did not receive any European Gastroenterology Federation (UEGF) in 1991. As Presi- attention and not a single question from the audience or chairpersons. dent, I served during 3 years as a member of UEGF Council together Very disappointed, we decided to visit Olympus in Hamburg with our Secretary (Isabel Polanco, then Peter Milla). It was a and convinced them to produce a slim endoscope suitable for constant concern for us to convince our members to attend the children. We became the pioneers of paediatric GI endoscopy. annual UEG Week, and to avoid a loss of our identity. The ‘‘new’’ diagnostic tool, rapidly adopted throughout Europe During my presidency, 3 Annual Meetings were organised. allowed our centre in Brussels to become the first paediatric In 1993 Birgitta Strandvik welcomed us in Go¨teborg where the 25th gastroenterology with an endoscopy unit attended by many fellows Anniversary of the Society was cheerfully celebrated. The trip to from all over Europe. Only 3 years after, endoscopy was the main Marstrand and the closing dinner marked by a paper plane shooting topic of the 1975 Brussels-Leuven ESPGA meeting. were memorable events. In 1994 our 27th Annual Meeting was also The first workshop accepted by the Council at the joint the 4th ESPGAN—NASPGN Joint Meeting in Houston Texas. meeting in Bern 1981 concerned paediatric endoscopy and inaugu- William Klish, helped by Carlos Lifshitz, was our active host. rated the concept of specific workshops that are nowadays routinely The science was excellent with 2 innovations: a Post-Graduate organised but then unauthorised. Michael Lentze’s organising Course of Paediatric Gastroenterology organised by Bill Balistreri talents saved this first workshop from a programmed disaster. I and a state of the art symposium on mucosal biology by Michael wish to thank him even after so many years. I was accepted as one of Lentze and Bufford Nichols, both well attended. I remember the youngest member (together with Pierre Rodesch and Jacques particularly my uncomfortable opening of a rodeo on the back of Schmitz, the future 8th president) and regularly pleaded for intro- a longhorn, fortunately very quiet, and the farewell banquet at the ducing new younger members and this was probably one of the fantastic NASA Space Center. Our 28th Annual Meeting organised reasons why the president Sandy McNeish proposed me as Council by Serem Freier was convened in Jerusalem. Prior to the meeting a member. During those 3 years I learnt how to manage what was then Postgraduate Course was once again, organised on ‘‘HLA from a relatively small but emerging society. structure to function.’’ I remember with pleasure the Son et Lumiere Eleven years later I organised the 25th annual meeting in presentation within the walls of the old city. At that meeting Samy Brussels, which coincided with the election of a new president to Cadranel was elected President; the Society was going forward. succeed Birgitta Strandvik. For the first time in our society, there It is thus with a free mind that I left Jerusalem with Franc¸oise was an election between 3 candidates: John Walker-Smith, Jacques to make a moving trip in Galilea. Schmitz, and myself. Although I was ‘‘playing at home,’’ to my great disappointment eventually Jacques won with only one vote Samy Cadranel, Belgium 1995–1998 difference. The next election in Jerusalem inaugurated the concept of the candidates presenting their program and I openly pleaded for (Fig. 9) enhancing ESPGHAN’s influence by promoting fellowships among To be elected as president of ESPGHAN represents a consid- young researchers from Europe but also from other continents. erable hallmark on the CV of any paediatric gastroenterologist and I Immediately after the ballot I was contacted by Ulysses had this honor in 1995, more than 20 years after becoming a member. Fagundes Neto, president of the LASPGHAN, who shared my Since my ESPGHAN journey started in 1970, I considered that to be views in broadening our joint ESPGHAN-NASPGHAN meetings part of such a prestigious scientific society was a must and a privilege (1978–85–90–94–98), to a wider organisation including Latin and I have been lucky to attend all but one of 46 annual meetings, America and Asian-Pacific societies. The federation (FISPGHAN) was established by the 4 societies (Ron Sokol followed by Harland Winter for NASPGHAN, Ulysses Fagundes Neto for Latin Amer- ica, Jeff Cleghorn for the Asian Pacific, and myself followed by Stefano Guandalini for Europe) with the objective to manage the first World meeting in Boston 2000, followed by Paris-France 2004, Igazu-Brazil 2008, and Taipei-Taiwan 2012. A new cycle has started in 2016 in Montreal-Canada. Jacques Schmitz the former president had planned East Euro- pean summer schools and our team, composed by Alfredo Guarino, Anna Maria Staiano, Angela Vegnente, Erki Savilhati, Jan Taminiau, Tamara Vukavic (the only fluent in Russian), and myself flew to St Petersburg where we were very surprised to find out that the responsible Russian delegate, Professor Vorontsov, was in Amster- dam! The course was the occasion of more surprises such as no projectors, no translators, although the course was held in the prestigious Academy of Sciences, formerly the illustrious Prince’s Youssoupov Palace, site of Raspoutine’s assassination. Another difficulty concerned the need to replace the 1996 meeting in Graz but, very conveniently, Berth Koletzko offered to organise it in Munich. It was a success except for my very poor prowess at blowing FIGURE 9. Samy Cadranel. the Alp horn presented by Michael Lentze at the gala dinner. www.jpgn.org S163 Supplement JPGN Volume 66, Supplement 1, April 2018

My presidency was the occasion of important decisions for We were driving in my car towards Brussels at a moderate speed on ESPGHAN’s future: signature of the JPGN contract with Raven the highway when I saw in the mirror a car coming behind me at a Press, participation as one of the 7 founding societies of the United very high speed. We were lucky to avoid the collision but my car European Gastroenterology Federation (UEGF) and promotion of ended upside down with Dominique on top of me in the passenger UEG Week and also joining the European Academy of Paediatrics seat. Miraculously none of us was hurt but we had to get out of the (EAP). In all these moves, I continued the work of my predecessors, car through the sunroof. The police transported us back to Roissy especially Birgitta Strandvik, with whom I share many ideas and, and we succeeded in booking a flight to Brussels just in time to needless to say, friendship because it was not easy to resist the reach my home where Peter Milla had just arrived and we could conservatism of some influent members. In the end the success of hold the scheduled meeting as if nothing had happened. The next JPGN, UEGF and to a lesser extent EAP proved we were right. morning, still scared but valiantly we took the train for a business The 1997 meeting in Thessaloniki was chaired by Sanda meeting in Amsterdam at ESPGHAN’s service! Nousia Arvanitakis, who had visited us in Brussels. Her daughter Finally, in few words, I happily enjoyed serving ESPGHAN. has become a prominent assistant professor in the adult gastroen- terology teaching hospital of my University in Brussels. Further Stefano Guandalini, Italy 1998–2001 happy memories, with the final meeting of my term in Toulouse 1998, chaired by Jean Pierre Olives, a dear friend with whom, since (Fig. 10) the early years of endoscopy, we had exchanged perspectives. After serving 6 years as Treasurer, I was elected to the Presi- However, the end of my presidency was not the end of action dencyinToulouseintheannualmeetingofMay1998,attheFifthJoint and it was my council that enthusiastically proposed Warsaw 1999 Meeting of ESPGHAN and NASPGN (in fact, at the time the North because we were convinced that young Hania Szajewska would do American Society hadn’t yet introduced the ‘‘H’’ for Haepatology in an excellent job. Together with Dominique Belli, the treasurer, we its acronym). I delivered my ‘‘acceptance speech’’ during the gala negotiated the financial terms, insisting in passing contracts at the dinner in an enchanted atmosphere in a cathedral, but the acoustics central level of ESPGHAN (another novelty). No doubt that for the were less than ideal, so I am not sure anyone heard (let alone remem- Marriott a payment in Swiss francs in Geneva was more attractive ber!) any of my words. One thing however my wife Greta still than zlotys (even if the literary translation means ‘‘golden’’). remembers vividly, as she was sitting at the ‘‘Presidents’ table’’: a Whereas today the role of the president of ESPGHAN can be spouse of a former President telling her: ‘‘Enjoy these three years: you compared to an orchestra director, with numerous soloists in charge will always be sitting at the honour table, and after that no more!’’ of specific tasks, it was not the case in the 1990s and the president At that time, preparations for the upcoming joint meeting relied mainly on the secretary and the treasurer. Dominique Belli with the 3 other international societies of Paediatric Gastroenterol- was the treasurer before and also after my presidency. Our under- ogy, Hepatology and Nutrition (NASPGHAN, the North American standing was excellent because of the similarity in many of our Society for Paediatric Gastroenterology, Hepatology, and Nutrition; points of view. I shared my term with 2 secretaries. First Peter Milla, LASPGHAN, the Latin American Society for Paediatric Gastroen- whose experience and perfect domination of his English mother terology, Hepatology, and Nutrition; and APPSPGHAN, the Asian tongue was a notable helpful advantage in a multilingual Council. Pan Pacific Society for Paediatric Gastroenterology, Hepatology, Peter and myself were also active at the levels of EAP (drafting the and Nutrition) were under way as the first world congress, an event criteria for a European recognition of our specialty at the tertiary going beyond the previous few joint meetings with NASPGN, was level) and UEGF where Peter continued as treasurer after his term as ESPGHAN President. Markku Maki, the second secretary of my term was straightforward and well organised and his sound common sense allowed a steady progress in our discussions. I still remember how helpful he was in backing my proposition for a new ESPGHAN logo, the very one we are still using now. I feel very proud of our logo with its playful and joyful simplicity, designed by a famous Belgian graphic artist after my suggestions. Remembering these events I am aware how faithfully all the members I quote served our Society and, not surprisingly, accom- plished great things during their notorious career in ESPGHAN: the presidents Sandy McNeish, Birgitta Strandvik, Jacques Schmitz, Peter Milla, Michael Lentze, Deidre Kelly, Ricardo Troncone, Berthold Koletzko; the secretaries Markku Maki, Peter Milla, Jean-Pierre Olives and currently my friend Genevie`ve Veereman; Dominique Belli my treasurer but also the following ones, that I consider as friends Jorge Amil Dias, Alan Phillips and currently Anna Maria Staiano; the successive European editors of JPGN John Walker-Smith, Jehan Desjeux, Michael Lentze, gentle David Branski who sadly passed away and to whom I paid regular visits in Israel and Raanan Shamir who replaced him before becoming the current president and, of course Hania Szajewska, the current editor, who fulfils the expectations we placed in her. I would like also to evoke the names of those who shared my adventures in endoscopy, Jean-Franc¸ois Mougenot and Martin Burdelski and in the study of Helicobacter, Giuseppina Oderda and Sibylle Koletzko. My reminiscences would be incomplete without telling of the narrow escape from the terrible car accident we had in 1997. Coming from Paris Dominique Belli joined me at Roissy airport. FIGURE 10. Stefano Guandalini.

S164 www.jpgn.org JPGN Volume 66, Supplement 1, April 2018 Supplement planned to take place in Boston in the year 2000. It occurred to me most if not all of the times! I liked this remark; I know it may not be that this was going to be a tremendous opportunity to seize in order really true, but thank you, Jan! My only regret at the Geneva to create a permanent organisation that will not only oversee every meeting: in thanking name by name every individual who worked 4 years the organisation of the world congress, but more: a steady with me in the Council, I totally forgot to thank Dominic Belli for body, similar to UEGF (the United European Gastroenterology what was indeed a marvellous organisation, to which he worked Federation), producing working group reports, position papers tirelessly with a minimal contribution from me. His name was in the and timely statements on a global scale, thus maintaining alive shortlist I had prepared, but for whatever reason my eyes did not throughout the 4 years in between congresses a vivid international catch it, and I was too excited in delivering my very last address to cooperation. notice it. Sorry, Dominic; please know this still sticks with me. I first presented this vision to the council of ESPGHAN in FISPGHAN was officially launched with a signing ceremony February of 1999. Here, on a cold Swiss winter morning in Vevey, by the 4 Presidents during the Boston World Congress: our first task Markku Maki (our Secretary) was open and balanced, but not was to set up working groups and work at the organisation of the enthusiastic as I had hoped; Hania Szajewska was instead quite next World Congress that would take place in Paris in 2004, and as cold, as she was of the opinion that a small Society, holding small- first President of FISPGHAN, I dedicated myself completely at scale meetings, was more conducive to exchange of ideas and making sure this will be a smashing success. Specific committees projects, and we were risking losing this when embracing such a were created, leaders appointed and charged with specific tasks, and larger audience and scope; a position held by others as well. But I progress reports were periodically done and reviewed. Olivier persevered, being convinced that the times of our small, closed Goulet was a stellar organiser, and I think everybody who was circle of illuminated people were gone, and we needed to open the present in July 2004 will agree that the congress, probably the doors and be ready to more intense comparison and collaboration largest ever until then for any ESPGHAN event, went extremely with the rest of the world. Eventually I did get the council’s well and was enjoyed by an impressive variety of international endorsement, and was thus ready to export the project of a Federa- participants. Among many memories of the event, the one that I tion to my colleagues who were at the time responsible for the other cherish the most to this day is the treat Olivier gave me: to start the Societies: Dick Colletti for NASPGHAN, Geoff Cleghorn for opening ceremony by entering the stage with him aboard his own APPSPGHAN, Ulysses Fagundes Neto for LASPGHAN. I do Fiat 500!! What a moment! We got a prolonged standing ovation remember Ulysses immediate, warm reception of the idea, Geoff’s that still resonates in my ears. similar positive response (he actually brought me later a bottle of a really outstanding Australian red wine to convince me that their Peter J. Milla, United Kingdom 2001–2004 great wines had nothing to envy to their Italian counterparts—and he did succeed!); the Americans (Harland Winter was often with (Fig. 11) Dick Colletti since he was the local organiser of the 2000 Boston meeting) took a bit longer to convince, but once they bought into the idea, their contribution was instrumental in shaping the bylaws and detailing all the financial aspects of it. The years of my presidency were characterised for me by a lot of travelling: in fact, I was elected in Toulouse in spite of the fact that since about 2 years I was already living in the USA, to me a great testimonial of the affection and esteem from the ESPGHAN membership that I will never forget. But as I was extremely respectful of the fact that ESPGHAN is a European Society, I made a point of having each and every one of the council meetings to be held in Europe. So we met in Geneva, in Rome, in Warsaw. Warsaw, in 1999, was going to be double first: for me, the first congress as President; and for Hania Szajewska the first congress as main organiser! Our collaboration was intense, constant and very productive; in spite of the time zone difference, we managed to exchange e-mails in real time many times a week, and often many times a day! She would come up with some questions, which I answered, or with some ideas, that I always liked, but to which I invariably added some refining touches, which I must say she always appreciated and accepted. The tension in both of us was evident, as we went carefully together through all possible details and minutia to be sure the congress was going to be flawless. And I think it was, as the only negative event was pouring rain on our outdoor gathering: but again who is to blame for that? The meeting in Geneva in 2001 was going to be my Pre- sident’s farewell congress. It was yet another successful meeting, in a typical ESPGHAN format and spirit, splendidly organised by Dominic Belli. In a salute Jan Taminiau, by then our new Secretary, gave to me during the gala dinner, he was very kind—as expected!—to me, praising my leadership and making a remark that stuck with me. He said I was always patient, listening to everybody’s positions and comments, and then eventually always ending up persuading everyone that the way I saw whatever the issue at stake was the right one; and this proved to be indeed right FIGURE 11. Peter J. Milla. www.jpgn.org S165 Supplement JPGN Volume 66, Supplement 1, April 2018

For me ESPGHAN was a large family who were bound of ESPHGAN was born with enthusiastic midwifery from Yigael together by good science and enjoyed having fun. Like all families Finkel, Clare Burnett, and Sarah Macdonald. The Nurses and there were differences of opinion but these were in the main settled Dieticians programme became a very much welcomed development by friendly but rigorous debate. During the 1990s the society was and contribution to ESPGHAN’s mission. growing in size and changes were occurring around us so that by the A Permanent Secretariat: From its inception the Society had time I was elected President it had become clear that our Society been dependent on the individual Officer’s university departments was at a crossroads and some of our institutions needed to change for administrative and secretarial support. Changes in academic life but others did not. My abiding memory of my time as President was were making this less and less possible. With the increasing size and that it was a period of great change and most of the changes seem complexity of the annual meeting, the growth in size, stature and over the intervening years to have stood the Society in good stead. function of the Society a permanent Society secretariat was Scientific excellence, good fellowship, and friendship remained the required. Eventually after examining a number of different models cornerstones but the expanding role and increasing size of our a tender was put out to companies in the business of Association Society resulted in alternative and additional routes being required management and a contract entered into with Colloquium. Industry in our endeavour to develop paediatric gastroenterology, haepatol- had supported the development of the Society in a variety of ways ogy, and nutrition in Europe to the standards of ESPGHAN. both financially and with hospitality. The February Council Meet- The Need for Change: the days of the close familial society of ing since the early years had been generously hosted in Vevey but friends were over. The dramatic and continuing increase in the changes of attitude by governments and NGO’s to the interface demand to attend the annual meeting prompted changes that would between the profession and the medical industry meant that this result in a more open society involving all of the membership and could no longer continue. The last Council meeting in Vevey was which truly represented paediatric gastroenterology, haepatology held in 2004 sending a clear signal that the Society was independent and nutrition in Europe. The society’s response for the need for of Industry. change affected all areas of activity of the society from the Presi- Technology had also developed and the rise of the personal dent, the election of officers, councillors and members, the provi- computer (PC) had invaded all our lives. The PC made possible data sion of a permanent secretariat, as well as to the mode of submission handling which most of us had only previously dreamt of. With the of abstracts to the Annual Scientific Meeting of the Society. secretariat also came sophisticated electronic means of handling Changes to the Society: It was clear that the Presidents abstracts. Even so, many members of the society preferred to submit responsibilities had increased markedly both in breadth and com- their abstracts for the Annual Meeting on paper forms. With the plexity since the early days of the Society. To such an extent that the increasing size of the Annual Meeting, by now up to 1500 delegates, Presidents effective 3 year term of office was reduced to 2 years by submission of abstracts by some electronically and by others on the time taken to understand all the areas of business which now paper forms was making abstract handling cumbersome. Prolonged included ever increasing cooperation with NASPGHAN and the rise debates at the AGM resulted in no paper forms for the 2003 meeting of FISPGHAN and a World Congress. For the incoming President and removal of the electronic form by January 2, 2003 made late ‘‘to hit the ground running’’ now was not possible. The obvious submission a thing of the past. solution was to alter the president’s term of office to include a year’s JPGN: An important area of change was that involving run-up as president elect together with being available to the JPGN. The editors and their editorial teams had worked hard to Council for a year after his term of office to ensure effective hand improve the journal. They were now being rewarded for this by over. In addition the officers: President, Secretary General, and achieving an impact factor of greater than 2. From the time of the Treasurer acted as Executive directors to carry out the day to day Journal’s founder Emi Lebenthal, it was always intended that the business of running the Society between Council Meetings. For this journal would be the mouthpiece of both NASPGHN and ESP- I was ably supported first by Jan Tamininau, then, Jean Pierre GHAN and that eventually it would be solely owned by the 2 Olives as Secretaries, and Dominique Belli as our long serving societies; this time was fast coming. The interface that the Societies Treasurer. It was great fun and increased our friendship. Without had with the publisher was far from ideal. In order to improve this them the changes to the society required that I now relate would not we joined forces with our friends in NASPGHN and formed a joint have occurred so smoothly. publication committee to put the Societies points of view to the The Society’s Officers, Councillors, and Members had from publisher more effectively. We duly became the owners. Over the the earliest days always been elected at the Annual General Meeting recent years we have retained the original publisher so that I held during the Annual Scientific Meeting of the Society. Usually believe our negotiations around post ownership changes have been only one-third at most of the membership attended. This meant that effective. the majority of the Society, as dictated by the Society’s constitution, ESPGHAN and Europe: ESPGHAN as a society was steadily did not take part in making major decisions concerning the Society. increasing its involvement in European affairs in a number of This was not a democratic way of conducting the Society’s busi- directions including the UEGF, training via the European Board ness. With the ever-growing society, in order, to involve the whole of Paediatrics of CESP and UEMS, European paediatrics and society and remain within our constitution elections were changed, medicines. The most visible evidence of this was the development to be carried out by a postal ballot. of a training syllabus for paediatric gastroenterology, haepatology, The Committees and Associate Members: The development and nutrition in Europe with notable contributions by John Walker- of specialism within gastroenterology, haepatology, and nutrition Smith, Deirdre Kelly, and Peter Milla, which was approved by the brought about the Committees of Gastroenterology and Hepatol- EBP and published in JPGN. The existence of a training syllabus ogy, which were inaugurated in 2004, but development was not and recognised centres for training greatly aided the acceptance in restricted to medicine with the growth in some countries in Europe many countries of Europe of paediatric gastroenterology, haepatol- of Nurses and Dieticians with a special interest and expertise in the ogy, and nutrition as a recognised subspecialty. The European area. This was largely brought about by the development and Medicines Evaluation Agency (EMEA) of the European Commis- growth of nutritional support and a variety of innovative methods sion recognised the increasing importance of ESPGHAN as the that required expertise for them to be successful. Not surprisingly voice of European paediatric gastroenterology, haepatology, and the nurses and dieticians involved felt the need for their own forum nutrition by inviting the Society to collaborate with them in the and so the Nurses and Dieticians programme as Associate Members evaluation of paediatric medicines by its Paediatric Expert Group.

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Despite the numerous changes, the expanding role and extend this way of democratic election to the officers of Council as increasing size of our Society, scientific excellence, good fellow- well, and this was institutionalised. ship, and friendship remained the cornerstones. The Annual Meet- Our relations to industry needed to be rethought. The first ing still opened with a Welcome Reception at which to meet old step was to hold the annual council meeting, which up to 2006 were friends with a drink in convivial surroundings, dancing was still ‘‘de held in Vevey, independently on neutral grounds in order to have rigeur’’ at the Farewell Dinner but who knows what the future the liberty for free decisions towards sponsors from industry, which holds; maybe there will be a return of the ESPGHAN Football plays an important role for the organisation of our meetings. Thanks Championship or even throwing the Wellington boot! to a wonderful council with Jean Pierre Olives as secretary, Jorge Amil Dias as treasurer, Steffen Husby, Andras Arato, Anna-Maria Michael J. Lentze, Germany 2004–2007 Staiano, David Branski as representative of the GI-committee and Raanan Shamir as representative of the Nutrition committee, we (Fig. 12) were always able to reach mutual decisions on our ways for future After so many wonderful years of a closed ‘‘family’’ shop, changes in our society. the society ‘‘among friends’’ moved in the beginning of the 21st One cornerstone of our annual meeting was the working century more and more into an internationally and globally recog- groups, discussing various aspects of our subspecialties. The work- nised organisation. Already under the presidency of Peter Milla the ing groups were independently holding meetings within the annual milestones for the future development were set and I saw it as the congress or apart from it. After institutionalisation of 2 more goal during my presidency to extend these footprints together with committees, that of gastroenterology and of haepatology, in addi- council into larger future global perspective. It was obvious to tion to the already 30 years existing committee of nutrition in 2004, foresee that our annual meeting would become larger with extended the chairmen of these committees became council members for 3 programs, which led to extensive parallel scientific oral and poster years. The growing number of working groups was allocated to the session, workings groups and symposia as well as early morning 3 committees. The working group activities were quite successful. and late afternoon symposia. The results of these trends were The IBD working group, which was meeting in Porto, were estab- discussed with friendliness, but were often controversial within lishing criteria for the diagnosis and therapies of IBD in childhood, the council and the AGM when trying to meet the new require- published 2005 as ‘‘Porto criteria for IBD.’’ Together with our ments. Changes in our constitution became necessary in regard to American colleagues the working group on gastroesophageal reflux membership. Already 2005 the proposal was made to extend our disease (GERD) elaborated guidelines of ESPGHAN and NASP- membership towards nurses and dieticians, which was decided at GHAN for the diagnosis and treatment of GERD. The working AGM in Dresden 2006. The election of new members was already group of ‘‘acute gastroenteritis’’ together with ESPID published decided as a general electronic postal ballot. It was only logical to evidence-derived guidelines for the management of acute gastro- enteritis in children in Europe 2008. The 3 committees initiated very well attended summer schools in their subspecialties all over Europe with great success. Many attendants of the summer schools started their career in subsequent years and became well known in academic medicine as prominent members of our society. The Eastern summer schools continued their successful work in Eastern Europe and are now extending their mission globally organising summer schools in the Middle East, Asia, and Africa. As one of the 7 founding sister societies, our relationship with UEGF was becoming an issue while UEFG meeting were growing into very big congresses with more than 10,000 participants. Peter Milla and I were for 3 years attend- ing the committee meeting of UEGF pursuing the interests of ESPGHAN. The impression by our adult gastroenterologist was that the contribution of ESPGHAN was rather limited at their annual meetings. In 2005, Peter Milla and I fought for more representation of paediatric topics at UEGF. Yigael Finkel as representative in the scientific committee of UEGF took the argu- ments for paediatric gastroenterology, haepatology and nutrition forward into the future organisation of meetings and in subsequent years the input by ESPGHAN into UEGF grew steadily thanks to his hard work and that of the following representatives of our society. Now ESPGHAN is very well represented at UEG meetings with postgraduate courses, symposia, workshops, and e-learning programs. The issue of ethics in medicine and science was brought up by Sandy McNeish and encouraged by Birgitta Strandvik. Various aspects like collaboration with industry, ethical standards in pub- lishing, plagiarism, and fraud in science were discussed in council and as results the necessity of a Committee on Ethics of ESPGHAN was seen and subsequently decided. Since then the Committee on Ethics became involved successfully in many aspects of our daily society life like in the ethics of publishing as well as in the regulations and relations to industry leading finally into a ‘‘code FIGURE 12. Michael J. Lentze. of conduct’’ put together by Hans van Goudoever. www.jpgn.org S167 Supplement JPGN Volume 66, Supplement 1, April 2018

After some decades of existence it became obvious that ESP- strengths and think about what to do next was great help in GHAN needed a logo for its recognition value to the public. A logo developing our strategy and clarifying our mission to promote care contest was initiated and among various proposals the one by Samy of children with gastroenterological, haepatological, and nutritional Cadranelwonthecontestandsincethanthe‘‘LittleMan’’incyanwith conditions through the production of new knowledge and the thecurvygutisrecognisedverywellasabrandofoursocietyonflyers, education of professionals working within Europe and beyond. congress emblems, internet presentations, and letters. Our first big task was to change the congress organisation and Despite the enormous growth of our society the friendly and association management in order to restructure the administration familial atmosphere remained in ESPGHAN. The spirit to be among and the governance of the Society. After a competitive tender, we friends, the wonderful annual meetings and the joy to belong to that appointed MCI, who worked with us very successfully for many 50 year old society has never diminished and I am convinced that years and I will always have great fondness for our first manager, the future of our society will be as inspiring and sparkling for our Maria Phillips and our congress organisers Henry Lushington and subspecialties as the colourful fireworks during the farewell dinner Sarah Lawrence. at the annual meeting in Dresden 2006. We also streamlined the rules and regulations for our highly successful committees and working groups and introduced budgets Deirdre Kelly, United Kingdom 2007–2010 and accountability for their members. A big achievement was the establishment of separate committees for Allied Health represen- (Fig. 13) tatives and Trainee members and ensuring that they became obser- I took over from Michael Lentze, which was a big step and I vers on Council so we could benefit from their ideas and build for had very big shoes to fill. Luckily, I had a great Council, with our future. The Trainee committee, (now called Young ESPGHAN) Riccardo Troncone as secretary and Jorge Dias as Treasurer. headed initially by Ron Bremner is now the largest committee in the Raanan Shamir, Annamaria Staiano, Alan Phillips, Alfredo Guar- Society and a source of most of our new and active members. ino, Gigi Veereman, Florence Lacaille, Sibylle Koletzko, Dusanka We felt it time to honour our long-serving distinguished Micetic-Turk, Andras Arato, Yvan Vandenplas, Hania Szajewska, members, and the first ESPGHAN Distinguished service award was David Branski and Dominique Turck, all there to help me at one presented to Professor John Walker-Smith in 2010. ESPGHAN has time or another. It was a time of great change for ESPGHAN and we always had a strong reputation for education and building on this worked hard to create a modern organisation, which maximised the tradition, we made partnerships with industry and established a talent in the society and made strong collaborations with industry, number of overseas postgraduate courses in China, Indonesia, and national and international societies. East Africa, not to mention the successful ESPGHAN Africa I introduced the annual Council strategy day with our much- diploma course, so well led by Michael Lentze and Jan Taminiau. loved facilitator, Val Glenny. Although there was a lot of scepticism Maintaining a clear and ethical relationship with industry about the project initially, the time away to allow us to focus on our was a key priority and we had many constructive discussions and developed guidelines as well as good relationship with our key partners in industry. We also built relationships with other national societies: NASPGHAN, through joint working committees and guideline groups and the joint Publication Committee of JPGN, which successfully re-negotiated a better contract with Lippincott; UEG (much helped by Peter Milla who was the Treasurer of UEGF), EASL, and EPA, through David Branski’s leadership. These important steps have been strongly consolidated by Bert Koletzko and Riccardo Troncone and it is wonderful to see the development of the Public Affairs Committee strengthening our profile in Europe and the world, making us the influential society we are today. And it was all a great deal of fun, lots of laughs, lots of good times andsome wonderfulannual meetings with an ever increas- ing number of delegates, but always the warmth and the friendship for each other which makes ESPGHAN a society like no other. Ricardo Troncone, Italy 2010–2013

(Fig. 14) I accepted the position of President Elect in 2009 at the end of my term as General Secretary. This has given to me the unique opportunity of being a witness, and to some extent a protagonist, to the life of the Society for a relatively long period. This period has been characterised by rapid growth of ESPGHAN and its arrival on a global scale. This process is still ongoing and it is important to look with great detail to some of its experiences, hoping to better interpret its evolution and to prepare the Society for its next challenges. The Growth: The Annual Meeting probably represents the most important event in the life of the Society. Nothing more than the number of registrants at the Annual Meeting gives us an idea of the steady growth the Society has undergone in the last decade. That process has had a number of implications, first of all the choice of the venue. Sorrento 2012 was the last meeting organised in a large FIGURE 13. Deirdre Kelly. hotel; since then it has been necessary to hire convention centres

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help the development of our subspecialty. Going with this momen- tum a new position on the ESPGHAN Council was created, the International Affairs Council member, to whom the organisation of educational activities outside of Europe has been entrusted. Again, with the intention of favouring the association of colleagues who operate outside of Europe to ESPGHAN, who are interested in participating to ESPGHAN activities, the concept of the corre- sponding membership, first reserved to paediatric gastroenterolo- gists already members of another society affiliated to FISPGHAN, was revised and expanded. At the same time access (online) to JPGN has been rendered easier. Beyond these decisions, the increasing global growth and influence of ESPGHAN is evident. A particular example is the prestige acquired by the Nutrition Committee of the Society; the value of the papers produced have in fact led to the general perception of ESPGHAN as the world leader in infant nutrition. The entrance of ESPGHAN on a global scale has also led to an appreciation for our relationships with our North American sister society NASPGHAN. Our most important area of collaboration has been the production of guidelines that have had, because sustained by both societies, an impressive impact (it is sufficient to mention those on gastroesophageal reflux and on constipation). One other important area of collaboration remains JPGN. The decision to have annual strategic meetings of the 2 editorial committees with the aim of discussing the editorial policy of the FIGURE 14. Ricardo Troncone. Journal has enhanced debate and favored the definition of common strategies. capable of hosting thousands of attendees. A few know that in Relation With Other Scientific Societies: In the years 2010– Sorrento it was decided that in the last days preceding the meeting to 2013 ESPGHAN has given increasing attention to relations to other close registration considering registrants had already surpassed the scientific societies, NASPGHAN and other FISPGHAN societies limits of capacity of the structure. The budget of the annual meet- having already been mentioned. For strategic importance was the ings has become remarkable and with it some financial risk to which strengthening of our relations with UEG. ESPGHAN is a founding the Society has become exposed in the case the expected number of member of UEG and ESPGHAN members, such as Peter Milla our participants is not reached. The decision of committing the Society treasurer for many years, have been leaders of UEG. However, the to such large financial enterprises, years in advance, without impact of ESPGHAN has not always paralleled its scientific knowing with certainty if the increase would have been confirmed strength. During the first part of this decade our relations have in the future, was very difficult. significantly improved. The contribution of ESPGHAN members to However, the expansion of the Society has caused not only the UEG Committees, Scientific Committee (Raanan Shamir, financial concerns, but has challenged the very nature of ESP- Sibylle Koletzko), Educational Committee (Alan Phillips, Lorenzo GHAN. The discussion of the scientific or professional (or even D’Antiga), Future Trends (Nikil Thapar), Public Affairs Committee better multiprofessional since the creation of the AHP membership) (Gigi Veereman) have been of great impact and very much nature of ESPGHAN had already started in previous years. That appreciated. The UEG President was formally invited to the ESP- debate eventually resulted in a revision of the criteria for member- GHAN strategy meeting held in 2012 in Jerusalem. The decision ship, with the elimination of the requirement for the new members that most tangibly shows how close we have become the with UEG to have presented at least once an abstract at an ESPGHAN meeting. is the choice of Vienna and the House of Gastroenterology as the That change alone has already generated a consistent increase in the venue where winter council meetings and ESPGHAN strategy number of members, and began to resolve, at least in part, the meetings have been taking place since 2013. discrepancy between the number of members (relatively small) and Again in the area of relations with other scientific societies of the large attendance at the annual meeting (much more than 10 particular importance are those with the National Societies of Paedi- times the number of members). atric Gastroenterology, Hepatology and Nutrition. Here much has The Global Dimension: Another aspect related to this process been done, but much more remains to be done. This is important for a of growth is the provenience of professionals attending the ESP- Society such as ESPGHAN that aims to become the house of all GHAN annual meeting. The number of those coming from extra- professionals involved in the care of children affected by gastroen- European Countries is impressive, a trend initiated in Istanbul 2010 terological, liver, and nutrition diseases. Great progress has been and confirmed in subsequent meetings. During the period of my achieved in the educational area with the proposition of syllabi to be presidency the educational offer by ESPGHAN beyond European adopted in the different European Countries, along with the effort to borders has shown a parallel trend. Examples are the courses see paediatric gastroenterology recognised as subspecialty in the organised in Asia (China, Indonesia), and also in Mexico. Of special Countries where still it is not formalised. And, again, in this educa- importance is the attention given to the educational requests coming tional area of importance are relations with the European Academy of from Africa. The meritorious initiative, led by Michael Lentze and Paediatrics, EAP, the paediatric branch of the UEMS, again in view of other ESPGHAN members, that has taken place in South Africa for rendering homogeneous the teaching programs all over Europe. the benefit of colleagues from the rest of the African continent Research: The evolution of ESPGHAN to a multiprofes- cannot be forgotten. That is leading to the creation of a group of sional society does not contradict its main feature that has greatly Paediatric gastroenterologists, that we hope may represent the first contributed to its success, its unique blend between friendship and nucleus leading to the creation of a continental society, which will scientific excellence. Production and diffusion of knowledge www.jpgn.org S169 Supplement JPGN Volume 66, Supplement 1, April 2018 remain the mission of ESPGHAN. Special efforts have been made Mary Fewtrell, Luisa Mearin, Piotr Socha, Yvan Vandenplas, Hans to encourage basic and translational research within the society. van Goudoever, Gabor Veres, and Nikhil Thapar and for the hard With the increased financial availability a significant amount of work of the members of the executive council including Sanja money has been allocated to awards recognising the scientific Kolacek (secretary 2012–2015), Gigi Veeremans (secretary 2015– merits of members, particularly the youngest, to funds favouring 2018), and Alan Phillips (treasurer 2012–2016). the exchange of experiences, and even most importantly, to scien- Annual Congress: ESPGHAN hosts the largest and most tific networking. In fact, working groups and special interest groups successful congress in the field worldwide, with attendance recently have grown in number and complexity. The Stockholm meeting in reaching more than 4000 delegates from all 5 continents, which 2012 was perhaps the strongest demonstration of enthusiasm and includes a broad spectrum of clinicians, clinical researchers, scien- the richness of scientific commitment during my presidency. That tists, AHPs, and trainees. To meet the increasing needs for clinical year the tradition to not have the ESPGHAN annual meeting during updates, we introduced in 2014 a new Clinical Practice Track, and the year of the world meeting was reconsidered due to the amount of in 2015 a new hands-on learning zone in endoscopy (with addition requests from members asking that the society meet. This was of motility in 2016), both of which have been highly successful. We established on the basis of the activity of working groups, their expanded the use of digital tools such as our interactive congress research and their scientific interests. Thanks to the commitment of app for handheld devices, ePosters, the Virtual Meeting Site, and the Birgitta Strandvik and her colleagues the meeting was highly Website on Demand, to enhance information sharing and conve- successful. The Society has further grown since then and this year nience for delegates. Since 2015 we are joined by patient and parent on the occasion of another world meeting, ESPGHAN will have its organisations with whom we wish to closely collaborate to achieve traditional annual meeting. This further demonstrates, if it is our goal to optimally support patients and their families. Our necessary, a society that maintains its DNA in the mission of members can also enjoy the added privileges of the ESPGHAN producing and diffusing science in the interest of children affected Members Lounge and the newly introduced Young ESPGHAN by digestive diseases. Lounge. With the rapid growth of the congress, the organisational aspect have become more demanding, and hence a new professional Berthold Koletzko, Germany 2013–2016 congress organisation was appointed in 2015, which resulted in an even more cost effective running of the meeting. (Fig. 15) Membership: The criteria for membership were modified in It has been a great privilege indeed to serve as president of 2014 towards becoming an inclusive association for all clinicians, ESPGHAN—a most impactful European voice on gut, liver, and researchers, AHPs, and trainees dedicated to paediatric gastroen- nutritional health of infants, children, and adolescents, with strong terology, haepatology, and nutrition. As a result, the number of global links and impact. ESPGHAN has steadily become stronger members has markedly increased to now over 900, with a particu- and more active than ever before in the now 5 decades since its larly encouraging increase of young members. To meet the demands foundation. This success is due to the dedicated work of many of a growing and increasingly active society, additional support for enthusiastic members. I am particularly grateful for the contribu- professional office management of the association was contracted tions of the committee and working group members, of the members in 2015. of the ESPGHAN council which during my term included Mark Code of Conduct: Our council developed the ESPGHAN Benninga, Ulrich Baumann, Lorenzo D’Antiga, Jernej Dolinsek, Code of Conduct and—after consultation with the membership— adopted it in 2015. Our Code of Conduct summarises the ethical foundations of ESPGHAN’s obligation to ensure that paediatricians and allied health care professionals acquire and maintain knowl- edge, skills, and values that are central to paediatrics and child health without undue bias based on commercial interests. Ethical challenges are addressed that may arise when ESPGHAN members who organise, teach, or serve other roles in medical education have financial relationships with companies that have a direct interest in recommendations. It also illustrates strategies for mitigating the potential of such financial relationships to influence professional education in undesired ways. ESPGHAN’s Code of Conduct also governs the relationship between ESPGHAN and industry repre- sentatives involved in the support of research and educational activities in the field of paediatric gastroenterology, haepatology, or nutrition. In addition to identifying the principles of transpar- ency, independence, and accountability, the Code of Conduct also provides a practical approach on how to maintain the independence and integrity of ESPGHAN’s related professional education while promoting a trustworthy relationship between ESPGHAN and commercial companies. It is rather encouraging that our Code of Conduct has since served as a model for similar initiatives of other associations. Committees, Special Interest Groups and Working Groups: Throughout the year, numerous activities are contributed by the members of ESPGHAN’s main Committees on Gastroenterology, Hepatology and Nutrition, and the many other Committees, Special Interest Groups, and Working Groups. They develop recommenda- tions and guidelines on pertinent issues in the field, facilitate and FIGURE 15. Berthold Koletzko. perform research, and engage in educational and other activities.

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We created the new Public Affairs Committee in 2013 to successful research activities based on the strong ESPGHAN raise awareness for PGHN themes among decision makers, with a network. particular focus on the European Commission and European Par- Education: In 2014, we published an updated European liament where repeated meetings and events were held to lobby for Training Syllabus in Paediatric Gastroenterology, Hepatology greater support for child health. The History Committee has been and Nutrition to define minimum requirements for training to newly formed in 2014 with the goals to compile the history of support recognition as a European Specialist in PGHN, along with PGHN and of ESPGHAN, and to build an ESPGHAN archive with a logbook on necessary achievements (8). The ESPGHAN Educa- records of the foundation of the society, annual meetings and other tion Partner Programme (EPP) was launched in 2015 as an up-to- activities. This publication on the occasion of the 50th anniversary date, independent, high-quality educational programme for health of ESPGHAN in 2018 is a main outcome. care professionals. It is designed and implemented in full compli- For a number of years, representatives of the national PGHN ance with current professional and Continuing Medical Education societies across Europe have met with the ESPGHAN officers at the (CME) standards and with our Code of Conduct, to promote ESPGHAN Congress to discuss issues of common interest and confidence in independence, integrity and credibility of ESPGHAN opportunities for harmonisation. The ESPGHAN National Societies and its industry partners. The key target groups include Trainee Forum was established in 2015 as a sustainable platform for Members and other young health care professionals (addressed collaboration and joint activities. primarily by the ESPHAN Summer Schools and the Young Investi- Research Networks and Collaborations Arising out of ESP- gator Forum), established specialists (addressed by the new Master GHAN: ESPGHAN aims to promote basic, translational and clini- Classes introduced in 2015 that are open only for ESPGHAN cal science in PGHN and to enhance financial and other means of members), as well as health care professionals from less privileged support for research, including collaborative and multidisciplinary areas (Eastern European Summer Schools, International Schools). research. The ESPGHAN strategy on research for promoting child The Way Forward: ESPGHAN needs to continue striving for health was formulated and published (7). The strong and active improving our ability to promote child health, to treat and prevent networks of leading experts in different areas of PGHN provide challenges to digestive health in children and adolescents, and to excellent opportunities for scientific collaboration and successful strengthen the knowledge base that is required to do so. Close multicentre research grant applications. This strategy has become collaboration among all health professionals involved in this area, rather successful as shown by the following examples. The Paedi- along with patients, families and the many involved stakeholders atric European Digestive Diseases Clinical Research Network and decision makers, will be key to achieving our goals. ESPGHAN (http://www.espghan.org/about-espghan/research/paediatric-euro- provides a strong platform and great opportunity for such a pean-digestive-diseases-clinical-research-network-peddcren/) was fruitful collaboration. established in 2013 with financial support from UEG to form a network of clinical trials for studying and ultimately providing effective medicines for infants, children and adolescents with REFERENCES disorders in the area of PGHN. The European Network Study on 1. Dicke WK, Weijers HA, Van de Kamer JH. Coeliac disease: the presence in wheat of a deleterious effect in cases of coeliac disease. Acta Paediatr Malnutrition and Outcome in Hospitalized Children in Europe 1953;42:34–42. supported by the European Society for Clinical Nutrition and 2. ESPGAN Committee on Nutrition. Guidelines on infant nutrition. II. Metabolism (www.espen.org) and by ESPGHAN explores the Recommendations for the composition of follow-up formula and Beikost. prevalence and effects of undernutrition among 2500 hospitalised Acta Paediatr Scand Suppl 1981;287:1–25. children in 12 countries, and it also studies opportunities for 3. ESPGAN Committee on Nutrition. Guidelines on infant nutrition. I.Re- nutrition screening. The European Commission (EC) funded the commendations for the composition of an adapted formula. Acta Paediatr ‘‘PreventCD’’ project (http://www.preventcd.com) which studies Scand Suppl 1977;262:1–20. the aetiology of coeliac disease and the effects of infant feeding 4. ESPGAN Committee on Nutrition. Guidelines on infant nutrition. III. on disease manifestation. The ‘‘Early Nutrition Project’’ also Recommendations for infant feeding. Acta Paediatr Scand Suppl 1982;302:1–27. funded by the EC (www.project-earlynutrition.eu) explores long- 5. Revised criteria for diagnosis of coeliac disease. Report of Working term effects of early nutrition on later health with a focus on Group of European Society of Paediatric Gastroenterology and Nutrition. opportunities for prevention of obesity and associated disorders. Arch Dis Child 1990;65:909–11. The EC funded ‘‘Paediatric Inflammatory Bowel Disease net- 6. Diagnostic criteria for food allergy with predominantly intestinal symp- work for Safety, Efficacy, Treatment and Quality Improvement toms. The European Society for Paediatric Gastroenterology and Nutri- of Care’’ (http://cordis.europa.eu/project/rcn/199745_en.html) tion Working Group for the Diagnostic Criteria for Food Allergy. J aims to establish a long term inception cohort of paediatric Pediatr Gastroenterol Nutr 1992;14:108–12. IBD patients and to perform a randomised clinical therapeutic 7. Koletzko B, Kolacek S, Phillips A, et al. Research and the promotion of trial. The European Union-funded regional project ‘‘Innovative child health: a position paper of the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol coeliac disease learning model for health care professionals in Nutr 2014;59:274–8. the Danube region’’ (http://www.interreg-central.eu/Content. 8. D’Antiga L, Nicastro E, Papadopoulou A, et al. European Society for Node/Focus-IN-CD.html) aims at strengthening knowledge and Paediatric Gastroenterology, Hepatology, and Nutrition. Syllabus for awareness on coeliac disease among health care professionals subspecialty training: moving towards a European standard. J Pediatr and the general public. Many more opportunities exist for Gastroenterol Nutr 2014;59:417–22.

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Chapter 9. Words From Partner Societies

Barbara Golden, yTom Stiris, zJulia´n Pane´s, §Leyla Namazova-Baranova, jjAndre´ Van Gossum, ôHeiner Boeing, #Zulfiqar A. Bhutta, Armando Madrazo, yyJames E. Heubi, zzNezha Mouane, §§Paul Fockens, and jjjjBerthold Koletzko

ABSTRACT

On the occasion of the 50th anniversary of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), its close partner associations submitted comments and felicitations which are presented here. These include words from the Latin American (LASP- GHAN), North American (NASPGHAN) and Panarabian Societies (PASP- GHAN) and the Commonwealth Association (CAPGHAN) of Paediatric Gastroenterology, Hepatology and Nutrition, the Federation of International Societies of Paediatric Gastroenterology, Hepatology and Nutrition (FISP- GHAN), the European Academy of Pediatrics (EAP), the European Pediatric Association/Union of National Pediatric Societies (EPA-UNEPSA), the International Pediatric Association (IPA), the European Crohn’s and Colitis Organisation (ECCO), European Society for Clinical Nutrition and Metab- olism (ESPEN) , the Federation of European Nutrition Societies (FENS), and United European Gastroenterology (UEG). Key Words: CAPGHAN, ECCO, ECCO, ESPEN, ESPEN, ESPGHAN, FENS, LASPGHAN, NASPGHAN, UEG

(JPGN 2018;66: S172–S178)

COMMONWEALTH ASSOCIATION OF PAEDIATRIC GASTROENTEROLOGY AND NUTRITION SPGHAN was formed when I was a medical student, full of medical knowledge but completely lacking in nutritional FIGURE 1. Berthold Koletzko. Eknowledge. However, I was very aware that hospital patients, who could not look after their own nutritional needs, were dying of starvation. ESPGHAN was not a minute too soon. Later, I spent consequences of malnutrition in surviving children, who are the nearly 2 decades in the Tropical Metabolism Research Unit in future of these countries, are lifelong and severe. Thus, thank Jamaica doing research in and managing young children with goodness for the enlightened founders and early members of severe acute malnutrition. More recently, the scourge of over- ESPGHAN who realised that their Society, while advancing weight and its consequences, have been occupying us and even interest, research, knowledge, and practice of the closely related our children and throughout the world: but famines and under- topics of gastroenterology, haepatology, and nutrition in Europe, weight are also still occurring particularly in African and Asian was not enough. countries where children form the majority of the population. The Many Commonwealth and other countries in Africa and Asia suffered and still suffer severe poverty, famines, and child- hood malnutrition. Sixteen years after ESPGHAN was founded, Received January 26, 2018; accepted January 29, 2018. in 1984, the ESPGHAN members John Walker-Smith and Sandy From the CAPGAN, the yEuropean Academy of Pediatrics, the zECCO, McNeishranahighlysuccessfulconference in London on diar- the §EPA/UNEPSA, the jjESPEN, the ôFENS, the #International Pedi- rhoea and malnutrition in children in the Commonwealth atric Association, the LASPGHAN, the yyNASPGHAN, the (CDMCC). This was followed by conferences in Delhi and Hong zzPASGHAN, the §§UEG, and the jjjjFISPGHAN. Address correspondence and reprint requests to Berthold Koletzko, MD, Professor of Paediatrics, LMU—Ludwig-Maximilians-Universita¨t Mu- nich, Dr von Hauner Children’s Hospital, University of Munich Medical Center, Lindwurmstr. 4, 80337 Mu¨nchen, Germany (e-mail: offi[email protected]). Copyright # 2018 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000001920 FIGURE 2. CAPGAN logo.

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Kong. At the Hong Kong conference, Commonwealth Associa- of our Tertiary working groupwhere you play an importantrole and now tion of Paediatric Gastroenterology and Nutrition (CAPGAN) provide the chair of this group. The EAP/UEMS acknowledge the was created and John Walker-Smith and Peter Sullivan were the important work ESPGHAN has been and is doing for children and first Chairman and Secretary, respectively, of its Council. A children’s health, being a leading organisation giving paediatric advice Constitution was created and accreditation by the Commonwealth on gastroenterology, haepatology, and nutritional issues. This is much Secretariat was received. Thus, CAPGAN was largely an off- needed in preserving child health, especially with the increasing inci- spring of ESPGHAN. Several otherseniorESPGHANmembers, dence of obesity and type 2 diabetes in the child-adolescent population. Alan Phillips (Past Treasurer of CAPGAN & ESPGHAN), and We also acknowledge your continuing efforts to provide guidelines and Bhupinder Sandhu (Past President, CAPGAN) in particular, have allyourresearchinput.Yourworktooptimisenutritionforthepremature contributed freely and willingly to the development of CAPGAN. infant has a great reputation in neonatal medicine. We wish you to However, of necessity, CAPGAN has a larger role in advocacy continue the successful activities in the years to come. We look forward and it tries to be as inclusive as possible when organising to strengthen our collaboration; together we will make a difference and conferences, which are now biennial. Thus, CAPGAN is attended we will have a stronger political voice when we speak on behalf of all by state of the art researchers as well as junior paediatric trainees children and their health. from very poor areas, and not just limited to Commonwealth countries. Our recent conference in September 2017 was in Professor Tom Stiris, President of European Lusaka, Zambia, while the next will be held in 2019 in Toronto, Canada. Academy of Pediatrics FISPGHAN was created in 2000 as an umbrella organi- sation of which ESPGHAN is a full member and CAPGAN is an associate member. CAPGAN has been particularly active in FISPGHAN and contributed to organising the 4 yearly World Conferences (WCPGHAN), from that in Paris 2004 till the next one in Copenhagen in 2020. CAPGAN also contributes to FISPGHAN’s Council meetings and Working Groups. Thus, we are indebted to ESPGHAN and particularly its founder and early members for our existence and development. We wish ESPGHAN all the very best for the next 50 years and beyond.

Barbara Golden, President of CAPGAN

FIGURE 5. Tom Stiris.

EUROPEAN CROHN’S AND COLITIS ORGANISATION

FIGURE 3. Barbara Golden.

EUROPEAN ACADEMY OF PAEDIATRICS FIGURE 6. ECCO logo.

European Crohn’s and Colitis Organisation (ECCO) joints the scientific community in the celebration of the 50th anniversary of ESPGHAN. The long history of the society is the best testimonial FIGURE 4. EAP logo. of a fruitful contribution to education and research in the fields of Pediatric Gastroenterology, Hepatology and Nutrition in Europe. ECCO shares with ESPHGAN the objective of improving research, Dear ESPGHAN and all its members. education, and collaboration in the area of inflammatory bowel ItisanhonourfortheEuropeanAcademyofPaediatrics(EAP),as diseases (IBD) for the purpose of improving the care of patients the paediatric section of European Union of Medical Specialties with IBD. Europe has outstanding specialists in paediatric IBD, the (UEMS), to pay a special tribute to ESPGHAN and congratulate you community of paediatricians devoted to the condition has devel- on your 50th anniversary. We especially value the collaborations oped initiatives that brought about substantial advances to the field, between the 2 societies and are proud to have ESPGHAN as member and there is a growing need of education on the topic among general www.jpgn.org S173 Supplement JPGN Volume 66, Supplement 1, April 2018 paediatric gastroenterologists. ECCO highly values the continued multiprofessional organisation whose aim is to promote child health collaboration with ESPGHAN in the development of joint guide- with special attention to the gastrointestinal tract, liver, and nutri- lines for the diagnosis and treatment of paediatric IBD, the guide- tional status. Our goals are very close—to spread science-based lines for development of clinical trials in the paediatric population information, promote the best practice of care and to provide together with the European Medicines Agency, as well as the joint high-quality education. We have a lot of common activities. Leading collaboration in educational activities. ECCO is willing to continue experts of EPGGHAN are involved in the scientific committees of the and expand these joint initiatives for the benefit of all our patients. EPA biannual Congresses—Europaediatrics to provide high-quality ECCO congratulates ESPHGAN for the successful trajectory in scientific topics in the field of their expertise for European paedia- these 50 years and wishes all the best for the future of the tricians. And vice versa, we also cooperate closely on providing scientific society. publications, educational programs and analytical statements. And we are positively looking forward to our common future—to accept Julia´n Pane´s, President of ECCO together the challenge and strive for a unified and constructive cooperation for the benefit of the future of our continent—our children! With warm regards.

Leyla Namazova-Baranova, EPA/UNEPSA President

FIGURE 7. Julia´n Pane´s.

FIGURE 9. Leyla Namazova-Baranova. EUROPEAN PEDIATRIC ASSOCIATION/UNION OF NATIONAL PEDIATRIC SOCIETIES EUROPEAN SOCIETY FOR CLINICAL NUTRITION AND METABOLISM

FIGURE 8. EPA-UNEPSA logo.

The European Pediatric Association/Union of National Pedi- atric Societies and Associations (EPA/UNEPSA) was founded more than 40 years ago and unites today 50 national and affiliated paediatric societies from all over Europe. The main goal of our Association is to gather the efforts of all European paediatric profes- FIGURE 10. ESPEN logo. sionals and scientists in order to improve child health care and quality of life. The European Pediatric Association complies with the strategy of building efforts for the better future of European children. On behalf of the European Society for Clinical Nutrition and One of the main vectors of our Association is cooperation among the Metabolism, its officers and members, I am delighted to congratu- leading medical, social and specialized societies—with all who want late you at the occasion of the celebration of the 50th anniversary of to improve child health and development by putting children and your Society. In many ways our both Societies are sharing the same young people into the centre of their activities. The European Society objectives: improving education, scientific research and clinical for Paediatric Gastroenterology, Hepatology and Nutrition (ESP- practice in the field of medical nutrition. ESPGHAN and European GHAN) is one of the key partners for EPA/UNEPSA. We are proud to Society for Clinical Nutrition and Metabolism (ESPEN) have the have longstanding and fruitful cooperation with ESPGHAN—the same pattern: multidisciplinarity. During the last decades

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ESPGHAN and ESPEN have closely collaborated: joint sessions at and FENS can refer to common scientific sessions at the European the respective Congresses, joint working groups, and collaboration Nutrition Conferences. In this way, all the input from the many in publishing joint Guidelines. Several eminent ESPGHAN mem- areas of nutrition research is important for the overall picture of a bers were involved in ESPEN Committees. Moreover many clin- strong common community. In this way, FENS is looking forward icians and scientists are members of both Societies. Thanks to the for successful collaboration between the 2 organizations also in efforts of the members of our both societies the importance of the future. clinical nutrition is now highly considered in the medical domain. However, it is the responsibility of our Societies to continue Heiner Boeing, FENS President developing the field of Clinical Nutrition. ESPEN is wishing you the best for the next decades!

Andre´ Van Gossum, ESPEN Chairman

FIGURE 11. Andre´ Van Gossum. FIGURE 13. Heiner Boeing.

FEDERATION OF EUROPEAN NUTRITION SOCIETIES FEDERATION OF INTERNATIONAL SOCIETIES FOR PEDIATRIC GASTROENTEROLOGY, The Federation of European Nutrition Societies (FENS) HEPATOLOGY AND NUTRITION would like to congratulate the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) on its The global Federation of International Societies for Pediatric 50th anniversary. It is not easy to remember the time period of the Gastroenterology, Hepatology and Nutrition (FISPGHAN) and its 1970s in which the European idea was restricted to the western member societies congratulate ESPGHAN on its 50th anniversary, countries and transnational collaboration limited to a few of them. It and for amazing achievements in the last 5 decades in promoting is important to realize that this medical discipline was already child health through research, education, and bringing people following the idea of a united Europe and many common interests together. FISPGHAN owes a lot to ESPGHAN. In fact, it was among the different national bodies. I have to admit that the the ESPGHAN president Stefano Guandalini who from 1998 nutrition societies started relatively late to be represented within onwards promoted the idea of holding World Congresses Pediatric an own organization at the European level compared to ESPGHAN. on Gastroenterology, Hepatology and Nutrition and convinced Nowadays, it is important that the various players in the area of partner societies that a global Federation should be created. At nutrition are working together in order to help science and policy the first World Congress held in Boston in the year 2000, FISGHAN recognizing that nutrition is one of the most important aspects for was formally established jointly by the Asian Pan Pacific health, well-being, and also cultural identity. In the past ESPGHAN

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(APPSPGHAN), European (ESPGHAN), Latin American (LASP- colleagues have had the privilege of working with ESPGHAN, GHAN), and North American (NASPGHAN) sister societies as full and I can attest to the passion of the engaged members who make up members, joined by the Commonwealth Association (CAPGAN) this body. Paediatricians have a responsibility to speak for children and later the Pan Arabian (PAPGHAN) societies as associate in all settings. We are united for education that advances the causes members. ESPGHAN was the co-host of the very successful second of children, we jointly advocate for policy and action that preserves world congress in Paris, France, in 2004 with Prof Olivier Goulet as the right to a healthy childhood. While ESPGHAN serves in one the congress president, and ESPGHAN members provided key way, we all serve together and have the additional benefit of contributions the Expert Working Groups of the Federation that working together on global task forces and committees. Congra- offered instructive updates on the approach to and management of tulations ESPGHAN for an astounding 50 years of advocating, key challenges in paediatric digestive health. A further remarkable educating, and providing a platform for paediatricians to unite for achievement is that the Young ESPGHAN team won the FISP- child health. We wish you the best for the 2018 Congress; the IPA GHAN expert team award at the WCPGHAN in Montreal, Canada enthusiastically supports your work, and wishes you success for the in 2016 and produced an outstanding teaching video on treatment of next 50 and beyond. acute gastroenteritis, which is now available at www.fispghan.org. FISPGHAN will need the future active support and contribution of Zulfiqar A. Bhutta, President of the ESPGHAN and its members for its continued success, and it is very much looking forward to co-hosting the next world congress jointly International Pediatric Association with ESPGHAN in Copenhagen in June 2020!

Berthold Koletzko, FISPGHAN President

FIGURE 17. Zulfiqar A. Bhutta.

FIGURE 15. Berthold Koletzko. LATIN AMERICAN SOCIETY FOR PEDIATRIC GASTROENTEROLOGY, HEPATOLOGY AND NUTRITION INTERNATIONAL PEDIATRIC ASSOCIATION

FIGURE 16. IPA logo. FIGURE 18. LASPGHAN logo.

On behalf of the International Pediatric Association (IPA), The Latin American Society of Pediatric Gastroenterology, we want to forward our esteemed felicitations and congratulations Hepatology and Nutrition (LASPGHAN) joins the celebration of the to the European Society of Paediatric Gastroenterology, Hepatol- 50th anniversary of the foundation of the European Society for ogy and Nutrition (ESPGHAN) for celebrating their 50th anniver- Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) sary. ESPGHAN’s continued work as a global advocate for in 2018. The history of gastroenterology in children starts during the advancements in novel research, education, quality of care, and XX century when there was the need of special care for diseases like best practices in paediatric gastroenterology, haepatology, and protracted diarrhoea, inborn errors of metabolism, metabolic diseases nutrition has been of significant benefit to paediatric practice in of bilirubins, coeliac disease, cystic fibrosis; and the acquisition of Europe and setting standards globally. I and several of my specific skills such as small bowel biopsies, parenteral nutrition,

S176 www.jpgn.org JPGN Volume 66, Supplement 1, April 2018 Supplement paediatric GI endoscopies and percutaneous liver biopsies in chil- meeting in Paris in 1978 and the creation of the World Congresses dren. The foundation of ESPGHAN in 1968 (ESPGAN at that time) as in 2000 with the first in Boston and thereafter in Paris, Iguassu Falls, the first paediatric GI society in the planet was the result of an increase Taipei, and most recently in Montreal, our Societies have been number of paediatricians involved in the care of GI and liver diseases. working more closely together. We look forward to the World Since then, ESPGHAN has become one of the corner stones in our Congress with ESPGHAN as the host in Copenhagen in 2020. As field promoting the development of science, education, and health President of NASPGHAN, I look forward to many years of produc- delivery to sick children. Also ESPGHAN has been a model for the tive collaboration of our Societies in the future. With close interac- emergence of other societies in the world; always open to collabora- tions with the ESPGHAN President, Ranaan Shamir, I have been tion in research, medical education and patient care. We all recognize working towards having our Societies work progressively more the social commitment and medical work ESPGHAN offers to the closely in the future by creating joint guidelines, clinical reports developing world specifically in Africa. Europeans colleagues should and position papers and having our committees more directly interact be proud for the countless academic, social, and scientific achieve- with each other as they work on mutually important clinical, research ments, and the colossal growth ESPGHAN has experienced during and educational challenges to our organizations. the last 50 years. The LASPGHAN congratulates all the ESPGHAN members, especially those who have played an active role on its James E. Heubi, MD, President, NASPGHAN brilliant history, for their performance and input to build a great example of a medical society. Let us all join ESPGHAN in Geneva 2018 and celebrate 50 years of success.

Armando Madrazo, President of LASPGHAN

FIGURE 21. James E. Heubi.

PAN-ARABIAN SOCIETY FOR PEDIATRIC FIGURE 19. Armando Madrazo. GASTROENTEROLOGY, HEPATOLOGY AND NUTRITION (PASPGHAN)

NORTH AMERICAN SOCIETY FOR PEDIATRIC GASTROENTEROLOGY, HEPATOLOGY AND NUTRITION

FIGURE 22. PASPGHAN logo.

FIGURE 20. NASPGHAN logo.

Congratulations to ESPGHAN on its 50th Anniversary. I have attended my first ESPGHAN meeting 13 years ago, NASPGHAN and ESPGHAN have had a longstanding collegial since then I attended most of its annual meetings. It is an excellent and collaborative relationship over the last 45 years since the creation opportunity not only to hear from my peers about their scientific of NASPGHAN. Our organizations have common goals to provide advances and to share their experience and new insights into educational, research, social interaction opportunities for our mem- different area of interest, it is also an excellent platform to meet bers and serve as important sources of information and advocacy for colleagues to develop a wide network of friends and contacts, many our patients. The Journal of Pediatric Gastroenterology Hepatology of whom are willing to give their time to support Training and and Nutrition, a joint venture of our Societies, has become an Sciences around the globe simply just to help others. I have enjoyed important vehicle for disseminating clinical and research discoveries being a part of ESPGHAN Regional Meeting in Collaboration with to our members. Since the first joint ESPGHAN-NASPGHAN TURKPGHAN and PASGHAN in November 2013 in Istanbul, and www.jpgn.org S177 Supplement JPGN Volume 66, Supplement 1, April 2018 have been honoured to host an ESPGHAN Scientific Session during It is a distinct pleasure to congratulate the ESPGHAN with the 14th PASGHAN Congress in November 2014 in Marrakech, their 50th anniversary. Your society was among the 7 European involving many of young researchers and doctors. ESPGHAN is an gastroenterological societies that decided to join forces 25 year ago important and great society with high ethical and scientific stan- and form United European Gastroenterology (UEG). This was dards, its’ opening influence widely on the quality of care and the evidently excellent strategic planning as UEG and the UEGW nature and direction of research all over the world, attending its’ are now among the most important meetings for our specialty with annual meeting is a must. around 14,000 participants each year and more than 3000 physi- cians participating in the postgraduate course. As UEG president I Prof Nezha Mouane, PASGHAN General feel it is important to have paediatric gastroenterology in the heart of the UEG. The developments in medicine are going faster than Secretary ever before and traditional borders between specialties are disap- pearing. To keep up with the current developments and provide the best care for our patients, we must know what’s happening ‘‘next door’’ and UEG provides this opportunity. At the same time UEG is trying to influence EU politics and make digestive health one of the priorities and provide more resources for research. And apart from this education and quality are also part of UEG’s target areas where we try to assist our member societies. I wish ESPGHAN a very happy birthday celebration and excellent health for the next 25 years to come! Yours sincerely,

Paul Fockens, UEG President 2018–2019

FIGURE 23. Nezha Mouane.

UNITED EUROPEAN GASTROENTEROLOGY

FIGURE 24. UEG logo. FIGURE 25. Paul Fockens.

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