1St LIVE WEBINAR 2Nd LIVE WEBINAR &

1st LIVE WEBINAR

Held on Thursday, April 9th 2020

Click here to access first recorded webinar

2nd LIVE WEBINAR

Held on Wednesday, April 15th 2020

Click here to access second recorded webinar

#WHITE_COAT_HEROS #STAY_SAFE BIOGRAPHY OF THE SPEAKERS

DR. MOHAMAD MIQDADY Division Chief, Ped. GI, Hepatology & Nutrition Division at Sheikh Khalifa Medical City in UAE Dr. Mohamad Miqdady is American Board certified in Pediatric Gastroenterology, Hepatology and Nutrition. He is the Division Chief, Ped. GI, Hepatology & Nutrition Division at Sheikh Khalifa Medical City in UAE. Also an Adjunct Staff at Cleveland Clinic, Ohio USA. Member of the FISPGHAN Council (Federation of International Societies of Pediatric Gastroenterology Hepatology, and Nutrition) Expert member FISPGHAN Malnutrition/ Obesity Expert team. Dr. Miqdady completed his Fellowship in Pediatric Gastroenterology at Baylor College of Medicine and Texas Children’s Hospital in Houston, TX, USA. He held the position of Assistant Professor at Jordan University of Science and Technology in Jordan for six years prior joining SKMC. Main research interests include feeding difficulties, picky eating, obesity, procedural sedation, allergic GI disorders and celiac disease. He has several publications and authored few book chapters including www.uptodate.com. On the Editorial Board of few journals including Gastroenterology & Hepatology.

DR. ROSAN MEYER Paediatric Allergy Research Dietitian Kings College, London Honorary Senior Lecturer, Imperial College, London UK Visiting Professo, KU Leuven, Belgium Rosan completed her degree in Dietetics in South Africa and specialised in paediatric nutrition in the UK. In 2004, she finished her MSc in Paediatric Nutrition and in 2008 her PhD at Imperial College London. She was the principal research dietitian at Great Ormond Street Hospital for Children until December 2015, leading a project on the impact of gastrointestinal food allergies on children and their families and after this worked with the allergy team at St. Thomas Hospital as research dietitian until 2018. In addition, she has a busy paediatric dietetic practice specialising in food allergy, feeding difficulties and faltering growth in London. She has published numerous articles and has co-authored a book on paediatric nutrition, food allergy, feeding difficulties and is in particular interested in the association between growth and food allergy. She is currently module leader for the Food Hypersensitivity Module that forms part of the MSc in Allergy at Imperial College London, and is honorary senior lecturer in paediatrics at the same university. She is also visiting Professor at KU Leuven, Belgium, on their MSc on Deglutology (swallow disorders). She is the chair of the European Section of the International Network for Diet and Allergy, secretary of the Allied Health and Primary Care Interest Group of EAACI and member of several EAACI task forces on food allergy.

DR. AHMAD ALKHABAZ Consultant Allergist & Clinical Immunologist Head of Pediatric Allergy and Clinical Immunology unit in Mubarak Al-Kabeer University Hospital in Kuwait Head of unit & consultant in Pediatrics & in Allergy, Asthma & Clinical Immunology. KIMS Tutor & Chair of exam committee. Graduate of Newcastle university in the UK. Completed Pediatric residency in McMaster Canada. Then a fellowship in Allergy & Clinical Immunology. He has researched in difficult asthma & the effect of nutrition. Food allergy & immunodeficiency. Dr. Ahmad has been a speaker in multiple local & regional conferences on the topics of food allergy, eczema, rhinitis, drug allergy & asthma. 1st LIVE WEBINAR

Held on Thursday, April 9th 2020 | 07:00 - 08:00 PM (UAE Local Time)

THE GUT MICROBIOTA AND ITS ROLE IN EARLY LIFE IMMUNITY AND THE DEVELOPMENT OF ALLERGIC DISEASE

DR. MOHAMAD MIQDADY

CLINICAL EVIDENCE FOR THE ROLE OF SYNBIOTICS IN ALLERGY MANAGEMENT

DR. ROSAN MEYER

#WHITE_COAT_HEROS #STAY_SAFE THE GUT MICROBIOTA AND ITS ROLE IN EARLY LIFE IMMUNITY AND THE DEVELOPMENT OF ALLERGIC DISEASE

DR. MOHAMAD MIQDADY Division Chief, Ped. GI, Hepatology & Nutrition Division at Sheikh Khalifa Medical City in UAE

The gut microbiota and its role in early life immunity and the development of allergic disease • • M. Miqdady, MD • American Board of Ped. GI • Chief, Ped. GI, SKMC, UAE Adjunct Associate Professor, UAE University

Apr-20 © M.Miqdady, M.D. 1 2

 ‐‐

Apr-20 © M.Miqdady, M.D. 3 Apr-20 © M.Miqdady, M.D. 4

COVID 19 & Allergies

 “Allergic diseases & asthma are not risk factors for SARS‐CoV‐2 infection”

 “Elderly age, high # of comorbidities & more prominent lab abnormalities were associated with severe patients”.

Apr-20 © M.Miqdady, M.D. 5 Apr-20 © M.Miqdady, M.D. 6

ALLERGIES ARE INCREASING GLOBALLY

Allergy –a global health problem– is one of the first detectable immune disorders in early life

Food allergies affect up to 8 % of infants & young children in the western world 1, with cow’s milk being their leading cause. 2-4

1. EAACI. Advocacy manifesto, tackling the allergy crisis in europe-concerted policy action needed, 2015 2. Rona, R. J. et al. The prevalence of food allergy: a meta-analysis. J Allergy Clin Immunol 120, 638-646,(2007). 3. Prescott, S. L. et al. A global survey of changing patterns of food allergy burden in children. World Allergy Organ J 6, 21, 2013. 4. Schoemaker, A. A. et al. Incidence and natural history of challenge-proven cow’s milk allergy in European children--EuroPrevall birth cohort. Allergy 70, 2015. The pattern of cow’s milk allergy (CMA) is becoming increasingly Q 2 aggressive

128% p<0.05 250

Prevalence is 2-5% +44.2% worldwide p<0.05 • The prevalence of Food induced anaphylaxis ? 200 admissions A. Increasing 150 of hospital

100 B. Decreasing Number Increasing trend of the number of hospital admissions for FIA among Italian C. Same children from 2006 to 2014 50 <4 years 5-14 years FIA: food-induced anaphylaxis 0

Fiocchi et al. Pediatr Allergy Immunol. 2010;21(S21):1-125 2006 2007 2008 2009 2010 2011 Prescott et al. World Allergy Organ. 2013;6(21) Skripak et al. J Allergy Clin Immunol. 2007;120:1172-77 Year Apr-20 © M.Miqdady, M.D. 9 Nocerino et al. J Allergy Clin Immunol. 2015;135:833-835 e833

The burden of allergy goes beyond symptoms

Strong rationale for developing effective strategies for infants at risk and with allergy

Physical Financial • Increased medical, • Increased risk of health and indirect future NCDs • costs • Psychological Social • • Distress for child • Isolation and parents • Fear of future • • Impact on QoL health problems

NCDs, non-communicable diseases; QoL, quality of life Pawankar et al. WAO, White Book on Allergy. Update 2013:5-55; Prescott, SL. J Allergy Clin Immunol. 2013;131(1):23-30; West et al. J Allergy Clin Immunol. 2015;135(1):3-13; Silverberg JI. J Allergy Clin Immunol. 2015 Mar;135(3):721-8; Gupta et al. JAMA Pediatr. 2013;167(11):1026-31; Patel et al. J Allergy Clin Immunol. 2011;128(1):110-115e1; 12 Dalgard et al. J of Inv Dermatol. 2015;135:984-91

Risk factors for the development of allergies Early life disruption in microbiota is associated with allergy development

Hereditary Gut Microbiota Environmental Factors challenge challenge

http://www.dailymail.co.uk/home/index.html Pollution Family History of C-Section Antibiotics Use Allergy & early sign of eczema Rodult et al. Thorax 2009;64(2):107-13

Marra et al. Chest 2006;129(3):610-8

Risk to develop allergy: Global Prevalence: Use in infancy & Increased risk of 1 2 15%-70% EU: 15%-35% childhood allergy: http://www.healio.com/dermatology/dermatitis/news/ Asia Urban: >50%2 Up to 10 - 20 courses3,4 Up to 20%5,6

1Bergmann et al., 1998, 2OECD data 2011, 3Sharland 2007, 4Blaser 2011, 5Patel et al., 2011, 6Ryan etal., 2013,

Cesarean Delivery Associated Childhood Diseases1

2Odds ratio (OR) with 95% CI versus vaginal delivery 3Increase not appreciated for male fetuses 4requiring hospitalization

1. Neu & Rushing, 2011 WHO, 2011

Q 3 • During this time; which of the following you believe is true A. Social distancing may increase the risk of allergy • B. Lockdown may increase risk of allergy • C. Routine use of PPE may decrease risk of latex • allergy among health care workers • D. Use of disinfectants does not disturb human microbiota

Apr-20 © M.Miqdady, M.D. 17 18 “You are not human, you are a walking bacterial colony” The “1st colonizers”: Jeroen Raes, Flanders Institute of Biology, TED talks 2012, http:www\\tedxbrussels.eu Establishing the symbiosis between the gut microbiota & immune system

Surface of approximately 300m2 100 trillion bacteria “Gut Microbiota”

70-80% of immune 100 million neurons cells Mitsuoka, 1992 & 2014 Wopereis et al., 2014

Early microbiome development in immune challenged population t microbiota alterations associate with foo allergies

Healthy, breastfed babies CMA babies with lower leels of healthy ifiobacteria dominated by healthy an higher leels of potentially harmfl Bifidobacteria Clostriia an bacteria

trong rationale for the nee of gt microbiota moification in the ietary preention an management of allergy

Gestational Environmental Clostridium and Eubacterium ssp. Bifidobacterium Other genera (not analyzed) Breastfeeding/ Complementary age exposure Mixed feeding feeding Roger et al. Microbiology 2010;156(11):3329-41; Scholtens et al. J Nutr. 2008;138:1141-7; Mitsuoka, T. Biosci Microbiota Food Health 2014;33:99-116; Thompson-Chagoyan et al. Pediatr Allergy Immonol. 2010;21(2):394-400; Candy et al. Clin Trans Allergy. 2017;7(1):10.

Strategies to manipulate gut microbiota colonization and function CMA infants often present with gt microbiota ysbiosis

Microbiota Modulation

HEALTHY DYSBIOSIS Supporting the existing . Nutrition Gut microbiota composition of healthy, Gut microbiota composition of CMA vaginally delivered breastfed infants infants . Prebiotics • igher leels of igher leels of potentially harmfl bacteria beneficial • ece leels of Pharma-approach bacterial beneficial species bacterial species . Probiotics

Bacteroides Bacteroides Clostridium Escherichia coli fragilis Enterococcus difficile Enterobacteriaceae . Bifidobacterium Staphylococcus FMT* Lactobacillus aureus

Mitsuoka, T. 2014. Establishment of intestinal bacteriology. Biosci Microbiota Food Health 33, 99-116. *FMT: Fecal microbiota transplantation Roger LC et al, Microbiology, 2010, 156(11):3329-41. West et al., JACI, 2015 Chua, M. C. et al.. J Pediatr Gastroenterol Nutr, (2017).

Can we support “healthy gut colonization early” in life? utline The Prebiotic Concept

 “a substrate that is selectively utilized by host •hy alleries in infancy are still iortant icrooraniss conferrin a health benefit” •is factors for alleries •ut icrobial dysbiosis allery •unoodulation re ro yn concets

Gibson GR et al, Nat Rev Gastroenterol Hepatol, 2017 idady 25

Composition of human breast milk

Macronutrients and human milk oligosaccharides (HMO) in human breast milk Fat 30-50 g/l Oligosaccharides 10-12 g/l Protein 9-10 g/l Lactose 53-61 g/l   “ Fatty Acids  Non-digestible30-50 g/lOligosaccharides ”  Amino Acids Human milk Cow's milk actose g g

Total oligosaccharies g Traces Gibson GR et al, Nat Rev Gastroenterol Hepatol, 2017 Newburg DS, Neubauer SH. In: Jensen RG (ed): Human milk composition, Academic Press 1995;273-349. Human milk oligo-saccharides (HMO’s)

. 150 – 200 components identified in 1 sample .  hich one of the folloin is true about rebiotics Extremely high structural diversity: 90% short chain, 10% long chain . uan il oliosacrrides coosition are very Complex composition supports HMOs to be multi-functional siilar aon all lactatin oen . Composition pending on: ifferent ’s have siilar function - genetics (Lewis factor) -- Epigenetics -- Diet ’s added to infant forula coe fro huan . Each HMO may have a special function source . “Natural HMO’s” rebiotics have a lon lastin iunoodulation effect

Apr-20 © M.Miqdady, M.D. 29 Single/ limited addition of HMOs to IF/FO may have modest impact !

–

•

Oozeer, R. et al. Am J Clin Nutr 2013;98:561S-571S. Newburg, D. S. J Pediatr Gastroenterol Nutr 2000;30(Suppl 2):S8-17. Kunz, C., Rodriguez-Palmero, M., Koletzko, B. & Jensen, R. Clin Perinatol 1999;26:307-333. Kunz, C., Rudloff, S., Baier, W., Klein, N. & Strobel, S. Annu Rev Nutr 2000;20:699-722. Apr-20 © M.Miqdady, M.D. 32

Presence of lactobacilli & bifidobacteria in human milk . The Bifido-bacteria is one of the most common bacteria found in human milk 1 Streptococcus . Staphylococcus The Bifido-bacteria is the first colonizer in 0.9 Serratia the infant gut Corynebacterium 0.8 Pseudomonas 0.7 Propionibacterium Ralstonia . 0.6 Among the Bifido-bacteria, B. breve is the Rothia abundance Sphingomonas 0.5 most commonly isolated species from Bradyrhizobium relative of Veillonella 0.4 human milk Bergmann H, Rodriguez JM, Salminen S and Szajewska H (2014). Probiotics in Gemella human milk and probiotic supplementation in infant nutrition: a workshop report. 0.3 . Lactobacilli is more prevalent in human milk Br J Nutr, 112:1119-1128. Granulicatella Hunt, K. M. et al. Characterization of the diversity and temporal stability of Proportion bacterial communities in human milk. PLoS One 6, e21313, Prevotella 0.2 doi:10.1371/journal.pone.0021313 (2011). – large intestine, role? Martin, R. et al. Human milk is a source of lactic acid bacteria for the infant gut. Actinomyces 0.1 J Pediatr 143, 754-758, doi:10.1016/j.jpeds.2003.09.028 (2003) Other Martin, R. et al. Isolation of bifidobacteria from breast milk and assessment of the bifidobacterial population by PCR-denaturing gradient gel electrophoresis and quantitative real-time PCR. Appl Environ Microbiol 75, 965-969, 0 Soto et al., 2014 doi:10.1128/AEM.02063-08 (2009). S1 S2 S3 S4

Complementary ynbiotic oncet Synergistic

SYNBIOTICS = PREBIOTICS + PROBIOTICS Prebiotic Probiotic Prebiotic Probiotic chosen to chosen for chosen to chosen for boost specific stimulate specific beneficial growth and beneficial indigenous effects activity of effects Probiotics are sent for beneficial probiotic a mission including microbiota their “Lunch-box”

Apr-20 © M.Miqdady, M.D. 36

Complementary Synergistic • Prebiotic Probiotic Prebiotic Probiotic chosen to chosen for chosen to chosen for • boost specific stimulate specific beneficial growth and beneficial indigenous effects activity of effects beneficial probiotic • microbiota • CLINICAL EVIDENCE FOR THE ROLE OF SYNBIOTICS IN ALLERGY MANAGEMENT

DR. ROSAN MEYER Paediatric Allergy Research Dietitian Kings College, London Honorary. Senior Lecturer, Imperial College, London UK. Visiting Professor KU Leuven, Belgium.

Clinical evidence for the role of synbiotics in allergy management Conflict of Interest

• Academic lectures: • Danone • Mead Johnson • Nestle • Academic grant – Danone • Nestle - CoMISS board

Dr. Rosan Meyer (RD,PHD) 9th of April 2020

Case Scenario Question 1: What can they do to improve their baby’s immunity when breastmilk is not available? • Baby C is 3 months of age, has eczema from 4 weeks of age and developed immediate symptoms (hives, and angioedema) when exposed to a bottle of infant formula. Up to that age he has been exclusively breastfed A: Nothing • SPT performed and has a 5 mm wheel to cow’s milk and egg, but negative to B: Avoid antibiotic and PPI use all other allergens C: Use any pre/probiotic supplement • Weight has dropped by 2 centiles D: Use a hypoallergenic formula with pre/probiotics/synbiotics • The parents want you to recommend a hypoallergenic formula as mum needs to go back to work when baby is 4 months of age and they are worried about growth. • They have 2 questions for you, as they have been doing some research on the internet:

Question 2: What can they do to help their baby Factors affecting the Intestinal Microbiota in Infants outgrow their allergy faster?

A: Nothing can be done B: Use a hypoallergenic formula with pre/pro/synbiotics C: Introduce solid food as soon as they are 17 weeks D: Use any pre/probiotic supplement

Gut microbiota in Immune Response Gut microbiota in Immune Response and Allergy • 8 cross sectional studies published assessing gut microbiota in children with established food and Allergy allergy (most with CMA)1 • Thompson-Chagyoyan et al.2

• In allergic infants, several studies show the presence of Aerobic Anaerobic bacteria Baseline 6 Baseline 6 Baseline 6 altered gut microbiota, or ‘dysbiosis’ (a breakdown in the months 1-6 months months Baseline 6 balance of intestinal bacteria) months • Bifidobacteria are the first colonisers of healthy infant gut • Children with CMA have lower gut microbiota diversity • Infants with IgE- mediated allergy typically have low levels of Bifidobacteria • Children with non-IgE mediated allergy have dysbiosis driven by Bacteroides and Alistipes • Points to potential role of probiotic with Bifidobacteria to CMA CMA correct dysbiosis • Kourosh et al.3 stool samples of children with IgE-mediated allergy, siblings and healthy controls were collected: 1. Moos W, et al. Biores Open Access. 2017 May 01; 6(1): 46. 2. Tamboli C, et al. Gut. 2004 Jan; 53(1): 1–4. • Food allergic children had enrichment for specific microbes within the Clostridia class and Firmicutes phylum 3. Thompson-Chagoyan OC, et al. Int Arch Allergy Immunol 2011; 156: 325-332 4. Kirjavainen PV, et al. Gut 2002; 51: 51–55 1. Marrs&Sim. Current Ped Reviews 2018; in print 5. Soto A, et al. J Pediatr Gastroenterol Nutr. 2014 Jul; 59(1): 78–88. 2. Thompson-Chagoyan et al. Pediatr Allergy Immunol 2010;21:e394-e400 6. Canani et al. Sci Rep. 2018 Aug 21;8(1):12500. Copyright Dr Rosan Meyer 2020 Copyright Dr Rosan Meyer 2020 5 7. Dong et al. Saudi J Biol Sci. 2018 Jul;25(5):875-880. 3. Kourosh et al. Pediatr Allergy Immunol. 2018;29:545-554 Has your practice in the dietary management of Dietary Allergy Management before and Now cow’s milk allergy changed in the last 5 years?

GUT Specific immune modulation MICROBIOTA Future • Exposure to specific fragments A: Yes • Beneficial bacteria

TOLERANCE Immune modulation via: B: No • Exposure to fragments of protein DEVELOPMENT Present • Specific oligosaccharides

STRATEGY • Active introduction of allergens

ALLERGEN Allergen avoidance Past • Maternal cow’s milk elimination AVOIDANCE • EHF,AAF • no introduction of allergenic food <1yr

TIME

What are we trying to achieve with the Breastmilk a Rich source of Pre and Probiotics active management of Food Allergy? • Breast-fed infants develop an intestinal flora dominated by Bifidobacteria and Lactobacilli with less pathogenic bacteria compared with formula-fed infants • Human milk oligosaccharides are an important components of the defence system of human milk, in particular due to its prebiotic effect • Human milk contains several genera of bacteria including Lactobacillus and Bifidobacterium

Important message to share with parents

Age in years

1. Newburg DS. J Pediatr Gastroenterol Nutr. 2000;30 Suppl 2:S8–17. 2. Morrow et al. J Nutr. 2005;135:1304–7. 3. Hunt et al. PLoS ONE 6(6): e21313. doi:10.1371. 4. Milani et al. Microbiology and Molecular Biology Reviews 2017;81:1-64 1. Saarinen & Kajosaari Lancet 1995 346 (8982): 10-65-9

The evolution of prebiotics to probiotics to Effect of Prebiotics on Atopic synbiotics in Hypoallergenic Formulas Dermatitis in Early life • Moro 2007: • Prebiotic supplemented extensively hydrolysed formula (short-chain galacto-oligosaccharides and long- chain fructo-oligosaccharides [scGOS/lcFOS]) reduces the incidence of atopic dermititis in early life

After 6 months1 After 2 years2 After 5 years3

symptom 30 30 25 25 27,9 26,5 related dermatitis 20 P<0.05 - 20 % 23,1 % P<0.05 15 P=0.014 * % 15 atopic

allergy * 10 *

of 13,6 5 10 9,8% any % 10% 0 of 5 0 Incidence ScGOS/lcFOS Control Presence (n=40) (n=49) Cumul. scGOS/lcFOS… scGOS/lcFOS… Control (n=104) Control (n=68)

1. Moro et al., 2007 2. Arslanoglu et al., 2008 Copyright Dr Rosan Meyer 2020 3. Arslanoglu et al., 2012 Copyright Dr Rosan Meyer 2020

Effect of Probiotics on Cow’s Milk Tolerance Effect on Probiotics on Functional Gastrointestinal • Canani et al 2013: Allergy • Study showed accelerated development of tolerance to Cow’s Milk Protein in infants with challenge confirmed CMA, given extensively hydrolysed casein formula (EHCF) containing probiotic Lactobacillus rhamnosus GG (LGG) • Canani et al 2017: • 330 subjects recruited: 110 per cohort (EHCF, • At 3 years patients on the LGG supplemented formula had less allergic manifestations including atopic eczema, EHCF+LGG, and healthy controls). • asthma and rhinoconjunctivitis The rate of 1 FGID was significantly lower in the EHCF+LGG cohort compared with the EHCF cohort (40% vs 16.4%; P < .05)

1. Canani RB, et al. J Allergy Clin Immunol 2012: 580-58,2 2. Canani et al. J Allergy Clin Immunol 2017 Copyright Dr Rosan Meyer 2020 Copyright Dr Rosan Meyer 2020

Effect of Synbiotics in Atopic Dermatitis Effects of AAF with Synbiotics on Growth in Infants with CMA • Van der AA 2010 (SYNBAD study group): • Infants with IgE-associated atopic dermatitis in the synbiotic group (scGOS/lcFOS and B breve M-16V) showed significantly greater improvement in severity of AD (SCORAD score) at 12 weeks and significant modulation of intestinal microbiota • Synbiotic effect remained at one-year follow-up

1. Van der Aa et al. Clin Exp Allergy 2010. Effect of Synbiotics on Dysbiosis in CMA

• Fox et al 2019 (ASSIGN): Impact of Synbiotics on Infections • A hypoallergenic1 amino acid based formula (AAF) + synbiotics (short & long chain fructo-oligosaccharides [scFOS/lcFOS] & B breve M-16V) shown to bring the gut microbiota closer to that of healthy breastfed infants vs standard AAF.

Increased level of infant-like Bifidobacteria

Decrease of adult-like E. rectale/ C. coccoides cluster Fox et al. Clin Transl Allergy (2019) 9:5 Candy et al, Ped Res, 2018; 83(3): 677-68 Copyright Dr Rosan Meyer 2020 Copyright Dr Rosan Meyer 2020

Effect of Synbiotics on concomitant Medication Use What practical advice will you provide the parents when introducing a synbiotic containing hypoallergenic?

A: No advice B: Advice on how the formula tastes C: Advice on impact on stool frequency and consistency D: Advice on how to mix the formula E: A combination of above

• Reduced use of antibiotics in children on synbiotic AAF: • Particularly amoxillin – P 0.004

Fox et al. Clin Transl Allergy (2019) 9:5 Copyright Dr Rosan Meyer 2020 Copyright Dr Rosan Meyer 2020

Practical Advice on Synbiotic Practical Advice for HCP containing Hypoallergenic Formula • Ensure that breastfeeding is supported • No harm reported in children that are not immunocompromised1 • Positioning/latch • One strain not the same as another • Elimination diet and frequency • Some data on reducing infections and also antibiotic use • Provide parents advice on how to introduce hypoallergenic formula: • Making up of feed or feeds and implication • Smell and taste of formula • Formula containing synbiotics must be made at room temperature so as not to negatively impact • Direct switch the efficacy of the probiotics • Graded introduction • Practical, clear dietetic advice regarding transition and preparation is key for parents using a • Flavour additions (if any) formula containing synbiotics • Discuss with parents stool frequency and consistency as well as flatus • Discuss with parents importance of dietary diversity and microbiota

1. Boyle R, et al. Am J Clin Nutr 2006;83:1256 – 64. Copyright Dr Rosan Meyer 2020 2. Nwaru et al. J Allergy Clin Immunol 2014;133:1084-91.

Conclusion

• Breastmilk is rich in factors that promote a healthy gut microbiome • If breastmilk is available, best source of pre and probiotics • Parents are often confused about pre, pro and synbiotics • Evidence published to support the use in hypoallergenic formulas Questions • Parents need advice on how to mix hypoallergenic formula with synbiotics

Held on Wednesday, April 15th 2020 | 07:00 - 08:00 PM (UAE Local Time)

COW MILK PROTEIN ALLERGY (CMPA) – DIAGNOSTIC DILEMMA?

DR. AHMAD ALKHABAZ

CLINICAL EVIDENCE FOR THE ROLE OF SYNBIOTICS IN ALLERGY MANAGEMENT

DR. ROSAN MEYER

#WHITE_COAT_HEROS #STAY_SAFE COW MILK PROTEIN ALLERGY (CMPA) – DIAGNOSTIC DILEMMA?

DR. AHMAD ALKHABAZ Consultant Allergist & Clinical immunologist. Head of Pediatric Allergy and Clinical Immunology unit in Mubarak Al-Kabeer University Hospital in Kuwait.

OUTLINE OF THE TALK

Knowledge of CMPA COW MILK PROTEIN ALLERGY Key factor missing among pediatricians and GP Cow milk protein basics. (CMPA) – DIAGNOSTIC DILEMMA? Component testing? The future? Symptoms role in diagnosis Remember! It’s a clinical diagnosis! Ahmad AlKhabaz, MBBS (UK), FRCP (Canada) Major diagnostic tools Allergy & Clinical immunology

Head of Pediatric Allergy & Clinical Immunology Sensitive and specific? Head of Allergy Fellowship Exam Committee False tests Mubarak Hospital, Kuwait. [email protected]

WORLD WIDE – A COMMON PROBLEM…

Variable non-specific symptoms POOR KNOWLEDGE AND A BIGGER Sensitive diagnostic test unavailable PROBLEM! Parent-reported CMPA is about 4 times higher. Parents (and doctors!) often put their children on unnecessary diet without an adequate medical and dietary supervision. Nutritional unbalances e.g. rickets. Anxiety to child and family Behavioral problems.

Anna Nowak-Węgrzyn, Allergy Asthma Proc. 2015 May-Jun; 36(3): 172–184

KNOWLEDGE OF FOOD ALLERGY AMONG HOSPITAL PEDIATRICIANS IN KUWAIT – PRE INACCURATE DIAGNOSIS OF CMPA PUBLICATION

Total Risk of rickets number Decreased bone mineralization of 58% questions Anemia = 38 Poor growth Hypo-albuminemia Mean correct Immediate clinical reactions (subtle!) answers = Severe chronic gastroenteropathy leading to malabsorption. 22.2

W. AlHerz, A. AlKhabaz, F. Alrefai, K. AlSaraf

COW MILK PROTEIN BASICS & Q: WHEY PROTEIN MAKES ABOUT 80% COMPENENT TESTING? OF COW MILK PROTEIN?

Yes No Correct answer: No MAJOR PROTEINS IN COW MILK ALLERGENS

Caseins (~80% total) Whey (~20%) Proteins (not fat / carbohydrate) 10-70 kD glycoproteins Heat resistant, acid stable Complexes, give ‘milky’ β-lactoglobulin [Bos d 5] appearance. α-lactalbumin [Bos d 4] Major allergenic foods (>85% of allergy) 10 % of all allergy. Children: milk, egg, soy, wheat Bovine immunoglobulins [Bos Adults: peanut, nuts, shellfish, fish Precipitated from skim milk by d 6] acid at pH 4.6. Bovine serum albumin [Bos Single food > many food allergies 4 basic caseins (αs1,αs2,β,κ d 7] Epitopes comprising 32%, 28%, 10%) Extensive heating destroys Linear vs conformational epitopes Heat resistant and more (bovine serum albumin, bovine B-cell vs T-cell epitopes allergenic. [Casein = Bos d 8] γ-globulin, and α-lactalbumin).

Jonathan M. Spergel, MD, PhD. Division of Allergy and Immunology. Children’s Hospital of Philadelphia

YOUNGER AGE + MORE SEVERE DERMATITIS = HIGHER RISK CMPA

Q: THE MAJORITY OF CMPA IS NON- IGE MEDIATED?

Yes Correct Answer: No No

MAJOR DIFFERENCES IN CMPA TYPES & PROGNOSTIC VALUE OF PRESENCE OF MANAGEMENT SENSITIZATION (IGE)

Non –IgE Mediated IgE Mediated Child has a higher risk of persistence of CMPA (IgE mediated).

Prevalence (2-7%) 45% 55% Sensitization below 2 years age.

Symptoms onset Days – Weeks Minutes – Hours Urticaria at diagnostic challenge. Severity Limited Life threatening CM exposure at maternity hospital. Persistence Resolves by 12 months age Up to teen years! Early sensitization to egg. Associated disease GERD, Eczema, EoE, ..etc Asthma, Rhinitis, Eczema…etc Anaphylaxis risk No Yes IgE is a risk factor for other atopy (persisit into school age) Nutritional support Calcium Calcium + Others (multiple!) Asthma (2 fold increase risk) Doctor in charge! GP/Pediatrician/GI Allergist Allergic Rhinitis (2 fold increase) Formula indicated eHF/ AAF? eHF/AAF Atopic Eczema (3 fold increase) Testing No (Patch?) Serum IgE-SPT

Other food allergies? Low risk High risk! J Allergy Clin Immunol. 2005 Oct;116(4):869-75. Saarinen KM, Savilahti E. Finland.

CLASSIFICATION OF MILK ADVERSE REACTIONS

DIAGNOSIS OF CMPA? Milk components Protein Sugar Adverse Allergy- Intoleran Sensitivity & Specificity reaction immune ce Classificati Non Lact IgE on SPT -IgE ose Patc – BAT h Test Seru ? test? m

NON IGE MEDIATED MILK ALLERGY

A clinical diagnosis Q: SERUM SPECIFIC IGE TESTING HAS HIGH Delayed onset / specific symptoms POSITIVE PREDICTIVE VALUE FOR CLINICAL Abstains from ingestion of cow milk protein (even if breast feeding) DIAGNOSIS? Trial extensively hydrolysed formula (2-3 weeks!) If not improved after (2-3 weeks) Switch to elemental formula Refer to gastroenterologist of allergist for evaluation and investigation Other GI diagnosis? Refer to gastroeneterologist , biobsy? Yes Correct answer: no Eczema? Refer to allergist for milk patch test? No PATCH TESTING PATCH TESTING (APT)

Relatively recent in the diagnosis of food allergy Reproducible (90% on Back) Safe: 1% risk systemic reaction Measure T-cell-mediated (Non IgE ) responses to food allergens. Occlusion for 48 hours and read at 72 hours. Most studies with foods have been performed with cow’s milk, hen’s egg and wheat only. APT has a higher diagnostic efficacy, than SPT for late phase clinical reactions (specially if eczema present ) Higher negative predictive value

De Boissieu D, Dupont C. Patch tests in the diagnosis of food allergies in the nursing infant. Eur Ann Allergy Clin Immunol 2003; 35:150–152.

IGE SENSITIZATION IS NOT ALWAYS EQUAL DIAGNOSTIC TOOLS – IGE MILK ALLERGY TO CLINICAL ALLERGY !!

DBPCFC (Double-Blind Placebo-Controlled Food Challenge) with medical history is the most specific and sensitive IgE against milk protein! diagnostic tool. Risk of serious anaphylasis, time consuming and expensive! Detection of specific IgE - for cow's milk extract or major milk components (alfa-lacto-albumin, beta-lacto-albumin, casein) Skin prick method (higher sensitivity) Serum (higher specificity) >95% confidence that no IgE allergy exist. (High NPV) Intradermal test (ID) is contraindicated and not predictive!

BAT (basophil activation test) - serum Activation of basophils via the IgE-receptor. Increase in surface markers Milk proteins! (CD63 and CD203c), which level of expression is measured by flow cytometry.

100% PPV FOR SKIN PRICK TESTING (IGE) = > 3 SKIN TESTING…. MM IS POSITIVE

Cow Milk ≥ 6 mm wheal SPT >8 associated with >95% likelihood of Egg ≥ 5 mm wheal (0-2 yrs age) clinical reactivity ≥ 7 mm wheal Anna Nowak- Wegrzyn Peanut Mount Sinai ≥ 4 mm wheal (0-2 yrs age) School of ≥ 8 mm wheal Medicine, New York

Sporik et al, clin exp allergy 2000

FOOD SPECIFIC SERUM COMPONENT TESTING – HELP YOUR IGE (>0.35 IS POSITIVE) MANAGEMENT PLAN!

Reaction to Reaction to backed milk (e.g. Component Code Heat Persistence milk cookies or cheese pizza) Bos Likely to outgrow High risk α-lactalbumin labile Low risk d 4 allergy (fresh milk) Bos Likely to outgrow High risk labile Low risk β-lactoglobulin d 5 allergy (fresh milk) High risk Bos Unlikly to outgrow Resistant (all forms of High risk Casein d 8 (high levels IgE) milk)

Shek LP, Humoral and cellular responses to cow milk proteins in patients with milk-induced, IgE-mediated and non-IgE-mediated disorders. Allergy. 2005;60(7):912-919. Wal JM. Bovine milk allergenicity. Ann Allergy Asthma Immunol. 2004;93(5 Suppl 3):S2-S11. Nowak-Wegrzyn A, Tolerance to extensively heated milk in children with cow’s milk allergy. J Allergy Clin Immunol. 2008;122(2):342-347.. Sicherer SH, Cow’s milk protein-specific IgE concentrations in two age groups of milk-allergic children and in children achieving clinical tolerance. Clin Exp Allergy. 1999;29(4):507-512. Boyano-Martínez T, Accidental allergic reactions in children allergic to cow’s milk proteins. J Allergy Clin Immunol. 2009;123(4):883-888. Caubet J, Utility of casein-specific IgE levels in predicting reactivity to baked milk. J Allergy Clin Immunol. 2013;131(1):222-224.CM Allergy Review. Diagnosis of cow’s milk allergy in children: determining the gold standard? Expert Rev Clin Immunol. 2014;10(2):257-267. Kim JS, Dietary baked milk accelerates the resolution of cow’s milk allergy in children. J Allergy Clin Immunol. 2011;128(1):125-131. Ito K, Futamara M, The usefulness of casein-specific IgE and IgG4 antibodies in cow’s milk allergic Sampson et al children. Clinical and Molecular Allergy. 2012;10:1:1-7.

BAT (BASOPHIL ACTIVATION) MANY UNPROVEN TESTS? CONFUSION +++

BAT could significantly reduce the need for OFC and improve the diagnosis and Symptoms of irritable bowel syndrome, autism, cystic fibrosis, management of patients with suspected peanut allergy rheumatoid arthritis and epilepsy? Weight gain? Other gastric symptoms? Lethargy?

N= 86 infants confirmed diagnosis CMPA with DBPCFC BAT had a sensitivity and specificity of 100% (if IgE positive) Examples of unproven tests: IgG (food tolerance/ food print test) Vega testing (Skin electrode) The BAT seems reliable and cost-effective to diagnose patients with an IgE-mediated cow's milk allergy. K-Test (fingers on machine!) Hair testing Iridology In IgE-sensitized patients, a BAT might replace a DBPCFC. Applied kinesiology (muscle test)

The Basophil Activation Test reduces the need for a food challenge test in children suspected of IgE-mediated cow's milk allergy, Clin Exp Allergy. 2019;49:350–356. Janneke Ruinemans-Koerts1. Netherlands IGG TEST – AAAAI POSITION STATEMENT 2010 TESTING FOR CMPA – SUMMARY

No evidence to support its use, Do not recommend testing in the initial approach! scientific basis or repeatability. Total IgE : not helpful in diagnosis but predicts persistence! Organizations: Skin prick test: If IgE mediated symptoms (e.g urticarial/ anaphylaxis) ; Age? American Academy Allergy Symptoms? Asthma & Immunology Serum specific IgE: higher false positives. (AAAAI) Patch testing (France!): high negative predictive value Canadian Society Allergy & Clinical Immunology (CSACI) IgG4 testing: indicate exposure not allergy. Mucosal biopsies: rule out other pathology! Not sensitive for CMPA. European Academy Allergy & Clinical Immunology (EAACI) Open challenge in infants suspected of CMA – accepted , double blind is still gold standard Recommended AGAINST using IgG testing to diagnose food allergies or food Guidelines for the diagnosis and management of cow’s milk protein allergy in infants. Arch. Dis. Child. 2007, intolerances / sensitivities. 92, 902–908. Vandenplas, Y.

TAKE HOME MESSAGES

Cow milk protein allergy is a heterogeneous group of diseases that are immune mediated (IgE and non IgE) While some are simple and managed by the general pediatricican (e.g non IgE type), others are complex and often requires multiple specialist support THANK YOU… Inadequate diagnosis or management leads to nutritional and life risk complications. Diagnosis is mainly clinical While many tests are available, many false tests are available too! Caution must be taken when doing or interpretation any test. Should be done by an expert allergist. Test can help in management and introduction of milk and identify prognosis of disease. More research both epidemiological and systematic needed in our region WHEN SHOULD AAF BE USED IN CLINICAL PRACTICE

DR. ROSAN MEYER Paediatric Allergy Research Dietitian Kings College, London Honorary. Senior Lecturer, Imperial College, London UK. Visiting Professor KU Leuven, Belgium.

When should AAF be used in Clinical Practice Conflict of Interest

• Academic lectures for: Nutricia/Danone, Nestle, Mead Johnson • Academic Grant: Nutricia/Danone • Advisory board: Nestle -CoMISS

Rosan Meyer (RD,PhD) Paediatric Allergy Dietitian April 2020

Do you think the current guidelines are clear in Case Presentation regards to when Amino Acid Formula Should be • Baby C is referred at 6 months for: used? • Eczema from 6 weeks of age – on daily steroids in the creases • Poor feeding – does not stay on the breast for more than 3 min • Abdominal pain – does not sleep for more than 1 hr without A: Yes waking up in pain • Mucusy stools with streaks of blood (not that frequent) B: No • Faltering growth: • dropped > 2 centiles (now at -2 z-score for weight) • Dropped 1 centile in length (now at -0.66 z-score) • SPT = 4 mm wheal to CM, all other negative • Mixed IgE and non-IgE mediate CMA diagnosed • Elimination 4 weeks and reintroduction • Mum wants to start with solid food • Breastfed, but mu has to go back to work and wants to have a formula during the day

DRACMA Guidelines ESPGHAN Guidelines for CMA Transfer of Allergens through Breast Milk

Milk protein (β-lactoglobulin) from cow’s milk

Soya (isoflavone) found In breastmilk of mothers iMAP Guidelines for non-IgE consuming soya mediated CMA EAACI Guidelines for Food Allergy Egg protein (ovalbumin) detected in woman eating Raw/cooked egg (no Difference in levels) Franke et al. AmJ Clin Nutr 2006;84:406 –13. Vadas et al. JAMA. 2001;285:1746-1748 Palmer et al. Clin Exp Allergy 2005; 35:173–178 Peanut protein detected in Restani et al. Ann Allergy Asthma Immunol 1999;84:353–360 Lactating women

Breastmilk in Allergy Management Case Presentation • Baby C is referred at 6 months for: • Eczema from 6 weeks of age – on daily steroids in the creases • Aim to follow WHO guidelines (6 months exclusive • Poor feeding – does not stay on the breast for more than 3 min breastfeeding) – remember WHO suggests breast • Abdominal pain – does not sleep for more than 1 hr without feeding until 2 years of age waking up in pain • Mucusy stools with streaks of blood (not that frequent) • Support CMA infants/mother • Faltering growth: • dropped > 2 centiles (now at -2 z-score for weight) • Continue breast feeding where possible • Dropped 1 centile in length (now at -0.66 z-score) • Support mum to avoid CMP (other allergens) • SPT = 4 mm wheal to CM, all other negative • Maternal calcium and vit D (iodine) intake • Mixed IgE and non-IgE mediate CMA diagnosed • Elimination 4 weeks and reintroduction • Mum wants to start with solid food • Breastfed, but mu has to go back to work Munasir & Muktiarti. Asia Pac Allergy 2013;3:23-28 Restani et al. Ann Allergy Asthma Immunol 1999;84:353–360. and wants to have a formula during the day Hill et al. Clinical and Experimental Allergy, 2007;37:808–822 Thomassen et al. JPGN 2017;64: 806–811. What hypoallergenic formula would you choose Formulas suitable for CMA for this child?

A Extensively hydrolysed formula Extensively Hydrolysed Formula B Soya Formula Intact non-milk Proteins Amino Acid Formulas C Partially Hydrolysed formula D Amino Acid Formula

Soya EHF – whey EHF – casein

Muraro et al. Allergy 69 (2014)

DRACMA ESPGHAN (2012) (2010) Current Published Guidelines on CMA Middle East Clinical presentation 1st choice Australian Guidelines (2009) BSACI (2014) Guidelines 2019 1st choice

Anaphylaxis AAF AAF AAF AAF AAF eHF if < 6 months Acute urticaria or No specific mention, but eHF Soya if > 6 months eHF angioedema eHF in general as 1st line

eHF if < 6 months No specific mention, but eHF but if symptoms Atopic Soya if > 6 months EHF if no eHF eHF in general as 1st line whilst exclusively eczema/dermatitis eHF if >6 months if also treatment breastfed then AAF improvement presenting with faltering growth EoE within 2 to 4 AAF AAF (for EGID) AAF AAF weeks, eHF if < 6 months No specific mention but • DRACMA guidelines 2010 – international and specific to CMA Gastroesophageal particularly in Soya if > 6 months eHF (unless faltering eHF eHF in general as 1st line reflux disease eHF if >6 months if also • Middle East guidelines (step down and treatment) 2019 infants with treatment growth then AAF) sensitization presenting with faltering growth • EAACI 2014 – Food Allergy and Anaphylaxis against multiple eHF if < 6 months Cow’s milk protein- AAF (complicated by Soya if > 6 months eHF (unless faltering eHF • ESPGHAN 2012 – specific to CMA induced enteropathy foods an AAF growth faltering) eHF if >6 months if also growth then AAF) • NIAID 2010 – Diagnosis and Management of Food Allergy should be presenting with faltering growth FPIES considered eHF AAF eHF AAF • Many national and local guidelines exist eHF if < 6 months No specific mention, but Muraro et al. Allergy 69 (2014) 1008–1025. Vandeplas et al. Arch Dis Child 2007;000:1–9. Fiocchi et al. WAO Soya if > 6 months eHF (unless faltering Proctocolitis eHF eHF in general as 1st line 2010Koletzko et al. JPGN 2012;55: 221–229. Boyce et al. J Allergy Clin Immunol 2010;126:S1-S58. Fox et al. eHF if >6 months if also treatment growth then AAF) Clin Transl Allergy. 2019 Aug 12;9:40. Vandenplas et al. Nutrients. 2019 Jun 26;11(7) presenting with faltering growth

Growth Concerns in CMA – Length

(1) Symptoms not fully resolved on an EHF – 7 studies Early Onset (2) Faltering growth/failure to thrive - 8 studies onset (3) Multiple food eliminations - 6 studies (4) Severe complex gastrointestinal food allergies, (5) Eosinophilic esophagitis (EoE) – 7 studies Late (6) Food protein induced enterocolitis syndrome (FPIES) - 0 onset • n = 100 (mean age 7 months) (7) Severe eczema – 4 studies • Fall in length coincided with symptom appearance of CMPA and (8) Symptoms whilst breast-feeding – 4 studies elimination diet (3-12 months) Isolauri et al. J Pediatr 1998;132:1004-9 Meyer et al. J Allergy Clin Immunol Pract. 2017 Nov 3. pii: S2213-2198(17)30727-4

AAF and Length Growth

• Studies have documented failure of EHF and GROWT impact on growth: H First author Type of Study Patient Characteristics Outcome on Growth – Isolauri et al: Niggemann et al Randomized CMA + eczema as 1° symptom Height-for-age was significantly higher (p = 0.04) in infants eHF vs. AAF Infants on AAF – Similar energy intake, but length increase Hill et al Prospective Suspected non-IgE CMA All infants with growth failure at baseline (4/18) achieved normal was higher (p=0.006) in the AAF group. All put on AAF Infants + children growth with AAF

Sicherer et al Non-randomized IgE CMA No significant effect on growth at 4-mo visit (18/31), 8/31 had – Niggeman et al: All put on AAF Infants + children previously been on eHF • Similar energy intake, but significantly Borschel et al Non-randomized Chronic diarrhea + allergic and/or Significant increases in weight-for-age and height-for-age in all All on AAF digestive disorder children. Greater impact on growth in younger subjects. better height growth in children on the Infants + children AAF Isolauri et al Randomized CMA + eczema Signiﬁcant increases in weight- (p= 0.09) & length-for-age eHF vs. AAF Infants (p=0.006) in AAF group vs. eHF group

McLeish et al Randomized Suspected non-IgE CMA Both groups were undernourished at beginning of the study, but eHF vs. AAF + persistent diarrhea at 24 months there were no statistical differences in growth Infants + children between the 2 groups.

Vanderhoof et al Prospective CMA + failed eHF + weight loss Significant increase in weight (+0.433 z-score) at wk 12. Length All on AAF Children increased over this period (NS).

Berni Canani et al Randomized CMA No differences in length, weight, head circumference eHF vs. AAF (+HC) Infants + children between three groups after 12 months Isolauri et al. J PEDIATR 1995;127:550-7 Niggemann, et al. Pediatr Allergy Immunol. 2001;12:78-82. Hill, et al. J Allergy Clin Immunol. 1995;96:386-94. Sicherer, et al. J Pediatr. 2001;138:688-93. 5. Borschel, et al. BMC Pediatr. 2014;14:136. Isolauri, et al. J Pediatr. 1995;127:550-7. McLeish, et al. Arch Dis Child. 1995;73:211-5. Vanderhoof, et al. J Pediatr Gastroenterol Nutr. 2016;63:531-3. Berni Canani, et al. J Pediatr Gastroenterol Nutr. 2017;64:632-8. Niggeman et al. Pediatr Allergy Immunol 2001: 12: 78–82

Case Presentation • Baby C is referred at 6 months for: • Eczema from 6 weeks of age – on daily steroids in the creases ECZEMA • Poor feeding – does not stay on the breast for more than 3 min • Abdominal pain – does not sleep for more than 1 hr without Author Type of Study Patient Characteristic Outcome on Eczema waking up in pain Niggeman et al. Randomized eHF Eczema+ IgE mediated No difference in SCORAD before and vs AAF /non-IgE mediated after using EHF or AAF at 3 months • Mucusy stools with streaks of blood (not that frequent) allergy/ mixed IgE and or 6 months’ • Faltering growth: non-IgE mediated • dropped > 2 centiles (now at -2 z-score for weight) allergy • Dropped 1 centile in length (now at -0.66 z-score) Isolauri et al. Randomized eHF Eczema + CMA. No difference between the groups • SPT = 4 mm wheal to CM, all other negative vs AAF before and at the end of the study. Kaczmarski et al. Prospective Eczema + CMA No differences in SCORAD • Mixed IgE and non-IgE mediate CMPA diagnosed observational between the groups failing/not study. failing the eHFs. • Mum wants to start with solid food Leung et al. Randomized Eczema (some were The median changes for cross over AAFsensitised) SCORAD and its area, intensity and • Breastfed, but mum has to go back to work vs pre-existing pruritus not significant during the and wants to have. a formula during the day formula active or placebo phase

Niggeman et al. Pediatr Allergy Immunol 2001: 12: 78–82 Faltering Growth with Multiple other Case Presentation • Baby C is referred at 6 months for: Atopic Symptoms • Eczema from 6 weeks of age – on daily steroids in the creases Publications Breast feeding Severe GI Growth Multiple Atopic • Poor feeding – does not stay on the breast for more than 3 min symptoms Faltering Allergies Dermatitis • Abdominal pain – does not sleep for more than 1 hr without waking up in pain Hill et al.22 + + + 45 • Mucusy stools with streaks of blood (not that frequent) Sicherer et al. + + • Faltering growth: Kaczmarski et + + • dropped > 2 centiles (now at -2 z-score for weight) al.76 • Dropped 1 centile in length (now at -0.66 z-score) Isolauri et al.6 + + + • SPT = 4 mm wheal to CM, all other negative De Boissieu et + + + • Mixed IgE and non-IgE mediate CMPA diagnosed al.15 • Mum wants to start with solid food De Boissieu et + + + al.7 • She has to go back to work and wants to have Vanderhoof et + + a formula during the day al.17 Lucarelli et al.82 + + +

20 Meyer et al. J Allergy Clin Immunol Pract. 2017 Nov 3. pii: S2213-2198(17)30727-4

Findings when AAF is indicated?

• Failure on an EHF • EoE • Growth faltering, in particular with multi-system involvement (gastrointestinal tract/and or skin) and multiple food eliminations • Anaphylaxis

• No studies have highlighted differences in outcomes between AAF formulas

Meyer et al. J Allergy Clin Immunol Pract. 2017 Nov 3. pii: S2213-2198(17)30727-4

”Checklist” for Making an Appropriate Choice • Is breastfeeding possible – if so this should be promoted • Underlying diagnosis and clinical indications • Has the hypoallergenic formula been tested in children with CMPA as per current guidelines • Growth and nutritional adequacy data (published) • Micronutrient content and suitability for the child • Local availability: • Reimbursement versus self-pay • Cost of hypoallergenic formula • Age of child: formula and taste acceptance • Nutritional status of child • Other: religious (ingredients), dietary (multiple foods allergies, vegan/vegetarian….

Practical Tips for Introduction of Hypoallergenic Formulas Conclusion • Important to support breastfeeding in children with CMA Breast fed Child Formula Fed Child • Breastfeeding mothers need advice on their diet - Wait for child to be -Cutting out breastfeed and wait for hungry/thirsty • The following conditions warrant the use of an AAF as first line natural hunger - > 6 months feeder beaker formula: -> 6 months feeder beaker (avoid may be an option (avoid a • Failure on an EHF, EoE and anaphylaxis valve) valve) • Growth faltering, in particular with multisystem involvement(gastrointestinal - Taste of formula? - Taste of formula? tract/and or skin) and multiple food eliminations and anaphylaxis -Mixing of breast with - Mixing of formula with • The decision of using and AAF should include an allergy focused hypoallergenic formula with hypoallergenic formula – history caution! depends on type of allergy -Flavour additions as LAST RESORT - Flavour additions as LAST • Use of AAF for diagnosis should be carefully considered in line with RESORT the service and reimbursement • Patient should be monitored whilst on an AAF to establish when Curtis et al. Arch. Dis. Child. Fetal Neonatal Ed. 1999;81;F141-F143 Du Toit et al. Arch. Dis. Childhood 2010, August [epub] allergy is outgrown and when challenge/milk ladder can be started 1st and 2nd ALEXA Live Webinars • Allergy Experts In Action QUESTIONS & ANSWERS

1. What is the role of postbiotics in immunity? See this publication https://www.ncbi.nlm.nih.gov/pubmed/31276034 2. Asthma, cesarean section and food allergy, what is the present advice? No official advice from allergy bodies, but acknowledgment that his impacts on the microbiota. 3. Is there a possibility that a baby gets allergic in toddlerhood while there’s no trace during his infancy? Yes 4. There are multiple formula with different strains available in markets, does it all equal or depends on number and amount? There are just 2 formulas with 2 strains and one contains a prebiotic with the probiotic. There are differences which are visible in the research. 5. Please share experience with prematurity and hypoallergenic formulas. Hypoallergenic formulas have not been tested in preterm infants. 6. If SPT shows egg allergy even before introducing egg what to do? Challenge to egg in a controlled environment and if no reaction actively introduce 7. Sometimes we have a challenge when we have a baby who is absolutely breast fed and his mother is on strict exclusion diet but he is still experiencing allergic manifestations! What is your recommendations? Check EAACI guidelines. 8. Can we provide hypoallergenic formula for non breast fed babies without allergy risks? No – this can increase the risk of the non allergic baby developing an allergy as they are not being exposed. 9. What is the best food to start weaning? Vegetables. 10. Is there be a dose dependent response to the amount of pro/prebiotics added to a formula and the benefits they provide to the gut or is the strain more important? Both is important – strain and dose. 11. Does pumping and storing affect breastmilk microbiome composition? Storing in particular freezing affects many of the bioactive factors including the microbiota in the breastmilk. 12. What happen if u stop taking probiotics? That depends on the age and length of taking the probiotic. 13. After weaning child how long do we use Pre and Probiotics? There are no specific studies to suggest when to stop, but studies on clinical impact have studied results after supplementation for 3-6 months. 14. Do dead probiotics confer any benefits? Yes - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3909163/ 15. For how long does mother use synbiotic formula for her baby? Until its clinically acceptable to stop as the formula is part of the cow’s milk allergy treatment. 16. Why is market full with many milk formulas and why is it used too much? And why there aren’t breastfeeding promotions and baby friendly initiatives steps? The reasons are multi-factorial and well debated in the peer reviewed press. WHO highly promotes breastfeeding and baby friendly initiates, but it is up to individual countries and healthcare services to implement them. 17. How long should I give Hypoallergenic formula for a baby? When to go back to regular formula? This depends on ige/spt test when they are ready to be challenged and in non-IgE mediated allergy trial can occur around 1 year of age. 18. Whether whey or casein based partially hydrolyzed formula better? For cow’s milk allergy, no partially hydrolyzed formula is recommended for treatment. 19. Do you also advise the mother who breastfeeds to go on a hypoallergenic diet? No, unless the baby exhibits symptoms in which case a targeted elimination of for example just milk is suggested. See below references. 20. Newborn baby passes stool after every breastfeed how to manage such a case? This falls within the normal stooling of a breastfed baby. 21. Breast milk is complete compatible. We should promote it more, in your opinion which milk brand is more near to breast milk? There is no brand that can be compared to breast milk as breast milk is unique. However all brands have to have ingredients that match growth to breastfed infants. 22. Which one is more important for infants, prebiotic or probiotics? Both are important. 23. Are synbiotics safe to use in premature babies or children under 3 months of age? Synbiotics have not been studies in premature babies, but have been studied in children from birth and are safe to use. 24. Is elimination of certain foods from mother diet can improve atopic reactions in her infant? As allergens can transfer through breastmilk, targeted maternal elimination of allergens may improve symptoms. https://www.ncbi.nlm.nih.gov/pubmed/?term=Meyer+AND+non-IgE+AND+breastmilk 25. Is there any role of probiotics and prebiotics in the treatment of constipation in children? Please see recent systematic review: https://www.ncbi.nlm.nih.gov/pubmed/31778407 26. We know that Chinese mothers are adapted to eat strange animals and insects which we now know that it transmits covid-19. So why their babies fed with breast milk were not immune against the virus? The host of covid 19 has not yet been fully confirmed as the intermediary animal has not been found. Vertical transfer of covid-19 virus does not occur intrauterine, please refer to: https://www.ncbi.nlm.nih. gov/pubmed/32151335 27. I’m seeing more of breast fed infant who show igE mediated allergic symptoms when mothers switch to formula, how does this fit with the research. Is this real life vs lab experiments? This is well described in the literature that on first exposure of formula babies develop cow’s milk allergy. The baby would have been exposed to cow’s milk protein through breastmilk, so sensitization would have occurred in this way. 28. If mother is a known case of covid 19 What about breast feeding? Please see guidance from WHO. http://www.emro.who.int/nutrition/nutrition-infocus/breastfeeding- advice-during-covid-19-outbreak.html 29. Is there any role of long term use of probiotics for reducing Allergies? The latest meta-analysis indicates in particular lactobacillus GG during pregnancy and early childhood may be of benefit to preventing atopic eczema. See also WAO recommendations from 2015. 30. What is the difference of pre and probiotics? https://www.ncbi.nlm.nih.gov/pubmed/30219638 31. For how much time pre /probiotics should be used? Studies have used them for 3-6 months to prove clinical impact. 32. How to prevent allergy? Many guidelines papers have been published on this complex question. Suggest you look at EAACI, AAP, AAAAI, ASCIA, APAPARI guidelines as a good overview. 33. For sick patients in NICU, which is better, to give lactobacillus or bifidobacteria or both and in what counts. Particularly for those with multiple courses of antibiotics who are deprived of breast milk and those with feeding intolerance. Need to be careful with probiotics in nicu on immunocompromised patients. See metanalysis. https://www.ncbi.nlm.nih.gov/pubmed/26624488 34. Is buffalo milk or goat milk better than cow milk? Any difference between A1 and A2 milk ? No protein homology is high and there are 9 proteins in cow’s milk in a2 milk just 1 of them is removed, so allergenic potential is the same. 35. Synthetic Prebiotics are immunomodulators, can they match to natural human milk? There is good data to show that they do. 36. How much difference of microbiota between infants born with c section vs vaginal delivery? There are significant differences. https://www.ncbi.nlm.nih.gov/pubmed/?term=Delivery+mode+shapes +the+acquisition+and+structure+of+the+initial+microbiota+across+multiple+body+habitats+in+newborns 37. What is the difference between spontaneous vaginal delivery and c section delivery as allergies? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505471/ 38. Is goat milk better than cows milk in preventing allergy? No the protein homology is around 95%. 39. Do you advice these days mother breastfeed her child? I always advise mothers to breastfeed even during these days. Position papers have been published to advise on what to do with covid 19 and breastfeeding. 40. Usually mothers complain of not getting enough milk. I usually attribute that to breastfeeding positioning, latching and frequency of feeding. Is there anything in particular that you would advise ? Agree with this – in addition to maternal diet, fluid intake and stress needs to be assessed. 41. Is it recommended to supplement healthy baby with pre or probiotics? There are no current recommendations for healthy babies to routinely take pre or probiotics. 42. Can probiotics cause allergy? If contaminated with cow’s milk yes. There are case studies reporting this. 43. In chronic diarrhea which medicine and milk is preferred? Can not answer the question about medicine. Once bacterial, viral and parasitic causes have been ruled out, inflammatory factors and allergy need to be considered. When breastmilk (the preferred feed) is not available the feed needs to be individualised based on these findings. 44. The role of synbiotic in exclusive breast feed with colic. No studies at the moment on synbiotics in colic. 45. How does formula feed affect gut flora? Formula fed infants not supplemented with pre-, pro- or synbiotics have distinct gastro-intestinal microbiome signatures, which appear to underlie the difference in various health outcomes. 46. HMO’s in a mother’s breast milk does not get affected by her diet Maternal diet does impact on HMO: https://www.sciencedaily.com/releases/2017/01/170123151401.htm 47. Is it safe to give probiotics for allergic pt who receiving chemotherapy? Probiotics are contraindicated for any patient that is immunocompromised. 48. In children at high risk of developing food allergies, would it be an option to administer synbiotics early to reduce that risk of allergy? This has not been fully established through research. 49. Are strawberries, eggs, fishes, bananas and chocolate can aggravate wheezy chest? As used to be told before? We are always asked this question in clinics by parents. No it does not. There is no evidence of this causing wheeziness, unless this is a child that has an allergy to eggs, bananas and fish. 50. How bacteria could be transmitted through breast milk? Breastmilk contains bacteria – transferred through the enteromammary pathway. See Jost et al. Environmental Microbiology (2013) 51. What food in weaning is good for infant for gut flora? What should be do’s n don’ts? Fruit, vegetables and grains increase diversity of microbiota. These foods also are often sources of prebiotics: Do – introduce a variety of foods Don’t – delay the introduction of any foods.