Review

Children’s interstitial and diffuse lung disease

Steve Cunningham, Adam Jaffe, Lisa R Young

Lancet Child Adolesc Health Children’s interstitial and diffuse lung disease (chILD) is a rare heterogenous group of conditions, with symptoms often 2019; 3: 568–77 overlapping with more common conditions, impeding diagnosis and frustrating parents and clinicians alike. Clinical Published Online collaborations are improving diagnostic precision, disease phenotyping, mechanistic understanding, and interventional June 18, 2019 therapeutic capability; however, with over 200 conditions, chILD requires greater aligned international collaboration to http://dx.doi.org/10.1016/ S2352-4642(19)30117-8 address the knowledge gaps. The use of genetics plays an increasing part in diagnosis, and thus might help to align Paediatric Respiratory current classification systems. Empirical therapeutics are few, of no proven benefit, and with important side-effects, Medicine, Centre for particularly in infants. Novel therapeutics postulated for several chILD conditions on the basis of mechanistic Inflammation Research, observations are in development and represent real hope for those conditions to which they apply. Broader therapeutics University of Edinburgh, against the downstream effects (ie, fibrosis) are under consideration for chILD conditions, but require adequately Edinburgh, UK (Prof S Cunningham MBChB); validated biological outcome measures, which the chILD community urgently needs to address. School of Women’s and Children’s Health, University Introduction many controversies are still present in basic areas such as of New South Wales, NSW, Rare diseases, or so-called orphan diseases, are defined understanding pathogenesis and natural history, and Sydney, Australia (Prof A Jaffe MD); and by the EU as diseases with a prevalence of less than specific therapies are frequently absent for most forms of Department of Paediatrics, one per 2000, or in the USA as less than one per 1650 chILD. These challenges can be overcome with a Vanderbilt University, (ie, <200 000 individuals in total in the USA). Children collaborative international approach, which must be Nashville, TN, USA who have interstitial and diffuse lung disease (chILD) aligned if the needs of the patients are to be satisfied and (L R Young MD) represent one such group of rare disorders and most to advance the field. Correspondence to: Prof Steve Cunningham, commonly present in early childhood with associated 1 Department of Child Life and need for complex lifelong health-care support. ChILD Defining chILD Health, University of Edinburgh, represents a heterogeneous group of rare, chronic ChILD is a useful acronym, but as many of the diseases Royal Hospital for Children and respiratory diseases,2 with a reported prevalence of do not have primary pathogenesis in the interstitium, Young People, 3 Edinburgh EH16 4TJ, UK 1·5–3·8 per 1 million in Australia and 3·6 per 1 million various synonymous names are also in common usage 4 [email protected] in the UK and Ireland. Incidence is also variably re­ to better reflect the broader grouping of conditions. ported, ranging from 0·13 per 100 000 children per year in Germany5 to 10·8–16·2 per 100 000 children per year in Denmark.6 Although many individual chILD diseases Key messages are ultra-rare (prevalence <1 per 50 000), the published • Children’s interstitial and diffuse lung disease (chILD) data on their collective occurrence are probably typically presents with non-specific features (eg, cough underestimates, attributable in part to differing case and tachypnoea), which is often more severe or persistent ascertainment methods and disease definitions, coupled than expected following an acute viral respiratory with restricted access to genetic testing and general poor infection, or in older children indolent in onset of recognition. Although disease-causing mutations are symptoms and signs; clinical awareness of potential chILD considered common in rare conditions, relatively few in these circumstances helps to speed up diagnosis and have been identified to our knowledge across the spectrum reduce parental frustration of chILD. Patients with chILD face additional barriers to • There are several classification systems, but of greater 7 receiving equitable health care. A survey of chILD family importance is the application of standard investigation experiences in the UK identified important themes: poor pathways for potential chILD (guidelines are available) and inconsistent knowledge among physicians and health and liaison with teams with specialist knowledge at an professionals; scarcity of appropriate information for early opportunity patient and parent education and the need for improved • Parents of children with chILD wish for better com­munication; the need for support to navigate complex multidisciplinary team approaches, both for diagnosis health systems; improved provision of nutritional, psycho­ and for ongoing clinical care, within and across logical, and nursing support; and the need for more health-care sites research and the development of new treatments. In a • Empirical therapies are most commonly used in conditions US study focused on a specific type of chILD, called in which inflammation is present, although the evidence neuroendocrine cell hyperplasia of infancy (NEHI), delays for the balance of benefits and harm is incompletely in diagnosis were common. Specifically, median symptom understood onset was at 3 months of age, whereas median age at • Novel therapeutics are in development both for specific 8 diagnosis was not until 8·5 months. Children with conditions and for the downstream effects of airway bronchiolitis obliterans are often diagnosed 24 months or inflammation (ie, fibrosis); international alignment will 9 more after disease onset. Although important progress in be important to deliver these trials chILD research has been made in the past two decades,

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The American Thoracic Society Committee on chILD and the chILD Research Network recommend diffuse Panel: Examples of children’s interstitial and diffuse lung lung diseases,10,11 whereas others use diffuse parenchymal disease clinical context and pathogenesis lung disease. In this Review, chILD is used to reflect Altered lung development diffuse disorders of the lung in children. • Alveolar capillary dysplasia with misalignment of the With over 200 conditions under the umbrella term pulmonary veins chILD, the debate continues as to the optimal approach • Pulmonary hypoplasia for organising the field—ie, whether to lump conditions • Pulmonary interstitial glycogenosis 12 together or split them into individual conditions. Those • Multiple genetic causes* in favour of combining conditions propose that chILD diseases can be con­sidered as manifestations of either Genetic disorders of surfactant production and metabolism abnormal airway, mesenchymal, or pulmonary vascular • Disruption of SFTPB, SFTPC, or ABCA3* maturation, with some diseases resulting from a possible Associated with other genetic syndromes so-called second hit phenomenon (ie, a susceptible lung • Niemann Pick develops chILD following a secondary insult such as an • Gaucher infection). Those in favour of splitting the conditions • Dyskeratosis congenita look to precisely delineate specific chILD entities. One • Hermansky-Pudlak syndrome of the most accepted classification systems is that • Neurocutaneous disorders originally proposed in a landmark study by Deutsch and colleagues;13 however, a systematic review1 from 2015 Connective tissue diseases or other immune-mediated identified four different proposed classification systems disorders from 2003–2013 and many inconsistencies of definition. • Systemic juvenile idiopathic arthritis Classification systems commonly delineate conditions • Dermatomyositis or polymyositis for children under and over 2 years of age; however, this • Mixed connective tissue disease artificial boundary has limitations in practice particularly • Systemic lupus erythematosus in relation to an overlapping age range for genetically • COPA syndrome diagnosed conditions. Expe­rience has emphasised the Vascular or lymphatic disorders need for revision, refine­ment, and alignment of existing • Pulmonary capillaritis classification systems to better incorporate the growing • Pulmonary lymphangiectasia number of genetic mechanisms,­ cases diagnosed without lung biopsy, and entities in older children that might Related to injury or exposure bear greater resemblance to adult forms of interstitial • Post-infectious bronchiolitis obliterans lung disease.14 • Hypersensitivity pneumonitis • Radiation pneumonitis or fibrosis Disease mechanisms and recognising a potential • Drug-induced disease chILD condition *See table. ChILD occurs in a wide variety of clinical contexts associated with seemingly disparate initiating causes but many shared downstream pathways of pathogenesis interstitial lung disease, such as connective tissue (panel, table, appendix). Commonly implicated mech­ diseases, stem cell or solid organ transplantation, or See Online for appendix anisms focus on the importance of lung injury and clinical history of an inhalational injury or environmental repair, often in conjunction with genetic suscept­ibility, exposure. Clinical signs include clubbing, subcostal abnormal lung development, and systemic diseases retractions, chest wall deformity including either pectus with pulmonary involvement. A central paradigm for excavatum (such as with surfactant disorders), or pectus interstitial lung disease in both children and adults has carinatum (more typical in airway disorders associated focused on the contribution of repetitive microinjury to with air-trapping such as NEHI and bronchiolitis alveolar epithelial cells, which leads to aberrant repair obliterans), and hypoxaemia.­ On auscultation, crackles or during tissue regeneration.15 wheeze might be present, although a third of children Children with chILD typically present with non-specific might have normal auscultation. Children might also features of cough and tachypnoea, or have unexpect­edly have features of pulmonary hypertension.16 Family history, severe or persistent respiratory morbidity in the neonatal including that of interstitial lung disease in adults, might period or later in life after an acute viral respiratory be helpful to assist diagnosis but is present only in a infection. Failure to thrive is particularly common in minority of patients. History and physical examination are infants and young children. Older children might present rarely sufficient for diagnosis, but are crucial to prompt with indo­lent dyspnoea either at rest or with exercise evaluation for possible chILD among an otherwise wide intoler­ance. ChILD might also be suspected in patients differential diagnosis of respiratory symptoms. Thus, to with underlying disorders strongly associated with aid the practitioner, the term chILD syndrome has been www.thelancet.com/child-adolescent Vol 3 August 2019 569 Review

Inheritance Clinical presentation Treatment approach ABCA3 deficiency (ABCA3) Autosomal recessive Loss of functional protein causes severe respiratory Reported responses to immune failure in newborn babies, or gradual development suppression with of respiratory symptoms in older children and hydroxychloroquine; azithromycin; adults lung transplantation considered COPA syndrome (COPA) Autosomal dominant Autoimmune interstitial lung, joint, and kidney Janus kinase inhibitors; lung disease arising in the first two decades of life transplantation considered Pulmonary alveolar proteinosis (colony X-linked Primary PAP; dyspnoea and cough in early Whole lung lavage stimulating factor 2 receptor α [CSF2RA]) childhood Pulmonary alveolar proteinosis (colony Autosomal recessive Primary PAP; dyspnoea and cough in early Whole lung lavage stimulating factor 2 receptor β [CSF2RB]) childhood Filamin A syndrome (FLNA) X-linked recessive Dyspnoea in infancy Symptomatic; lung transplantation considered Alveolar capillary dysplasia with Autosomal deominant Acute respiratory distress within first few hours of Lung transplantation considered misalignment of the pulmonary veins (usually with paternal birth; without transplant few survive to 1 year (FOXF1) imprinting) Immunodeficiency 21: profound deficiency PAP form is autosomal Profound B-cell loss with normal T-cell numbers Haematopoietic stem-cell with pulmonary alveolar proteinosis dominant leads to opportunistic infection and PAP transplantation (GATA2) Interstitial lung and liver disease Autosomal recessive Failure to thrive, hypotonia, intermittent lactic Symptomatic; whole lung lavage (MARS [methionyl-tRNA synthetase]) acidosis, severe cirrhosis, respiratory failure (PAP), considered and interstitial lung disease in infancy or early childhood Brain lung thyroid syndrome (NKX2-1) Autosomal dominant Infant respiratory distress and recurrent Symptomatic; lung transplantation pulmonary infection with associated considered hypothyroidism and neurological impairment Lung disease, immunodeficiency, and Autosomal recessive Failure to thrive in infancy with immunodeficiency Haematopoietic stem-cell chromosome breakage syndrome and viral induced fatal lung disease transplantation (NSMCE3) Infantile onset pulmonary alveolar Autosomal dominant Onset of dyspnoea and respiratory distress often Haematopoietic stem-cell proteinosis (OAS1) associated with a viral infection; transplantation hypogammaglobulinaemia and splenomegaly Surfactant protein B deficiency (SFTPB) Autosomal recessive Acute neonatal fatal respiratory distress; Symptomatic; lung transplantation some reports of dyspnoea in older children considered Surfactant protein C mutation (SFTPC) Autosomal dominant Acute neonatal respiratory distress, but also Consider corticosteroids and presents in older children and adults hydroxychloroquine; lung transplantation considered in severe or progressive cases Lysinuric protein intolerance (SLC7A7) Autosomal recessive Short stature, hepatosplenomegaly; recurrent Poor response to GMCSF; infection; early childhood respiratory failure in low protein diet and citrulline some (PAP); pulmonary fibrosis in a third in later supplementation life Acinar dysplasia (TBX4) Autosomal dominant Acute fatal neonatal respiratory insufficiency; Lung transplantation considered patellar aplasia or hypoplasia syndrome; pulmonary arterial hypertension Sting associated vasculopathy with onset Autosomal dominant Infant onset systemic inflammation with skin Janus kinase inhibitors in infancy (TMEM173) lesions, vasculopathy, and pulmonary fibrosis

See appendix for full version. PAP=pulmonary alveolar proteinosis. GMCSF=granulocyte-macrophage colony-stimulating factor.

Table: Genetic mutations associated with children’s interstitial and diffuse lung disease

proposed to refer to such a constellation of historical deficiency is normal; the diagnostic challenge is to information, physical examination findings, hypoxaemia, ascertain whether the clinical course is as expected or or diffuse radiological abnormalities.10 whether further investigation is required for a concur­ Diagnosis is made difficult in conditions that chILD rent secondary genetic disorder of altered surfactant might mimic—ie, those in babies born prematurely or production or metabolism.17 who have complicating factors at birth such as chorio­ amnionitis, neonatal sepsis, or meconium aspiration. In Approach to diagnosis terms of babies with severe respiratory distress requiring In children with respiratory symptoms and signs that are ag­gressive ventilation, forms of chILD such as inherited considered to be non-typical for their clinical situation, the surfactant deficiency or lung development abnormalities first step is to exclude more common causes of chronic should be considered. In premature babies, surfactant respiratory symptoms (ie, cystic fibrosis, primary ciliary

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dyskinesia, structural heart disease, immunodeficiency walk tests, and cardiopulmonary exercise testing are also and associated infection, recurrent aspiration, or struc­tural possible, but with data restricted by age and capability in airway abnormalities), acknowledging that such comor­ children with severe disease.20 bidities might sometimes accompany chILD. Asses­sment In children who, either for age or capability reasons, of the clinical context and disease severity is crucial to cannot perform volitional pulmonary function tests, guiding the pace and approach to diagnostic evaluation. For non-volitional tests could provide valuable information example, factors such as predisposing disorders, family but in general are more difficult to perform and stan­ history, immunodeficiency, the presence of hypoxaemia,­ dardise across centres than are volitional tests. Infant pulmonary hypertension, or failure to thrive, and a trend pulmonary function test­ing, although recommended10 towards disease progression or improvement, will and able to help physicians to determine abnormality in influence the order and speed of specific tests done and the NEHI21 and in interstitial lung disease caused by SFTPC relative use of non-invasive versus invasive evaluations mutations,22 is technically challenging to standardise such as lung biopsy. A history and physical examination even when substantial resources are present.23 Multiple might provide impor­tant clues that streamline subsequent breath washout, a measure of ventilatory inhomogeneity, evaluations, particularly through identification of under­ can be standardised across centres24 and has shown lying systemic disorders or environmental exposures. some potential for chILD.20 As a tidal breathing test, Routine laboratory investigations (including complete multiple breath washout can be performed across all blood count, serum markers for renal, hepatic, and thyroid ages and might be more sensitive than spirometry.20 function, and quantitative immunoglobulins) are used to Work of breathing, also a hallmark of chILD, is being screen for systemic or multiorgan disease. Serological explored with potential for disease monitoring.25 studies for autoantibodies are particularly important in Oxygen saturation measured by a pulse oxygen older children and those with evidence of pulmonary saturation (SpO2) monitor can reflect pulmonary disease haemorrhage, renal involvement, and articular, cutaneous, and is the principle measure within chILD severity 26 or systemic disease. Similarly, IgG precipitin testing to scales. SpO2 testing is valuable because measurements allergens has a role, although with incomplete sensitivity can be made across a spectrum both passively when at and specificity, in those with suspected hypersensitivity rest and dynamically at times of physi­ological stress pneumonitis (ie, a hyper­sensitivity to birds). (eg, sleep or exercise, including feeding as a proxy in A stepwise approach involves non-invasive tests and infants). However, to be of value the measurement of invasive studies if needed, including assessment of oxy­ SpO2 has to be standardised; the chILD-EU group has For more on the European Management Platform for genation and ventilation, pulmonary function testing, recommended to measure SpO2 in room air when a Childhood Interstitial Lung chest imaging, and consideration of bronchoscopy and child is at rest for 5 min (and to accept a desatu­ration Diseases (chILD-EU) see potentially lung biopsy. Genetic testing has a growing role nadir of 80% before recom­mencing supplemental http://www.childeu.net 27 in many countries and might obviate the need for more oxygen if required). SpO2 can also be measured during invasive studies including lung biopsy, and thus should be dynamic tests, for children who might otherwise show considered early in the evaluation in the appropriate SpO2 within a normal range. SpO2 measured while clinical context, particularly in neonates with respiratory asleep (or during exercise for older children) can provide failure and children with a family history of interstitial a more sensitive assessment of pulmonary function lung disease. The published literature indicates that than when measured when awake at rest,8 but the historically, even with a thorough evalua­tion, a specific standard­isation of these measurements to allow inter- cause is not identified in 10–30% of chILD cases.3 site comparisons has been unreliable so far. Many children with resolved hypo­xaemia associated with Investigations NEHI would probably show borderline hypoxaemia if Pulmonary function appropriately dynamically challenged. Forced vital By definition, lung function is impaired in chILD, and capacity is a core biological surrogate outcome for the challenge is to measure the physiological effect clinical trials of novel therapeutics in adult interstitial across the range of age, severity, and disease found. lung disease,28 but a similar capability for chILD in Proportionately, most chILD conditions arise in ages in school-aged children has not been shown and should be which volitional respiratory function, most commonly a key goal for international collaboration. Producing a measured by spirometry, is difficult to obtain (ie, 6 years). biological pulmonary surrogate measure in preschool When volitional tests are possible, spirometry, lung children is an equally pressing goal. volumes, transfer factor, and exercise challenge (ie, 6-min walk test) can provide valuable data. Cross-sectionally, Imaging chILD conditions are associated with reduced forced vital CT imaging of the chest is a pivotal and ubiquitous capacity. Longitudinal observational data supporting investigation within diagnostic algorithms when inves­ prognostic outcomes are sparse although some data are tigating a diagnosis of chILD.10,27 CT helps to identify and available for ABCA3 mutations,18 sarcoidosis,19 and differentiate diffuse, nodular, cystic, bronchiectatic, and hypersensitivity pneu­monitis.20 Diffusion capacity, 6-min atelectatic or consolidative qualities well, but image www.thelancet.com/child-adolescent Vol 3 August 2019 571 Review

A B

C D

E

Figure: Examples of chest CT findings in children’s interstitial and diffuse lung disease (A) Ground glass opacification of the right middle lobe and lingula consistent with neuroendocrine cell hyperplasia of infancy. Patient is a 2-year-old child. (B) 3-year-old child with surfactant protein C (SFTPC) gene mutation shows diffuse ground glass opacity and reticulation. (C) 15-year-old patient with systemic sclerosis shows dense subpleural predominant opacities. (D) Findings of subpleural nonspecific overall pleural ground glass opacities and reticulation in a teenager with mixed connective tissue disease who was asymptomatic from a pulmonary standpoint. (E) Scattered irregular ground glass opacities in a 10-year-old child with dyspnoea and restrictive lung disease. Consider lung biopsy if no systemic condition, pulmonary impairment is severe or progressive, and genetic testing is unrevealing.

qual­­ity (and interpretability) is affected by a host of As an individual diagnostic test, CT imaging of the factors related to the manufacturer, scan protocol set up,29 chest has low sensitivity and specificity for many chILD and patient preparation (ie, breathing spon­taneously, conditions, with a few exceptions, most notably NEHI me­chanically, or pressure gaited). Use of phantoms and with a 78% specificity and 100% sensitivity in one series protocols across sites can reduce the variability for some of patients (figure A).30 Patterns of diffuse ground glass of these factors, but the speed of technological progress opacity and reticulation are reported as common in enabling rapid scanning without anaesthesia in young infants and young children with surfactant genetic children adds complexity and variance. disorders (figure B), but the sensitivity and specificity

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have not been formally evaluated. In other conditions, Genetics such as connective tissue disorders (figures C, D), pat­ The revolution in capability, speed, and costs for terns in CT imaging of the chest might help to define the diagnosis of genetic conditions are anticipated to provide nature and extent of the disease, enabling management a substantial and beneficial disruption to current chILD to be focused on the underlying systemic disease process classification, diagnosis rates, and management. Next- so that lung biopsy might not be required for further generation sequencing with whole exomes or whole characterisation. If less invasive investi­gations, including genomes sequenced particularly of trios (ie, the index CT imaging of the chest, do not identify a cause of chILD and both biological parents), will substan­tially disease and clinical severity warrants, lung biopsy might increase the likelihood of gene identification and be indicated to support a more definitive diagnosis discovery. Familial genetics are identified in at least (figure E). 20% of adult idiopathic pulmonary fibrosis,43 with the Variance of CT image quality and resolution, paediatric family linkage yet to be adequately quantified. compounded by variability in reporting of CT imaging of Autosomal dominant inheritance patterns, particularly the chest for detection of chILD31 (even when aligned to a those with incomplete penetrance or variable natural scoring system) might be improved by automated CT history, might present great challenges for segregation image analysis scoring systems that are in development analysis, because the assumption that asymp­tomatic for adult interstitial lung disease32 and have modest family members are genetically unaffected cannot be correlation with clinical factors.33 A validated CT scoring made. Despite these limitations, a genetically supported system for chILD is missing. Despite ongoing reductions definitive diagnosis might greatly enhance time-sensitive in dose schedules, radiation exposure will continue to clinical decision making without the associated risk of restrict the frequency and resolution of CT imaging of lung biopsy when considering lung transplantation or the chest in young children. MRI is making some palliation (ie, surfactant B deficiency or alveolar capillary inroads to CT imaging of the chest, with most value in dysplasia with misalignment of the pulmonary veins). the follow-up of specific diagnoses,34 rather than as a The known genes causing chILD are summarised in the diagnostic tool in de-novo suspected chILD. There is table. In some countries (eg, the USA, the UK, Germany, also early work developing a role for ultrasound of the and Australia), gene panels of the most common chest in interstitial lung disease in adult idiopathic35 and candidates are avail­able. In one study,3 even in a well connective tissue disorders.36 However, CT imaging of characterised cohort, positive genetic diagnoses were the chest will probably stay the principle tool for only found in 14 (12%) of 115 patients. assessing structural lung disease associated with chILD Whether embedding whole exome or whole genome for some years and as such, standardisation of image sequencing in health care is cost-effective is still to be acquisition and analysis32 and a better understanding proven and is under evaluation by the Children with pathoradiological correlations as in adult interstitial Interstitial Lung Disease Research Network in Australia lung disease33 are required. and New Zealand (chILDRANZ) as part of Australian For more on Australian Genomics. This approach has many challenges in­cluding Genomics see https://www. Histology consent, ethics, data custodianship, privacy, and under­- australiangenomics.org.au/ Histology has been the historical gold standard for standing the large amount of variants of unknown diagnosis of chILD and the basis of all key classification significance produced by such sequencing coupled with systems,11,37,38 but genetic testing is increasingly im­ limitations in feasibility of functional studies to test and pinging on this role. Although lung biopsy can provide confirm the consequences of identified variants. a diagnosis in most cases,39 the biopsy has important limitations and is not without risk. Samples are Multidisciplinary team working in chILD invasively obtained, cannot be readily repeated, and Multidisciplinary teams should be a core standard for might not adequately represent an area of the lung with chILD diagnosis and clinical management. Diagnoses disease. For a sufficient lung sample to be obtained in of chILD commonly require a consensus agreement infants and young children, an open or video-assisted intertwining clinical, radiological, and histopathological transthoracic surgery biopsy is most often done; evidence. In the past two decades, the recognition transbronchial biopsy is not appropriate. Tissue that many of the diseases have an immunological or processing is crucial,40 and with few global histological genetic cause has meant expanding the team to include experts for these rare conditions, diagnostic variance immunologists, rheumatologists, genetic counsellors, is also added. Although in a single expert centre and geneticists. The rarity of the conditions implies a interpathologist agreement for chILD was 90% (189 of benefit in the advice from experienced multidisci­ 211 chILD cases),41 international agreement among plinary teams to revise diagnoses and offer advice on pathologists has not been reported: areas with important management.37 Networks have proven invaluable in and significant diagnostic variance has been described establishing multidisciplinary teams for diagnosis and among an international group of clinicians, and this management advice. In chILD, the first collaboration variance can now be addressed.42 was the chILD Research Network (chILDRN) in the USA. www.thelancet.com/child-adolescent Vol 3 August 2019 573 Review

This multicentre network established and evaluated academically delivered randomised controlled trial classification systems,11,38 developed a national chILD (NCT02615938) of hydroxychloroquine. Challenges of registry operating under single institutional review board global regulatory frame­works are still present. The reliance,44 and published a clinical practice guideline.10 In delivery of effective, low-cost therapeutic interventional Europe, chILD-EU has established a European registry trials for rare disease outside the industry would benefit that can support clinical trial research, provided standard from efficient global regulatory frameworks. Global operating procedures for investigating suspected cases, chILD registry infrastructures could also help to support and a guideline for the diagnosis and treatment of chILD,27 novel regulatory initiatives for rare disease including supported by a European Research Society Clinical EMA PASS (post-authori­sation safety study), PAES Research Collaboration.45 In Australasia, chILDRANZ has (post-authorisation efficacy study), and FDA PAS (post- established monthly multidisciplinary peer review of approval study),50 delivering novel therapeutics earlier For more on the French chILD cases and a chILD registry.3 France also has a rare chILD than standard regulatory approval routes to patients but network RespiRare® see network supporting diagnosis and management.46 With retaining regulatory safety controls. Clinical registries http://www.respirare.fr an advancing role for genomics in treatment, prognosis,47 have been pivotal in delivering these regulatory studies and trial design, the need to link future clinical quality in cystic fibrosis.50 ChILD registries, as academically registries to genomic and other so-called omic registries driven, often charitably funded entities, have substantial to optimise the potential of the data is increasingly sustain­ability challenges: two national databases have recognised in chILD and other orphan diseases. been halted because of an absence of funding (ie, Multidisciplinary teams should also deliver clinical Australasian Registry Network of Orphan Lung Disease care. Parents report variable access to trained specialist and British Paediatric Orphan Lung Disease Registry). nursing, dietetic support, and psychological support, Greater international collaboration­ with intuitive low- to deliver appropriate care of respiratory support therapies cost platforms with common data fields wouldbe (ie, oxygen), nutrition (ie, in failure to thrive) and support helpful for enhancing chILD research and clinical of development with a chronic illness often with poorly management across all health-care economies. defined future outcome.7 Such perspectives are supported by observational data.48 Physiotherapist, pharmacy, and Empirical therapies in chILD social care support are also pivotal within teams. Expert There are no randomised controlled trials of medicines in team members should ensure that those delivering care chILD. Observational data are too scarce, and often locally are provided with comprehensive up-to-date anecdotal. In a few conditions, specific therapeutics have a clinical information and sick day management plans. mechanistically plausible role and observed clinical benefit (in­cluding inhaled granulocyte-macrophage colony- Therapeutics for chILD stimulating factor [GMCSF] in autoimmune pulmonary Most medicines prescribed for chILD have been adopted alveolar proteinosis, and biologics [ie, rituximab] and empirically into practice. The barriers to introducing immuno­­modulatory therapies in connective tissue new therapeutics are in part the reduced financial disorders), but these therapeutics are likely to treat benefits to the pharmaceutical industry (which the relatively few of the chILD conditions. Most common is orphan and paediatric drug legislation is trying to that a rapidly deteriorating chILD case forces a clinical address), part restricted funding for academia (ie, with decision to treat, often at a time when a diagnosis is 7000 rare diseases, funding of individual conditions is uncertain. In a Delphi consensus among chILD clinicians, extremely competitive), part unpreparedness by clinicians corticosteroids were the most common empirical therapy, (eg, inability to present well characterised populations), together with hydroxychloroquine­ and azithromycin.27 part regulatory (eg, evolving trial design for rare and Important side-effects of these therapies balance their ultrarare conditions), and part absence of suitably defined potential benefits.51 Empirical therapies are untargeted and meaning­ful trial outcomes (ie, requiring agreement by used primarily against what are considered inflammatory regulators, clinicians and industry). processes; attempted suppres­ ­sion of inflammation with Clinicians have developed registry and diagnostic corti­costeroids is common, as is steroid sparing with support infrastructures (see multidisciplinary team hydroxychloroquine, and the anti-inflammatory and biotic mentioned earlier) that are now providing capacity to role of azithromycin. Improved mechanistic understanding present well characterised chILD populations. The might lead to development of more targeted therapies. result of this development is better diagnostic precision Corticosteroids are the most commonly used anti- and longitudinal characterisation of standardised inflammatory in chILD, with an established role in lung patient outcomes (eg, to aid clinically meaningful disease related to systemic inflammatory conditions trial outcomes). Patient-reported outcomes and health- (ie, systemic lupus erythematosis and dermatomyositis) related quality-of-life scoring systems to support patient and are now superseded in these conditions by biologics. centred management options are now developed for In chILD conditions without substantial inflammation chILD.49 Platforms have also been developed to support (ie, NEHI), corticosteroids are not effective.52 Patients interventional clinical trials for chILD, including an with pulmonary interstitial glycogenosis, arising at a

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similar age as NEHI (typically younger than 2 years), pathway interference, or mitigating end-stage pathology might benefit from corticosteroids,­ 53 creating some alternative approaches. clinical uncertainty around corticosteroid use in this age Gene transfer has been shown in experimental models group unless a definitive diagnosis is established.54 In in vivo for chILD conditions. Hereditary pulmonary deteriorating cases, cortico­steroids are sometimes used alveolar proteinosis with correction of CSF2RA mutations in prolonged high doses, the benefits of which probably using lentivirus63 has been shown, but potentially of more have to be balanced againts their substantial long-term value could be correction of autoimmune pulmonary harm. European countries have wide variance in their use alveolar proteinosis (accounting for 90% of all cases with of corticosteroids,55 but to harmo­nise practice, the chILD- neu­tralising antibodies to GMCSF), which has been EU Delphi consensus provided dosing recommendations shown in a knockout mouse model with lentiviral- from which better observational data of effect might be transferred GMCSF cDNA.64 Surfactant dis­orders (in obtained.27 No evidence exists for the benefit of one particular surfactant protein B deficiency) also have corticosteroid over another, but common practice is for potential for gene correction, both by vector-delivered pulsed methyl­prednisolone in acute or deteriorating cDNA transfer, but also by use of antisense oligo­ conditions and oral prednisolone for chronic use, with nucleotides (as in eteplirsen and nusinersen). In another anti-inflammatory doses anecdotally adopted from other strategy, induced pluripotent stem cells have also been conditions. In idiopathic pulmonary fibrosis, an adult used to correct pulmonary alveolar proteinosis in CSF2RB- disorder, mortality was higher in patients treated with deficient mice models.65 Novel therapeutics for cystic commonly used anti-inflammatory therapies than in fibrosis have shown the great potential for protein those on placebo,56 and thus caution and controlled trials modification in conditions in which nuclear protein are essential for their use in chILD. misfolding causes loss of function. Bithiazole correctors Hydroxychloroquine is an immunosuppressant inhib­ have shown the capacity to correct disease-causing ABCA3 iting T-cell function and has been reported to be used in misfolded proteins in in-vitro studies.66 Receptor signal approximately 50% of chILD cases, with variable frequency pathway interruption with JAK inhibitors interfere with of use from country to country in the EU.57 Response to the JAK-STAT signalling pathway and have a role in hydroxychloroquine has been reported in some cases of interferonopathies such as coatomer subunit alpha SFTPC58 and ABCA3 mutations,59 but these data are syndrome67 and Sting associated vasculopathy with onset uncontrolled and represent a small proportion of treated in infancy.68 To date, observational data exist only from cases and with important side-effects for children. small series, but the mechanistically plausible benefits A trial is in progress to test the risks and benefits of appear worthwhile. Receptor blockade with the competitive hydroxychloroquine in chILD (NCT02615938). recombinant nebulised GMCSF has good associated Azithromycin has antibiotic, anti-inflammatory, and improvement in patients with autoimmune pulmonary immunomodulatory effects, and with fewer side-effects alveolar proteinosis and anti-GMCSF antibodies, with than hydroxychloroquine is commonly used in chILD. A responses in 24 (62%) of 39 of patients.69 great improvement in a single patient with ABCA3 Two antifibrotics (pirfenidone and nintedanib) are mutation was reported,60 and the survival benefit is licensed in adult idiopathic pulmonary fibrosis and are substantial in children with diffuse panbronchiolitis,61 able to slow the rate of decline in forced vital capacity. but in most other conditions azithromycin­ is used in Pirfenidone has anti-inflammatory and, by reducing combination with corticosteroids or hydroxychloroquine, fibroblast activity, anti-fibrotic mechanisms of action. or both, making determination of benefits difficult. The Nintedanib exerts inhibitory effects on a range of growth negative effects of azithromycin on the lung micro­ factors associated with the development of fibrosis (eg, biome and microbiological resistance are important platelet-derived, fibroblast, and vascular endothelial considerations. receptor growth factors). The side-effect profile of these Whole lung lavage for pulmonary alveolar proteinosis therapies (con­sidered of particular relevance to use in is standard practice and available globally in selected juveniles) and the confinement of idiopathic pulmonary centres. Although safe and effective,62 the intervention is fibrosis to an older adult population (>50 years) are invasive and time consuming to administer. relevant considerations regarding potential therapeutic development for younger populations­ (<18 years). Potential future therapeutics However, fibrosis does exist in children with lung Potential therapeutics for chILD conditions are being disease and is considered a critical contributor to mor­ developed both by evolving mechanistic knowledge of bidity and mortality. Key difficulties for a potential specific chILD conditions and through the devel­opment therapy are the diverse range of chILD conditions that of drugs that can interrupt pathways that cause the might be associated with fibrosis, ethical conditions pathology associated with chronic lung injury, restricting investigation (particularly repeated biopsy particularly in relation to fibrosis. As in other conditions, sampling and radiological imaging), and the very primary genetic correction is considered a principle limited experience for patho­radiological calibration of aim, with downstream protein correction, signal fibrosis against clinically meaningful outcomes of www.thelancet.com/child-adolescent Vol 3 August 2019 575 Review

5 Griese M, Haug M, Brasch F, et al. Incidence and classification of Search strategy and selection criteria pediatric diffuse parenchymal lung diseases in Germany. Orphanet J Rare Dis 2009; 4: 26. We each initially identified references for this Review on the 6 Kornum JB, Christensen S, Grijota M, et al. The incidence of basis of our knowledge of the field. Additionally, we searched interstitial lung disease 1995–2005: a Danish nationwide population-based study. BMC Pulm Med 2008; 8: 24. PubMed using the search terms “Interstitial Lung Disease” 7 Gilbert C, Bush A, Cunningham S. Childhood interstitial lung (restricted age 0–18 years), “Children’s Interstitial Lung disease: family experiences. Pediatr Pulmonol 2015; 50: 1301–03. Disease”, and where relevant investigations (ie, pulmonary 8 Nevel RJ, Garnett ET, Schaudies DA, Young LR. Growth trajectories function, exercise testing, CT imaging, histology, genetics) and oxygen use in neuroendocrine cell hyperplasia of infancy. Pediatr Pulmonol 2018; 53: 656–63. and treatments (ie, corticosteroids, hydroxychloroquine, 9 Kim CK, Kim SW, Kim JS, et al. Bronchiolitis obliterans in the azithromycin, GMCSF) to identify additional studies, 1990s in Korea and the United States. Chest 2001; 120: 1101–06. published in English, from Jan 1, 1995, to Nov 6, 2018. 10 Kurland G, Deterding RR, Hagood JS, et al. An official American Thoracic Society clinical practice guideline: classification, The final reference list was generated on the basis of inclusion evaluation, and management of childhood interstitial lung disease of historical landmark studies, originality, and relevance to the in infancy. Am J Respir Crit Care Med 2013; 188: 376–94. broad scope of this Review. 11 Fan LL, Dishop MK, Galambos C, et al. Diffuse lung disease in biopsied children 2 to 18 years of age. Application of the chILD classification scheme. Ann Am Thorac Soc 2015; 12: 1498–505. relevance to children, families, and licensing authorities. 12 Nicholson AG, Bush A. Classification of diffuse lung disease in The plasticity of fibrosis is increasingly understood and, infants. Am J Respir Crit Care 2007; 176: 1060–61. in the context of paediatric lung disease associated with 13 Deutsch GH, Young LR, Deterding RR, et al. Diffuse lung disease in young children: application of a novel classification scheme. fibrosis, might represent an additional opportunity for Am J Respir Crit Care Med 2007; 176: 1120–28. therapeutic interventions.70 14 Soares JJ, Deutsch GH, Moore PE, et al. Childhood interstitial lung diseases: an 18-year retrospective analysis. Pediatrics 2013; 132: 684–91. Conclusion 15 Nathan N, Corvol H, Amselem S, Clement A. Biomarkers in Children’s interstitial lung disease is now often bet­ Interstitial lung diseases. Paediatr Respir Rev 2015; 16: 219–24. ter diagnosed than previously, with some diseases 16 Clement A. 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