Review
Children's interstitial and diffuse lung disease

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Summary

Children's interstitial and diffuse lung disease (chILD) is a rare heterogenous group of conditions, with symptoms often overlapping with more common conditions, impeding diagnosis and frustrating parents and clinicians alike. Clinical collaborations are improving diagnostic precision, disease phenotyping, mechanistic understanding, and interventional therapeutic capability; however, with over 200 conditions, chILD requires greater aligned international collaboration to address the knowledge gaps. The use of genetics plays an increasing part in diagnosis, and thus might help to align current classification systems. Empirical therapeutics are few, of no proven benefit, and with important side-effects, particularly in infants. Novel therapeutics postulated for several chILD conditions on the basis of mechanistic observations are in development and represent real hope for those conditions to which they apply. Broader therapeutics against the downstream effects (ie, fibrosis) are under consideration for chILD conditions, but require adequately validated biological outcome measures, which the chILD community urgently needs to address.

Introduction

Rare diseases, or so-called orphan diseases, are defined by the EU as diseases with a prevalence of less than one per 2000, or in the USA as less than one per 1650 (ie, <200 000 individuals in total in the USA). Children who have interstitial and diffuse lung disease (chILD) represent one such group of rare disorders and most commonly present in early childhood with associated need for complex lifelong health-care support.1 ChILD represents a heterogeneous group of rare, chronic respiratory diseases,2 with a reported prevalence of 1·5–3·8 per 1 million in Australia3 and 3·6 per 1 million in the UK and Ireland.4 Incidence is also variably reported, 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 are ultra-rare (prevalence <1 per 50 000), the published data on their collective occurrence are probably underestimates, attributable in part to differing case ascertainment methods and disease definitions, coupled with restricted access to genetic testing and general poor recognition. Although disease-causing mutations are considered common in rare conditions, relatively few have been identified to our knowledge across the spectrum of chILD. Patients with chILD face additional barriers to receiving equitable health care. A survey7 of chILD family experiences in the UK identified important themes: poor and inconsistent knowledge among physicians and health professionals; scarcity of appropriate information for patient and parent education and the need for improved communication; the need for support to navigate complex health systems; improved provision of nutritional, psychological, and nursing support; and the need for more research and the development of new treatments. In a US study focused on a specific type of chILD, called neuroendocrine cell hyperplasia of infancy (NEHI), delays in diagnosis were common. Specifically, median symptom onset was at 3 months of age, whereas median age at diagnosis was not until 8·5 months.8 Children with bronchiolitis obliterans are often diagnosed 24 months or more after disease onset.9 Although important progress in chILD research has been made in the past two decades, many controversies are still present in basic areas such as understanding pathogenesis and natural history, and specific therapies are frequently absent for most forms of chILD. These challenges can be overcome with a collaborative international approach, which must be aligned if the needs of the patients are to be satisfied and to advance the field.

Section snippets

Defining chILD

ChILD is a useful acronym, but as many of the diseases do not have primary pathogenesis in the interstitium, various synonymous names are also in common usage to better reflect the broader grouping of conditions. The American Thoracic Society Committee on chILD and the chILD Research Network recommend diffuse lung diseases,10, 11 whereas others use diffuse parenchymal lung disease. In this Review, chILD is used to reflect diffuse disorders of the lung in children.

Key messages

  • Children's

Disease mechanisms and recognising a potential chILD condition

ChILD occurs in a wide variety of clinical contexts associated with seemingly disparate initiating causes but many shared downstream pathways of pathogenesis (panel, table, appendix). Commonly implicated mechanisms focus on the importance of lung injury and repair, often in conjunction with genetic susceptibility, abnormal lung development, and systemic diseases with pulmonary involvement. A central paradigm for interstitial lung disease in both children and adults has focused on the

Approach to diagnosis

In children with respiratory symptoms and signs that are considered to be non-typical for their clinical situation, the first step is to exclude more common causes of chronic respiratory symptoms (ie, cystic fibrosis, primary ciliary dyskinesia, structural heart disease, immunodeficiency and associated infection, recurrent aspiration, or structural airway abnormalities), acknowledging that such comorbidities might sometimes accompany chILD. Assessment of the clinical context and disease

Pulmonary function

By definition, lung function is impaired in chILD, and the challenge is to measure the physiological effect across the range of age, severity, and disease found. Proportionately, most chILD conditions arise in ages in which volitional respiratory function, most commonly measured by spirometry, is difficult to obtain (ie, 6 years). When volitional tests are possible, spirometry, lung volumes, transfer factor, and exercise challenge (ie, 6-min walk test) can provide valuable data.

Multidisciplinary team working in chILD

Multidisciplinary teams should be a core standard for chILD diagnosis and clinical management. Diagnoses of chILD commonly require a consensus agreement intertwining clinical, radiological, and histopathological evidence. In the past two decades, the recognition that many of the diseases have an immunological or genetic cause has meant expanding the team to include immunologists, rheumatologists, genetic counsellors, and geneticists. The rarity of the conditions implies a benefit in the advice

Therapeutics for chILD

Most medicines prescribed for chILD have been adopted empirically into practice. The barriers to introducing new therapeutics are in part the reduced financial benefits to the pharmaceutical industry (which the orphan and paediatric drug legislation is trying to address), part restricted funding for academia (ie, with 7000 rare diseases, funding of individual conditions is extremely competitive), part unpreparedness by clinicians (eg, inability to present well characterised populations), part

Empirical therapies in chILD

There are no randomised controlled trials of medicines in chILD. Observational data are too scarce, and often anecdotal. In a few conditions, specific therapeutics have a mechanistically plausible role and observed clinical benefit (including inhaled granulocyte-macrophage colony-stimulating factor [GMCSF] in autoimmune pulmonary alveolar proteinosis, and biologics [ie, rituximab] and immunomodulatory therapies in connective tissue disorders), but these therapeutics are likely to treat

Potential future therapeutics

Potential therapeutics for chILD conditions are being developed both by evolving mechanistic knowledge of specific chILD conditions and through the development of drugs that can interrupt pathways that cause the pathology associated with chronic lung injury, particularly in relation to fibrosis. As in other conditions, primary genetic correction is considered a principle aim, with downstream protein correction, signal pathway interference, or mitigating end-stage pathology alternative

Conclusion

Children's interstitial lung disease is now often better diagnosed than previously, with some diseases mechanistically understood and potential therapeutic development in key conditions. Genetics will hold the key for some conditions, but many others will need detailed studies. Challenges are, however, that global access to chILD diagnostics is highly variable and retention of key registry infrastructures is fragile. Clinical communities can support chILD best by adopting common standardised

Search strategy and selection criteria

We each initially identified references for this Review on the basis of our knowledge of the field. Additionally, we searched PubMed using the search terms “Interstitial Lung Disease” (restricted age 0–18 years), “Children's Interstitial Lung Disease”, and where relevant investigations (ie, pulmonary function, exercise testing, CT imaging, histology, genetics) and treatments (ie, corticosteroids, hydroxychloroquine, azithromycin, GMCSF) to identify additional studies, published in English, from

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