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Chronic Interstitial Lung Diseases in Children: Diagnosis Approaches

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Expert Review of Respiratory Medicine

ISSN: 1747-6348 (Print) 1747-6356 (Online) Journal homepage: http://www.tandfonline.com/loi/ierx20

Chronic interstitial lung diseases in children:


diagnosis approaches

Nadia Nathan, Laura Berdah, Keren Borensztajn & Annick Clement

To cite this article: Nadia Nathan, Laura Berdah, Keren Borensztajn & Annick Clement (2018):
Chronic interstitial lung diseases in children: diagnosis approaches, Expert Review of Respiratory
Medicine, DOI: 10.1080/17476348.2018.1538795

To link to this article: https://doi.org/10.1080/17476348.2018.1538795

Accepted author version posted online: 22


Oct 2018.

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Publisher: Taylor & Francis

Journal: Expert Review of Respiratory Medicine

DOI: 10.1080/17476348.2018.1538795
Chronic interstitial lung diseases in children: diagnosis approaches

Nadia Nathan, 1,2, Laura Berdah,1, Keren Borensztajn2, Annick Clement1,2

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1. Service de pneumologie pédiatrique, Centre national de référence des maladies
respiratoires rares RespiRare, Hôpital Armand Trousseau, Assistance Publique Hôpitaux

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de Paris (AP-HP), Paris 75012, Fr.
2. Sorbonne Université and Inserm UMRS933, Paris 75012, Fr.

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Corresponding author
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Nadia Nathan
Pediatric Pulmonology Department
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Sorbonne Université and Hôpital Trousseau AP-HP
26 avenue du Dr Arnold Netter, 75012-Paris, Fr.
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Tel : +33(1) 44 73 66 18
Fax : +33(1) 44 73 67 18
nadia.nathan@aphp.fr
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Abstract

Introduction: Children interstitial lung disease (chILD) is a heterogeneous group of rare


respiratory disorders characterized by inflammatory and fibrotic changes of the lung
parenchyma. They include: ILD related to exposure/environment insults, ILD related to
systemic diseases processes, ILD related to primary lung parenchyma dysfunctions and ILD
specific to infancy.

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Areas covered: This review provides an update on chILD pathophysiology and diagnosis
approaches in immunocompetent children. It includes current information on genetic causes.

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Expert commentary: ChILD covers a large spectrum of entities with heterogeneous disease

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expression. Various classifications have been reported, but none of them seems completely
satisfactory. Recently, progress in molecular genetics has allowed identifying some genetic
contributors, with, so far, a lack of correlations between gene disorders and disease
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expression. Despite improvements in patient management, chILD prognosis is still burdened
by significant morbidity and mortality. Ongoing international collaborations will allow
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gathering larger longitudinal cohorts of patients to improve disease knowledge and
personalized care. The overall goal is to help the children with ILD to reach the adulthood
transition in a better condition, and to structure genetic counseling for their family.
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Key words
Pediatric interstitial lung disease, chILD, diagnosis approach, classification, genetics,
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surfactant
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Introduction

Interstitial lung disease (ILD) in children is a heterogeneous group of rare respiratory


disorders of known and unknown etiologies that are mostly chronic and associated with high
morbidity and mortality. ILD are characterized by inflammatory and fibrotic changes of the
lung parenchyma structure that typically result in the presence of diffuse infiltrates on lung
imaging, and abnormal pulmonary function tests with evidence of a restrictive ventilatory

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defect and/or impaired gas exchange [1].

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1. Definition and classification

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2.1 Definition

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The lung interstitium is a support tissue and is composed of 3 parts: the axial interstitium for
the bronchovascular tree, the parenchymal interstitium for the pulmonary parenchyma
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structure, and the peripheral interstitial for the component adjacent to the pleura [2]. Diseases
of the lung interstitium are usually designated as ILD, a term that is not correct as, in most
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situations, the pathological processes do not affect exclusively the support tissues of the
respiratory system. The term of diffuse lung diseases offers a better designation of these
disorders, which can involve the alveolar structure as well as the distal part of the small
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airways and the conducting zone, i.e. the terminal bronchioles. In keeping with the generally
disease designation in clinical practice, the term ILD will be used in the present review, with
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the understanding that it refers to disorders that affect the respiratory function of the lung and
consequently the pulmonary structure responsible of the diffusion of gases between blood and
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air (i.e. the alveolar epithelium, the interstitium, and the pulmonary capillary endothelium)
[3,4].
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2.2 Classification
Many different approaches have been used for the classification of ILD, with major shifts
observed over time based on improvements in clinical investigation tools which include chest
imaging and close collaboration with pathologists. In adult patients, initial descriptions were
histopathological, with proposed 4 distinct subgroups: usual interstitial pneumonia,
desquamative interstitial pneumonia (DIP) and a closely related pattern termed respiratory
bronchiolitis-associated interstitial lung disease, acute interstitial pneumonia (formerly
Hamman-Rich syndrome), and non-specific interstitial pneumonia (NSIP). Progressively, this
historical gold standard has been replaced by a multi-disciplinary approach that has led to
define 7 specific entities and to provide standardized terminology and diagnostic criteria. This
approach resulted in an international multidisciplinary consensus classification of interstitial
pneumonias published in 2002 by the American Thoracic Society (ATS) / European
Respiratory Society (ERS) that was updated in 2013 [5,6]. The strategies developed for adult
ILD classification were similarly used for children ILD (chILD), with initially mainly
histologic descriptions [7]. Progressively, multi-disciplinary classification schemes that

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include patient age and clinical situations were set up, providing the basis for clinico-
radiologic-pathologic diagnosis [8,9]. Patient age is clearly an important issue as the cellular

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and molecular events associated with the ongoing lung growth and maturation processes are
known to interfere with the clinical expression of the pathological disorders [10].

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Consequently, the chILD research cooperative group and the European (EU)-chILD
collaboration network have individualized the ILD more prevalent in children less than 2 yr
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old, and the ILD not specific to children age [8]. ILD observed mainly during infancy include
developmental disorders and growth abnormalities, neuroendocrine cell hyperplasia, and
pulmonary interstitial glycogenesis [11,12]. The other pediatric ILD can be grouped into: ILD
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related to exposure/environment insults, ILD related to systemic diseases processes, ILD


related to primary lung parenchyma dysfunctions [1,13–17].
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2.3 Epidemiology
Estimated prevalence reported in several studies showed large variations that range from 0.1
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to 16.2 cases per 100,000. These numbers are difficult to ascertain and may be under-
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estimated due to the lack of standardized definitions, the differences in the studied patient
populations, and the absence of organized reporting systems. From the limited published data
composed mainly of case reports and small series, it seems that pediatric ILD occur more
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frequently in the younger age and in boys. In addition, nearly 10 % of cases would be familial
[18–20].

The present review summarizes current information on ILD diagnosis in immuno-competent


children, with a focus on genetic causes.

2. Clinical features and initial investigations


3.1 Clinical presentation of chILD
The clinical manifestations are often subtle and non-specific. The onset of symptoms is, in
most cases, insidious and many children may have had symptoms for years before the
diagnosis of ILD is confirmed. The clinical manifestations vary from asymptomatic
presentation with radiological features suggestive of ILD to more characteristic presence of
respiratory symptoms and exacerbations [21]. Common symptoms at presentation include dry
cough, dyspnea, and chest wall retraction, exercise limitation and frequent respiratory
infections. Unexplained fever is also reported, mainly in infants. Failure to thrive, tiring

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during feeding (in young children) and weight loss are common symptoms in young children
[3,8]. A history of wheezing may be observed [22]. The frequent clinical findings are

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tachypnea, inspiratory crackles and retraction. Other findings associated with an advanced
stage of lung disease include finger clubbing and cyanosis during exercise or at rest.

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Thorough physical examination includes the search for respiratory and non-respiratory
manifestations such as joint pain, cutaneous rashes and recurrent fever suggestive of
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underlying systemic diseases.

3.2 Chest imaging


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Chest imaging is an important component of disease diagnosis. Plain radiographs are usually
performed in a child suspected of ILD at first presentation, but the information provided is
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often limited and the key tool for diagnosis is the high resolution computed tomography
(HRCT), which can visualize the parenchymal structure to the level of the secondary
pulmonary lobule. HRCT technique for ILD diagnosis has been extensively discussed. To
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optimise spatial resolution, there is a general agreement to use thin sections, the smallest field
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of view and a sharp resolution algorithm [23]. The most common HRCT feature of ILD is
widespread ground-glass attenuation. Intralobular lines, irregular interlobular septal
thickening and honeycombing are less common findings. Large subpleural air cysts in the
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upper lobes adjacent to areas of ground-glass opacities have been also reported in young
children with ILD. These cysts are interpreted as paraseptal or irregular emphysema. HRCT is
useful for ILD diagnosis but is most of the time insufficient to determine the ILD aetiology.
Consequently, in most situations, diagnosis investigations including molecular studies and
lung tissue analysis are warranted. In this context, HRCT is helpful to guide the selection of
lung area to be biopsied. It is proposed that it also may contribute to monitor disease
progression [24–28]. However, evaluation is still needed to support a role of HRCT as a
follow up tool in pediatric patients. Recently, the use of magnetic resonance imaging in the
follow-up of pediatric ILD is being discussed, and much effort is currently being engaged to
significantly improve image quality [29].

3.3 Lung function


Pulmonary function tests do not provide specific information. It may represent a useful
investigation tool for both the diagnosis and the follow-up of ILD in older children and
adolescents. Generally, in ILD, pulmonary function abnormalities reflect a restrictive
ventilatory defect with reduced lung compliance and decreased lung volumes. Vital capacity

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(VC) is variably diminished; the decrease in total lung capacity (TLC) in general is relatively
less than in VC. Functional residual capacity (FRC) is also reduced but relatively less than

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VC and TLC, and residual volume (RV) is generally preserved; thus, the ratios of FRC/TLC
and RV/TLC are often increased. Airway involvement is observed only in a minority of

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patients. Lung diffusing capacity of carbon monoxide (DLCO) or transfer factor (TLCO) is
often markedly reduced and may be abnormal before any radiological findings. Hypoxemia as
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defined by a reduced resting arterial oxygen saturation (SaO2) or a reduced resting arterial
oxygen tension is often present. Hypercarbia occurs only late in the disease course. During
exercise the above described dysfunctions become even more pronounced. Thus, gas
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exchange during exercise might be a more consistent and sensitive indicator of early disease
[1,8].
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3.3 Other explorations


Bronchoscopy with bronchoalveolar lavage (BAL) allows to assess and sample the airways
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and distal parenchyma. It provides specimen for cytological microbiologic and molecular
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studies; its primary usefulness is to search for infections. It may also orient the diagnosis in
situations of alveolar hemorrhage, alveolar proteinosis, or aspiration with lipid-laden
macrophages [30].
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Lung biopsy and histological investigations are important investigations, in line with
increasing recognition of the different patterns of ILD and their clinical significance.
However, it is critical to take into consideration that they are invasive [31]. Consequently, as
reported by the European consortium for chILD, histological evaluation of lung tissue usually
represents the final step of a series of diagnostic approaches [8]. The methods used to obtain
lung tissue, should balance their invasiveness against the potential for obtaining adequate and
sufficient tissue for diagnosis. The techniques of choice are open lung biopsy and video
assisted thoracoscopy biopsy. The place of other methods such as transbronchial lung biopsy
and percutaneous needle lung biopsy remains to be established in pediatric ILD. Samples
should be fixed for light microscopy (staining, immunohistochemistry), but also prepared in
Glutaraldehyde-buffer for electronic microscopy (EM) and frozen for eventual molecular
genetics analyses [8,32]. The lung histological patterns which can be observed in pediatric
ILD include mainly: DIP, NSIP, and lymphocytic interstitial pneumonia (LIP). DIP is
characterized by airspaces filled with alveolar macrophages, thickened alveolar septa,
scattered mixed inflammatory cells and minimal fibrosis. Many alveolar spaces are lined by
hyperplastic type 2 alveolar epithelial cells (AEC). As example, surfactant disorders have

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reported to be associated with a DIP pattern on light microscopy and to dense lamellar bodies
aspects on EM analysis [33]. NSIP encompasses a broad spectrum of abnormalities with

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varying degrees of alveolar wall inflammation or fibrosis. The cellular pattern of NSIP is
characterized by mild to moderate interstitial chronic inflammation and type 2 AEC

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hyperplasia in inflammation areas. It has been reported in a variety of underlying conditions
including connective tissues diseases and surfactant disorders. LIP features include a marked
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diffuse infiltrate of mature lymphocytes, plasma cells and histiocytes within the pulmonary
interstitium, particularly the alveolar walls. They are often associated with either connective
tissues disorders or immunodeficiency states, both congenital and acquired [7,14]. EM
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analysis can also be of importance in addressing specific diagnoses. As example, glycogen


accumulation within the interstitial cells has been associated with pulmonary interstitial
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glycogenosis [34]. Finally, it is of importance also to consider that, depending on disease


presentation and suspected diagnosis such as sarcoidosis, tissue biopsy may concern more
accessible organs than the lung, such as the skin or the liver.
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Based on the clinical context, other investigations could be proposed at patient presentation.
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They include echocardiography, mainly for estimation of pulmonary artery pressure if


pulmonary hypertension is suspected; blood laboratory tests for evaluation of the immune
function, search for autoantibodies, or other biological parameters dictated by the clinical
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situation.

3. ILD diagnostic approaches

A large number of pathological situations can impair gas exchange and contribute to
progressive lung damage and ILD. Consequently, diagnosis approaches need to be organized
by cause, with a clinical evaluation requiring a careful history paying attention to exposures
and systemic diseases. Indeed, from a number of reports it is noteworthy that lung insults
caused by substances from the environment or in the context of systemic diseases are largely
under-estimated and should be more often considered in the diagnostic process. Importantly,
information on relatives or siblings with similar lung conditions are critical and should be
thoroughly gathered. Accordingly, once the diagnosis of ILD is established on clinical,
radiological, and functional findings, a step-by-step etiological diagnostic approach is
required [1]. Numerous ILD classifications have been reported. In the present review, we
chose to use a clinical approach as diagnostic strategy, with the various pediatric ILD
gathered into 4 groups: ILD related to exposure/environment insults, ILD related to systemic

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diseases processes, ILD related to primary lung parenchyma dysfunctions, and ILD specific to
infancy (Table 1).

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4.1 ILD related to exposure/environment insults

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They refer to diseases caused by a critical dose of exposure to components with the lung,
inducing clinical manifestations and biological impairments. The adult literature has provided
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extensive lists of involved and candidate molecules. In children, less is known about the
potential lung involvement of these molecules. It is important to stress out that pediatric
exposure-related diseases is certainly under-estimated as the diagnosis is less often discussed
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than in adults [35,36]. Indeed, pediatricians and other child health care providers do not
usually have the expertise necessary to retrace an environmental history that has to take into
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account the home environment but also the daycare, playgrounds, hobbies of the pediatric
patient [37].
Hypersensitivity pneumonitis (HP) is a cell-mediated immune reaction to inhaled antigens in
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susceptible persons. The responsible antigens have to be searched first in the home
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environment as well as in relation to certain hobbies. HP are often diagnosed in children at the
chronic stage of the disease resulting of a long-term exposure to low levels of inhaled
antigens. Children can develop inflammatory reactions in the lung without noticeable
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symptoms for months. The classical clinical presentation includes non-productive cough,
dyspnea, malaise, asthenia and occasional cyanosis [38]. The most frequent types of HP
include bird fancier’s diseases, humidifier lung diseases, and chemical lung diseases. Bird
fancier’s diseases, or bird breeder’s disease are induced by exposure to birds antigens mainly
from avian droppings and feathers [39,40]. The disease can occur shortly after the onset of the
exposure, or more often after a chronic exposure. Importantly, a suspicion of HP should be
raised in case of respiratory symptoms in exposed patients who have only one pet bird at
home. Humidifier lung diseases, as well as air conditioner lung, misting fountain lung,
basement lung diseases and hot tube lung are caused mainly by free-living amoeba and
nematodes, as well as bacteria and fungi [41,42]. Chemical lung diseases can be induced by
various inorganic antigens such as inhaled paints, plastics, wax, talcum etc... [43]. In all cases,
once exposure history is suspected, the intervention of an expert environment advisor is
mandated to assess the exposure and environmental measurements and biologic tests are
necessary to make the causal link between the ILD and the exposure. Serum-precipitating IgG
antibodies against the offending antigen will be searched for. However, even if presents, the
clinical relevance of the positivity of these antibodies has to be discussed as it is observed in

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up to 50% of serum samples of exposed but asymptomatic individuals. Overall, no diagnostic
tests are pathognomonic for HP, and only a compatible exposure history and a bundle of

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biological and radiological signs can be predictive for HP. BAL is neither specific of HP but
an alveolitis with a T CD8 lymphocytosis must evoke the diagnosis. Of importance, HP is

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usually highly sensible to corticosteroids, and a quick and positive response to this treatment,
combined with a removal of the causal exposure, can be a supplemental tool for HP diagnosis.
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Medications, radiations and drugs can also cause ILD. Drugs used in inflammatory or cancer
pediatric diseases can cause ILD. They include anti-inflammatory agents (e.g. aspirin,
etanercept), immunosuppressive and chemotherapeutic agents (e.g. azathioprine,
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methotrexate, cyclophosphamide), antibiotics, cardiovascular agents, and, for teenagers, illicit


drugs.
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4.2 ILD related to systemic diseases processes


They include a number of pathological conditions. Connective tissues diseases (CTD) are a
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heterogeneous group of autoimmune and inflammatory disorders that share a common


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pathophysiology targeting the connective tissues of the body. In childhood, the main CTD
disorders involving the lung are rheumatoid arthritis, systemic sclerosis, systemic lupus
erythematosus. The other include Sjögren syndrome, dermatomyositis and polymyositis,
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ankylosing spondylitis, and mixed connective tissue disease [44].


Pulmonary vasculitis affecting small vessels (arterioles, venules, and capillaries) can also be a
cause of ILD. They include the anti-neutrophil cytoplasmic antibody (ANCA)-associated
vasculitis (Wegener’s granulomatosis, Churg-Strauss syndrome, and microscopic
polyangiitis); anti-glomerular basement membrane (GBM) disease; Henoch-Schönlein
purpura and cryoglobulinemia vasculitis [17]. Recently, genetic forms of autoinflammatory
disorders involving the lung were also described [45]. Vasculitis can also be diagnosed in
situations of diffuse alveolar hemorrhage (DAH). DAH syndromes are caused by the
disruption of alveolar-capillary basement membrane as a consequence of injury to the alveolar
septal capillaries, and less commonly to the arterioles and venules. The hallmarks are intra-
alveolar accumulation of red blood cells, fibrin, and hemosiderin-laden macrophages. It is
important to point out that approximately one third of patients with DAH do not manifest
hemoptysis, and BAL can be extremely helpful if this entity is suspected by showing the
presence of siderophages or red blood cells within the alveoli. In children, situations of DAH
in the context of other disorders are reported in several forms of vasculitis discussed above
but also in dysimmune and allergic disorders such as coeliac disease. Vasculitic syndromes

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that affect large/medium vessels (such as Kawasaki’s disease, polyarteritis nodosa) only
occasionally affect the lung.

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Granulomatous disorders are characterized by the presence of granulomas defined as a focal
aggregation of monocellular and giant cells surround by inflammatory cells. Granulomas

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constitute the result of tissue injury that can be triggered by a variety of agents including
micro-organisms, antigens, chemical, drugs and other irritants. In other situations, including
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sarcoidosis, the etiologic factors remain to be determined. Sarcoidosis is the most frequent
cause of granulomatous ILD. It is a chronic inflammatory disease that is supposed to be the
result of a genetic susceptibility, associated with environmental antigens that remain to be
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identified [46]. The current concept is that a still unknown stimulus activates quiescent T cells
and macrophages leading to recruitment and activation of mononuclear cells, with, as a
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consequence, granuloma formation, alveolitis, and in some cases interstitial lung fibrosis. The
granuloma can develop in many organs, mainly the lung. In children, sarcoidosis is rare and
affects mostly black pre-teenagers. The diagnosis is based on a combination of suggestive
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clinical and biological features, with histologically-documented noncaseating granuloma, in


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the absence of other known causes of granuloma formation. The disease is often severe in
children, presenting as a multi-organic disorder with general symptoms at the forefront (fever,
asthenia). Clinical manifestations in sarcoidosis depend on the organ or system involved.
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Clinical findings mainly include respiratory manifestations, lymphadenopathy, skin lesions,


ocular and central nervous system abnormalities. However, pulmonary symptoms can be
absent in almost half of the patients with a thoracic sarcoidosis. The most common
radiographic findings are hilar lymph node enlargements, with or without ILD. Lung function
test can highlight restrictive pulmonary pattern and abnormal diffusing capacity. BAL may
document a lymphocytic alveolitis with increased CD4/CD8 ratio, and elevated serum
angiotensin-converting enzyme may provide additional evidence of sarcoidosis [47].
Other granulomatous diseases in children include infectious diseases and Crohn’s disease.
Several metabolic disorders can be associated with ILD. Among them, Gaucher's disease, an
autosomal recessive disease is the most common lysosomal storage diseases. It is caused by a
genetic deficiency of the gluco-cerebrosidase lysosomal enzyme that catalyses the breakdown
of glucocerebroside, a cell membrane constituent of red and white blood cells. Niemann-Pick
diseases (A, B, C) are rare genetic diseases primarily due to deficiency of sphingomyelinase
resulting in the accumulation of sphingomyelin within lysosomes in the macrophage-
monocyte phagocyte systems of multiple organs, mainly the brain, spleen, liver, lung, and
bone marrow. Histology demonstrates lipid laden macrophages in the marrow, as well as

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"sea-blue histiocytes" on pathology [48]. Hermansky-Pudlak syndrome is a heterogeneous
group of autosomal recessive disorders associated with accumulation of a ceroid-like

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substance in lysosomes of a variety of tissues. It is characterized by albinism, bleeding
tendency associated to poor platelet aggregation, and systemic complications associated to

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lysosomal dysfunction [49].
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4.3 ILD related to primary lung parenchyma dysfunctions
This group share common histopathological description, with preserved pulmonary
architecture, hyperplasia of type 2 AEC, interstitial infiltrates composed of immune-
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/inflammatory cells and scattered myofibroblasts, and the alveolar space filled with either
immuno/inflammatory cells, desquamated materials, or components derived from surfactant
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lipid and protein complex. They include mainly surfactant disorders, DAH, eosinophilic lung
disease, lymphatic disorders and lung infections. Surfactant disorders are reviewed in the next
section.
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DAH can be observed in various clinical situations with or without systemic diseases. In the
absence of systemic findings, isolated pulmonary capillaritis should be discussed with the
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search for positivity of the anti-glomerular basement membrane antibody with linear deposits
in the lung tissue biopsy as well as suggestive serologic features such as p-ANCA antibodies.
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Cow’s milk allergy (Heiner’s syndrome) and diseases induced by environmental factors such
as pesticide should also be evocated. Idiopathic pulmonary hemosiderosis is a diagnosis of
exclusion based on patient presentation with acute, subacute, or recurrent DAH, on the results
of lung biopsy showing evidence of ‘bland’ pulmonary hemorrhage (ie, without capillaritis or
vasculitis), and after exclusion of the conditions listed above. In this situation, red blood cells
leak into the alveolar space without evidence of damage and/or inflammation of the alveolar
capillaries [50].
Eosinophilic lung diseases constitute a diverse group of disorders of various origins. The
diagnosis is suggested by the presence of pulmonary infiltrates on chest imaging and
peripheral eosinophilia. It is confirmed by the presence of increased amounts of eosinophils in
BAL and/or lung tissue eosinophilia. The search for an etiology includes a combination of
clinical and laboratory investigations. Eosinophilic lung diseases of known cause in children
include mainly allergic bronchopulmonary aspergillosis, parasitic infections and drug
reactions. Eosinophilic lung diseases of unknown cause comprise Loeffler syndrome
(characterized by migrating pulmonary opacities), acute eosinophilic pneumonia, and chronic

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eosinophilic pneumonia. The idiopathic hyper-eosinophilic syndrome is a rare disorder; it is
characterized by prolonged eosinophilia and a multiorgan system dysfunction due to

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eosinophil infiltration with pulmonary involvement documented in almost half of the patients
[51].

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Lymphatic disorders can be classified as primary or secondary. Congenital errors of lymphatic
development can lead to primary pulmonary lymphatic disorders that include lymphangiomas
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and lymphangiomatosis, lymphangiectasis, and lymphatic dysplasia syndrome (congenital,
yellow nail syndrome). Secondary forms of lung lymphatic disorders result from a variety of
processes such as chronic airway inflammation that impair lymph drainage and increase
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lymph production [52].


The role of infection, mainly viral, in the development and progression of ILD is sustained by
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a number of human and experimental reports. From recent knowledge, it is strongly suggested
that latent viral infections may be involved in the pathogenesis of ILD, through targeting of
the alveolar epithelium. The main virus implicated include adenovirus, members of herpes
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virus family human (Epstein-Barrr virus and cytomegalovirus), and respiratory syncitial virus.
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Number of other viruses can also be involved such as Influenza A, hepatitis C, or even
Human immunodeficiency virus in immunocompetent children.
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4.4 ILD specific to infancy


Neuroendocrine cell hyperplasia of infancy (NEHI) is a non-lethal disease characterized by a
tachypnea without respiratory failure in very young infants. The human airway epithelium
contains highly specialized pulmonary neuroendocrine cells. These cells are the first
specialized epithelial cells to appear in the lung. Their function remains unknown but is
hypothysed to act as mechano and chemo-sensors and to secrete amines and vasopeptides
such as gastrin-releasing peptide (GRP) or bombesin. As normal bombesin level decreases
after mid-gestation, its overexpression in NEHI could be attributed to a non-regression of
neuroendocrine cells. Some molecular defects have recently been documented [53–55].
Clinical presentation is typically a respiratory distress with tachypnea that usually evolves
spontaneously well [56]. Pseudo-asthmatic presentations have been reported with wheezing
and air-trapping [57]. The lung imaging is characterized by geographic ground-glass
opacifications mainly in the right middle lobe and the lingula. On lung biopsy, the abnormal
histological findings are minor: hyperplasia of neuroendocrine cells within terminal
bronchioles documented by bombesin immunohistochemistry; light thickening of the airway
smooth muscle; aspecific increase of the alveolar macrophages [58,59].

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Pulmonary interstitial glycogenosis (PIG) is also a non-lethal disease of unknown

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pathogenesis, reported in neonates with respiratory distress syndrome developed shortly after
birth. Very few cases have been described so far but it seems to have a male preponderance.

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The histological hallmark of PIG is the accumulation of monoparticulate glycogen in the
mesenchymal cells on lung biopsy. It is thought to represent a developmental cell disorder
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that leads them to accumulate glycogen within their cytoplasm [60]. A histological PIG aspect
can be isolated or associated with other pathological conditions such as meconium inhalation,
other lung growth development anomalies, and cardiovascular diseases [34]. It is discussed
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that PIG could meet “chronic pneumonitis in infancy” as this remains a generalized term.
Diffuse developmental disorders are severe and often lethal conditions [61]. Acinar dysplasia
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and congenital alveolar dysplasia are characterized by an arrested development at the


pseudoglandular or canalicular /saccular stages respectively. Alveolar capillary dysplasia with
misalignment of pulmonary veins (ACD/MPV) associates an aberrant parenchymal
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development of the lung with thickened interstitium, a poor capillary bed, and in most cases,
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the presence of pulmonary veins in the bronchovascular axis instead of at the periphery of the
lobule. The newborns present with refractory hypoxemia and severe pulmonary hypertension.
The diagnosis is usually made on autopsies. Recently, mutations in TBX4 and FGFR2 have
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been associated with syndromic acinar dysplasia [62,63]. The majority of the described cases
of ACD/MPV have been found to be related to FOXF1 mutations or to mutations in the
FOXF1 enhancer. Extra-pulmonary disorders are documented in more than half of the cases:
congenital heart diseases, digestive malformations or malrotations, and genitourinary
malformations [64–66].
Other alveolar growth disorders may be linked to Filamin A defects. Filamin A is a ubiquitous
cytoskeletal protein interacting with actin. Mutations in FLNA have been associated with
dominant syndromic ILD. FLNA is located on the X chromosome and female have been more
described than male [67]. Chest imaging show marked emphysema of the lungs, lobular septal
thickening and diffuse patchy atelectasis [68]. In addition to lung manifestations,
periventricular nodular heterotopias, dental and dermal anomalies, heart diseases and
impaired psychomotor development and cognition are reported.

5. Genetic causes of pediatric ILD

Genetic factors are important contributors to pediatric ILD. Genetic variations have been

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mainly described in genes encoding (or interacting with) the surfactant proteins (SP): SP-C
(SFTPC) and the ATP-binding cassette-family A-member 3 (ABCA3) (ABCA3), and less

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frequently in the genes encoding NKX homoeobox 2 (NKX2)-1, (NKX2-1), SP-B (SFTPB),
SP-A (SFTPA). In situations of pulmonary alveolar proteinosis (PAP), genetic variations in

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genes encoding the methionyl-tRNA synthetase (MARS) (MARS) and the granulocyte-
macrophage colony-stimulating factor (GM-CSF) receptors (CSF2RA and CSF2RB) have
been reported [69].
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5.1 Genetic disorders of SP metabolism
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SFTPC mutations have been associated with various forms of ILD, with heterogeneous
clinical presentations from severe neonatal respiratory distress to children and adult ILD and
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lung fibrosis. SP-C is first produced as a pro-protein and then processed through several
proteolytic steps to a mature peptide of 35 amino acids (4 kDa). The inheritance pattern is
autosomal dominant, with incomplete penetrance and severity. Approximately, half of the
pt

mutations are de novo mutations. To date, more than 40 different mutations have been
reported [70–72]. One missense mutation, the c.218T>C (p.Ile73Thr) is reported in roughly
ce

one third of the cases [73–76].


ABCA3 is a lipidic transporter of the hydrophobic SP-B and SP-C into lamellar bodies.
Ac

Genetic ABCA3 disorders were first reported in a group of full term babies with severe
respiratory diseases occurring shortly after birth and with mostly rapid fatal outcome [77]. It
is now known that bi-allelic mutations can also be diagnosed in older children with ILD, and
in adult with fibrosing ILD. ABCA3 disorders include mainly hereditary deficiencies in an
autosomal recessive inheritance. However, heterozygous ABCA3 mutations have also been
associated with an increased risk of neonatal respiratory distress in late preterm newborns.
The increasing number of mutations documented in a heterozygous state suggests that ABCA3
defects may be the most common causes of inherited surfactant diseases [78]. To date, more
than 200 mutations have been reported in ABCA3, located on chromosome 16, with various
heterogeneous clinical expressions, even in siblings [79–81]. One variant, c.875A>T
(p.Glu292Val), observed in 0.4% of the general population, is found in 4% of a cohort of
infants with respiratory distress [82].

Lung disorder resulting from NKX2-1 dysfunction was first reported in an infant with
neonatal thyroid disease and respiratory failure [83]. It has since been associated with the
“brain-lung-thyroid” syndrome. The inheritance pattern is autosomal dominant, with

t
ip
incomplete penetrance and severity for each of the 3 involved organs, even in a single family
[84]. Approximately half of the mutations are de novo mutations. NKX2-1 is a transcription

cr
factor, located on chromosome 14, that promotes SFTPB, SFTPC and ABCA3 transcription in
the alveolar epithelial cells. To date, over 50 mutations have been described, with no recurrent

us
mutation identified [85].
an
SP-B deficiency was the first surfactant disorder to be described in 1993 in a full-term infant
with progressive and fatal respiratory failure [86]. Since this first report, other cases have
been reported; most of them being fatal despite aggressive treatments and mechanical
M

supports. However, few cases with late survival have also been described. The inheritance
pattern is autosomal recessive. SFTPB, is located on human chromosome 2. SP-B is first
ed

produced as a pro-protein and is then processed through proteolytic cleavages of the NH2 and
COOH termini to a mature peptide of 79 amino acids (8 kDa). Presently, more than 40
different mutations have been reported, with the frameshift mutation 121ins2, resulting in a
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premature termination codon, being found in approximately two thirds of cases [87,88].
ce

SP-A the most abundant SP, is a hydrophilic protein that belongs to the C-type lectin family
(collectines). The human SP-A locus consists of 2 functional genes: SFTPA1 and SFTPA2,
Ac

with a pseudo gene (SFTPA3) in between, on chromosome 10. After processing, SP-A1 and
SP-A2 assemble to a large multimeric octadecameric “bouquet-like” protein structure [89,90].
To date, mutations have been mainly documented in SFTPA2 in adult patients. The phenotype
associates various forms of fibrosing ILD, and adenocarcinoma of the lung [91–93]. Recently,
our group identified a germline mutation in SFTPA1 in a family with various forms of ILD in
an infant, in children and in adults, some of them also presenting with an adenocarcinoma of
the lung. The penetrance was incomplete [94].
5.2 Other genetic disorders
MARS deficiencies were first described in PAP by a whole exome sequencing (WES)
approach. The patients presented mostly severe and early forms of PAP, some of them being
associated with liver and brain involvement [95]. MARS is an ubiquitary enzyme that
catalyzes the ligation of methionine to tRNA. It is encoded by MARS, which is located on
chromosome 12. Less than 10 bi-allelic mutations have been reported in patients, most of
them being originated from La Reunion Island and carrying the same ancestral mutated allele.
To date, the relationship between the MARS mutations and the PAP phenotype is not clearly

t
ip
understood.

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Very rare cases of pediatric PAP have been associated with GM-CSF receptor defects [96,97].
The clinical presentation is heterogeneous, with patients being diagnosed in adulthood. The

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effects of GM-CSF are mediated through heterodimeric cell surface receptors that are
expressed on a number of cell surfaces including macrophages, neutrophils and type 2 AEC.
an
The GM-CSF receptors are composed of α chains encoded by the CSF2RA gene and β chains
encoded by the CSF2RB gene. It is suggested that the GM-CSF receptor defect could be
responsible for a lack of efficiency of the alveolar macrophages in recycling the SP, that
M

accumulate in the alveolar space.


ed

Other genetic disorders include auto-inflammatory diseases linked to defects in genes


encoding the stimulator of interferon, STING, also known as transmembrane protein 173
(TMEM173), and the non-clathrin-coated vesicular coat proteins (COPs), mainly the
pt

Coatomer Protein (COP)-α (COPA) [98]. STING, a stimulator of interferon genes, plays an
ce

important role in innate immunity. It is encoded by TMEM173, located on chromosome 5.


Dominant gain-of-function mutations of TMEM173 have been associated with an up-
regulation of Interferon (IFN) secretion, causing auto-inflammatory and auto-immune
Ac

disorders [99–101]. The diseases, initially described as “STING-associated vasculopathie of


infancy” (SAVI), have also been reported in adult patients [102]. COP-α is a protein involved
in the retrograde transport of the cargo proteins between the golgi and the endoplasmic
reticulum. Mutations in COPA, located on chromosome 1, have recently been described and
are associated with childhood onset of multi-organic disorders including ILD, DAH, but also
kidney, joint, and immunologic disorders [103–105]. For both STING and COPA disorders,
the inheritance pattern is dominant, with an incomplete penetrance of the disease.
6. Expert Commentary

Pediatric ILD comprises a large spectrum of rare respiratory disorders, some of them being
more prevalent in either infants or older children. The age at onset and the disease expression
are highly heterogeneous. Several classifications have been proposed so far based on
histological descriptions and patient presentations. However, none of them appears to be

t
completely satisfactory. As such, surfactant molecular disorders have been recently described

ip
in NEHI patients. The development of molecular diagnosis, especially with the generalization
of next generation sequencing, allows to document genetic disorders in an increasing number

cr
of chILD [106]. In the next years, the classifications will include these novel findings on
underlying molecular mechanisms. Along with a better description of the pathologies, there is

us
an urgent need for more specific treatments and care. To date, the therapeutic managements of
most pediatric ILD remain limited and are mainly based of the use of corticosteroids.
an
However, their efficacy is highly variable, most likely due to the vast heterogeneity of the
diseases. New therapeutical strategies targeting specific molecular mechanisms are in
M
progress. They include the use of tyrosine kinase inhibitor or transforming growth factor
inhibitor in children. In addition, lung transplantation is being developed for pediatric
patients. So far, pediatric lung transplantation has been reported in a limited number of
ed

patients with surfactant disorders (SFTPB, SFTPC, ABCA3), SAVI and COPA syndrome, and
in a few cases of developmental disorders, but it remains an exceptional procedure available
pt

in a small number of countries [107,108].


ce

7. Five-year view

A better understanding of the pathophysiological mechanisms and the natural course of the
Ac

diseases is a crucial issue. The rarity of the diseases makes this goal a challenge that deserves
international clinical and scientific collaborations to gather large longitudinal cohorts of
patients, and to develop ongoing basic research. Recently, a European research group of
clinicians and researchers has been launched by the European Cooperation in Science and
Technology (COST) action (CA-1625) and is currently developing multidisciplinary
approaches on clinical issues and is exploring the various preclinical models of ILD. It will
provide new insights into the molecular / environmental basis of ILD pathogenesis (including
genetic factors causing familial diseases) in children. As such, it is expected that newly
identified molecular defects and markers will help predicting clinical courses and tailoring
individual therapies.

Key issues

• Interstitial lung disease (ILD) is a heterogeneous group of rare respiratory disorders that
include ILD related to exposure/environment insults, ILD related to systemic diseases
processes, ILD related to primary lung parenchyma dysfunctions, and ILD specific to

t
infancy.

ip
• Current chILD classifications remain unsatisfactory, due to the complexity of the
underling mechanisms and the variability of the disease expression.

cr
• ChILD are mostly severe diseases with high morbidity and mortality.

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• Management strategies and therapeutic options remain limited.
• Genetic factors are important contributors to chILD pathogenesis, and it is anticipated that
genetic testing will have an important role in chILD clinical practice in the next years.
an
Surfactant disorders play important roles in the development of various forms of chILD.
In addition to surfactant genes, other disease-causing genes are increasingly implicated in
M
chILD pathogenesis.
• chILD phenotypic expression is highly variable and, currently, no correlations between
disease presentation and molecular defect could be documented.
ed

• International networking is in progress to help deciphering the chILD molecular


mechanisms, predicting disease courses and improving patient management.
pt
ce

Acknowledgements
The authors would like to thank the Assistance Publique Hôpitaux de Paris, Sorbonne
Université, Paris, France, and the national networks for rare lung diseases: Centre de
Ac

référence des maladies respiratoires rares (RespiRare), Centre de référence des maladies
pulmonaires rares (OphaLung) and Filière de soins pour les maladies respiratoires rares
(RespiFIL). The ILD cohort is developed in collaboration with the Rare Cohort Disease
(RaDiCo)-ILD project (ANR-10-COHO-0003), the FP7-305653-child-EU project and the
COST Action European network for translational research in children's and adult interstitial
lung disease (COST-ILD) project (CA16125).

Funding
The authors’ work is supported by grants from the Institut National de la Santé et la
Recherche Médicale (INSERM), the Legs Poix from the Chancellerie des Universités (grants
2013 n°1305, 2014 n°1405, 2015 n°1015, 2016 n°2077 and 2017 n°DP2017/1860), Paris, the
European Union’s Seventh Framework Program (FP7-ChILD-EU 2007-2013) under grant
agreement n°305653, as well as funding from the patient organizations Respirer c’est Grandir
and Belleherbe Association.

Declaration of Interest

t
ip
The authors have no other relevant affiliations or financial involvement with any organization
or entity with a financial interest in or financial conflict with the subject matter or materials

cr
discussed in the manuscript apart from those disclosed.
Reviewers Disclosure

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Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.
an
Abbreviations
M
ABCA3 ATP-Binding Cassette-Family A-Member 3
ACD/MPV Alveolar Capillary Dysplasia/Misalignment of Pulmonary Veins
ed

AEC Alveolar Epithelial Cells


ANCA Anti-Neutrophil Cytoplasmic Antibody
ATS American Thoracic Society
pt

BAL Broncho Alveolar Lavage


chILD Children ILD
ce

COP Coatomer Protein


COST Cooperation in Science and Technology
Ac

CTD Connective Tissues Diseases


DAH Diffuse Alveolar Hemorrhage
DIP Desquamative Interstitial Pneumonia
DLCO Lung Diffusing Capacity of Carbon monoxide
EM Electronic Microscopy
ERS European Respiratory Society
EU European Union
FRC Functional Residual Capacity
GBM Glomerular Basement Membrane
GMCSF Granulocyte-Macrophage Colony-Stimulating Factor
GRP Gastrin-Releasing Peptide
HP Hypersensitivity Pneumonitis
HRCT High Resolution Computed Tomography
IFN Interferon
ILD Interstitial Lung Disease
LIP Lymphocytic Interstitial Pneumonia

t
ip
MARS Methionyl-t-rna Synthetase
NEHI NeuroEndocrine cell Hyperplasia of Infancy

cr
NKX2 NK2 Homeobox
NSIP Non-Specific Interstitial Pneumonia

us
PIG Pulmonary Interstitial Glycogenosis
RV Residual Volume
an
SaO2 Arterial Oxygen Saturation
SAVI STING-Associated Vasculopathie of Infancy
SP Surfactant Protein
M

STING Stimulator of Interferon Genes


TLC Total Lung Capacity
ed

TLCO Transfer Factor


VC Vital Capacity
WES Whole Exome Sequencing
pt
ce

Reference annotations

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Ac

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Table 1: Diagnosis approaches of pediatric ILD
ILD related to ILD related to systemic ILD related to lung ILD specific to infancy
exposure/environment diseases processes primary parenchyma
insults dysfunctions
Hypersensitivity Connective tissue Surfactant disorders Neuroendocrine cell
pneumonitis diseases hyperplasia of infancy
Medication, Drugs Vasculitis Diffuse alveolar Pulmonary interstitial
Radiation exposure hemorrhages glycogenosis
Granulomatous Eosinophilic lung Diffuse developmental

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disorders diseases disorders

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Metabolic disorders Lymphatic disorders

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Viral infections

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