Pediatric Pulmonology 50:1383–1392 (2015)

Childhood Interstitial Lung Disease: A Systematic Review

Neil J Hime, PhD,1,2 Yvonne Zurynski, PhD,1,2 Dominic Fitzgerald, PhD,3,4 Hiran Selvadurai, PhD,3,4
Amy Phu, MScMed (ClinEpid),1,2 Marie Deverell, PhD,1,2 Elizabeth J Elliott, MD,1,2,5 and Adam Jaffe, MD6,7
Summary. Objectives: Childhood interstitial lung disease (chILD) is a group of rare chronic and
complex disorders of variable pathology. There has been no systematic review of published
chILD research. This study aimed to describe chILD classification systems, epidemiology,
morbidity, treatments, outcomes, and the impact of chILD on families and the burden on health
services. Methods: A systematic literature search for original studies on chILD was undertaken
in the major biomedical databases to the end of December 2013. Epidemiological studies, case
series and studies describing classification systems were included. Single case studies were
excluded. Results: The search yielded 37 publications that met study criteria. Four different
chILD classification systems have been proposed in the past decade. The incidence of chILD
has been estimated at 0.13–16.2 cases/100,000 children/year. One to five new cases presented
to individual hospitals each year. In developed countries, the median mortality was 13%
(6–19%). Morbidity and outcomes were highly variable and not systematically reported.
Corticosteroids and hydroxychloroquine were the most common treatments. The impact of
chILD on families and the burden on health services has not been studied. Conclusions: The
heterogeneity of the chILD group of disorders, different determinations of what constitutes a
chILD disorder and, a paucity of large epidemiological studies precludes consolidation of results
across studies. Consensus on chILD classification is needed to support diagnosis and allow
direct comparisons of research evidence. Active disease surveillance and international patient
registries are required to advance understanding and management of chILD. Pediatr Pulmonol.
2015;50:1383–1392. ß 2015 Wiley Periodicals, Inc.

Key words: Childhood interstitial lung disease; chILD syndrome; Interstitial lung
disease; Diffuse lung disease.

Funding source: Australian Government Department of Health, Chronic Disease

Prevention and Service Improvement Fund., National Health and Medical Research
Council of Australia (Number 1021480).

INTRODUCTION
Childhood interstitial lung disease (chILD) describes a as well as immunological problems. These disorders have
heterogeneous group of rare chronic respiratory disorders variable lung pathology associated with poor gas
in children, particularly in infants under 2 years of age, exchange.1–4 chILD is clinically complex and associated
which includes growth and developmental abnormalities with high morbidity and mortality.4,5 The typical features

1 7
Discipline of Paediatrics and Child Health, Sydney Medical School, The Discipline of Paediatrics, School of Women’s and Children’s Health,
University of Sydney, Sydney, Australia. UNSW Medicine, The University of New South Wales, Sydney, Australia.
2
Australian Paediatric Surveillance Unit, Kids Research Institute, West- Conflict of interest: None
mead NSW 2145, Australia.


Correspondence to: Professor Adam Jaffe, School of Women’s and
3
Department of Respiratory Medicine, The Children’s Hospital at West- Children’s Health, Medicine UNSW, University of New South Wales, c/o
mead, Westmead NSW 2145, Australia. Sydney Children’s Hospital, High Street, Randwick, New South Wales
2031, Australia E: adam.jaffe@unsw.edu.au
4
Discipline of Paediatrics and Child Health, Sydney Medical School, The
University of Sydney Clinical School, Sydney, Australia. Received 30 June 2014; Revised 23 December 2014; Accepted 15 January
2015.
5
The Children’s Hospital at Westmead, Sydney, Australia.
DOI 10.1002/ppul.23183
6
Department of Respiratory Medicine, Sydney Children’s Hospital, Published online 30 April 2015 in Wiley Online Library
Randwick NSW 2031, Australia. (wileyonlinelibrary.com).

ß 2015 Wiley Periodicals, Inc.

1384 Hime et al.

of chILD are breathlessness and hypoxemia in the examined the full texts of potentially relevant studies and
presence of diffuse lung infiltrates on radiography or studies that fit the inclusion/exclusion criteria were
computed tomography. The term “diffuse lung disease” included for review. To identify additional studies for
has often been used interchangeably, because the inclusion, NH and AP screened the reference lists of
interstitial compartment is not always involved.1,2 review articles and relevant studies. Only articles in
Recently, the term “chILD syndrome” has been adopted English were retrieved.
by the American Thoracic Society Committee on chILD
and the chILD Research Network in order to provide a set Study Inclusion Criteria
of criteria to aid the diagnosis of uncommon causes of
Studies reporting original data in children aged 0–18
diffuse lung disease phenotypes in infants.1
years, on the following aspects of chILD were included:
chILD differs from ILD in adults in that it is much rarer
classification systems, frequency (population prevalence/
and, includes pathologies that are unique to infants and
incidence or hospital-based case series), symptoms,
young children (e.g., pulmonary interstitial glycogenosis
morbidities, treatments, outcomes, impacts on families,
(PIG),6 neuroendocrine cell hyperplasia of infancy
burdens on health services. Because chILD encompasses a
(NEHI)7, and chronic pneumonitis of infancy,8 and
heterogeneous group of disorders, this review is not limited
genetic abnormalities that cause ILD in childhood (e.g.,
to studies that included all chILD disorders but also
surfactant protein deficiencies9). Conversely, common
includes studies that investigated specific chILD disorders.
adult ILD such as usual interstitial pneumonia (UIP) is
While we have used the currently accepted terminology
rarely described in children.
of “chILD” in this systematic review, many of the
Because individual disorders within the chILD group
epidemiological, and case series studies included for
are extremely rare, this hinders research into this
review were conducted prior to the development of the
important area.10 Given the chronicity and high morbidity
recent proposed classification schemes.
of chILD, the impact on families and burden on health
services are likely to be significant.
In this systematic literature review we aim to describe: Study Exclusion Criteria
Case studies reporting single patients or family groups
 classification systems that have been applied to chILD were excluded. Studies involving adults (over 18 years of
 the frequency of chILD in populations and the age) were excluded unless they reported sub-analyses of
frequency of incident cases in hospitals children. Studies reporting diagnostic evaluation without
 the morbidity, treatment, and outcomes of chILD reporting on morbidity, treatment or outcome were
 the impact of chILD on families and the burden on excluded. Studies with insufficient detail to determine
health services how and in whom the research was conducted were
excluded. Also excluded from this review were common
causes of diffuse lung disease that are not encompassed
METHODS within “chILD syndrome”. As stated in the current clinical
Identification of Relevant Studies practice guidelines, these common causes include: cystic
fibrosis, congenital, or acquired immunodeficiency, con-
The following databases were searched: Medline genital heart disease, bronchopulmonary dysplasia, pulmo-
(1946–2013), Embase (1966–2013), Evidence-Based nary infection, primary ciliary dyskinesia presenting with
Medicine (EBM) Reviews—Cochrane Database of newborn respiratory distress, and recurrent aspiration.1
Systematic Reviews (2005–2013), EBM Reviews—
Cochrane Central Register of Controlled Trials (1991– Data Extraction
2013), Informit—Australasian Medical Index (1968–
2009), Informit—Health Collection (1977–2013), and NH and AP extracted data. Where possible, units of
clinicaltrials.gov (2000–2013). frequency were adjusted to facilitate comparisons
The following Medical Subject Headings (MeSH) were between studies.
used in search strategies: lung diseases, interstitial;
incidence; prevalence; public health; economics, medi- RESULTS
cal; cost-benefit analysis; health services; health care
Literature search
rationing; health care costs. Forty text words (supple-
mentary material, S1) were applied to searches indepen- A total of 37 studies of chILD disorders were included
dent of MeSH terms. The methodological filters “all child (Fig. 1).
(0–18 years)” and “humans” were applied to all searches
in Medline. NH and AP identified potentially relevant  4 presented classification systems for chILD
studies through screening of titles and abstracts. NH  4 estimated population prevalence or incidence
Pediatric Pulmonology
 Childhood Interstitial Lung Disease 1385

included a group of disorders with onset of disease in

infancy. Chronic aspiration syndromes, resolving acute
respiratory distress syndrome and bronchopulmonary
dysplasia were excluded. In the most recent chILD
classification system, proposed by the American Thoracic
Society Committee on chILD and the chILD Research
Network, the term “chILD syndrome” was used to
exclude common causes of diffuse lung disease such as
cystic fibrosis, congenital heart disease, bronchopulmo-
nary dysplasia, and pulmonary infection; it recognised
that some chILD conditions may be asymptomatic when
identified.1 It was acknowledged that many of the diffuse
lung diseases (proposed by Deutsch et al.2) may present as
chILD syndrome.

Frequency of chILD in Populations and Hospitals

Three studies12–14 reported estimates of the frequency
of chILD in populations (Table 2). Each study used
different methods of case ascertainment and case
definitions. Incidence estimates varied from 0.13 cases/
100,000 children <17 years of age/year in Germany12 to
Fig. 1. Results of literature search strategy. 10.8–16.2 cases/100,000 children <15 years of age/year
in Denmark.13 Griese et al.12 conducted active surveil-
lance in pediatric hospitals whereas Kornum et al.13
ascertained cases from a review of International Statisti-
 5 reported hospital-based incident cases of chILD cal Classification of Diseases (ICD) codes applied to
within a specific time period hospital inpatients and outpatients. Dinwiddie et al.14
 33 described morbidities, treatments, and/or outcomes conducted active surveillance of idiopathic ILD in the
United Kingdom and Ireland with reporting by respiratory
Some studies reported data applicable to more than one pediatricians over a three-year period. The prevalence rate
of the categories above. We found no studies that reported (includes prevalent and incident cases) was 0.36 cases per
impacts on families or burdens on health services. 100,000 children <17 years of age.
The prevalence of an individual chILD disorder,
Classification Systems Applied to chILD hypersensitivity pneumonitis, was estimated at 0.4
Four studies published between 2004 and 2013 cases/100,000 children <16 years of age (Table 2).15
describe classification systems for chILD (Table 1). There Five hospital-based studies of chILD10,16–19 indicate
are inconsistencies in the definitions of chILD, each that between 1.3 and 5.2 new cases of chILD present to
classification system included different disorders. pediatric or referral hospitals each year (Table 3).
Based on 185 cases of ILD in immunocompetent
children in the 0–18 year age group, the European Morbidity, Treatment, and Outcomes Associated
Respiratory Society Taskforce11 defined sub-groups With chILD
according to aetiology and histopathology, modifying a Thirty three studies2,8,10,11,14,15,16–42 reported morbidi-
classification of interstitial pneumonias in adults. Deutsch ty, treatment and/or outcomes associated with chILD
et al.2 classified 187 cases of diffuse lung disease using (Supplementary material, S2). Thirteen studies described
clinical data, imaging, and lung biopsy in children aged chILD disorders as a group and 20 studies described
less than two years. They defined “diffuse lung disease” specific chILD disorders.
and included a broad range of diseases, some of which Descriptions of clinical features were generally limited
primarily affect distal airways outside of the interstitium. to presenting symptoms and signs, most commonly
The classification had an emphasis on pathological dyspnoea, tachypnoea, hypoxemia, cyanosis, digital
findings and, disorders considered more prevalent in clubbing, and failure to thrive.10,11,17,18,22 Severe respira-
infancy were distinguished from other diffuse lung tory deficit that limited physical activity was reported20
diseases. In 2010 Clement et al.5 proposed a step-wise and recurrent respiratory infections were a component of
approach to diagnosis of chILD in which specific the morbidity profile of chILD (14.5% of cases21). chILD
disorders were grouped by aetiology. This classification also occurred as a co-morbidity associated with other
Pediatric Pulmonology
1386 Hime et al.
TABLE 1— Classification Systems Applied to chILD (or Diffuse Lung Disease)

Study Basis of classification Definition Major classification categories

Clement, Aetiology and histopathology Chronic ILD in children – “the presence of  diffuse parenchymal lung disease of known
200411 respiratory symptoms and/or diffuse infiltrates association
on chest radiograph, abnormal pulmonary  idiopathic interstitial pneumonias
function test with evidence of restrictive  other forms of interstitial pneumonia
ventilatory defect and/or impaired gas  congenital disorders
exchange, and persistence of any of these
findings for >3 months.”
Deutsch, Pathology with an emphasis Diffuse lung disease – “a heterogeneous group  diffuse developmental disorders
20072 on disorders more of uncommon disorders characterized by  growth abnormalities reflecting deficient
prevalent in infancy impaired gas exchange and diffuse infiltrates alveolarization
by imaging.”  specific conditions of undefined aetiology
 surfactant dysfunction disorders
 disorders related to systemic disease processes
 disorders of the normal host
 disorders of the immunocompromised host
 disorders masquerading as ILD
Clement, Aetiology and ILD specific chILD – “a heterogeneous group of respiratory  exposure-related ILD
20105 to infancy disorders that are mostly chronic and  systemic disease-associated ILD
associated with high morbidity and mortality.  alveolar structure disorder-associated ILD
These disorders are characterized by  ILD specific to infancy
inflammatory and fibrotic changes that affect
alveolar walls. Typical features include diffuse
infiltrates on chest radiograph, abnormal
pulmonary function tests with evidence of a
restrictive ventilatory defect (in older
children) and/or impaired gas exchange.”
Kurland, As described by Deutsch chILD syndrome – diffuse lung disease in Categories described by Deutsch et al.2 for
20131 et al. but excluding children <2y of age with common causes of paediatric diffuse lung disease were presented,
common causes of diffuse diffuse lung disease excluded as the primary many of these entities are included in chILD
lung disease diagnosis and the presence of at least three of: syndrome. CT, computed tomography
 respiratory symptoms
 respiratory signs
 hypoxemia
 diffuse abnormalities on chest X-ray or
CT scan

CT, computed tomography.

diseases (53% of cases12, 29% of cases21). chILD centres rather than on the type of chILD.11 In 38 cases of
disorders have a wide range of severities. At the most diffuse lung disease in Germany, hydroxychloroquine was
severe, respiratory distress soon after birth is associated used twice - in one of two cases of surfactant protein C
with surfactant protein B deficiency,29 ABCA3 muta- deficiency, with a good response and, in one of four cases
tions27–29 and thyroid transcription factor-1 (TTF-1) of ABCA3 mutations, with no response.12 Other, less
mutations.30–32 Respiratory failure occurred in all cases commonly used, medications were azithromycin,26,28
of surfactant protein B deficiency.29 Respiratory distress azathioprine,15 cyclophosphamide,34 and colchicine.34
was observed in 100%30 and 76%31 of cases of TTF-1 Oxygen therapy was used in 28–88% of
mutations with lung disease, 44% of cases of chronic cases.10,11,12,14,16,18 Lung transplantation was rare, and
pneumonitis of infancy8 and, 18%26 and 29%29 of cases of occurred in cases of surfactant protein B deficiency,24,25,42
surfactant protein C deficiency. surfactant protein C deficiency,42 ABCA3 mutations,42
Corticosteroids were used to treat 59-96% of cases of TTF-1 mutation,30 chronic pneumonitis of infancy,8 and
chILD.10,11,12,14,16,18 Hydroxychloroquine was used in 5- idiopathic pulmonary fibrosis.34,42 Among 187 children
50% of cases.11,12,14,18 Study reports were not sufficiently aged less than 2 years with diffuse lung disease only 2%
detailed to enable an analysis of which treatments were had a lung transplant.2
used in specific chILD disorders, however in a review of For chILD disorders overall mortality ranged from 6%
case management in pediatric respiratory departments to 30% (Table 4). The study with the highest reported
across Europe, the preferred use of either steroids or mortality2 was comprised of a patient group from the
hydroxychloroquine was more dependent on the various USA and Canada with onset of diffuse lung disease at less
Pediatric Pulmonology
 Childhood Interstitial Lung Disease 1387
TABLE 2— Frequency of Child and Specific chILD Disorders in Populations

Number Prevalence or
Study Population Condition and case criteria Method of cases incidence estimatea
chILD group of disorders
Dinwiddie, <17y of age, chILD: lung biopsy-confirmed Active surveillance of paediatric 46 0.36 cases/100,000
200214 United chILD of unknown cause, active pulmonologists (questionnaires childrenb
Kingdom cases (not new) in clinical distributed every 3–6 months)
and practice
Ireland,
1995–1998
Kornum, <15y of age, ILD with sub-analysis of chILD: Review of Danish National Registry 1424 10.8 cases/100,000
200813 Denmark, first-time hospital discharge or of Patients children/year
1995–2005 hospital outpatient clinic visit (1995–2000)
given an ICD code applicable to 16.2 cases/100,000
ILD children/year
(2001–2005)
Griese, <17y of age, chILD: (neonates) gestation >36 Active surveillance of paediatric 38 0.13 cases/100,000
200912 Germany, weeks, respiratory distress >6 hospitals via the German children/year
2005–2006 weeks duration, disease newly Surveillance Unit for Rare
diagnosed by bronchoalveolar Paediatric Disorders
lavage, lung biopsy or genetic (questionnaires distributed
test (children) newly diagnosed monthly)
disease >6 weeks duration
Specific chILD disorders
Buchvald, <16y of age, Hypersensitivity pneumonitis: Review of ICD codes of the 19 0.4 cases/100,000 children
201115 Denmark, lung biopsy-confirmed cases Discharge Register of
1998–2009 Copenhagen University Hospital
and cross reference of identified
cases with Department of
Pathology records

ICD, International Statistical Classification of Diseases.

a
The units of population frequency have been adjusted from those originally reported so as to present consistent units across studies.
b
Reported as a prevalence rate, which includes both prevalent and incident cases over a three-year period.

than 2 years of age and a mean age at follow-up of 2.6 patients aged less than two years, reported mortality rates
years. Other studies from developed countries that of 33%22 and 75%.17 For studies conducted in developed
reported mortality included patient groups with variable countries with cohorts spanning childhood and adoles-
periods of follow-up, extending to 17 or 18 years of age. cence, mortality ranged from 6% to 19% (median, 13%).
Two studies from India (excluded from Table 4), with Among these studies the longest follow-up periods were

TABLE 3— Frequency of Presentation of Incident Cases of chILD to Hospital

Number of cases/
Study Patient group Case ascertainment hospital/yeara
Fan, 199710 <18y of age, three referral hospitals (one Cough, tachypnoea, rales, exercise intolerance or 2.2
paediatric), USA, 1980–1994 hypoxemia for at least one month and diffuse
infiltrates on chest imaging
Coren, 199916 <18y of age, a single paediatric hospital, Severe and progressive respiratory distress and diffuse 3.4
United Kingdom, 1991–1998 infiltrates on chest imaging
Vijayasekaran children (age unspecified), a single Progressive cough, dyspnoea and chest imaging 4.0
200617 paediatric hospital, India, 2000–2004 abnormalities suggestive of chILD
Paiva, 200718 <18y of age, a single paediatric hospital, Presence of dyspnoea, crackles or diffuse 1.3
Brazil, 1984–2004 interstitial infiltrates on imaging for at least one
month
Soares, 201319 <18y of age, a single paediatric hospital, Review of clinical data, chest imaging, lung biopsy and/ 5.2
USA, 1994–2011 or genetic test (criteria for inclusion not specified)
and application of results to a classification system
for diffuse lung disease in infants2
a
The number of cases per hospital per year were calculated by us. The total numbers of all children presenting to hospital per annum were not
reported in these studies.

Pediatric Pulmonology
1388 Hime et al.
TABLE 4— Childhood mortality associated with chILD and specific chILD disorders

Case number and age

Condition Mortality (%) at onset of symptomsa Studyb
chILD group of disorders
chILD 6 n ¼ 185 <18 years Clement, 200411
chILD 8 n ¼ 25 <18 years Paiva, 200718
Diffuse lung disease 11 n ¼ 93 <18 years Soares, 201319
Diffuse lung disease 13 n ¼ 38 <17 years Griese, 200912
chILD 15 n ¼ 99 <18 years Fan, 199710
chILD (idiopathic) 15 n ¼ 46 <17 years Dinwiddie, 200214
chILD 19 n ¼ 27 <18 years Coren, 199916
Diffuse lung disease 30 n ¼ 187 <2 years Deutsch, 20072
Specific chILD disorders
SP-B deficiency 100 n¼7 <2 months Nathan, 201223
100 n¼6 at birth Turcu, 201329

SP-B deficiency (with lung transplant) 33 n¼3 <2 months Hamvas, 199724
58 n ¼ 12 <9 months Palomar, 200625
SP-C deficiency 0 n ¼ 22 <3 years Thouvenin, 201026
9 n ¼ 22 <9 years Nathan, 201223
14 n¼7 <3 years Turcu, 201329
ABCA3 mutations 42 n ¼ 12 <1 year Turcu, 201329
50 n ¼ 10 <1 year Flamein, 201228
88 n ¼ 16 <1 year Shulenin, 200427
100 n¼6 <2 years Deutsch, 20072
TTF-1 mutations 16 n ¼ 25c <1 year Carre, 200931
25 n ¼ 20 at birth Hamvas, 201330
50 n¼2 <2 months Nathan, 201223
50 n¼2 at birth Guillot, 201032
NEHI 0 n¼9 1–14 months Lukkarinen, 201333
Idiopathic pulmonary fibrosis 0 n ¼ 11 <2 years Hacking, 200035
90 n ¼ 10 <1 year Osika, 199734
Fibrosing alveolitis 0 n ¼ 14 3–16 years Steinkamp, 199036
Fibrosing alveolitis with desquamative 16 n ¼ 25 <12 years Sharief, 199437
interstitial pneumonitis
Desquamative interstitial pneumonitis 30 n¼7 <1 year Avital, 199440
39 n ¼ 28 <17 years Stillwell, 198038
Chronic interstitial pneumonitis 0 n¼3 <1 year Kerem, 199039
Chronic pneumonitis of infancy 22 n¼9 <1 year Katzenstein, 19958
a
Where age of onset of symptoms were not reported a conservative age of onset is given based on the age of the patient group.
b
Two studies17,22 from undeveloped countries have been excluded.
c
Patients with lung disease. In this study some patients had thyroid and/or neurological phenotypes without lung involvement and these have not
been included.
SP, surfactant protein; ABCA3, ATP-binding cassette sub-family A member 3 protein; TTF-1, thyroid transcription factor-1 protein; NEHI,
neuroendocrine cell hyperplasia of infancy.

510 and 6 years.19 For specific chILD disorders, mortality while others were weaned from oxygen and became
was highest for surfactant protein B deficiency (100% asymptomatic.26 In some children, fibrosing alveolitis with
without a lung transplant)23,29 and ABCA3 mutations (42– desquamative interstitial pneumonitis was non-responsive
100%). 2,27–29 Mortality was also associated with to treatment and fatal while other patients recovered with
surfactant protein C deficiency,23,29 TTF-1 muta- no requirement for ongoing treatment.37
tions,23,30–32 idiopathic pulmonary fibrosis,34 desquama-
tive interstitial pneumonitis,37,38,40 and chronic
Impact of chILD on Families and Burden on Health
pneumonitis of infancy8 Mean duration of follow-up
Services
after diagnosis ranged from 1 to 9.8 years.
Outcomes varied considerably, even among individuals We identified no studies examining the impact of chILD
diagnosed with the same chILD disorder. For example, on families or the burden on health services. We have
surfactant protein C deficiency was fatal in some patients29 recently reported on health service use associated with a
Pediatric Pulmonology
 Childhood Interstitial Lung Disease 1389

single case of surfactant protein C deficiency, demonstrat- our inclusion criteria) than we expected. This is because
ing the significant burden of chILD on health services.43 studies of cases of newly identified chILD disorders have
generally been concerned with diagnostic evaluation44,45
DISCUSSION and symptomatology and did not provide sufficient detail
on morbidities, treatments, or outcomes to meet the
In this systematic review of the literature on chILD we inclusion criteria for this systematic review of the
have identified significant gaps in research knowledge in literature. For example, we only identified a single study
the field. Because chILD is rare there have been few that provided outcome data on multiple cases of NEHI.33
studies of large patient groups and these studies have used A limitation of the search criteria used in this systematic
different case inclusion/exclusion criteria. The different review is that some studies that included mortality data
methods used in the studies included in this review along may not have fulfilled our study inclusion criteria. Other
with the heterogeneity of the chILD group of disorders published studies that would have met our inclusion
mean that results are not directly comparable between criteria have been published since December 3013.46–48
studies. Notwithstanding these difficulties, this systematic The diversity of outcomes associated with chILD
review indicates that: reflects the wide range of aetiologies and clinical
presentations. chILD is commonly associated with severe
 chILD is associated with high morbidity and mortality
respiratory deficit that limits physical activity, may
but there is wide variability between and within chILD
impede physical growth, and necessitates respiratory
disorders
support, usually oxygen supplementation. It is possible
 no specific treatment is effective for all cases of chILD
that the morbidity in this review is skewed towards more
 the impact of chILD on families and the burden on
severe cases because mild cases are less likely to be
health services has not been evaluated
identified in hospital record reviews. In some studies only
 there is a need to establish surveillance, registries and
children who had a lung biopsy were included, implying a
randomised controlled trials to provide an evidence
sample skewed towards severe disease. Not all cases of
base to inform prognosis, resource requirements, and
chILD require lung biopsy for diagnosis. For example,
treatments.
NEHI can be diagnosed from chest computed tomography
The few studies that estimated the incidence or and pulmonary function test findings consistent with air
prevalence of chILD used different methods to identify trapping and obstruction, without the need for a lung
cases, different inclusion criteria and different popula- biopsy.49,50 Furthermore, genetic diagnosis has helped
tions. The understanding of which disorders constitute the avoid the need for lung biopsy in children with inherited
chILD group has changed since the publication of the surfactant disorders. Prospective, cohort studies including
population-based studies. Therefore, the true frequency of well phenotyped groups would give a more accurate
chILD in the population is unknown. The highest reported picture of the morbidity associated with chILD.
incidence of chILD in the general population, 10.8–16.2 At 13%, childhood mortality associated with chILD is
cases/100,000 children/year was estimated from cases high, but varies considerably both between and within
ascertained from ICD codes assigned at diagnosis.13 This chILD disorders. Age of disease onset may contribute to
is likely to be a significant overestimate as some ICD outcome, worse outcomes being associated with earlier
codes included in that study were not specific to chILD onset of disease.2 Among inherited surfactant disorders
and clinical investigations beyond “first-time diagnosis” the type of mutation will influence outcome. In 2014, a
would have resulted in some alternative diagnoses. review of 185 cases of chILD or neonatal respiratory
Hospital-based studies show that pediatric hospitals failure associated with homozygous or compound
encounter very few cases of chILD each year. Although heterozygous ABCA3 mutations was published.51 That
chILD registries exist in the USA, Europe and Australia study found that by 1 year of age all children (n ¼ 45) with
they are not currently relational, which potentially hinders two ABCA3 mutations likely to result in non-functional
epidemiological research. proteins (“null” mutations) had died or undergone lung
This systematic review includes studies that reported transplantation compared with 62% of children with non-
on the morbidities, treatments and/or outcomes associated null ABCA3 mutations that did not reliably predict
with multiple cases of chILD. These studies were prognosis. chILD inherited surfactant disorders are
conducted over a period of several decades, during which associated with high morbidity and mortality but for
time the classification scheme for chILD was evolving most of these disorders there is considerable heterogene-
and some chILD disorders were identified (e.g., NEHI). ity in the severity of disease.
As such, we have included studies that have used older Among studies in our review that reported outcomes,
pathologic terms (e.g., fibrosing alveolitis). Our system- the duration of follow-up varied or was not reported,
atic literature search uncovered fewer studies related to restricting comparisons between studies. Furthermore, no
the more newly identified chILD disorders (that also met study has reported outcomes beyond 6 years follow-up. In
Pediatric Pulmonology
1390 Hime et al.

many studies11,12,14,16,20 definitions of outcomes were on families. This remains to be demonstrated through
limited to imprecise descriptions such as “improved” or rigorous study.
“stable” making them difficult to interpret. The classification and nomenclature of chILD has
Since each individual chILD disorder is rare, and rapidly evolved over recent years as underlying genetic
therefore rarely encountered by pediatricians, diagnosis causes and new diseases such as NEHI7 have been
may be difficult. Diagnostic delay may have a negative identified. The changes in nomenclature and classification
impact on outcome, especially in chILD disorders that causes confusion amongst clinicians who rarely encoun-
progress rapidly, atlhough we did not find evidence for ter these conditions.61
this. Only two studies12,23 reported the time taken to Recent American Thoracic Society clinical practice
determine a diagnosis but neither study analysed the guidelines for chILD1 highlight that the term “interstitial”
association between time to diagnosis and outcome. is confusing in children who present with the clinical
The evidence base for chILD treatments is limited features of chILD but with the histopathological process
because the disorders are so rare and there have been no occurring outside the intersititium. The guidelines
clinical trials. The general principle of treatment is that proposed that the term “diffuse lung disease” encompass
minimising inflammation may prevent progression to specific chILD diagnoses, as a subset of “chILD
fibrosis.53 Corticosteroids and hydroxychloroquine are syndrome”. chILD syndrome includes cases that remain
widely used in the treatment of chILD, not always with unclassified. Classification is also hampered by the use of
success. Both have anti-inflammatory properties but similar terms for different entities such as infantile
they also may have other effects, for example hydroxy- cellular interstitial pneumonitis and chronic pneumonitis
chloroquine may inhibit the intracellular processing of of infancy.2
the precursor protein of surfactant protein C.54 As These changes in classification schemes are also a
chILD disorders are generally incurable, supportive care potential limitation of our systematic review as some
(nutritional supplementation, influenza vaccination, relevant papers may not have been included due to
oxygen supplementation) is important.55 chILD disor- different diagnostic labels being used inconsistently.
ders have a diverse range of aetiologies and pulmonary Furthermore, some of the studies in our review have
pathologies, thus a common treatment strategy is included diseases that do not fit into the current
unlikely to be effective for all chILD disorders. Current classification for chILD.
treatments are not based on rigorous scientific evidence Despite their limitations, the current chILD classifica-
but on the experience of individual health professionals tion systems serve the important function of distinguish-
and the preferences of individual centres. There is an ing these disorders from ILD more commonly seen in
impetus to standardise treatment, follow-up, and adulthood. It is likely that the classification of chILD will
collection of biological samples in observational studies continue to evolve over the next few years and systematic
with a view to providing evidence to support the first terminology will be an important step forward. The
randomised controlled trial of treatment for chILD.56 It inadequacy of ICD codes for the classification of rare
is hoped that the establishment of the United States diseases such as chILD is also an impediment to research.
chILD Research Network (ChILDRN)56 and a recent There are initiatives by Orphanet to assign specific codes
s3.0 million European FP7 grant58 will help to achieve (Orpha Codes) to individual rare disorders.62 These would
that aim. complement ICD codes and, if adopted by clinicians and
The impact of chILD on families and the burden on researchers, would aid in data pooling to improve
health services has not been studied. Bronchopulmonary statistical power and meta-analysis.
dysplasia, a diffuse lung disease2 that is usually associated In conclusion, the disorders that together constitute the
with prematurity58 and is not a chILD disorder1 has been group of diseases known as chILD are extremely
studied in this context.59,60 These studies give an heterogeneous and associated with high morbidity and
indication of the health services burdens and costs that mortality. Prospective, active surveillance of chILD
might be expect for chILD. The median length of the first through strategic international collaboration is needed
hospital stay for children with bronchopulmonary to provide more accurate estimates of frequency. It is
dysplasia was 120 days, at a median cost of US important that a single classification system for chILD is
$172,717.59 An analysis of health services use and costs adopted globally to support direct comparisons of
for a single case of chILD due to surfactant protein C research evidence. Patient registries and randomised
deficiency showed 443 days of in-patient care at a cost of controlled intervention trials through international col-
AUS$966,531.43 Families caring for children with laboration are required to provide an evidence base for
bronchopulmonary dysplasia incur loss of wages, loss improving the lives of children with these rare disorders.
of jobs, and emotional stress associated with caring for Studies that go beyond describing subjective outcomes
their child.59,60 From what is known about the chronic and describe quality of life (e.g., need for oxygen,
morbidity of chILD it is likely that there is a high impact exercise capability, school attendance, regularity of
Pediatric Pulmonology
 Childhood Interstitial Lung Disease 1391

symptoms, and duration) will support prognosis. For 15. Buchvald F, Petersen BL, Damgaard K, Deterding R, Langston C,
health services planning and to support families, the Fan LL, Deutsch GH, Dishop MK, Kristensen LA, Nielsen KG.
impacts of chILD should be addressed in prospective Frequency, treatment, and functional outcome in children with
hypersensitivity pneumonitis. Pediatr Pulmonol 2011;46:
studies. Determining the burden of chILD on health 1098–1107.
services requires descriptive statistics beyond simply 16. Coren ME, Nicholson AG, Goldstraw P, Rosenthal M, Bush A.
counting the number of cases. Rigorous study of the Open lung biopsy for diffuse interstitial lung disease in children.
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children. J Pediatr (Rio J) 2007;83:233–240.
The authors declare no conflict of interest. 19. Soares JJ, Deutsch GH, Moore PE, Fazili MF, Austin ED, Brown
RF, Sokolow AG, Hilmes MA, Young LR. Childhood interstitial
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Pediatric Pulmonology