Interstitial Lung Diseases

i n C h i l d ren , A d o l e s c e n t s ,
a n d Yo u n g A d u l t s
Different from Infants and Older Adults
Teresa I-Han Liang, MD, FRCPCa,1, Edward Y. Lee, MD, MPHb,*

KEYWORDS
 Interstitial lung disease (ILD)  Childhood interstitial lung disease (chILD)  Diffuse lung disease
 High-resolution computed tomography (HRCT)

KEY POINTS
 Interstitial lung disease (ILD) in children, adolescents, and young adults is a heterogeneous group of
disorders with diverse clinical and imaging manifestations.
 Although childhood ILD (chILD) pathologies in infants and young children do overlap with ILD in
adults, major differences in pathology and clinical presentations exist.
 ILD in this population remains a challenging and multidisciplinary diagnosis, with no standardized
approach to diagnosis and management.
 It is imperative to establish the immune status of the patient when evaluating suspected ILD in this
population, as it affects the pathology that can manifest and prognosis.

INTRODUCTION the multidisciplinary collaborative efforts of the

chILD Research Co-operative of North America
Interstitial lung disease (ILD) consists of a large (chILDRN), based on review of lung biopsies of
and heterogeneous group of rare pulmonary disor- 187 infants from 11 pediatric institutions with
ders, characterized by abnormalities involving the diffuse lung disease.3,4 Although this classification
alveoli and airway.1–4 However, as many of these was widely accepted and incorporated into official
pathologies involve beyond or do not involve the American Thoracic Society (ATS) clinical practice
interstitium at all, ILD in children and infants guidelines in 2013, it only systematized patients
(chILD) is often considered a syndrome of diffuse younger than 2 years.
ILD.5 Underlying chILD pathologies are markedly Subsequently in 2015, chILDRN published an
different from adult ILD. For example, the adult expanded classification to include older children
ILD idiopathic pulmonary fibrosis, or the corre- from 2 to 18 years of age.3 The updated classifica-
sponding pathologic diagnosis of usual interstitial tion was based on a retrospective review of lung
pneumonia, has not been convincingly reported biopsies in 191 patients between 2 and 18 years
in children or teenagers,3 and conversely, the of age from 12 North American institutions with
chILD disorders neuroendocrine cell hyperplasia diffuse lung disease.3 This classification divides
in infancy (NEHI) and pulmonary interstitial patients into immunocompromised and immuno-
glycogenosis have not been reported in adults.3 competent clinical status (Table 1), and further
The widely accepted chILD classification was classifies the immunocompetent patients into pri-
initially developed and published in 2007, through mary lung disease, lung disease related to
radiologic.theclinics.com

a
Department of Radiology, University of Alberta, Stollery Children’s Hospital, Edmonton, Alberta, Canada;
b
Department of Radiology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
1
Present address: #203 11010 – 101 St. NW, Edmonton, Alberta T5H 4B9, Canada.
* Corresponding author. Department of Radiology, 300 Longwood Avenue, Boston, MA 02115.
E-mail address: [email protected]

Radiol Clin N Am 58 (2020) 487–502

https://doi.org/10.1016/j.rcl.2020.01.001
0033-8389/20/Ó 2020 Elsevier Inc. All rights reserved.
488 Liang & Lee

Table 1
Adapted 2015 chILD Research Co-operative of North America Classification of childhood interstitial
disease (chILD) in children to young adults

Category Disease
Immunocompetent:
Primary lung disease in immunocompetent 1. Infectious/Postinfectious constrictive obliterative
host bronchiolitis
2. Hypersensitivity pneumonitis
3. Aspiration syndromes and exogenous lipoid
pneumonia
4. Eosinophilic pneumonia
5. Idiopathic pulmonary hemosiderosis
Lung disease related to systemic disease 1. Immune-related disease; for example, vasculitis,
connective tissue disease, and autoimmune pulmo-
nary alveolar proteinosis
2. Storage diseases; for example, Gaucher disease
3. Sarcoidosis
4. Langerhans cell histiocytosis
Sequelae and ongoing disorders of infancy 1. Surfactant deficiency
2. Neuroendocrine hyperplasia of infancy
Immunocompromised:
Immunocompromised host 1. Lymphocytic interstitial pneumonitis with human
immunodeficiency virus/AIDS or combined
immunodeficiency
2. Treatment-related disorders: organizing pneumonia
3. Disorders related to rejection: bronchiolitis
obliterans
Adapted from Fan LL, Dishop MK, Galambos C, et al. Diffuse lung disease in biopsied children 2 to 18 years of age. Appli-
cation of the chILD Classification Scheme. Ann Am Thorac Soc 2015;12(10):1498-505.

systemic disease, and patients with sequelae or the 2015 chILD classification scheme with clinical
diagnoses of disorders of infancy (see Table 1). examples highlighting the imaging features to help
Immunocompromised patients had the highest re- the general radiologist aid in an efficient and accu-
ported mortality rate of 52.8%,3 whereas immuno- rate multidisciplinary diagnosis of chILD.
competent patients had markedly improved
mortality rates, with reported mortality rates
IMAGING TECHNIQUES
ranging from 7.1% to 20.0% in the subgroups.3
Chest Radiography
Patients with chILD most commonly present
with cough, exercise intolerance, dyspnea, hypox- Chest radiography is an excellent initial screening
emia, crackles, and tachypnea, although rarely, imaging modality for patients with suspicion of
patients can present with a normal examination.3,6 chILD, as it uses low radiation dose, is easily
Interestingly, Fan and colleagues3 reported that reproducible, and readily accessible.4,7 Once a
clinical symptoms are less common in the older chILD diagnosis has been established, it also can
population, in comparison with the previously re- be used to follow the course of disease.4,7–9 The
ported prevalence in infants younger than 2 years, most commonly seen radiographic abnormality is
implying that older children may have more hyperinflation, although chest radiographic find-
insidious symptoms and present later in disease,6 ings remain nonspecific, and a normal chest radio-
making the clinical diagnosis a challenge. graph does not exclude a diagnosis of chILD.4,9,10
Given its rarity and diverse imaging manifesta- Prior studies have reported an inferior degree of
tions, and in conjunction with an often nonspecific confidence and accuracy of chest radiography in
clinical examination, chILD in children and teen- the assessment of diffuse pediatric lung disease,
agers presents a challenge to the clinicians and with reported accuracies as low as 34%.8 There-
radiologist. Therefore, this article discusses the fore, further characterization to improve diagnostic
utility of available imaging techniques and the accuracy and confidence with computed tomog-
associated common imaging findings, and reviews raphy (CT) is typically necessary.11
 Childhood Interstitial Lung Disease 489

Computed Tomography perilymphatic, and random. Centrilobular nodules

are found centrally within the secondary pulmo-
CT, usually without intravenous contrast and
nary lobule, and can be seen in infectious and
ideally performed as high-resolution CT (HRCT)
inflammatory entities involving the small airways,
technique, has become the standard imaging mo-
such as infectious bronchiolitis or hypersensitivity
dality for evaluation of suspected chILD, as it al-
pneumonitis. In contrast, perilymphatic nodules
lows confirmation of disease, superior
are found along the interlobular septa, fissures,
characterization of the extent and distribution of
and bronchovascular bundles, and can be seen
disease, and identification of any unique imaging
in sarcoidosis (Fig. 1). Miliary and random nodular
features.4,8–10 In addition, as chILD can often be
patterns are not commonly seen in chILD.
patchy, CT can recommend an ideal biopsy site
and guide preoperative planning.4,8–10
Ground-glass opacification
In more recent years with the CT technologic ad-
Ground-glass opacification is visualized as hazy
vances, volumetric high-resolution scanning of the
air space opacification with preservation of the
entire chest can be performed in seconds.4,9 Thus,
bronchovascular structures, whereas consolida-
older patients typically do not need to be sedated,
tion represents solid air space opacification10,14;
and can be imaged during quiet respiration or
however, both imaging characteristics are
following breath-hold maneuvers,4,9,10 as general
nonspecific. Ground-glass opacification can be
anesthetic should be avoided because it is inva-
seen in underinflated lungs, especially in the lung
sive, expensive, subject to procedural risks, and
bases when imaged in expiration or with shallow
possibly associated with adverse neurocognitive
inspiration.10 When ground-glass opacification is
effects.10,12,13 Another challenge in imaging chil-
seen with superimposed interlobular and intralob-
dren with general anesthesia is that the pathology
ular septal thickening, it is described as a “crazy-
can be obscured, as children are particularly prone
paving” pattern (Fig. 2), and can be associated
to atelectasis due to high chest wall compliance
with a diverse range of entities, including pulmo-
and underdeveloped collateral ventilation system
nary alveolar proteinosis (PAP), pulmonary hemor-
(pores of Kohn and channels of Lambert).10,12
rhage syndromes, lipoid pneumonia, diffuse
Additional challenges in the younger child include
alveolar disease, organizing pneumonia, and
lower lung volumes, associated with poor inspira-
pneumocystis pneumonia.7,10
tion, small patient size, and rapid respiratory
motion.4
Air-trapping
CT imaging manifestations of chILD remains
Air-trapping appears as hypodense regions with
diverse, but typically includes nodules, ground-
less than normal increase in attenuation and lack
glass opacification, consolidation, air-trapping,
of normal volume reduction with expiration
cysts, interlobular and intralobular septal thick-
(Fig. 3).14 It is not uncommon to see a few subseg-
ening, linear and reticular markings, and architec-
mental (lobular) hypodense foci in the lungs of
tural distortion and traction bronchiectasis in
healthy children, especially in the posterior juxta-
fibrotic disease.4,7,10 These CT imaging descrip-
pleural region, and should not be confused with
tors have specific terminology and definitions as
pathology.10
per the Nomenclature Committee of Fleischner
Society.14
Cyst
Cysts appear as round hypodense, well-defined
Pulmonary nodule structures that usually contain air, but can contain
Pulmonary nodules can be classified according to fluid or solid material.14 Cysts can be seen in mul-
their distribution as either centrilobular, miliary, tiple chILD entities, including pulmonary

Fig. 1. A 17-year-old girl with sarcoid-

osis, who presented with fatigue and
weight loss, and found to have an
elevated ACE level. Noncontrast axial
(A) and coronal (B) CT images demon-
strate hilar lymphadenopathy (arrow),
diffuse nodular and confluent ground-
glass opacities, and peri-lymphatic nod-
ules in the interlobular septa and bron-
chovascular bundles, strongly
supporting the diagnosis of sarcoidosis.
490 Liang & Lee

Fig. 2. A 13-year-old boy with chILD

of uncertain etiology. Noncontrast
axial (A) and coronal (B) CT images
demonstrate bilateral multifocal
geographic ground-glass opacities
with superimposed interlobular and
intralobular septal thickening
affecting all lobes in keeping with a
crazy-paving CT pattern.

Langerhans cell histiocytosis (LCH) (Fig. 4) and CHALLENGING ASPECTS OF INTERSTITIAL

disorders of surfactant metabolism (see Fig. 19).10 LUNG DISEASE IN ADOLESCENTS AND
YOUNG ADULTS FOR GENERAL
Pulmonary fibrosis RADIOLOGISTS IN 2019
Pulmonary fibrosis associated with chILD and ILD
can develop, and manifest on CT as thicker-walled chILD remains a complex diagnosis, and the re-
stacked cysts known as honeycombing, in addi- ported accuracy and diagnostic confidence of a
tion to traction bronchiectasis and architectural correct diagnosis using HRCT in children is lower
distortion (Fig. 5).10,15 than in adults,11 mostly thought to reflect the
greater diversity of lung diseases in the pediatric
population.11 In addition, it is important to recog-
Magnetic Resonance Imaging
nize that the ability to determine the correct diag-
MR imaging is a superb imaging modality for nosis is dependent on the type of disease, the
assessment of the mediastinum and chest wall, quality of the study, and the expertise of the inter-
and offers the absence of ionizing radiation. How- preter. Even pediatric thoracic radiologists may
ever, it remains limited in the imaging of chILD. only achieve a correct first-choice diagnosis of
This is mainly due to a combination of low proton chILD in fewer than 50% of cases,17 although prior
content in the lungs, inevitable respiratory motion diagnostic performance studies are confounded
artifact as the images are obtained over a period by inconsistent results and imprecise and
of free breathing, and inferior spatial resolution outdated histopathologic classification
relative to CT.4 Sodhi and colleagues16 previously schemes.10 Therefore, it is imperative to use a
investigated the utility of MR imaging in the evalu- multidisciplinary approach among the clinician,
ation of chILD in comparison with HRCT, and radiologist, and pathologist in the assessment of
found that 3T MR imaging was able to detect patients with suspected chILD to optimize diag-
consolidation (Fig. 6), parenchymal bands, and fis- nosis and management.
sural thickening, but remained limited in evaluation Although challenging due to the diverse pathol-
of septal thickening, ground-glass opacity, nod- ogies and variable imaging manifestations, the
ules (Fig. 7), and cysts, which often are essential role as a radiologist is to identify any
diagnostic and differentiating features of chILD. unique features to suggest a favored or narrowed
Therefore, at the current time, MR imaging re- differential diagnosis. This can direct the next
mains limited in the clinical application of chILD, appropriate serologic assay, bronchoalveolar
particularly for initial evaluation. lavage (BAL), or genetic test, and potentially

Fig. 3. A 13-year-old boy with asthma

who presented with shortness of
breath. Noncontrast axial inspiratory
(A) and expiratory (B) CT images
demonstrate patchy and geographic
mosaic attenuation, which on the
expiratory CT image does not in-
crease in attenuation nor decrease
in volume, most pronounced in the
bilateral lobes (arrows), in keeping
with air-trapping.
 Childhood Interstitial Lung Disease 491

Fig. 4. A 3-year-old girl with LCH, sta-

tus post chemotherapy. Noncontrast
axial (A) and coronal (B) CT images
demonstrate multiple bilateral thin-
walled (mildly irregular) cysts in the
lungs (arrows), in keeping with the
known diagnosis of LCH.

Fig. 5. A 15-year-old girl with systemic

sclerosis and diffuse fibrotic pulmonary
disease. Noncontrast axial (A, B) CT im-
ages demonstrate subpleural cystic
changes, in keeping with honeycomb-
ing (arrow), traction bronchiectasis,
patchy ground-glass opacification,
interlobular septal thickening, and sub-
pleural linear reticular markings, consis-
tent with diffuse pulmonary fibrosis.

Fig. 6. An 18-year-old boy with pulmonary alveolar proteinosis (PAP) and pulmonary hemorrhage after full lung
lavage. Noncontrast axial T1-weighted (A) and coronal T1-weighted (B) MR images demonstrate diffuse bilateral
airspace opacification. Frontal chest radiograph (C) demonstrates dependent airspace and interstitial opacities
within the left greater than right lungs, and noncontrast coronal CT image (D) demonstrates diffuse ground-
glass opacification with interlobular septal thickening, in keeping with a crazy-paving pattern, compatible
with the diagnosis of PAP.
492 Liang & Lee

Fig. 7. A 9-year-old girl with history

of acute myelocytic leukemia status
post treatment. Axial (A) and coronal
(B) T2-weighted Half Fourier Single
Shot Turbo Spin Echo (HASTE) MR im-
ages demonstrate multiple nodules
(arrows) in the right upper lobe.

obviate the need for a lung biopsy, such as in the airway obstruction due to inflammatory tissue
setting of NEHI or bronchiolitis obliterans in the and fibrosis, and associated with sequelae of
appropriate clinical setting.4,10,18,19 It can be highly prior infection from various respiratory viruses,
beneficial when extrapulmonary imaging manifes- but particularly with adenovirus.7,24
tations, such as thymic enlargement and calcifica- On chest radiographs, hyperinflation is the
tion in LCH, esophageal dysfunction in systemic most common abnormality, with additional find-
sclerosis or aspiration, and pectus excavatum in ings including atelectasis and bronchial thick-
chronic surfactant dysfunction related to ABCA3 ening, but milder disease also can have a
gene mutation are present and help suggest the normal chest radiograph.7,10,24 HRCT demon-
diagnosis.10 strates characteristic mosaic attenuation, due to
The other challenge lies in the substantial vari- vascular shunting in the hypoventilated areas
ation and absence of clear guidelines for moni- and reduced perfusion due to constriction of ves-
toring patients with chILD with diagnostic sels from tissue hypoxia. On expiratory images,
imaging.10 This is because the imaging findings air-trapping is present, reflecting small airways
on CT do not always correlate with pulmonary disease, and mild to marked bronchiectasis,
function testing (PFT), or predict response to reflecting larger airways disease (Fig. 8).10,24
treatment or outcome.10 For example, patients Although definitive diagnosis remains by lung bi-
with asymptomatic connective tissue disease opsy, a 3-part COB diagnostic scoring system
with normal PFT often have ILD on imag- with a diagnostic specificity of 100% has been
ing.10,20,21 Conversely, it is not unusual for proposed, potentially obviating the need for lung
asymptomatic HRCT lung abnormalities to persist biopsy, with points given for a typical clinical his-
in LCH for many years after treatment.22,23 In tory of postinfectious COB, history of prior adeno-
addition, there are no specific HRCT findings to virus infection, and characteristic mosaic
predict which patients progress to clinically sig- attenuation on HRCT.10,24,25
nificant pulmonary fibrosis.10,20,21
Environmental agents: hypersensitivity
SPECTRUM OF INTERSTITIAL DISEASE
pneumonitis
Primary Lung Disease in an
Hypersensitivity pneumonitis (HP), also known as
Immunocompetent Host
extrinsic allergic alveolitis, is a form of immune-
Infectious/postinfectious: constrictive mediated ILD that develops in response to
obliterative bronchiolitis repeated inhalation of finely dispersed organic an-
Postinfectious constrictive obliterative bronchio- tigens. Acute, subacute, and chronic forms have
litis (COB) is a chronic respiratory condition char- been described, with repeated exposures poten-
acterized by severe and fixed lower respiratory tially leading to irreversible lung damage.26 HP

Fig. 8. An 18-year-old girl with prior

history of adenovirus and diagnosis
of postinfectious constrictive oblitera-
tive bronchiolitis (COB). Noncontrast
axial inspiratory (A) and expiratory
(B) CT images demonstrate mosaic
attenuation with multiple areas of
air-trapping (arrows), most prominent
in the lingula in keeping with postin-
fectious COB.
 Childhood Interstitial Lung Disease 493

Fig. 9. A 14-year-old boy diagnosed

with hypersensitivity pneumonitis
(HP) to birds, who responded well to
steroid treatment. Noncontrast axial
(A, B) CT images demonstrate bilat-
eral diffuse ground-glass opacities
with mild septal thickening and
lobular spared areas, compatible
with the diagnosis of acute HP.

remains uncommon in childhood, with nonspecific subacute HP may persist for several weeks.10
symptoms often resulting in a delay in diagnosis. Also, HRCT findings of pulmonary fibrosis may
Affected pediatric patients with acute HP can pre- persist and potentially progress, even despite
sent with symptoms mimicking a flu-like illness, removal of the offending antigen.10,26,27
including high fever, chills, dry cough, dyspnea,
and malaise, whereas children with chronic HP, Aspiration syndromes and exogenous lipoid
the more commonly reported form of HP, present pneumonia
with progressive and insidious nonspecific symp- Chronic aspiration is commonly seen in children with
toms of exercise intolerance, cough, weight loss, recurrent lower respiratory tract infections, and is
and fever.7,26 Although it can manifest identically predicted to be present in 26% to 49% of children
on imaging to the adult form, in contrast to adult with chILD.6,7,28 CT findings typically include bron-
HP, which can result from a wide variety of occu- chial wall thickening, centrilobular or tree-in-bud
pational and environmental exposures to mi- nodules, or consolidation in the dependent (poste-
crobes, animal and plant proteins, and rior and basal) portions of the lung (Fig. 10).7,29
chemicals, HP in children most commonly results The presence of bronchiectasis and fibrosis has
from repeated exposures to an array of birds, been suggested to correlate with cases with greater
and is associated with an overall excellent prog- severity and chronicity.29 Imaging findings sugges-
nosis.26 Additional antigens in HP in children tive of esophageal dysfunction, such as a patulous
include mold spores and methotrexate.7,26 or dilated esophagus, may further suggest the pres-
On chest radiographs and HRCT, acute HP clas- ence of chronic aspiration (see Fig. 10).29
sically shows ground-glass opacities (Fig. 9), Exogenous lipoid pneumonia in the pediatric
which can resemble pulmonary edema or pneu- population is most commonly associated with
monia.7,10 In the subacute phase of HP, HRCT aspiration of mineral oil used to treat chronic con-
shows poorly defined centrilobular nodules, stipation.7 Affected pediatric patients may remain
ground-glass opacities, and evidence of air-trap- asymptomatic or present with nonspecific clinical
ping.7,10 There is relative sparing of the upper symptoms, such as cough, chest pain, tachypnea,
lung zones in both the acute and subacute phases. and fever.30,31 Risk factors and comorbidities
In chronic HP, subpleural reticular markings, archi- include gastroesophageal reflux, aspiration syn-
tectural distortion, and honeycombing related to dromes, force-feeding, choking, feeding in a
pulmonary fibrosis are seen.7,10 Although clinical recumbent position, neurologic conditions, intrac-
symptoms typically resolve within a few days of table seizures, and gastrointestinal conditions,
starting treatment and ceasing exposure to the such as chronic constipation, obstruction, Hirsch-
inciting antigen, HRCT findings of acute and sprung disease, and malnutrition.31

Fig. 10. An 11-year-old girl with

Rubinstein-Taybi syndrome, develop-
mental delay, failure to thrive, and
chronic aspiration and respiratory
symptoms. Contrast-enhanced axial
CT images in soft tissue window
setting (A) and lung window setting
(B) demonstrate ground-glass opaci-
ties and more confluent consolida-
tion in right greater than left lobes
with bronchial wall thickening, mu-
cous plugging, bronchiectasis, and a patulous esophagus with an air-fluid level, consistent with chronic
aspiration.
494 Liang & Lee

chronic setting, it may be isolated (ICEP) or

accompanied by systemic manifestations, such
as in eosinophilic granulomatosis with polyangii-
tis (EGPA), previously known as Churg-Strauss
syndrome, an uncommon necrotizing medium-
vessel vasculitis, typically associated with
asthma, allergic rhinitis, and peripheral eosino-
philia.7,32 Unlike adults, EGPA is rare and more
severe in children with variable presentations,
more frequently associated with cardiomyopathy,
and can be antineutrophil cytoplasmic antibody
negative in up to 40% of cases.7,32
Fig. 11. A 17-year-old girl with cerebral palsy who Although imaging findings often are nonspecific
presented with a low-grade fever and cough. with diffuse or local pulmonary infiltrates, the pres-
Contrast-enhanced axial CT image demonstrates right ence of classic features of multifocal peripheral
middle lobe consolidation (arrow) with negative fat pulmonary consolidation, often with perilesional
density Hounsfield units, in keeping with exogenous
halos of ground-glass (Fig. 12) and pleural effu-
lipoid pneumonia. (Courtesy of Dr Ricardo Restrepo,
Department of Radiology, Nicklaus Children’s Hospi-
sions, can favor the diagnosis of EP. However,
tal, Miami, FL.) diagnosis still depends on the presence of
peripheral blood eosinophilia (although not always
present), and most importantly, alveolar eosino-
The most frequent imaging findings include philia on BAL.32
airspace and ground-glass opacification,30,31
and less frequently on CT, interstitial septal thick- Idiopathic pulmonary hemosiderosis
ening and a crazy-paving appearance can be Idiopathic pulmonary hemosiderosis (IPH), first
observed. However, lipoid pneumonia can be described by Virchow in 1864, is characterized
definitively diagnosed on CT when the consoli- by alveolar capillary hemorrhage with deposition
dated lung parenchyma, typically in the bilateral and accumulation of hemosiderin in the lungs.33,34
lower lobes or right upper lobe, demonstrates The pathophysiology remains unclear, but multiple
negative Hounsfield unit values corresponding hypotheses, including autoimmune, environ-
to fat density, typically between 21 and 90 mental, allergic, and genetic theories, have been
HU (Fig. 11).7,30 proposed.34 Although the exact incidence is
largely unknown, it has been reported to occur be-
Eosinophilic pneumonia tween 0.24 and 1.26 patients per million in select
Eosinophilic pneumonia (EP) is characterized by pediatric populations.33 Recent literature suggests
significant eosinophil infiltration of the alveolar that patients with Down syndrome are at a higher
spaces and interstitium,32 and can be catego- risk for developing pulmonary hemosiderosis and
rized into primary EP with an unknown cause, are associated with more severe disease.35 In
and secondary EP related to a known cause, contrast to adults, children with IPH have a more
such as parasite infection, allergic bronchopul- rapid and severe prognosis, with mortality rates
monary aspergillosis, or drugs.32 Primary idio- estimated up to 50%.33,35 Two distinct phases
pathic EP can occur in an acute or chronic have been described in IPH: an acute phase and
setting (IAEP and ICEP, respectively), and are a chronic phase. The acute phase is characterized
both reported to be extremely rare in the pediatric by alveolar hemorrhage, and potentially respira-
and teenage populations, with an estimated IAEP tory failure, whereas in the chronic phase, the pa-
prevalence of less than 1 in a million.32 IAEP is tient typically presents with symptoms of severe
often associated with respiratory distress and disease, such as cyanosis or clubbing, and right
smoke or irritant exposure, whereas in the heart failure due to pulmonary fibrosis.34

Fig. 12. An 11-year-old boy with

elevated immunoglobulin E and serum
eosinophils. Noncontrast axial CT im-
ages (A, B) demonstrate multiple pe-
ripheral consolidative opacities with
relative central clearing and adjacent
ground-glass opacities in the left lower
lobe, compatible with a diagnosis of
eosinophilic pneumonia.
 Childhood Interstitial Lung Disease 495

Diagnosis of IPH in children is often delayed or includes pulmonary vasculitis syndromes and
misdiagnosed because of the variable and insid- connective tissue disorders, nonspecific interstitial
ious presentation and lack of awareness of the pneumonia (NSIP), pulmonary hemorrhage, auto-
condition.33,34 Clinical symptoms include cough, immune PAP, and other diagnoses.3
hemoptysis, fever, and dyspnea, with the classic
clinical triad of hemoptysis, iron deficiency ane- Pulmonary vasculitis syndromes: systemic lupus
mia, and pulmonary infiltrates on chest imaging.33 erythematosus Vasculitis disorders of childhood
Although the presence of hemoptysis is useful for include a spectrum of disorders, including granu-
diagnosis, its absence does not exclude IPH. In lomatous polyangiitis (GPA, formerly known as
fact, hemoptysis remains rare in children, likely Wegner granulomatosis) and systemic lupus ery-
secondary to the inability to expectorate, with re- thematosus (SLE).10 Unlike adult-onset SLE, inter-
ported rates of up to 62% at time of diagnosis.33 stitial disease is uncommon in childhood-onset
Given the challenging diagnosis, confirmation usu- SLE, with only 8% of patients reported to have
ally requires bronchoscopy with BAL to identify abnormal imaging findings, suggesting that
hemosiderin-laden macrophages, or potentially a asymptomatic children with SLE do not require
lung biopsy to exclude other disease processes.34 HRCT screening.10,36 When pulmonary disease is
Imaging findings remain nonspecific and depen- present in childhood-onset SLE, it is frequently in
dent on the phase involved. In the acute phase of the form of vasculitis with pulmonary hemor-
IPH, findings include airspace opacities (Fig. 13) rhage.10 Acute pulmonary hemorrhage can be
and/or consolidation reflecting alveolar hemor- identified with the presence of ill-defined fluffy
rhage, in a predominantly hilar, perihilar, and lower ground-glass opacities, sparing the lung periphery
lobe distribution, with relative sparing of the lung (Fig. 14). With repeated hemorrhage, mild intersti-
apices and costophrenic sulci.34 The airspace tial fibrosis and interlobular septal thickening can
opacities and consolidation usually decrease or be seen.7,37
clear within 3 days of presentation, at which time
Connective tissue disorders: systemic sclerosis
reticular opacities may become evident.34 Intersti-
The connective tissue disorders of childhood are
tial deposition of the hemosiderin-laden macro-
frequently associated with pulmonary disease.
phages can result in interlobular and intralobular
For example, pulmonary disease has been re-
septal thickening, which can manifest as the
ported in up to 90% of pediatric patients with juve-
crazy-paving pattern when superimposed on a
nile systemic sclerosis (scleroderma).38 Systemic
background of ground-glass opacification.34 In pa-
sclerosis is a rare autoimmune connective tissue
tients with repeated pulmonary hemorrhage in the
disorder with proliferative small vessel vasculop-
chronic phase, findings of pulmonary fibrosis can
athy and obliterative microvascular disease.
be seen.34 Pleural involvement is uncommon in
Juvenile systemic sclerosis is a rare subgroup,
IPH, but can manifest as a hemothorax, potentially
with disease onset in patients younger than
with a fluid-fluid level of layering blood products,
16 years old.38 The main prognostic factor in sys-
and nonresolving or recurrent hemothoraces may
temic sclerosis in both the juvenile and adult pop-
result in formation of a fibrothorax, which appears
ulations is the involvement of the cardiopulmonary
as pleural thickening and calcification and can
system, with the development of ILD being most
result in a persistently collapsed “trapped” lung.34
common, as well as pulmonary arterial hyperten-
sion and heart failure.38 On HRCT, these patients
Lung Disease Related to Systemic Disease
often present with an NSIP pattern, described as
Immune-related disease fine reticular markings and ground-glass opacities
Disorders related to systemic immune-mediated in the lower lobes with subpleural sparing and in an
disease, as per the ATS proposed classification, apicobasal gradient distribution.38 CT also may

Fig. 13. A 9-year-old girl with recur-

rent pulmonary hemorrhage, but no
active hemorrhage. Noncontrast axial
(A) and coronal (B) CT images demon-
strate diffuse subtle nodular ground-
glass opacities and innumerable cysts,
compatible with idiopathic pulmo-
nary hemosiderosis.
496 Liang & Lee

Fig. 14. A 22-year-old woman with

systemic lupus erythematosus who
presented with intermittent chest
pain and hemoptysis. Noncontrast
axial (A) and coronal (B) CT images
demonstrate bilateral ground-glass
and reticular opacities, sparing the
periphery of the lung in the upper
and lower lobes, in keeping with
alveolar hemorrhage.

reveal mediastinal lymphadenopathy, esophageal the lungs, skin, kidneys, conjunctivae, and
dilatation, and pleural effusions,38 although the heart.40–42 Pulmonary involvement, although infre-
incidence of these findings is lower in the pediatric quent, is correlated with severe forms of disease,
population, possibly due to shorter disease dura- and is secondary to the deposition of the Gaucher
tion.38 If the patient develops progressive pulmo- cells within the alveolar, interstitial, subpleural, and
nary fibrosis, subpleural cysts, traction peribronchovascular spaces.42,43 In addition, arte-
bronchiectasis, and honeycombing may be riovenous shunting, most commonly as a compli-
observed (see Fig. 5). cation of chronic liver disease (hepatopulmonary
syndrome), can be observed.42
Autoimmune pulmonary alveolar proteinosis Chest radiographs may demonstrate reticulo-
PAP comprises of a broad group of rare diseases nodular opacities, and on HRCT, interstitial thick-
characterized by the accumulation of pulmonary ening (both interlobular and intralobular), ground-
surfactants in the alveolar space.39 This can be glass opacities, consolidation, and bronchial wall
caused by altered surfactant production, removal, thickening can be seen41,42 (Fig. 15A). Hilar and
or both. Although much rarer in children, autoim- mediastinal lymphadenopathy, thymic, hepatic,
mune PAP is typically secondary to disruption of and splenic enlargement (Fig. 15B, C) can further
the granulocyte-macrophage colony-stimulating support the diagnosis of Gaucher disease.41
factor receptor (GM-CSF) signaling via neutraliza- Although children receiving enzyme replacement
tion of the GM-CSF autoantibodies.39 Serology therapy for Gaucher disease may see gradual
testing has excellent sensitivity and specificity, improvement of pulmonary abnormalities on imag-
and can be used to help diagnose patients with ing, it is important to be aware that imaging find-
autoimmune PAP.39 On HRCT, the crazy-paving ings may not completely resolve.43
pattern is characteristic, but not specific for PAP
(see Fig. 6); therefore, BAL and sometimes lung bi- Sarcoidosis
opsies are required for definitive diagnosis and Sarcoidosis is characterized by the presence of
exclusion of alternative diagnoses.39 noncaseating granulomas,44 and is well recog-
nized and characterized in the adult population.
Storage disease In contrast, pediatric (juvenile) sarcoidosis re-
Lysosomal storage disorders composes a large mains markedly rare, estimated to affect children
group of inherited metabolic diseases character- 10 times less frequently, and with an
ized by lipid-laden “foamy” macrophage accumu- equal gender distribution.44–47 Pediatric sarcoid-
lation in various tissues resulting from enzyme osis is most commonly diagnosed in adoles-
deficiencies, with Gaucher and Niemen-Pick dis- cents, but has been reported in infants and
eases representing the most well-known en- young children.44 In younger children, pediatric
tities.7,10 Gaucher disease is the most common sarcoidosis typically manifests as the clinical
lysosomal storage disease, and estimated to triad of rash, arthritis, and uveitis,45 whereas in
affect 1 in 100,000 live births (although markedly older children, sarcoidosis manifests similar to
more common in those of Ashkenazi Jewish the adult form as a multisystem disorder, with
descent).7 Gaucher disease is due to the deficient lungs being the most commonly involved, in up
activity of the enzyme b-glucocerebrosidase, to 92%.44,45,47 The predominant symptom in
resulting in glucocerebroside within the macro- the older patients is a mild, dry, chronic cough.45
phages (Gaucher cells) in the spleen, liver, bone Similar to the adult patients, serum angiotensin-
marrow, brain, osteoclasts, and less commonly converting enzyme (ACE) levels are often
 Childhood Interstitial Lung Disease 497

Fig. 15. A 3-year-old boy with type 1 Gaucher disease on enzyme replacement therapy, who presented for
workup of an incidental hepatic mass (not shown). Contrast-enhanced axial CT image in lung window setting
(A) demonstrates diffuse ground-glass opacities and mild interlobular and intralobular septal thickening. Axial
CT image in soft tissue window setting (B) demonstrates bilateral mediastinal, hilar, and axillary lymphadenop-
athy. Axial T2-weighted MR image with fat suppression (C) demonstrates splenomegaly, supporting the diagnosis
of Gaucher disease.

elevated, and should be measured when a diag- involved in children, but are spared in adults.49,50
nosis of sarcoidosis is considered; however, it is The peripheral cysts can rupture, resulting in spon-
nonspecific and can be elevated in multiple taneous pneumothoraxes, a well-recognized
conditions.44–47 complication in approximately 10% to 20%.49
When pulmonary involvement is present, the Rarely, pneumomediastinum from air leakage
most common imaging pattern is hilar lymphade- from the pulmonary interstitium may occur.49 As
nopathy, usually bilateral (see Fig. 1).44,45 Paren- parenchymal destruction and fibrosis progresses,
chymal disease occurs in approximately 65% of pulmonary arterial hypertension and cor pulmo-
children, but isolated parenchymal disease re- nale may result, eventually leading to end-stage
mains rare, and typically involves the intersti- disease and death.49 The presence of a thymic
tium.44 Typical sarcoidosis parenchymal imaging mass or calcification may help favor the diagnosis
findings include peribronchovascular and intersti- of LCH.23 HRCT imaging allows a confident pro-
tial thickening and peribronchovascular nod- spective diagnosis, and imaging findings are
ules44,46 (see Fig. 1). Although imaging findings thought to correlate well with severity of functional
can be indicative, pediatric sarcoidosis remains a impairment and pathologic findings, although not
diagnosis of exclusion, suggested by clinical and predictive of prognosis, and is recommended in
imaging manifestations, but usually requiring all patients newly diagnosed with LCH.49
confirmation with histopathology.46
Immunocompromised Host
Langerhans cell histiocytosis Lymphocytic interstitial pneumonitis
LCH is characterized by accumulation of dendritic Lymphocytic interstitial pneumonia (LIP) is a rare
cells (Langerhans cells) in various organs, which disorder confined to the lungs, characterized by
can result in fibrosis, scarring, and cyst forma- dense alveolar septal and interstitial reactive
tion.48 In contrast to the adult form of LCH, which lymphocyte and plasma cell infiltrates.51 LIP has
is typically related to smoking and involves the been strongly associated with infection, and in
lungs, LCH in children is often a multisystem dis- children, LIP is particularly common, but not exclu-
ease potentially involving all organs, including the sive to children with human immunodeficiency vi-
bones, skin, liver, spleen, and central nervous sys- rus (HIV), estimated to occur in approximately
tem.23,48 Pulmonary involvement, especially iso- 30% to 40%.51,52 Patients older than 2 years typi-
lated, is seen in only a minority of cases, with cally have an insidious clinical presentation, with a
reported estimates of approximately 20% to nonproductive cough, mild hypoxemia, general-
50%.48 Clinical presentation can vary, and up to ized lymphadenopathy, and finger clubbing.52–54
a quarter of patients remain asymptomatic; com- The US Centers for Disease Control and Preven-
mon presentations include dyspnea, nonproduc- tion (CDC) has previously established character-
tive cough, and constitutional symptoms.49 istic clinical and radiological features to obviate
Pulmonary LCH imaging findings in children are the need for a lung biopsy.52 The radiological
similar to adults, with the presence of nodular or criteria were defined by the persistence of diffuse,
diffuse reticulonodular opacities and cysts, often symmetric, reticulo-nodular or nodular pulmonary
irregular in shape (see Fig. 4). The lung bases opacification (Fig. 16), with or without mediastinal
near the costophrenic angles are almost always adenopathy for at least 2 months, without an
498 Liang & Lee

Fig. 16. A 15-year-old girl with lym-

phocytic interstitial pneumonia (LIP)
and history of human immunodefi-
ciency virus on retroviral therapy.
Noncontrast axial (A) and coronal (B)
CT images demonstrate multiple
ground-glass opacities, diffuse bron-
chiectasis, and multiple cysts (arrows)
in the left upper lobe, in keeping
with diagnosis of LIP.

identifiable pathogen or response to antibiotic opacification surrounded by a ring of consolida-

therapy.52,54 Additional findings include character- tion, is seen infrequently (Fig. 17), approximately
istic cysts; subpleural, interlobular, and peribron- 20%, but felt to be relatively specific, although it
chovascular micronodules; bronchiectasis, and can be seen in other entities, such as invasive
less frequently ground-glass opacities (see fungal infections, GPA, pulmonary infarct, and
Fig. 16) and pleural effusions.51–53 There has lymphoproliferative disorders.14,55–57 Mediastinal
been conflicting literature regarding the clinical im- lymphadenopathy and pleural effusions also can
plications of resolved radiographic LIP findings in be infrequently seen.55,56
the HIV-infected pediatric patient, with no defini-
tive correlation identified.54 Disorders related to rejection: bronchiolitis
obliterans
Treatment-related disorders: organizing Bronchiolitis obliterans (BO) is a serious late irre-
pneumonia versible and progressive complication, thought to
Organizing pneumonia occurs as a pulmonary represent chronic rejection after allogeneic bone
response to injury, incited by secondary causes marrow/stem cell or lung transplantation, clini-
such as infection, asthma, drug reaction, aspira- cally defined by chronic airflow obstruction and
tion pneumonia, autoimmune disease, chemo- pathologically characterized by fibrosis and oblit-
therapy, transplantation, or other disorders, with eration of bronchioles.58,59 The clinical correlate
resultant intraluminal inflammatory granulation tis- (without histopathology diagnosis) of airflow
sue and fibrosis in the bronchi, alveolar ducts, and obstruction, based on spirometry criteria (forced
airspaces.55,56 When no identifiable cause is iden- expiratory volume in 1 second [FEV1]/forced vital
tified, this is described as cryptogenic organizing capacity of less than 0.7 or FEV1 less than 75% of
pneumonia.56 predicted value) or imaging findings, and with the
Organizing pneumonia has variable imaging exclusion of respiratory tract infection, is BO syn-
manifestations. However, the most frequent drome (BOS).58–60 Affected pediatric patients
pattern is bilateral asymmetric patchy airspace with BO/BOS present with nonspecific and insid-
opacities, often in a subpleural, peribronchial, or ious symptoms of dyspnea, cough, exercise intol-
bandlike distribution.55,56 These lesions may be erance, and wheezing.59 Multiple risk factors are
migratory on follow-up studies.56 Additional imag- associated with BO; however, the most important
ing findings may include ground-glass opacities, is the presence of chronic graft versus host dis-
consolidation with air bronchograms, small ease (GVHD).60,61
nodular or linear ill-defined opacities, bronchial On imaging, findings of bronchiolitis, with
wall thickening and dilatation, or larger nodules mosaic attenuation and air-trapping, bronchiec-
or masses.56 The reversed halo “atoll” sign, tasis, and peribronchial thickening, are seen58–60
defined as a focal rounded ground-glass (Fig. 18). Siegel and colleagues62 have previously

Fig. 17. An 18-year-old girl previously

healthy, with biopsy-proven orga-
nizing pneumonia. Noncontrast axial
(A, B) CT images demonstrate bilat-
eral reverse halo “atoll” lesions in
the left upper and bilateral lower
lobes, in keeping with the diagnosis
of organizing pneumonia.
 Childhood Interstitial Lung Disease 499

Fig. 18. An 11-year-old girl with history of acute myeloid leukemia status post bone marrow treatment 2 years
ago, complicated by chronic graft versus host disease (GVHD). Noncontrast coronal inspiratory (A) and expiratory
(B) CT images demonstrate diffuse bilateral lobular air-trapping in keeping with bronchiolitis obliterans (BO).

demonstrated the superior sensitivity of expiratory On imaging, there may be diffuse ground-glass
thin-section CT, in comparison with inspiratory opacification, interlobular septal thickening, and
thin-section CT scans in older children and teen- a crazy-paving pattern on HRCT.4 In older pa-
agers, and more recently, Togni Filho and col- tients, the ground-glass opacities may appear
leagues61 have recommended the exclusion of diffuse or patchy, the septal thickening can appear
inspiratory phase in the HRCT protocol, and to fine or coarse with architectural distortion, and
only use the expiratory phase for the diagnosis of pulmonary cysts may develop and progress over
BO to minimize radiation exposure in children. time (Fig. 19).10 Associated pectus excavatum
has been reported, and hypothesized to represent
sequelae of chronic restrictive lung disease in the
Sequelae and Ongoing Disorders of Infancy developing chest wall.4,64

Surfactant deficiency disorders Neuroendocrine cell hyperplasia of infancy

Surfactant dysfunction disorders can be attributed NEHI, characterized by abnormally increased
to mutations in multiple genes, including genes for bombesin-immunopositive airway neuroendocrine
surfactant protein B (SFTPB), surfactant protein C cells in the absence of additional abnormalities, is
(SFTPC), and adenosine triphosphate-binding typically diagnosed in full-term infants before the
cassette transporter protein A3 (ABCA3).4 age of 2 years.4,65 Affected patients usually pre-
Although these diseases typically present early in sent with a prolonged course of tachypnea, hyp-
the neonatal periods, SFTPC and ABCA3 muta- oxia, and retractions that do not improve with
tions can have variable clinical presentations, corticosteroids.4,66 Due to the nonspecific presen-
and may remain asymptomatic until later in tation, diagnosis up to the age of 4 years has been
childhood or adulthood.4,63 Although genetic reported.67 However, most of these patients pre-
testing may identify many known mutations in sur- sent early, and typically improve within 1 to
factant disorders, histopathological confirmation 2 years.65,66 Interestingly, Lukkarinen and col-
is typically sought to confirm diagnosis.4 leagues67 recently followed patients with NEHI

Fig. 19. A 21-year-old woman who

presented with a 6-year history of
dyspnea on exertion and found to
have a surfactant protein C mutation.
Noncontrast axial (A) and coronal (B)
CT images demonstrate innumerable
subpleural and paraseptal cysts and
septal thickening, compatible with
surfactant dysfunction interstitial
lung disease.
500 Liang & Lee

Fig. 20. A 4-year-old boy with chronic

increased work of breathing without
an infectious etiology and not
improving on steroids. Noncontrast
axial (A) and coronal (B) CT images
demonstrate diffuse ground-glass
opacification within the right middle
lobe and lingula, compatible with a
diagnosis of neuroendocrine cell hy-
perplasia of infancy (NEHI).

up to the age of 10 years, and found 6 of the 9 pa- Application of the chILD classification scheme.
tients developed nonatopic asthma, suggesting its Ann Am Thorac Soc 2015;12(10):1498–505.
relationship to bronchial obstruction, which is not 4. Liang T, Vargas SO, Lee EY. Childhood interstitial
definitively seen on histopathology. (diffuse) lung disease: pattern recognition approach
NEHI characteristically presents with ground- to diagnosis in infants. AJR Am J Roentgenol 2019;
glass opacities within the right middle lobe and 212:1–10.
lingula and diffuse air-trapping, without airway 5. Deterding R. Evaluating infants and children with
or additional parenchymal abnormalities interstitial lung disease. Semin Respir Crit Care
(Fig. 20).4,65 HRCT has been reported to have Med 2007;28:333–41.
up to 100% specificity, potentially obviating the 6. Deutsch GH, Young LR, Deterding RR, et al, Pathol-
need for lung biopsies in patients with classic ogy Cooperative Group, ChILD Research Co-opera-
symptoms and imaging findings, although tive. Diffuse lung disease in young children:
HRCT remains unable to exclude NEHI as a po- application of a novel classification scheme. Am J
tential diagnosis.4,18 Recently, an increased api- Respir Crit Care Med 2007;176:1120–8.
cal anterior-posterior lung diameter has also 7. Semple TR, Ashworth MT, Owens CM. Interstitial
been recommended to support a diagnosis of lung disease in children made easier.well, almost.
NEHI.68 Radiographics 2017;37:1679–703.
8. Copley SJ, Coren M, Nicholson AG, et al. Diagnostic
SUMMARY accuracy of thin section CT and chest radiography
of pediatric interstitial lung disease. AJR Am J
chILD in the older child and teenagers can pose a Roentgenol 2000;174:549–54.
diagnostic challenge given the rarity and variable 9. Lee EY. Interstitial lung disease in infants: new clas-
and often nonspecific clinical and imaging mani- sification system, imaging technique, clinical pre-
festations. On review of the available imaging sentation and imaging findings. Pediatr Radiol
techniques with emphasis on HRCT and of the 2013;43:3–13.
recommended chILD classification in this popula- 10. Guillerman RP. Imaging of childhood interstitial lung
tion with imaging examples to highlight unique fea- disease. Pediatr Allergy Immunol Pulmonol 2010;23:
tures, the general radiologist should feel more 43–68.
confident, in conjunction with the multidisciplinary 11. Lynch DA, Hay T, Newell JD Jr, et al. Pediatric
team, to expedite an appropriate and accurate diffuse lung disease: diagnosis and classification
diagnosis. using high resolution CT. AJR Am J Roentgenol
1999;173:713–8.
DISCLOSURE 12. Long FR. High-resolution CTof the lungs in infants and
The authors have nothing to disclose. young children. J Thorac Imaging 2001;16:251–8.
13. Schneuer FJ, Bentley JP, Davidson AJ, et al. The
REFERENCES impact of general anesthesia on child development
and school performance: a population-based study.
1. Clement A, Nathan N, Epaud R, et al. Interstitial Paediatr Anaesth 2018;28(6):528–36.
lung diseases in children. Orphanet J Rare Dis 14. Hansell DM, Bankier AA, MacMahon H, et al.
2010;5:22. Fleischner Society: glossary of terms for thoracic im-
2. Das S, Langston C, Fan LL. Interstitial lung disease aging. Radiology 2008;246:697–722.
in children. Curr Opin Pediatr 2011;23:325–31. 15. Deterding RR. Children’s interstitial and diffuse lung
3. Fan LL, Dishop MK, Galambos C, et al. Diffuse lung disease - progress and future horizons. Ann Am
disease in biopsied children 2 to 18 years of age. Thorac Soc 2015;12(10):1451–7.
 Childhood Interstitial Lung Disease 501

16. Sodhi KS, Sharma M, Lee EY, et al. Diagnostic utility the epidemiology, diagnosis, and treatment. Pediatr
of 3T lung MRI in children with interstitial lung dis- Pulmonol 2016;51(2):203–16.
ease: a prospective pilot study. Acad Radiol 2018; 33. Zhang Y, Luo F, Wang N, et al. Clinical characteris-
25:380–6. tics and prognosis of idiopathic pulmonary hemosi-
17. Schneebaum N, Blau H, Soferman R, et al. Use and derosis in pediatric patients. J Int Med Res 2019;
yield of chest computed tomography in the diag- 47(1):293–302.
nostic evaluation of pediatric lung disease. Pediat- 34. Khorashadi L, Wu CC, Betancourt SL, et al. Idio-
rics 2009;124:472–9. pathic pulmonary haemosiderosis: spectrum of
18. Brody AS, Guillerman RP, Hay TC, et al. Neuroendo- thoracic imaging findings in the adult patient. Clin
crine cell hyperplasia of infancy: diagnosis with Radiol 2015;70(5):459–65.
high-resolution CT. AJR Am J Roentgenol 2010; 35. Alimi A, Taytard J, Taam RA, et al. Pulmonary hemo-
194:238–44. siderosis in children with Down syndrome: a na-
19. Moonnumakal SP, Fan LL. Bronchiolitis obliterans in tional experience. Orphanet J Rare Dis 2018;
children. Curr Opin Pediatr 2008;20:272–8. 13(1):60.
20. Panigada S, Ravelli A, Silvestri M, et al. HRCT and 36. Lilleby C, Aalokeen TM, Johansen B, et al. Pulmo-
pulmonary function tests in monitoring of lung nary involvement in patients with childhood-onset
involvement in juvenile systemic sclerosis. Pediatr systemic lupus erythematosus. Clin Exp Rheumatol
Pulmonol 2009;44:1226–34. 2006;24:203–8.
21. Wells AU. High-resolution computed tomography in 37. Guillerman RP, Brody AS. Contemporary perspec-
the diagnosis of diffuse lung disease: a clinical tives on pediatric diffuse lung disease. Radiol Clin
perspective. Semin Respir Crit Care Med 2003;24: North Am 2011;49(5):847–68.
347–56. 38. Valeur NS, Stevens AM, Ferguson MR, et al. Multi-
22. Ha SY, Helms P, Fletcher M, et al. Lung involvement modality thoracic imaging of juvenile systemic scle-
in Langerhans’ cell histiocytosis: prevalence, clin- rosis: emphasis on clinical correlation and high-
ical features, and outcome. Pediatrics 1992;89: resolution CT of pulmonary fibrosis. AJR Am J Roent-
466–9. genol 2015;204(2):408–22.
23. Odame I, Li P, Lau L, et al. Pulmonary Langerhans 39. Griese M. Pulmonary alveolar proteinosis: a compre-
cell histiocytosis: a variable disease in childhood. hensive clinical perspective. Pediatrics 2017;140(2)
Pediatr Blood Cancer 2006;47:889–93. [pii:e20170610].
24. Colom AJ, Teper AM. Post-infectious bronchiolitis 40. Copley SJ, Padley SP. High-resolution CT of paediat-
obliterans. Pediatr Pulmonol 2019;54(2):212–9. ric lung disease. Eur Radiol 2001;11:2564–75.
25. Yalçin E, Dogru D, Haliloglu M, et al. Postinfectious 41. McHugh K, Olsen EØE, Vellodi A. Gaucher disease
bronchiolitis obliterans in children: clinical and radio- in children: radiology of non-central nervous system
logical profile and prognostic factors. Respiration manifestations. Clin Radiol 2004;59:117–23.
2003;70:371–5. 42. Gulhan B, Ozcelik U, Gurakan F, et al. Different fea-
26. Fan LL. Hypersensitivity pneumonitis in children. tures of lung involvement in Niemann-Pick disease
Curr Opin Pediatr 2002;14(3):323–6. and Gaucher disease. Respir Med 2012;106(9):
27. Hartman TE. The HRCT features of extrinsic allergic 1278–85.
alveolitis. Semin Respir Crit Care Med 2003;24: 43. Goitein O, Elstein D, Abrahamov A, et al. Lung
419–26. involvement and enzyme replacement therapy in
28. Fan LL, Mullen AL, Brugman SM, et al. Clinical spec- Gaucher’s disease. QJM 2001;94:407–15.
trum of chronic interstitial lung disease in children. 44. Keesling CA, Frush DP, O’Hara SM, et al. Clinical
J Pediatr 1992;121(6):867–72. and imaging manifestations of pediatric sarcoidosis.
29. Cardasis JJ, MacMahon H, Husain AN. The spec- Acad Radiol 1998;5:122–32.
trum of lung disease due to chronic occult aspira- 45. Fretzayas A, Moutsaki M, Vougiouka O. The puzzling
tion. Ann Am Thorac Soc 2014;11(6):865–73. clinical spectrum and course of juvenile sarcoidosis.
30. Zanetti G, Marchiori E, Gasparetto TD, et al. Lipoid World J Pediatr 2011;7(2):103–10.
pneumonia in children following aspiration of mineral 46. Nathan N, Sileo C, Calender A, et al. Paediatric
oil used in the treatment of constipation: high- sarcoidosis. Paediatr Respir Rev 2019;29:53–9.
resolution CT findings in 17 patients. Pediatr Radiol 47. Hoffmann AL, Milman N, Byg KE. Childhood
2007;37(11):1135–9. sarcoidosis in Denmark 1979-1994: incidence, clin-
31. Marangu D, Gray D, Vanker A, et al. Exogenous li- ical features and laboratory results at presentation
poid pneumonia in children: a systematic review. in 48 children. Acta Paediatr 2004;93(1):30–6.
Paediatr Respir Rev 2019. https://doi.org/10.1016/j. 48. Smets A, Mortele K, de Praeter G, et al. Pulmonary
prrv.2019.01.001. and mediastinal lesions in children with Langer-
32. Giovanni-Chami L, Blanc S, Hadchouel A, et al. hans cell histiocytosis. Pediatr Radiol 1997;
Eosinophilic pneumonitis in children: a review of 27(11):873–6.
502 Liang & Lee

49. Bano S, Chaudhary V, Narula MK, et al. Pulmonary noninfectious lung pathologies after allogenic hema-
Langerhans cell histiocytosis in children: a spectrum topoetic stem cell transplantation. Biol Blood Marrow
of radiologic findings. Eur J Radiol 2014;83(1):47–56. Transplant 2015;21(3):531–8.
50. Seely JM, Salahudeen S Sr, Cadaval-Goncalves AT, 59. Kurland G, Michelson P. Bronchiolitis obliterans in
et al. Pulmonary Langerhans cell histiocytosis: a children. Pediatr Pulmonol 2005;39:193–208.
comparative study of computed tomography in chil- 60. Bergeron A, Cheng GS. Bronchiolitis obliterans syn-
dren and adults. J Thorac Imaging 2012;27(1):65–70. drome and other late pulmonary complications after
51. Panchabhai TS, Farver C, Highland KB. Lympho- allogeneic hematopoietic stem cell transplantation.
cytic interstitial pneumonia. Clin Chest Med 2016; Clin Chest Med 2017;38(4):607–21.
37:463–74. 61. Togni Filho PH, Casagrande JLM, Lederman HM.
52. Pitcher RD, Beningfield SJ, Zar HJ. Chest radiographic Utility of the inspiratory phase in high-resolution
features of lymphocytic interstitial pneumonitis in HIV- computed tomography evaluations of pediatric pa-
infected children. Clin Radiol 2010;65:150–4. tients with bronchiolitis obliterans after allogenic
53. Becciolini V, Gudinchet F, Cheseaux JJ, et al. Lym- bone marrow transplant: reducing patient radiation
phocytic interstitial pneumonia in children with exposure. Radiol Bras 2017;50(2):90–6.
AIDS: high-resolution CT findings. Eur Radiol 2001; 62. Siegel MJ, Bhalla S, Gutierrez FR, et al. Post-lung
11:1015–20. transplantation bronchiolitis obliterans syndrome:
54. Lynch JL, Blickman JG, terMeulen DC, et al. Radio- usefulness of expiratory thin-section CT for diag-
graphic resolution of lymphocytic interstitial pneu- nosis. Radiology 2001;220(2):455–62.
monitis (LIP) in children with human 63. Gower WA, Nogee LM. Surfactant dysfunction. Pae-
immunodeficiency virus (HIV): not a sign of clinical diatr Respir Rev 2011;12:223–9.
deterioration. Pediatr Radiol 2001;31:299–303. 64. Doan ML, Guillerman RP, Dishop MK, et al. Clinical,
55. Mehrjardi MZ, Kahkouee S, Pourabdollah M. Radio- radiological and pathological features of ABCA3
pathological correlation of organizing pneumonia mutations in children. Thorax 2008;63(4):355–73.
(OP): a pictorial review. Br J Radiol 2017;90: 65. Brody AS, Crotty EJ. Neuroendocrine cell hyperpla-
20160723. sia of infancy (NEHI). Pediatr Radiol 2006;36:1328.
56. Long NM, Plodkowski AJ, Schor-Bardach R, et al. 66. Soares JJ, Deutsch GH, Moore PE, et al. Childhood
Computed tomographic appearance of organizing interstitial lung diseases: an 18-year retrospective
pneumonia in an oncologic patient population. analysis. Pediatrics 2013;132(4):684–91.
J Comput Assist Tomogr 2017;41:437–41. 67. Lukkarinen H, Pelkonen A, Lohi J, et al. Neuroendo-
57. Kim SJ, Lee KS, Ryu YH, et al. Reversed halo sign crine cell hyperplasia of infancy: a prospective
on high-resolution CT of cryptogenic organizing follow-up of nine children. Arch Dis Child 2013;98:
pneumonia: diagnostic implications. AJR Am J 141–4.
Roentgenol 2003;180:1251–4. 68. Mastej EJ, DeBoer EM, Humphries SM, et al. Lung
58. Uhlving HH, Anderson CB, Christensen IJ, et al. Bi- and airway shape in neuroendocrine cell hyperpla-
opsy-verified bronchiolitis obliterans and other sia of infancy. Pediatr Radiol 2018;48:1745–54.