Paediatric Respiratory Reviews 12 (2011) 230–237

Contents lists available at ScienceDirect

Paediatric Respiratory Reviews

Mini-symposium: Interstitial Lung Disease

Paediatric Interstitial Lung Disease: Classification and Definitions

Megan K. Dishop *
Department of Pathology, The Children’s Hospital, University of Colorado-Denver

EDUCATIONAL AIMS

In reading this article, the reader will come to appreciate that:

 The nomenclature for interstitial lung diseases [ILD] has changed considerably in recent years.
 The identification of specific genetic defects, such as the surfact protein deficiencies, has facilitated a better understanding of the
clinico-pathological correlations of these rare conditions.
 The development of large national and international databases of rare lung diseases promises to assist in the development of better
treatment strategies for children with ILD.

A R T I C L E I N F O S U M M A R Y

Keywords: Classifications of interstitial (diffuse) lung disease in adults and children have undergone significant
paediatric revision in recent years, with advances in our understanding of new entities and the biology and
interstitial lung disease prognostic significance of certain histologic patterns. The contributions of the European Respiratory
diffuse lung disease Society Task Force on Interstitial Lung Disease in Children and the North American Children’s Interstitial
classification
Lung Disease Group are reviewed, and a clinicopathologic classification of paediatric diffuse lung disease
surfactant
is summarized. Clinical characteristics and histologic definitions are also presented for selected entities
glycogenosis
neuroendocrine cell hyperplasia
within this classification, specifically, acinar dysgenesis, congenital alveolar dysplasia, alveolar capillary
bronchiolitis obliterans syndrome dysplasia with misalignment of pulmonary veins, abnormalities of alveolar growth, pulmonary
pneumonitis interstitial glycogenosis, neuroendocrine cell hyperplasia of infancy, surfactant dysfunction disorders,
obliterative bronchiolitis, hypersensitivity pneumonitis, and immunologic disorders. More uniform
application of this diagnostic terminology in the future will allow more meaningful comparisons of
different patient populations, radiologic-pathologic correlation, and development of disease-specific
therapeutic strategies.
ß 2011 Published by Elsevier Ltd.

* Department of Pathology, B120, The Children’s Hospital, 13123 E. 16th Avenue,
Aurora, Colorado 80045 USA. Tel.: +720 777 4337; fax: +720 777 7119.
E-mail address: dishop.megan@tchden.org.
Abbreviations: ABCA3, ATPase binding cassette transporter subfamily A3 gene; ACD/
MPV, alveolar capillary dysplasia with misalignment of pulmonary veins; AGA,
alveolar growth abnormality; AIP, acute interstitial pneumonia; BOS, bronchiolitis
obliterans syndrome; CFA, cryptogenic fibrosing alveolitis; CPI, chronic pneumo-
nitis of infancy; CSF2Ra, colony stimulating Factor 2 receptor alpha; COP,
cryptogenic organizing pneumonia; DAD, diffuse alveolar damage; DIP, desqua-
mative interstitial pneumonia; FB, follicular bronchiolitis; HP, hypersensitivity
pneumonitis; ICIP, infantile cellular interstitial pneumonia; ILD, interstitial lung
disease; IPF, idiopathic pulmonary fibrosis; LAM, lymphangioleiomyomatosis; LCH,
Langerhans cell histiocytosis; LIP, lymphoid interstitial pneumonia; NEHI,
neuroendocrine cell hyperplasia of infancy; NSIP, nonspecific interstitial pneumo-
nia; OB, obliterative bronchiolitis; PAP, pulmonary alveolar proteinosis; PF,
pulmonary fibrosis; PIG, pulmonary interstitial glycogenosis; SFTPB, surfactant
protein B gene; SFTPC, surfactant protein C gene; RB-ILD, respiratory bronchiolitis-
interstitial lung disease; TTF1/NKX2.1, thyroid transcription factor gene; UIP, usual
interstitial pneumonia.
CLASSIFICATIONS OF INTERSTITIAL LUNG DISEASE: HISTORICAL
REVIEW AND RECENT ADVANCES
Since the initial classification of adult interstitial lung disease
by Liebow and Carrington in 1969, there have been a number of
proposals and revisions to this classification, culminating most
recently in a revised American Thoracic Society/European Respira-
tory Society classification of idiopathic interstitial pneumonias in
2002 (Table 1).1 A further study from this group characterizing
nonspecific interstitial pneumonia (NSIP) followed in 2008.2 This
classification system emphasizes recognition of pathologic pat-
terns and correlation with clinical and imaging features for final
clinical-radiologic-pathologic diagnosis. This construct has been
useful in providing unifying terminology for classification of
idiopathic pneumonias in adults, although it is not easily applied to
children, as the types of interstitial lung disease differ considerably

1526-0542/$ – see front matter ß 2011 Published by Elsevier Ltd.

doi:10.1016/j.prrv.2011.01.002
 M.K. Dishop / Paediatric Respiratory Reviews 12 (2011) 230–237
Table 1
Classification of Diffuse Parenchymal Lung Disease (Adapted from the ATS/ERS
International Multidisciplinary Consensus Classification 2002)
IDIOPATHIC INTERSTITIAL PNEUMONIA
Idiopathic pulmonary fibrosis (IPF)
Other:
Desquamative interstitial pneumonia (DIP)
Respiratory bronchiolitis-interstitial lung disease (RB-ILD)
Acute interstitial pneumonia (AIP)
Cryptogenic organizing pneumonia (COP)
Nonspecific interstitial pneumonia (NSIP)
Lymphoid interstitial pneumonia (LIP)
DIFFUSE PARENCHYMAL LUNG DISEASE OF KNOWN CAUSE
(ex. environmental, drug-related, collagen vascular disease)
GRANULOMATOUS DIFFUSE PARENCHYMAL LUNG DISEASE
(ex. sarcoidosis)
OTHER FORMS OF DIFFUSE PARENCHYMAL LUNG DISEASE
(ex. eosinophilic pneumonia, histiocytosis X, lymphangioleiomyomatosis, etc.)
in these two groups, and relatively few disorders in children
remain idiopathic after correlation with clinical history or further
investigation.
The histologic patterns of NSIP, lymphoid interstitial pneumo-
nia (LIP), and desquamative interstitial pneumonia (DIP) are
recognized in children, but typically have different implications for
aetiology and pathogenesis. In a series of 25 cases of childhood ILD
from the United Kingdom (excluding infection, organizing
pneumonia, obliterative bronchiolitis, primary lymphatic disor-
ders, storage disease, and alveolar proteinosis), the common
histologic patterns in childhood were follicular bronchiolitis (FB),
LIP, NSIP, DIP, and chronic pneumonitis of infancy (CPI).3 Usual
interstitial pneumonia (UIP) and acute interstitial pneumonia (AIP)
were not seen in this series. Indeed, the pattern of UIP is
exceedingly rare in children, but has been reported as a pattern
of genetic surfactant disease in one case. While desquamative
interstitial pneumonia is a smoking-related disease in adults, a
similar pattern in infants implies instead a genetic disorder of
surfactant metabolism. Similar to adults, a pattern of nonspecific
interstitial pneumonia in children and adolescents should prompt
exclusion of autoimmune disease or hypersensitivity pneumonitis,
and may also be seen in older children with ATP-binding cassette
sub-family A member 3 protein [ABCA3] or surfactant protein C
[SFTPC] gene mutations. CPI and infantile cellular interstitial
pneumonia (ICIP)/pulmonary interstitial glycogenosis (PIG) are
examples of histologic patterns which are seen only in infants and
are non-existent in adulthood.
Recognizing these differences between adult and paediatric
lung disease and in light of confusion in terminology among some
paediatric entities, there has been attention in recent years to
establishing a classification of paediatric diffuse lung disease,
including interstitial disease, which would serve as a construct for
diagnostic decision-making and also present unifying terminology
to guide clinical therapy in this special age group.4–6 In 2004, the
European Respiratory Society Task Force published a survey of
European centers which reported the relative incidence of different
forms of paediatric lung disease and related clinical data (Table 2).7
In 2007, a group of North American paediatric hospitals reported
their experience with wedge lung biopsy for diffuse disease in
infants (less than 2 years of age), including clinical presentation,
consensus pathologic review of biopsy slides, and outcome data
(Table 3).8,9 During the same time period, there have been a
number of advances in our understanding of the genetic etiologies
of paediatric lung disease. For example, neuroendocrine cell
hyperplasia of infancy was described as a new form of paediatric
diffuse lung disease in 2004.10 The spectrum of genetically-
determined lung diseases in children also continues to expand,
231
Table 2
European Respiratory Society Task Force Classification of Diffuse Parenchymal Lung
Disease in Children (Adapted from Clement et al.7)
IDIOPATHIC INTERSTITIAL PNEUMONIAS
NSIP cellular/fibrotic
DIP
LIP
DAD (AIP)
OP (COP)
UIP (?Familial CFA/IPF)
CP
DIFFUSE PARENCHYMAL LUNG DISEASE OF KNOWN ASSOCIATION
(ex. environmental, hypersensitivity pneumonia, drug-related, collagen vascular
disease, aspiration, infection)
OTHER FORMS OF INTERSTITIAL PNEUMONIA
Sarcoidosis
Eosinophilic pneumonia
LCH
LAM
Alveolar proteinosis
Idiopathic/infantile pulmonary haemosiderosis
Persistent tachypnea of infancy
Pulmonary interstitial glycogenosis
CONGENITAL DISORDERS
DIP (Inborn errors of metabolism)
LIP (Immunodeficiency syndromes)
Lipoid pneumonia (Inborn errors of metabolism)
?NSIP/UIP (Familial CFA)
Disease-specific (? Hermansky-Pudlak syndrome)
Alveolar proteinosis (Surfactant protein B deficiency)
Other surfactant deficiencies (ex. Surfactant protein C deficiency)
NSIP: Nonspecific interstitial pneumonia, DIP: Desquamative interstitial pneumo-
nia, LIP: Lymphoid interstitial pneumonia, DAD: Diffuse alveolar damage, AIP:
Acute interstitial pneumonia, OP: Organizing pneumonia, COP: Cryptogenic
organizing pneumonia, UIP: Usual interstitial pneumonia, CFA: Cryptogenic
fibrosing alveolitis, IPF: Idiopathic pulmonary fibrosis, CP: Chronic pneumonitis,
LCH: Langerhans cell histiocytosis, LAM: Lymphangioleiomyomatosis.
with the recent discoveries of ABCA3 and CSF2Ra gene mutations in
genetic surfactant disorders, TTF1/NKX2.1 gene mutations/dele-
tions in brain-lung-thyroid syndrome, and FOXF1 gene mutations/
deletions in alveolar capillary dysplasia with misalignment of
pulmonary veins.11–15
DEFINITIONS AND HISTOLOGIC CRITERIA
Based on the 2007 classification of paediatric diffuse lung disease,
the major entities are defined and described in the following
sections. While some of these are well-described relatively common
entities seen also in adults, emphasis is placed on rare entities and
newly described entities unique to the paediatric population.
Histologic patterns are correlated with their disease associations
in each section and also summarized in Table 4.
DISORDERS OF NEONATES AND INFANTS
Acinar dysplasia
Acinar dysplasia is a rare severe primary developmental
disorder characterized by diffuse bilateral impairment of devel-
opment of the pulmonary acini.16 Histologically, the respiratory
bronchioles are surrounded by malformed and poorly subdivided
parenchyma, mimicking growth arrest at the pseudoglandular
stage of development. There are virtually no saccular or alveolar
spaces necessary for gas exchange and affected neonates die within
hours of delivery. Although likely due to a genetic abnormality
affecting early lung development, the specific etiology remains
unknown.
232 M.K. Dishop / Paediatric Respiratory Reviews 12 (2011) 230–237

Table 3 Histologically, ACD/MPV is characterized by severe abnormal-

Children’s Interstitial Lung Disease (chILD) Network Classification of Diffuse Lung
ities of both the pulmonary vasculature and lobular architecture
Disease in Children (Adapted from Deutsch et al.8)
(Figure 1). The small pulmonary artery branches show marked
DISORDERS MORE PREVALENT IN INFANCY
medial hypertrophy and prominent muscularization of the
Diffuse developmental disorders
Acinar dysplasia intralobular arterioles. The veins and venules are typically dilated
Congenital alveolar dysplasia and congested. Although the largest pulmonary veins may be
Alveolar capillary dysplasia with misalignment of pulmonary veins normally located in the interlobular septa, the smaller dilated veins
Growth abnormalities reflecting deficient alveolarization and venules are abnormally positioned, accompanying the artery
Pulmonary hypoplasia
Chronic neonatal lung disease (prematurity)
branches. There is also a striking reduction in the capillary bed,
Related to chromosomal disorders with most capillaries in the center of the widened alveolar walls,
Related to congenital heart disease lacking the usual proximity to the alveolar epithelium. Approxi-
Specific conditions of uncertain etiology mately one-third of cases also show pulmonary lymphangiectasia.
Neuroendocrine cell hyperplasia of infancy
The lung parenchyma is also abnormally developed, with
Pulmonary interstitial glycogenosis
Surfactant dysfunction disorders simplified lobular architecture.
Surfactant protein B (SFTPB) mutations
Surfactant protein C (SFTPC) mutations Genetic surfactant disorders
ABCA3 mutations
Surfactant dysfunction disorders without known genetic aetiology
Pulmonary alveolar proteinosis
The surfactant dysfunction disorders (inborn errors of surfac-
Chronic pneumonitis of infancy tant metabolism) are a group of rare lung diseases occurring
Desquamative interstitial pneumonia predominantly in infants and children caused by mutations in
Non-specific interstitial pneumonia genes affecting surfactant production and processing.20 The three
DISORDERS RELATED TO SYSTEMIC DISEASE PROCESSES major causative genes are the ABCA3 gene on chromosome
Immune-mediated/collagen vascular disorders 16p13.3, the surfactant protein C (SFTPC) gene on chromosome
Storage disease 8p21, and the surfactant protein B (SFTPB) gene on chromosome
Sarcoidosis
2p12-p11.2.11,21–24 Abnormalities in the GM-CSF receptor alpha
Langerhans cell histiocytosis
Malignant infiltrates chain (CSF2RA) gene have been recognized also as a cause of
familial pulmonary alveolar proteinosis.12 Mutations or deletions
DISORDERS OF THE NORMAL HOST (NON-IMMUNOCOMPROMISED)
in the thyroid transcription factor (TTF1/NKX2.1) gene cause brain-
Infectious/Post-infectious processes
Related to environmental agents lung-thyroid syndrome and may result in abnormal surfactant
Hypersensitivity pneumonitis; Toxic inhalation protein production.13,14 Mutations in the SFTPB and ABCA3 genes
Aspiration syndromes have an autosomal recessive pattern of inheritance, SFTPC and
Eosinophilic pneumonia
TTF1/NKX2.1 abnormalities are autosomal dominant, and CSF2RA
DISORDERS OF THE IMMUNOCOMPROMISED HOST gene abnormalities are X-linked.
Opportunistic infections The histologic manifestations of the surfactant disorders appear
Related to therapeutic intervention
to vary depending on the causative gene, the severity of clinical
Related to transplantation and rejection
Diffuse alveolar damage, unknown aetiology manifestations, and age at biopsy. In infancy, a number of
overlapping histologic patterns have been described, including
DISORDERS MASQUERADING AS INTERSTITIAL LUNG DISEASE
pulmonary alveolar proteinosis (PAP), chronic pneumonitis of
Arterial hypertensive vasculopathy
Congestive changes related to cardiac dysfunction infancy (CPI), and desquamative interstitial pneumonia (DIP),
Veno-occlusive disease whereas nonspecific interstitial pneumonia (NSIP) and usual
Lymphatic disorders interstitial pneumonia (UIP) patterns have been described in older
children and adolescents. Surfactant protein B deficiency, a disease
of neonates, typically results in a variant PAP pattern with granular
Congenital alveolar dysplasia PAS-positive eosinophilic proteinaceous alveolar material and
prominent uniform alveolar epithelial hyperplasia, but relatively
Congenital alveolar dysplasia is another rare abnormality of little evidence of lobular remodeling or inflammation. Electron
lung development which is considered to be a severe form of microscopy typically shows deficient mature lamellar bodies and
primary lung hypoplasia, and mimics growth arrest at the saccular increased multivesicular bodies and multilamellated structures.25
stage of development.17 Despite term gestation, children with ABCA3 deficiency may have a PAP (Figure 2) or DIP pattern in
congenital alveolar dysplasia have lungs with incomplete alveo- neonates and young infants, or an NSIP pattern with focal proteinosis
larization. The airspaces are elongated with primary septa, but and cholesterol clefts (endogenous lipoid pneumonia) in older
incomplete formation of secondary septation. Similar to the children.22 ABCA3 deficiency is associated with absent lamellar
saccular stage of development, the interstitium is also expanded bodies or distinctive round electron-dense bodies within small
by loose mesenchyme and a more complex capillary configuration abortive lamellar bodies.25 Older infants with surfactant protein C
than typically seen at term gestation. deficiency typically show a pattern of CPI, characterized by relatively
inconspicuous proteinosis material and more prominent cholesterol
Alveolar capillary dysplasia with misalignment of pulmonary veins clefts, lobular remodeling, and interstitial smooth muscle.26 SFTPC
mutations may also cause chronic interstitial pneumonia and
Alveolar capillary dysplasia with misalignment of pulmonary pulmonary fibrosis in adults.27 No consistent abnormalities of
veins (ACD/MPV) is a rare fatal developmental lung abnormality lamellar bodies have been associated with SP-C deficiency.
resulting in severe pulmonary hypertension of the newborn,
typically in the first days of life.18,19 ACD/MPV may be familial and Alveolar growth abnormalities
may be associated with other congenital abnormalities, particu-
larly cardiac defects and gastrointestinal tract abnormalities. In ‘‘Alveolar growth abnormalities’’ (AGA) is a term which refers to
2009, FOXF1 gene mutations and deletions were described as the a common histologic pattern of chronic lung disease in infancy due
cause of ACD/MPV.15 to insufficient alveolar growth and development, reflected
 M.K. Dishop / Paediatric Respiratory Reviews 12 (2011) 230–237 233

Table 4
Histologic patterns of paediatric diffuse lung disease.

HISTOLOGIC PATTERN KEY FEATURES ASSOCIATED DISEASES

AGA Enlarged poorly septated airspaces Chronic neonatal lung disease (prematurity)
Pulmonary hypoplasia
Chromosomal syndromes
Congenital heart disease
PIG (ICIP) Increased mesenchymal cellularity in interstitium with vacuolated matrix Lung injury in infants associated with:
Alveolar growth abnormalities
Meconium aspiration
Pulmonary hypertension
Other
PAP Fine granular or globular intraalveolar eosinophilic material Genetic surfactant disorders
Immune defects
DIP Marked increase in intraalveolar macrophages Genetic surfactant disorders
Toxic inhalation
Drug reactions
CPI Chronic lobular remodeling with interstitial smooth muscle, Genetic surfactant disorders
increased alveolar macrophages, cholesterol clefts, focal proteinosis material
NSIP Diffuse mild to moderate interstitial lymphocyte infiltrate Autoimmune disease
Hypersensitivity pneumonitis
Genetic surfactant disorders in older children
LIP Diffuse marked interstitial lymphocyte infiltrate Autoimmune disease (Sjögren syndrome)
Immunodeficiency (HIV/AIDS)
FB Reactive lymphoid hyperplasia of mucosal-associated lymphoid Autoimmune disease (Juvenile idiopathic
tissue including prominent germinal center formation arthritis, other)
Immunodeficiency (HIV, CVID, other)
OB Submucosal airway fibrosis, narrowing or obliterating the airway lumens Post-viral infection
Stevens-Johnson syndrome
GVHD
Chronic lung allograft rejection
PF End-stage diffuse prominent interstitial fibrosis; Honeycombing Autoimmune disease
Genetic surfactant disorders

AGA: Alveolar growth abnormalities, PIG: Pulmonary interstitial glycogenosis, ICIP: Infantile cellular interstitial pneumonia, PAP: Pulmonary alveolar proteinosis, DIP:
Desquamative interstitial pneumonia, CPI: Chronic pneumonitis of infancy, NSIP: Non-specific interstitial pneumonia, LIP: Lymphoid interstitial pneumonia, FB: Follicular
bronchiolitis, OB: Obliterative/constrictive bronchiolitis, PF: Pulmonary fibrosis.

histologically by airspace enlargement and simplification (defi-
cient alveolar septation) (Figure 3A). When severe, AGA may
manifest as cystic change with variable interstitial fibrosis, often
accentuated in the subpleural regions. Most commonly, the AGA
pattern is the consequence of insufficient prenatal development
(pulmonary hypoplasia), or the postnatal effects of hyaline
membrane disease due to prematurity (chronic neonatal lung
disease/‘‘new’’ bronchopulmonary dysplasia).28–31 Other factors
which contribute to poor alveolarization may include underlying
congenital heart disease, chromosomal disorders, and/or super-
imposed respiratory illness in the first months of life during the
period of most rapid postnatal alveolarization. Specifically,
children with Down syndrome, with or without associated
congenital heart disease, often have an underlying abnormality
of airspace enlargement and widened alveolar ducts, classically
manifesting as a subpleural zone of small cysts on chest CT.32 The

Figure 2. Genetic disorder of surfactant metabolism due to ATP-binding cassette

Figure 1. Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/
MPV). At low power, ACD/MPV shows abnormal congested veins and venules
accompanying pulmonary artery branches in the bronchovascular bundles.
Lymphatic dilation in the interlobular septa is a feature in approximately one-
third of cases. At higher power (not shown), the capillaries are decreased in number
and centrally placed within the alveolar walls.
sub-family A member 3 protein (ABCA3) mutations. In early infancy, the genetic
disorders of surfactant metabolism are typically characterized by marked diffuse
alveolar epithelial hyperplasia, variable interstitial widening with early lobular
remodeling, and intraalveolar proteinosis material with foamy macrophages. The
differential diagnosis in this case should include genetic mutation(s) in ABCA3,
SFTPB (surfactant protein B), and SFTPC (surfactant protein C).
234 M.K. Dishop / Paediatric Respiratory Reviews 12 (2011) 230–237
Figure 3. Alveolar growth abnormality with pulmonary interstitial glycogenosis. A. A pattern of abnormal alveolarization can be seen in the setting of chronic neonatal lung
disease due to prematurity, pulmonary hypoplasia, chromosomal abnormalities, and congenital heart disease. This histologic pattern is characterized by alveolar
enlargement and deficiency in secondary alveolar septation. The airspaces are often rounded or elongated in shape. B. Not uncommonly, alveolar growth abnormalities are
associated with a secondary patchy expansion of the interstitium by mesenchymal cells (pulmonary interstitial glycogenosis).
AGA pattern serves as a useful histologic descriptor in cases in
which the cause is likely multifactorial or cases in which a clinical
correlate has not been recognized.
Regardless of aetiology, alveolar growth abnormalities are often
accompanied by some degree of secondary pulmonary arterial
changes due to the increased vascular resistance resulting from the
deficient capillary bed. AGA are also commonly associated with
pulmonary interstitial glycogenosis (see below), a feature which
may explain acute exacerbation of known chronic neonatal lung
disease.
Pulmonary interstitial glycogenosis
Pulmonary interstitial glycogenosis (PIG), also called infantile
cellular interstitial pneumonia (ICIP) or cellular interstitial
pneumonitis of infancy, is a poorly understood entity of the infant
lung characterized by interstitial expansion due to increased
mesenchymal cellularity (Figure 3B).33,34 These interstitial cells
have bland uniform ovoid nuclei with pale chromatin and
increased cytoplasmic glycogen demonstrable by PAS stain or
electron microscopy. Although PIG is thought to be a reactive
condition of the growing infant lung, the interstitial cells are not
inflammatory cells (leukocytes or histiocytes), but instead appear
to be more similar to fibroblastic cells. PIG is a vastly under-
recognized and underreported histologic pattern, and is a
relatively common feature of biopsies for diffuse lung disease in
infants less than six months of age, particularly those with other
superimposed forms of lung injury, for example, AGA, pulmonary
arteriopathy, meconium aspiration, compressed lung adjacent to
congenital lung malformations, and others. While PIG may be
diffuse, many cases show only a patchy distribution, perhaps
leading to underrecognition of this process. Infants with PIG
usually improve clinically over time and with steroid therapy. The
prognosis is generally good, although clinical outcome is largely
dependent on the severity and/or reversibility of any associated
lung disease. Neither term describing this disorder is entirely
satisfactory, as ICIP creates confusion with CPI and PIG creates
unfortunate confusion with glycogen storage disease. As patho-
genesis and cell of origin become better understood, the diagnostic
terminology should be re-evaluated.
Neuroendocrine cell hyperplasia of infancy
Neuroendocrine cell hyperplasia of infancy (NEHI) is an entity
described in 2005 as the pathologic correlate of the clinical
syndrome of persistent tachypnoea of infancy. These patients
typically present with tachypnoea, hypoxia, and retractions.10
Chest x-ray shows hyperexpansion, and chest CT demonstrates
patchy ground-glass opacities, most prominently in the central
right middle lobe and lingula. While NEHI patients typically come
to medical attention in infancy, symptoms may persist in toddlers
and older children. The pathogenesis is not understood, and it
remains unclear whether NEHI is an intrinsic abnormality of
airway development influenced by genetic factors, or whether it is
secondarily induced by preceding airway injury, viral infection,
environmental influences, or chronic hypoxia.
Lung biopsy in these patients is surprisingly ‘‘normal’’ by H&E
stain, with only minimal, if any, airway changes (Figure 4A). Non-
specific airway abnormalities may include a mild increase in airway-
associated lymphoid tissue, mild reactive epithelial hyperplasia,
mildly increased airway smooth muscle, and increased numbers of
clear cells in the bronchiolar epithelium. Diagnosis is confirmed by
using immunohistochemistry to demonstrate increased neuroen-
docrine cells. Bombesin is the immunohistochemical antibody most
widely studied and provides the basis for standardization of
diagnosis (Figure 4B). Guidelines for histologic diagnosis include:
(1) neuroendocrine cells in at least 75% of total airway profiles, (2)
neuroendocrine cells representing at least 10% of epithelial cells in
individual airway profiles, (3) large and/or numerous neuroepithe-
lial bodies, and (4) absence of other significant airway or interstitial
disease. The absence of superimposed pathologic processes is an
important criterion, since secondary neuroendocrine cell hyperpla-
sia has been associated with a number of lung disorders including
bronchopulmonary dysplasia, cystic fibrosis, pulmonary hypoplasia,
mechanical ventilation, acute lung injury, and smoke exposure. It
should be emphasized that NEHI is a clinical-radiographic-
pathologic diagnosis, and definitive diagnosis should be made only
in the appropriate clinical setting and with supportive imaging
characteristics.
DISORDERS OF THE NORMAL HOST
Obliterative bronchiolitis
Obliterative bronchiolitis (OB), also called constrictive bronch-
iolitis, is the pathologic process underlying bronchiolitis obliterans
syndrome (BOS), a constellation of clinical findings including an
obstructive pattern on pulmonary function tests and evidence of
mosaic perfusion and air-trapping on expiratory chest CT.35 BOS is
relatively common in children, and the differential diagnosis
 M.K. Dishop / Paediatric Respiratory Reviews 12 (2011) 230–237 235

Figure 4. Neuroendocrine cell hyperplasia of infancy (NEHI). NEHI is a clinicopathologic syndrome characterized by persistent tachypnoea and oxygen requirement in infants
and young children. A. Histologically, there are very few abnormalities by routine light microscopy. Subtle clues to diagnosis in this case include alveolar duct expansion
(hyperinflation) and large club-like projections of cuboidal cells at the interface of the respiratory bronchiole and alveolar ducts (large neuroepithelial bodies). B.
Immunohistochemistry for bombesin highlights increased numbers of neuroendocrine cells (at least 10%) within the airway epithelium.

includes prior viral infection, chronic aspiration injury, Stevens-
Johnson syndrome, chronic airway rejection in lung transplant
recipients, and chronic graft versus host disease in bone marrow
transplant recipients. Histologically, OB is characterized by varying
degrees of airway fibrosis, ranging from mild subepithelial fibrosis
with luminal constriction to complete fibrosis with obliteration of
the airway lumen. The presence of ‘‘unpaired’’ pulmonary artery
branches and secondary findings, such as mucus stasis, airspace
distention, increased foamy macrophages, and cholesterol clefts,
are helpful clues to diagnosis.
Hypersensitivity pneumonitis
Similar to adults, hypersensitivity pneumonitis (HP) is often
diagnosed clinically by history of environmental exposure and by
imaging and serologic studies.36 Environmental exposures in
children are typically related to bird or fungal antigens, rather than
occupational exposures as seen in adults. Histologic features of HP
on lung biopsy are the same in children and adults: lymphocytic
bronchiolitis, lymphocytic interstitial infiltrates (NSIP pattern),
and small poorly-formed granulomas and giant cells in a perairway
distribution. Chronic hypersensitivity pneumonitis may produce
interstitial fibrosis and cystic remodeling of the lung also.
DISORDERS ASSOCIATED WITH SYSTEMIC DISEASE
Autoimmune/rheumatologic disease
Autoimmune and rheumatologic diseases represent a challen-
ging and dynamic field within diagnostic lung pathology. Just as
there is a wide distribution of autoimmune disease based on
clinical and serologic findings, similarly the pathologic findings
show a wide spectrum of disease. Involvement of multiple
anatomic compartments of the lung (alveoli, interstitium, airways,
vasculature, and/or pleura) is typical. Common histologic patterns
in the rheumatologic disorders include FB and other forms of
lymphoid hyperplasia37,38 (Figure 5A), NSIP pattern (Figure 5B), LIP
pattern, interstitial fibrosis, chronic pulmonary vascular disease,
pleuritis, and pleural fibrosis. Interstitial plasma cells help to
support an autoimmune aetiology. In general, juvenile idiopathic
arthritis in children is often associated with lymphoid hyperplasia
and chronic airway disease. Dermatomyositis may also show
prominent lymphoid hyperplasia and interstitial fibrosis. Systemic
lupus erythematosus shows either chronic lung disease or an acute
pneumonitis pattern. Pleuritis and pleural fibrosis also tend to be
prominent features of lupus. Scleroderma-related lung disease is
often severe, causing interstitial fibrosis and severe arterial disease

Figure 5. Pathologic manifestations of immunologic disease. A. Lymphoid hyperplasia is a histologic pattern which should suggest the presence of immunodeficiency or
autoimmune disease in children and adolescents. B. This case of juvenile idiopathic arthritis is associated with a cellular and fibrosing non-specific interstitial pneumonia
(NSIP) pattern. In children and adolescents, this histologic pattern raises a differential diagnosis of the genetic disorders of surfactant metabolism (ABCA3, SFTPC gene
mutations) and hypersensitivity pneumonitis.
236 M.K. Dishop / Paediatric Respiratory Reviews 12 (2011) 230–237
with intimal fibrosis. Sjögren syndrome may be associated with
patchy or diffuse LIP pattern, lymphocytic bronchiolitis, or FB.
Chronic lung disease is occasionally the first manifestation of
systemic autoimmune disease and these associated histologic
patterns are important to recognize in order that further
evaluation for autoimmune disease can be pursued.
DISORDERS OF THE IMMUNOCOMPROMISED HOST
Immunocompromised and immunosuppressed patients are
susceptible to a wide spectrum of lower respiratory tract
infections, including bacterial, viral, fungal, and parasitic aetiol-
ogies, and these patients may undergo lung biopsy for evaluation
of acute respiratory failure or nodular disease. In addition to these
acute infectious patterns, some patients with primary or acquired
immunodeficiency present with chronic airway or interstitial lung
disease. Specifically, pulmonary lymphoid hyperplasia is a
common manifestation of immunodeficiency disorders. Human
immunodeficiency virus infection may result in follicular lym-
phoid hyperplasia and/or LIP pattern in both adults and children.
Epstein-Barr virus-induced lymphoid proliferation should also be
considered with a pattern of FB. Common variable immunodefi-
ciency classically produces a pattern of FB. Some T cell
immunodeficiencies also may produce lymphocytic bronchiolitis
and perivascular lymphocyte infiltrates. Other rare disorders
which should be considered in the presence of FB, LIP, or other
lymphoid infiltrates in children include autoimmune lymphopro-
liferative syndrome, autoimmune polyendocrinopathy syndrome,
and IPEX (immune dysregulation, polyendocrinopathy, entero-
pathy, X-linked) syndrome.
CONCLUSIONS
The current classification of paediatric lung disease is a
clinicopathologic system which offers a diagnostic construct and
a common language for paediatric pulmonologists, radiologists,
and pathologists. While this has been an important advance in
the field, there are a few aspects of the classification that deserve
further attention in the future. It is organized primarily
according to clinical factors rather than anatomic distribution
of disease, which is desireable for classification according to
aetiology and pathogenesis, but sometimes difficult to apply for
radiologists and pathologists during the diagnostic evaluation
process. The pulmonary haemorrhage syndromes and pulmonary
vascular diseases are incompletely described in this system and
the brief classification does not conform to the WHO classifica-
tion of pulmonary hypertension. As our understanding of
aetiology and pathogenesis of paediatric lung disease continues
to evolve, it is likely that the 2007 proposed classification of
paediatric diffuse lung disease will require ongoing revision and
re-organization.
PRACTICE POINTS
 Inherited disorders of surfactant metabolism are unified
by presence of alveolar epithelial hyperplasia, pulmonary
alveolar proteinosis, foamy macrophages, and variable
chronic lobular remodeling.
 Alveolar growth abnormalities are a group of disorders
with alveolar simplification and include chronic lung
disease associated with prematurity, lung hypoplasia,
chromosomal disorders, and congenital heart disease.
 Pulmonary interstitial glycogenosis is an underrecognized
form of reactive interstitial cellularity in infants.
 Neuroendocrine cell hyperplasia of infancy is the patho-
logic correlate to the clinical syndrome of persistent
tachypnoea of infancy.
 Common histologic patterns associated with immunode-
ficiency and autoimmune disease in children include
follicular bronchiolitis, lymphoid interstitial pneumonia,
and non-specific interstitial pneumonia.
 The differential diagnosis of chronic interstitial lung
disease in older children and adolescents includes the
genetic disorders of surfactant metabolism, hypersensi-
tivity pneumonitis, and autoimmune/rheumatologic dis-
ease.
RESEARCH DIRECTIONS
 The natural history and pathogenesis of pulmonary
interstitial glycogenosis.
 The pathogenesis of neuroendocrine cell hyperplasia of
infancy.
 Genetic causes of disorders of surfactant metabolism and
primary developmental disorders (acinar dysgenesis,
congenital alveolar dysplasia).
 The histopathologic patterns and distinguishing features
of autoimmune disease and primary immunodeficiency
disorders.
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