Children's Interstitial Lung Diseases in Early Infancy

Bonnie H. Arzuaga, Tina Mathai and Owais Khan

Neoreviews 2013;14;e562
DOI: 10.1542/neo.14-11-e562

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Article pulmonology

Children’s Interstitial Lung Diseases in Early

Infancy
Bonnie H. Arzuaga, MD,* Practice Gaps
Tina Mathai, MD,*
Recently described interstitial lung diseases of infancy are frequently not considered in
Owais Khan, MD*
the differential diagnosis of persistent tachypnea and prolonged oxygen requirement.

Author Disclosure Abstract

Drs Arzuaga, Mathai,
and Khan have
disclosed no financial
relationships relevant
to this article. This
commentary does not
contain a discussion of
any unapproved/
investigative use of
a commercial product/
device.
Children’s interstitial lung disease is a group of relatively rare pulmonary disorders that
can present in the neonatal or early infancy periods. A classification scheme was devel-
oped in 2007 to aid clinicians and researchers in more accurate recognition and diag-
nosis. Infants who present with a prolonged oxygen requirement and/or persistent
tachypnea may suffer from one of these conditions. Although more widely described
afflictions, such as pulmonary hypoplasia or genetic errors of surfactant metabolism,
may be considered in the differential diagnosis of these symptoms, a few of the remaining
disorders have been only recently described, making them important entities to become
familiar with in contemporary medical practice. This article describes the lesser-known
conditions that have the potential to cause significant pulmonary disease in infancy.
Objectives After completing this article, readers should understand that:

1. The differential diagnosis for prolonged requirement of supplemental oxygen in an

infant may include atypical prolonged respiratory distress syndrome of the newborn,
chronic lung disease, genetically based surfactant deficiency, and children’s
interstitial lung disease.
2. Evaluation of children’s interstitial lung disease includes chest radiographs, high-
resolution chest computed tomography scan, and pulmonary function tests. Definitive
diagnosis can be made only via lung biopsy.
3. Discovering the underlying etiology for prolonged respiratory distress is important for
prognostication.

Introduction
Children’s interstitial lung disease (chILD), also referred to as rare diffuse lung disease, is
a heterogeneous group of uncommon disorders that present
in childhood. The actual incidence and prevalence of these
diseases are currently difficult to estimate because of their di-
Abbreviations verse nature and suboptimal identification strategies; how-
ACDMPV: alveolar capillary dysplasia with misalignment ever, one study from the United Kingdom and Ireland
of the pulmonary veins estimated the prevalence of lung biopsy-proven disease to
chILD: children’s interstitial lung disease be 0.36 per 100,000 overall, which experts in this field believe
HRCT: high-resolution chest computed tomography may be an underestimation. (1) Of the biopsies reviewed in
scan one of the largest reported series, 68% of them represented
NEHI: neuroendocrine cell hyperplasia of infancy disorders more prevalent in early infancy, making familiarity
PIG: pulmonary interstitial glycogenosis with them vitally important for neonatologists and pediatric
PPHN: persistent pulmonary hypertension of the pulmonologists. (2)
newborn In comparison with interstitial lung disease of adults and
RDS: respiratory distress syndrome of the newborn children that is caused by pulmonary injury and repair, the
disorders specific to infants arise at various stages in fetal

*Section of Neonatology, Department of Pediatrics, Comer Children’s Hospital, University of Chicago, Chicago, IL.

e562 NeoReviews Vol.14 No.11 November 2013

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development. They manifest within the newborn period
or early infancy and present clinically with nonspecific
clinical signs and symptoms that can be easily confused
with respiratory distress syndrome of the newborn
(RDS).
A classification scheme for chILD (Table 1) was devel-
oped in 2007 to aid in alleviating confusion among prac-
titioners due to conflicting nomenclature in the literature
and to help improve diagnosis. In this scheme, the disor-
ders prevalent in infancy are divided into diffuse devel-
opmental disorders, specific conditions of undefined
etiology, genetically based surfactant dysfunction disor-
ders, and growth abnormalities with deficient alveolarization.
(3)
Although practitioners generally consider the more
common lung growth abnormalities and genetic surfac-
tant disorders when evaluating a neonate with persistent
unexplained respiratory distress, the remaining disorders
have the potential to be overlooked in the initial evalua-
tion of these patients. Therefore, the focus of this article is
on diffuse developmental disorders, as well as the specific
conditions of undefined etiology. A few of these disorders
Classification of Diffuse
Table 1.
Lung Disease in Childhood;
Disorders More Prevalent in
Infancy
Diffuse developmental disorders
• Alveolar capillary dysplasia with misalignment of
pulmonary veins (ACDMPV)
• Congenital alveolar dysplasia
• Acinar dysplasia
Specific conditions of undefined etiology
• Neuroendocrine cell hyperplasia of infancy (NEHI)
• Pulmonary interstitial glycogenosis (PIG)
Surfactant dysfunction disorders
• Surfactant protein B (SFTPB) mutation
• Surfactant protein C (SFTPC) mutation
• ABCA3 mutation
• Histology consistent with surfactant dysfunction
disorder without a yet recognized genetic etiology
Growth abnormalities reflecting deficient alveolarization
• Pulmonary hypoplasia
• Chronic neonatal lung disease
• Abnormalities related to congenital heart disease or
chromosomal disorders
Adapted from Deutsch GH, Young LR, Deterding RR, et al. Diffuse
lung disease in young children. Application of a novel classification
scheme. Am J Respir Crit Care Med. 2007;176:1122
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pulmonology interstitial lung disease
have been described only within the past decade, making
them unfamiliar yet important entities for the modern
clinician’s differential diagnosis.
Case Presentation
A male infant is born at 36 weeks’ gestation, weighing
2,625 g, to a 39-year-old Caucasian woman, gravida 4
para 3 following preterm labor. The mother had no sig-
nificant medical problems and her previous children were
all healthy. The infant’s Apgar scores are 9 and 9 at 1 and
5 minutes, respectively, and he is admitted to the new-
born nursery.
Two hours after delivery, he develops persistent grunt-
ing, nasal flaring, and retractions. He is placed on oxygen
and transferred to the regional perinatal center for further
management. The following day, he requires intubation
and subsequently receives two doses of exogenous surfac-
tant for presumed RDS. He is extubated by his fifth day
after birth. He continues to require supplemental oxy-
gen via high-flow and eventually low-flow nasal cannula
for the next month. He fails multiple attempts to wean
to room air by becoming repeatedly tachypneic and hyp-
oxic with oxygen saturation percentages in the 80s with
each trial.
Because of his prolonged oxygen need, a high-resolution
chest computed tomography scan (HRCT) is obtained,
which demonstrates large lung volumes with diffuse hazy
opacities present within the lung tissue. Serum genetic
studies for inborn errors of surfactant metabolism are sent
and return with no significant mutations in the genes for
surfactants B or C or the ABCA3 transporter protein. A
preliminary broad diagnosis of chILD is made. The child
is sent home with supplemental oxygen to be followed
by pediatric pulmonology as an outpatient. By age 7
months, he is able to be weaned from oxygen and does
well on room air.
Diffuse Developmental Disorders of the Lung
Alveolar capillary dysplasia with misalignment of the pul-
monary veins (ACDMPV) is the most common diffuse
developmental disorder of the lung, and consists of the
malposition of pulmonary veins adjacent to small pulmo-
nary arteries, medial hypertrophy of pulmonary arteries
and arterioles, and reduced capillary density with lobular
maldevelopment (Figure 1). (3)(4) ACDMPV was first
described in 1947 as a condition involving either both lungs
uniformly or only a portion of a single lobe. Since this early
description, more than 100 cases have been reported. (4)
ACDMPV is a rare fatal developmental lung disorder
of neonates and infants, with more than 90% of affected
NeoReviews Vol.14 No.11 November 2013 e563
pulmonology interstitial lung disease
patients born at term. (4) Infants present with acute re-
spiratory failure early in life, manifested as tachypnea, cy-
anosis, and symptoms similar to persistent pulmonary
hypertension of the newborn (PPHN). The onset of re-
spiratory failure and cyanosis often occurs within 48 hours
after birth. (4) The etiology of ACDMPV is unknown,
but is believed to be due to abnormalities in the primary
molecular mechanisms of lung and pulmonary vascular
development. (3)
Clinical evaluation of these infants includes chest ra-
diographs and an echocardiogram. Laboratory tests are
not pathognomonic. Chest radiographs may show hazi-
ness or ground-glass opacities, but in some cases can also
be interpreted as normal. (4) Echocardiogram should be
obtained to exclude cardiac causes for PPHN. Findings
may demonstrate suprasystemic right ventricular pres-
sures and right to left shunting across the patent ductus
arteriosus and/or patent foramen ovale.
ACDMPV is definitively diagnosed by histological ex-
amination of lung tissue on autopsy or ante mortem lung
biopsy. (4) Pathology may demonstrate failure of forma-
tion and ingrowth of alveolar capillaries, abnormal air-
blood barriers, and anomalous veins in bronchovascular
bundles. (5) Genetic testing is available for a FOXF1 mu-
tation or deletion, a gene that has been implicated in up
to 40% of cases.
Treatment is often similar to that of neonates who
present with PPHN. Strategies include high-frequency
ventilation or surfactant administration. Pulmonary vaso-
dilation with inhaled nitric oxide may result in a transient
response, but most cases have documented deterioration
within a few hours. Overall, response to therapy is often
minimal and not sustained. This disease is generally fatal,
although evidence of a less-severe phenotype compatible
Figure 1. Alveolar capillary dysplasia. A. Abnormal pulmonary veins running alongside the
bronchi and pulmonary artery branches. B. The distal air spaces are separated by thick-walled nary mesenchymal cells or is
septa containing a small number of vessels showing little contiguity with the air space caused by a nonspecific reaction
epithelium. (Reprinted from Wright C. Congenital malformations of the lung. Curr Diagn of lung injury is currently under
Pathol. 2006;12(3):198 with permission from Elsevier Limited)
e564 NeoReviews Vol.14 No.11 November 2013
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with prolonged survival may exist. (4) Lung transplanta-
tion may be considered in certain cases if early diagnosis is
achieved.
The remaining developmental disorders included in
the classification scheme are congenital alveolar dysplasia
and acinar dysplasia. Acinar dysplasia is exceedingly rare
and is characterized by an absence of alveolar develop-
ment, with airways distal to the bronchi composed of ir-
regularly branching bronchiolar structures lined by ciliated
epithelium. It is invariably fatal and has been described in
only a handful of cases. (6) Congenital alveolar dysplasia is
an arrest of alveolar development at a later fetal stage than
acinar dysplasia. Although there is debate as to whether
these entities represent varying severity of the same disease,
misalignment of blood vessels is not found in either,
thereby differentiating them from ACDMPV. (7)
Pulmonary Interstitial Glycogenosis
Pulmonary interstitial glycogenosis (PIG) is a clinical en-
tity that was initially described in 2002. (8) It has been
included in the classification scheme of chILD as a specific
condition of undefined etiology. (3) Most infants who
have this disorder present within 24 hours after birth with
symptoms mimicking those of RDS due to surfactant de-
ficiency. (8) Clinical signs include acute respiratory dis-
tress and hypoxia, occasionally progressing toward the
need for intubation. Many infants may receive exogenous
surfactant because of misdiagnosis but do not show sig-
nificant improvement. (8)
PIG is histologically characterized by deposition of
glycogen within the cells of the pulmonary interstitium,
leading to widening of interalveolar septae (Figure 2).
There is no marked accumulation of cells or proteina-
ceous material within the alveolar spaces. Often times,
other inflammatory or infec-
tious causes have been ruled
out. (8)(9) Although PIG is
usually an isolated finding in
term neonates, diffuse or patchy
deposition of glycogenated inter-
stitial alveolar cells do accompany
other pulmonary conditions,
(10) particularly disorders of
lung growth deficiency or mal-
development. Whether the path-
ophysiology of PIG is due to an
abnormal aberration of pulmo-
debate. (9)(11)

Figure 2. Pulmonary interstitial anatomy. Source: http://www.bioscience.org/1997/v2/d/ with favorable response. Because
longwort/fig1.gif.
Most of what is currently known about PIG comes
from case reports. Neonates, most often boys, present
with rapid onset of respiratory distress and hypoxemia re-
quiring oxygen supplementation and, in some cases, me-
chanical ventilation. (9)(11) Radiographic findings at the
time of presentation are variable and nonspecific. Chest
radiographs often display severe diffuse interstitial opac-
ities with evident hyperinflation, similar to findings in
bronchopulmonary dysplasia. However, the rapid and
dramatic evolution of these findings without the previous
need of positive pressure ventilation would make the di-
agnosis of bronchopulmonary dysplasia unlikely. (11)
HRCT shows findings consistent with pulmonary inter-
stitial disease but are highly variable and nonspecific to
PIG. Currently, lung biopsy is the only means for defin-
itive diagnosis. (10)
Ehsan et al described spirometry findings in PIG as be-
ing consistent with significant restrictive lung disease
without obstruction and does not improve with broncho-
dilators. (9) Also observed was a reduction in pulmonary
diffusion capacity, likely due to the thickened alveolar
septae seen on biopsy. This eventually normalizes with
resolution of disease. However, forced vital capacity re-
mains low, as one would expect in diffuse interstitial lung
disease. (9)
Most cases of PIG show clinical and histological reso-
lution over time, leading to a favorable prognosis. Only
one death occurred of the seven infants in the original re-
ported series. This infant was born at 25 weeks’ gestation
and died from complications of cor pulmonale. (8) Over-
whelmingly, clinical improvement or complete resolution
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pulmonology interstitial lung disease
has been described in the small
number of other case reports that
have been published to date.
Morbidity and mortality have
been reported more often in
patients with underlying lung
growth abnormalities. (10) The
chILD Research Network re-
ported nine deaths in infants
whose lung biopsies demonstrated
diffuse lung growth abnormali-
ties with patchy PIG, suggesting
a confounding factor leading to
increased mortality.
As a treatment modality, cor-
ticosteroids have been used in
many reported cases of PIG,
PIG is not an inflammatory dis-
ease, the clinical improvement
observed following oral or systemic steroid therapy sug-
gests a possible role in acceleration of the pulmonary mat-
uration process. (8) However, many infants have also
clinically improved over time without the use of steroids.
Because of the limited amount of available literature,
more studies are needed to assess whether steroids do
in fact accelerate regression of disease.
Neuroendocrine Cell Hyperplasia of Infancy
Neuroendocrine cell hyperplasia of infancy (NEHI),
which was previously referred to in the literature as persis-
tent tachypnea of infancy, was first described and classified
in 2005 by Deterding and colleagues. (12) Infants in the
original series presented with persistent tachypnea and ox-
ygen requirement at age 0 to 11 months. These patients
suffered from persistent retractions, hypoxia, and tachyp-
nea and became of significant clinical concern at a mean
age of 3.8 months. Diffuse persistent crackles were the
most prominent finding on auscultation and only a few pa-
tients had wheezing or cough. Despite their symptoms, it
was noted that most patients had not required supplemen-
tal oxygen in the neonatal period and of those who did,
none had required it for more than 36 hours after birth.
The etiology on NEHI is currently unknown, although fa-
milial cases have been reported suggestive of a genetic predis-
position. In families described, the likely mode of inheritance
appears to be either autosomal recessive or autosomal domi-
nant with incomplete penetrance. (13)
Clinical evaluation for patients suspected to have NEHI
includes chest radiographs, HRCT, pulmonary function tests,
and, if needed, a lung biopsy. Chest radiographs demonstrate
NeoReviews Vol.14 No.11 November 2013 e565
pulmonology interstitial lung disease
hyperexpansion of the lungs. HRCT can be extremely helpful
due to specific features, although cannot be used to exclude
the diagnosis. The appearance of ground-glass opacities in
a subsegmental or segmental distribution, mainly within
the right middle lobe and lingula, is the most common find-
ing. This is in contrast to hereditary surfactant deficiency,
which demonstrates ground-glass densities in a more diffuse
pattern. Pulmonary hyperexpansion with air trapping is the
second most common finding. (14)
Lung biopsies show increased bombesin staining with
antibodies to neuroendocrine cell products without evi-
dence of significant inflammation. Changes in the pulmo-
nary vasculature consistent with pulmonary hypertension
are absent.
Most patients do not respond to treatment with either
bronchodilators or systemic glucocorticoids. The use of sup-
plemental oxygen is the most useful management strategy,
with the expectation that it will be needed for approximately
2 to 3 years in most cases. This disease is generally not fatal,
with most patients having a good overall prognosis. Occasion-
ally, mild exercise intolerance or intermittent tachypnea,
wheezing, and crackles can be expected as long-term conse-
quences. (12)(13)
Conclusions
Although rare, chILDs are an important group of disorders
to consider when faced with an infant requiring prolonged
supplemental oxygenation and/or persistent tachypnea. Each
individual disease has its own unique clinical course and prog-
nosis, underscoring the importance of accurate diagnosis.
Note: Readers may also wish to consult the Index of Suspi-
cion in the Nursery case in the September 2013 issue: http://
neoreviews.aappublications.org/content/14/9/e463.extract
American Board of Pediatrics Neonatal–Perinatal
Content Specifications
• Plan the ventilatory therapy for
infants with respiratory failure of
different etiologies.
e566 NeoReviews Vol.14 No.11 November 2013
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ACKNOWLEDGMENTS. The authors thank Dr Joseph
Hageman with assistance in the review of this manu-
script.
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 Children's Interstitial Lung Diseases in Early Infancy
Bonnie H. Arzuaga, Tina Mathai and Owais Khan
Neoreviews 2013;14;e562
DOI: 10.1542/neo.14-11-e562

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