interstitial lung disease in children younger than 2 years · interstitial lung disease in children...

Interstitial Lung Disease in Children Younger Than 2 YearsPaolo Spagnolo, MD, PhD, a Andrew Bush, MDb, c

aMedical University Clinic, Canton Hospital Baselland, and

University of Basel, Liestal, Switzerland; bRoyal Brompton

Hospital and Harefi eld NHS Foundation Trust, London,

United Kingdom; and cNational Heart and Lung Institute,

Imperial College, London, United Kingdom

Dr Spagnolo conceptualized the review article and

drafted the initial manuscript; Dr Bush developed

the review article and reviewed and revised the

manuscript; and both authors approved the fi nal

manuscript as submitted.

DOI: 10.1542/peds.2015-2725

Childhood interstitial lung disease

(chILD) comprises a large and

heterogeneous group of rare disorders

characterized by diffuse pulmonary

infiltrates, restrictive lung physiology,

and impaired gas exchange, which

are associated with substantial

morbidity and mortality.1–5 The term

“interstitial” is, however, misleading,

as most of these conditions are

associated with abnormalities that are

not limited to the lung interstitium

but extend to the alveolar and airway

compartments. Although it could be

argued that “diffuse lung disease” is a

better term, the term “chILD” is in fact

now well established in the literature.

Historically, terminology and

classification of interstitial lung disease

(ILD) in children have mirrored those

of adult disease, but this is generally

not helpful. Indeed, there are major

differences in disease etiology, natural

history, and management between

the pediatric age group, in whom ILD

most often develops primarily because

of an underlying developmental or

genetic abnormality, 6 and adults.

For instance, adult desquamative

interstitial pneumonia (DIP) is a

relatively benign smoking-related

condition, whereas pediatric cases

are often associated with surfactant

protein C (SP-C) and adenosine

abstractChildhood interstitial lung disease (chILD) represents a highly

heterogeneous group of rare disorders associated with substantial

morbidity and mortality. Although our understanding of chILD remains

limited, important advances have recently been made, the most important

being probably the appreciation that disorders that present in early life

are distinct from those occurring in older children and adults, albeit with

some overlap. chILD manifests with diffuse pulmonary infiltrates and

nonspecific respiratory signs and symptoms, making exclusion of common

conditions presenting in a similar fashion an essential preliminary step.

Subsequently, a systematic approach to diagnosis includes a careful history

and physical examination, computed tomography of the chest, and some

or all of bronchoscopy with bronchoalveolar lavage, genetic testing, and if

diagnostic uncertainty persists, lung biopsy. This review focuses on chILD

presenting in infants younger than 2 years of age and discusses recent

advances in the classification, diagnostic approach, and management of

chILD in this age range. We describe novel genetic entities, along with

initiatives that aim at collecting clinical data and biologic samples from

carefully characterized patients in a prospective and standardized fashion.

Early referral to expert centers and timely diagnosis may have important

implications for patient management and prognosis, but effective therapies

are often lacking. Following massive efforts, international collaborations

among the key stakeholders are finally starting to be in place. These have

allowed the setting up and conducting of the first randomized controlled

trial of therapeutic interventions in patients with chILD.

STATE-OF-THE-ART REVIEW ARTICLEPEDIATRICS Volume 137 , number 6 , June 2016 :e 20152725

To cite: Spagnolo P and Bush A. Interstitial

Lung Disease in Children Younger Than 2 Years.

Pediatrics. 2016;137(6):e20152725

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SPAGNOLO and BUSH

triphosphate binding cassette family

member 3 (ABCA3) mutations and

have a poor prognosis, particularly

if they present in the neonatal

period.1, 7–9 Similarly, idiopathic

pulmonary fibrosis, the most common

and severe of the idiopathic interstitial

pneumonias in adults, 10, 11 is not found

in children. On the other hand, there

are forms of ILD that are unique to

infants and children younger than 2

years of age, 7 hence the use of adult

terminology and classification does

not adequately address pediatric

entities. Therefore, new appropriate

codes have recently been added

for several chILD disorders in the

International Classification of Diseases, Ninth Revision.12 Moreover, the

multi-institutional ChILD Research

Cooperative has recently developed

a classification system specifically

for young children.7, 13 Despite

some conceptual and practical

limitations (eg, it focuses exclusively

on young children who underwent

diagnostic lung biopsy, thus providing

little guidance in cases without a

confirmatory lung biopsy, and does

not address properly those cases

showing features of >1 entity), this

classification system groups disorders

with similar clinical and/or pathologic

features, and provides consensus

terminology, diagnostic criteria, and

a useful framework for approaching

chILD, particularly entities unique

to young children (Table 1). The

chILD scheme is also applicable to

patients in the 2- to 18-year-old group,

although additional entities, such

as lymphoproliferative disorders,

hypersensitivity pneumonitis, or

pulmonary hemorrhage syndromes,

need to be included.14, 15

Signs and symptoms of chILD are

nonspecific, and the diagnosis

of chILD may not be considered

initially. In fact, the rarity of these

conditions hampers hugely the

acquisition of adequate knowledge,

which almost invariably results

in delayed diagnosis. Compared

with adult disease, 16 chILD

occurs far less frequently, with a

prevalence of idiopathic ILD among

immunocompetent children aged 0 to

16 years being estimated at 3.6 cases

per million, 17 although this is likely to

be an underestimate.18

Our understanding of chILD

remains incomplete. However,

important advances in disease

mechanisms, diagnostic approach,

and management have been recently

made. In this review, we summarize

and discuss these with special

attention to conditions that are

unique to infants.

DIAGNOSTIC APPROACH

The primary diagnostic step is to

identify children who require further

investigation for chILD. To this end,

2

TABLE 1 Classifi cation of ILD in Children Aged 0 to 2 Years

Category Examples of Specifi c Diagnoses

Diffuse developmental disorders Acinar dysplasia

Congenital alveolar dysplasia

Alveolar capillary dysplasia with misalignment of pulmonary veins

Alveolar growth abnormalities Pulmonary hypoplasia

Chronic neonatal lung disease

Associated with chromosomal disorders (eg, trisomy 21)

Associated with congenital heart disease

Specifi c conditions of undefi ned etiology NEHI

PIG

Surfactant dysfunction disorders Mutations in SP-B, SP-C, ABCA3, NKX2.1/TTF1; histology consistent with surfactant dysfunction

disorders but without documented genetic cause

Disorders related to systemic disorders Collagen vascular disease (systemic lupus erythematosus, systemic sclerosis, polymyositis/

dermatomyositis)

Storage diseases

Sarcoidosis

Langerhans cell histiocytosis

Malignant infi ltrates

Disorders of the normal host-presumed immune intact Infectious/postinfectious processes

Environmental agents (hypersensitivity pneumonitis, toxic inhalation)

Aspiration syndromes

Eosinophilic pneumonia

Disorders of the immunocompromised host Opportunistic infections

Iatrogenic

Related to transplantation and rejection

Diffuse alveolar damage (unknown etiology)

Disorders masquerading as ILD Arterial hypertensive vasculopathy

Congestive changes related to cardiac dysfunction

Veno-occlusive disease

Lymphatic disorders

Adapted from Deutsch GH, Young LR, Deterding RR, et al; Pathology Cooperative Group; ChILD Research Co-operative. Diffuse lung disease in young children: application of a novel

classifi cation scheme. Am J Respir Crit Care Med. 2007;176(11):1122.


PEDIATRICS Volume 137 , number 6 , June 2016

more common causes of diffuse

lung disease (eg, cystic fibrosis,

immunodeficiency, or congenital

heart disease) sharing a common

presentation with chronic respiratory

symptoms (eg, tachypnea, cough, and

hypoxemia) and diffuse radiographic

infiltrates should be excluded. Once

major non-chILD disorders have been

excluded, the term “chILD syndrome”

is used to refer to children who

meet at least 3 of the following 4

criteria: (1) respiratory symptoms

(cough, rapid breathing, or exercise

intolerance), (2) signs (resting

tachypnea, adventitious sounds,

retractions, digital clubbing, failure

to thrive, or respiratory failure),

(3) hypoxemia, and (4) appropriate

diffuse abnormalities on chest

imaging.1

A systematic approach to patients

with chILD is crucial in establishing

the diagnosis (Fig 1). Clinical

context can provide valuable

differential diagnostic clues. For

instance, neonates presenting

acutely with respiratory distress

and hypoxemia are more likely to

have developmental lung disorders,

whereas a family history of siblings

with similar lung conditions may

suggest a genetic or familial lung

disease, such as inborn errors of

surfactant metabolism. However,

further diagnostic testing is always

required; the pace of testing

depends on the clinical situation:

in an ill child, a lung biopsy may be

performed urgently, but if the child

is stable, it may be appropriate to

await the results of genetic testing.

It is important to plan investigations

so as to minimize the number of

general anesthetics for the child; so

for example, unless it is likely that

bronchoscopy will be diagnostic, and

obviate the need for a lung biopsy,

the procedure should probably be

better combined with lung biopsy

under the same anesthetic.

Lung Function Tests

Most experience is in older

children, whereas data in infants

are limited. The biggest data set is

in neuroendocrine cell hyperplasia

of infancy (NEHI), which is

characterized by airflow obstruction

and hyperinflation.19 At school age,

lung function tests typically show a

restrictive ventilatory defect with

reduced total lung capacity, forced

vital capacity, and forced expiratory

volume in 1 second with a normal or

elevated forced expiratory volume

in 1 second/forced vital capacity

ratio.20 Elevated residual volume and

residual volume/total lung capacity

ratio suggest air trapping.

Imaging

Chest computed tomography

(CT), compared with plain chest

radiographs, provides more

precise information about extent

and distribution of parenchymal

abnormalities. It is used to confirm

that chILD is indeed the underlying

problem and to guide the site of a

biopsy; in addition, it can sometimes

be used to make specific diagnoses.

Common radiographic patterns

include ground glass opacity

(GGO), geographic hyperlucency,

consolidation, septal thickening,

lung cysts, and nodules.21, 22 In

some cases, CT findings are highly

suggestive or even characteristic,

thus obviating the need for invasive

procedures.23 CT may also provide

prognostic information (eg, NEHI

has a favorable prognosis, whereas

growth abnormalities and surfactant

mutations carry substantial

mortality).

Bronchoalveolar Lavage

The most common indication for

pediatric bronchoalveolar lavage

(BAL) is detection of infection

both in immunocompromised

and immunocompetent hosts.24

Occasionally, this procedure may

also provide useful information in

children with suspected chILD.25

For example, in the appropriate

clinical setting, BAL may help to

identify diffuse alveolar hemorrhage

or aspiration by the presence of

hemosiderin-laden or lipid-laden

macrophages, respectively.6 Other

patterns of BAL cellularity (eg,

lymphocytosis or eosinophilia) are

less indicative of specific conditions.

Genetic Testing

If positive, genetic testing may allow

the diagnosis of known single-gene

disorders. However, at present, a

genetic cause has been identified

for only a minority of chILD (eg,

3

FIGURE 1Proposed fl owchart for investigating ILD in children (chILD). If the child is well and stable, progress to the more invasive investigations may not be indicated. (Reproduced with permission from Bush A, Cunningham S, de Blic J, et al. chiLD-EU collaboration. Thorax. 2015;70(11)1080.)


SPAGNOLO and BUSH

mutations in surfactant protein B [SP-B] and SP-C genes, the gene encoding

the surfactant processing protein

ABCA3 and thyroid-transcription-

factor 1 [TTF-1]).13 In addition, as

the results of genetic tests may not

be available for several weeks, a

lung biopsy may still be necessary to

make a secure diagnosis in severe or

progressive cases.

Lung Biopsy

Lung biopsy remains the gold

standard for chILD when less

invasive tests have failed to secure

a diagnosis.7 Open lung biopsy and

video-assisted thoracoscopy are

the most reliable ways to obtain

adequate tissue for diagnosis.7, 26

Whatever technique is used,

adequate processing of lung

biopsies is essential to ensure

optimal diagnostic yield.27 Similarly

important is that such biopsies are

interpreted by a pathologist with

expertise in pediatric lung disease.

TREATMENT OPTIONS AND OUTCOME

Most patients with chILD require

treatment of some sort. Management

is generally supportive, including

supplemental oxygen for chronic

hypoxemia, adequate nutrition,

proper immunization, avoidance

of environmental pollutants,

and treatment of intercurrent

infections. Further treatments can

be divided into specific therapies

(for example, etanercept for

sarcoidosis, inhaled granulocyte-

macrophage colony-stimulating

factor for pulmonary alveolar

proteinosis due to circulating anti–

granulocyte-macrophage colony-

stimulating factor autoantibodies)

and nonspecific pharmacological

treatment, which is based on small

case series and low-quality evidence

with treatment decisions being

made on a case-by-case basis.13

There are currently no randomized

controlled trials of any treatment

of chILD. Systemic steroids and

hydroxychloroquine remain the

treatment of choice for most patients

with chILD, based on the assumption

that suppressing inflammation may

prevent evolution to fibrosis.28

European treatment protocols have

recently been published.29

Systemic Steroids

Steroids can be administered orally

or intravenously depending on

disease severity.2 Oral prednisolone

is generally administered at a dosage

of 1 to 2 mg/kg per day, whereas

methylprednisolone is usually given

at a dosage of 10 to 30 mg/kg per day

for 3 consecutive days, followed by

single monthly pulses for a minimum

of 3 cycles.1, 30 Dosage and duration

of treatment depend on disease

severity and clinical response, and

should be weighed against the

morbidity of steroid treatment.

Broadly speaking, conditions that

tend to respond to steroid therapy

include DIP and nonspecific

interstitial pneumonia (NSIP) (when

no underlying diagnosis has been

made) and idiopathic pulmonary

hemosiderosis.3

Hydroxychloroquine

Hydroxychloroquine is an

antimalarial agent with a number

of immunologic effects that may

be beneficial in chILD.31 Recently,

Braun and colleagues32 performed

an extensive literature search and

identified 85 case reports or small

case series of children with ILD

treated with either chloroquine

or hydroxychloroquine published

between 1984 and 2013. Clinical

response varied widely, although,

overall, a positive treatment effect

was more likely to be seen in cases of

lymphocytic interstitial pneumonia,

idiopathic pulmonary hemosiderosis,

or cellular interstitial pneumonia. An

ophthalmologic examination at the

start of treatment is recommended

due to the known risk of ocular

toxicity.33

A number of other treatments

have been used in various

chILDs, including azithromycin,

methotrexate, azathioprine,

cyclosporine, and rituximab.

The evidence base for efficacy

is, however, even less than

for corticosteroids and

hydroxychloroquine.

Lung transplantation is an option for

children with end-stage disease, with

long-term outcomes comparable to

lung transplant recipients with cystic

fibrosis and pulmonary vascular

disease.34

The prognosis for children with

ILD is highly variable, with

pulmonary hypertension (PH)

being the single greatest clinical

predictor of mortality.7 Infants with

NEHI generally have a favorable

prognosis, although they may remain

symptomatic and require long-

term oxygen. At the other end of

the spectrum, children with growth

failure, PH, and severe fibrosis

have a poor prognosis. Indeed, in

the ChILD Research Cooperative

study of children <2 years of age,

mortality was highest (100%) in

developmental disorders and ABCA3

mutations, and lowest in NEHI,

pulmonary interstitial glycogenosis

(PIG), and SP-C mutations, 7 although

fatal cases of PIG and SP-C mutations

also have been described.35, 36

DISORDERS MORE PREVALENT IN INFANTS AGE 0 TO 2 YEARS

The initial classification, 7 although

an excellent first attempt, can

be criticized. It is based only on

biopsies, thus excluding conditions

not requiring a tissue diagnosis.

Newer work has highlighted other

disorders not covered by the original

classification, 14 and it includes

conditions (obliterative bronchiolitis

and bronchopulmonary dysplasia,

for example) that many would not

consider as chILD; and the fact

that the same condition can cause

>1 type of abnormality was not

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really appreciated.14 Clearly, chILD

classification is an ongoing work in

progress; nonetheless, the initial

article has given us a very useful

framework.

Diffuse Developmental Disorders

Diffuse developmental disorders,

which include acinar dysplasia,

congenital alveolar dysplasia,

and alveolar capillary dysplasia

associated with misalignment of

pulmonary veins (ACDMPV), are a

group of poorly understood primary

disorders that occur during the

earliest stages of lung development.

Accordingly, biopsies from these

patients display arrest in lobular

development, reduced alveolar

capillary density, and hypertensive

arterial remodeling.7 ACDMPV is also

characterized by markedly dilated

bronchial veins due to prominent

right-to-left intrapulmonary vascular

shunt (eg, pulmonary artery–

bronchial artery anastomoses, which

bypass the alveolar capillary bed;

the pulmonary veins themselves

are not in fact misplaced, what

is seen are the hypertrophied

bronchial veins).37 In addition,

ACDMPV is often accompanied by

cardiovascular, gastrointestinal, or

genitourinary system anomalies.

Without lung transplantation,

diffuse developmental disorders

are almost universally fatal due

to rapidly progressive respiratory

failure and PH, which develop within

days of birth.38 However, longer

survivors have also been reported.39

Recently, inactivating deletions

and point mutations within the FOX

transcription factor gene cluster on

16q24.1 have been identified in cases

of ACDMPV with distinct congenital

malformations, 40 suggesting the

utility of genetic testing in neonates

presenting with respiratory

failure and PH, especially when

gastrointestinal, cardiovascular, or

genitourinary abnormalities coexist.

Alveolar Growth Abnormalities

Alveolar growth abnormalities

are the most common cause

of chILD in infants.6, 7, 41 Unlike

diffuse developmental disorders,

in infants with alveolar growth

abnormalities, abnormal pulmonary

development is secondary and may

be seen in a variety of settings,

including pulmonary hypoplasia

associated with prenatal conditions

(eg, oligohydramnios, abdominal

wall defects, or neuromuscular

disease), prematurity (eg, chronic

neonatal lung disease), chromosomal

abnormalities (eg, trisomy 21; Fig

2 A–D), congenital heart diseases,

and, in term infants, postnatal lung

injury. Affected children present

with varying degrees of respiratory

distress and hypoxemia. Although

rarely diagnostic, characteristic

imaging findings are seen in specific

conditions. For instance, chronic

neonatal lung disease of prematurity

(which many would doubt is a

true chILD) is characterized by

hyperlucent areas corresponding to

alveolar enlargement and reduced

distal vascularization, and linear

opacities, which reflect fibrotic

changes.42 Histologically, disorders

in this category are characterized by

variable lobular simplification with

alveolar enlargement and deficient

septation. Mortality rate, at 34%, is

substantial with prematurity and

severity of the growth abnormality

representing the strongest predictors

of poor outcome.7

NEHI

NEHI is a disorder of unknown

etiology that typically manifests in

the first year of life with chronic

tachypnea, retractions, hypoxemia,

and crackles on chest auscultation.43

Chest radiograph almost invariably

shows hyperinflation, whereas

high-resolution CT (HRCT) imaging

typically shows air trapping in a

mosaic attenuation pattern affecting

at least 4 lobes; geographic GGO

is most conspicuous in the right

middle lobe and lingula.42 When

interpreted by experienced pediatric

5

FIGURE 2 A–C, Alveolar growth abnormality associated with trisomy 21 in a 3-year-old girl. CT scans showing diffuse GGO and consolidation involving mainly the posterior dependent regions of the lower lobes. D, Follow-up chest radiograph performed at the age of 8 years shows nearly complete resolution of the parenchymal abnormalities. All courtesy of Maurizio Zompatori, Bologna, Italy.


SPAGNOLO and BUSH

thoracic radiologists, the sensitivity

and specificity of HRCT for NEHI is

78% to 83% and 100%, respectively

(Fig 3 A–C), thus obviating the need

for a confirmatory lung biopsy.23

Diagnosis on biopsy is based on

essentially normal histology on

standard staining, with an increase

in Bombesin-positive cells on

specific staining. However, although

hyperplasia of neuroendocrine cells

within bronchioles (as demonstrated

by immunohistochemistry), the only

consistent pathologic finding, may

be seen in a variety of disorders,

including bronchopulmonary

dysplasia, bronchiolitis, and

PH, 14, 44, 45 neuroendocrine cell

prominence with otherwise normal

histopathology is a distinguishing

feature of NEHI.46 These other

conditions all have specific features,

which would preclude diagnostic

confusion with NEHI. Reported

familial cases suggest that NEHI may

have a genetic basis, 47 although,

to date, no mutation has been

consistently identified.48 Long-term

outcome is generally favorable with

most patients gradually improving

over time, although persistent

airway obstruction mimicking

severe asthma49 and relapse with

respiratory infection also have been

reported.19

PIG

PIG is a rare disorder that manifests

within the first few weeks of life

with respiratory distress and

diffuse interstitial infiltrates.50, 51

Histologically, PIG is characterized by

interstitial thickening by immature

vimentin-positive mesenchymal cells

containing abundant monoparticulate

glycogen, without inflammation or

fibrosis (Fig 4 A and B). Imaging

findings vary considerably based on

whether PIG occurs as an isolated

condition (diffuse PIG), or associated

with an underlying lung growth

disorder (patchy PIG).52, 53 Typical

HRCT features include GGO, reticular

changes, and hyperinflated areas

in a predominantly subpleural

distribution.41 In patchy PIG, these

abnormalities overlap with those of

the underlying lung growth disorder.

Long-term use of corticosteroids

is not recommended, particularly

in PIG occurring in the setting of

lung growth abnormalities, due to

their negative effect on postnatal

alveolarization and neurologic

development, and lack of efficacy.

Unlike diffuse PIG, which has an

excellent prognosis, the outcome

of PIG associated with growth

abnormality is variable, being related

to the severity of the primary lung

disorder.

Surfactant Dysfunction Disorders

The identification of mutations

within genes encoding proteins

involved in surfactant function

6

FIGURE 3A, HRCT in 2006 at presentation in a child aged 6 months with tachypnea and an oxygen requirement. Ground glass shadowing, especially in the right middle lobe and lingula, typical of NEHI, can be observed. B, Repeat HRCT in the same child in 2008, age 2 years. Although the ground glass shadowing has improved, the boy had in fact gone back into oxygen having been in air. A repeat biopsy, performed because of this atypical course, also showed classic NEHI. C, HRCT in 2015, age 9 years, still in low-fl ow oxygen at night. The abnormal shadowing has largely cleared.

FIGURE 4PIG. Surgical lung biopsy showing interstitial proliferation of mesenchymal cells with pale, glycogen-rich (periodic acid-Schiff positive) cytoplasm, at low (A) and higher (B) magnifi cation. Courtesy of Alberto Cavazza, Reggio Emilia, Italy.



and metabolism has dramatically

improved our understanding of these

disorders, which cause significant

morbidity and mortality in neonates,

older infants, children, and adults.54

Because surfactant dysfunction

disorders display considerable

overlap in their clinical and histologic

features, genetic analysis is essential

for establishing a specific diagnosis.

However, immunohistochemical and

ultrastructural examination also may

provide valuable diagnostic clues.

SP-B Defi ciency

SP-B deficiency is a rare autosomal

recessive disorder that most

frequently presents with rapidly

progressive neonatal respiratory

distress syndrome (RDS), 55 although

partial SP-B deficiency may be

associated with a milder phenotype

and longer survival (Table 2).56 More

than 40 loss-of-function mutations

within the SP-B gene, resulting in

partial to complete absence of SP-B

protein, have been identified thus

far. The most common one, a GAA

substitution for C at genomic position

1549 in codon 121 (the “121ins2”

mutation), which accounts for ∼70%

of cases of SP-B deficiency, results

in an unstable transcript and absent

pro- and mature SP-B protein.57

The absence of SP-B disrupts the

formation and structure of lysosome-

related secretory organelles, called

lamellar bodies (eg, on electron

microscopy, the well-organized

concentric rings of phospholipid

membranes that characterize

lamellar bodies are replaced by

large, disorganized multivesicular

bodies), thus leading to abnormal

surfactant composition and function.

Abnormal lamellar bodies on electron

microscopy are a strong pointer

to SP-B mutations. Histologically,

SP-B deficiency is characterized by

alveolar accumulation of granular,

eosinophilic, periodic acid-Schiff–

positive, lipoproteinaceous material.

Clinical estimates suggest an

incidence of 1 per million live

births. Most infants with SP-B

deficiency present within hours

of birth with respiratory failure

requiring mechanical ventilation.

Chest radiograph and HRCT

appearances mimic that of hyaline

membrane disease in premature

infants with diffuse haziness and

air bronchograms. However, infants

with SP-B deficiency are only

transiently or minimally responsive

to surfactant replacement and, with

rare exceptions, all patients succumb

without lung transplantation. The

rare infants with mutations that

allow for partial expression of the

SP-B protein appear to survive longer

and go on to develop chronic ILD.56

SP-C Defi ciency

SP-C deficiency was originally

described in an infant and mother

with NSIP and DIP, respectively.

Both carried a heterozygous

guanine-to-adenine substitution,

leading to skipping of exon 4 and

deletion of 37 amino acids.58 A

large 5-generation kindred was

later identified with 14 affected

family members, including 4 adults

with histologic usual interstitial

pneumonia and 3 children with NSIP,

all carrying a rare heterozygous

missense mutation predicted to

hinder processing of SP-C precursor

protein.59 More than 35 dominantly

expressed SP-C mutations have

been identified, half of which arise

spontaneously, thus resulting in

sporadic disease, whereas the

remainder are inherited. The most

common mutation, a T-to-C transition

at genomic position 1295, leads to a

threonine substitution for isoleucine

in codon 73 (I73T), and accounts for

a quarter of cases.60

The pathophysiology of lung disease

due to SP-C mutations is thought to

involve aberrant surfactant protein

folding, decreased endogenous SP-C

secretion, endoplasmic reticulum

stress, and apoptosis of alveolar type

II cells.61 Age at presentation and

natural history of lung disease are

highly variable: a large proportion

of patients present in late infancy/

early childhood; a minority present

acutely in early infancy (Fig 5 A and

B), whereas others are discovered in

adulthood. SP-C mutations account

for a large minority of familial cases

of pulmonary fibrosis, 62 whereas they

are a rare cause of sporadic forms of

7

TABLE 2 Surfactant Dysfunction Disorders

Disease SP-B Defi ciency SP-C Defi ciency ABCA3 Defi ciency Brain-Thyroid-Lung Syndrome

Locus SP-B SP-C ABCA3 NKX2.1/TTF-1

Chromosome 2p11.2s 8p23 16p13.3 14q13.3

Inheritance Autosomal recessive Autosomal dominant or sporadic Autosomal recessive Sporadic or autosomal dominant

Age of onset Birth Birth–adulthood Birth–childhood Childhood

Mechanism Loss-of-function Gain-of-toxic-action or dominant

negative

Loss-of-function Loss-of-function, (haploinsuffi ciency)

Phenotypes Neonatal RDS Neonatal RDS, ILD Neonatal RDS, ILD Neonatal RDS, ILD, childhood chorea,

congenital hypothyroidism

Natural history Generally lethal Variable Generally lethal, may be

chronic

Variable

Treatment Lung transplantation, or

compassionate care

Potential benefi t from early treatment

(eg, steroids or hydroxychloroquine);

supportive care or lung

transplantation if progressive

Lung transplantation (if

progressive)

Supportive care


SPAGNOLO and BUSH

idiopathic interstitial pneumonia.63

Whether the nature and location of

SP-C mutations affect the severity of

lung disease is unknown. However,

affected family members harboring

the same SP-C mutation display

considerable variability in the onset

and severity of lung disease.59 In this

regard, it is well established that viral

infection may trigger the disease and

negatively affect its clinical course.64, 65

Successful treatment with either

chloroquine or hydroxychloroquine

and prolonged survival of children

with SP-C mutations and ILD has

been reported (Fig 5C).66

ABCA3 Defi ciency

The membrane transporter ABCA3

facilitates the translocation of

phospholipids from the cytosol into

lamellar bodies for the production

of surfactant in type II alveolar

epithelial cells. Mutations within

ABCA3 are the most common genetic

cause of respiratory failure in full-

term infants.9, 67 In fact, affected

infants present in the neonatal

period with severe and progressive

RDS despite medical treatment.68

There is a genotype-phenotype

correlation; patients homozygous

for severe mutations invariably have

a neonatal presentation and death

in the first year of life, whereas

milder mutations permit prolonged

survival.9 However, ABCA3 mutations

have been identified also in older

children and even young adults with

ILD, usually with DIP.69 Distinctive

ultrastructural abnormalities

observed in the alveolar type II cells

of patients with ABCA3 mutations

include small, markedly abnormal

lamellar bodies with densely packed

phospholipid membranes and

electron-dense inclusions. Notably,

the family history is usually negative,

as the disease is inherited in an

autosomal recessive fashion.

NK2 Homeobox 1/TTF-1 Mutations

NK2 homeobox 1 (NKX2.1)/TTF-1

is critical for lung development,

surfactant homeostasis, and

innate immune responses. It is a

transcription factor for SP-B, SP-C,

and ABCA3. Deletions or loss-

of-function mutations on 1 copy

(“haploinsufficiency”) of NKX2.1

gene can result in severe RDS

and chronic ILD, 70 classically in

the form of “brain-thyroid-lung

syndrome, ” which is characterized

by hypothyroidism, muscular

hypotonia, developmental delay, and

choreoathetosis, as the gene is also

expressed in the thyroid gland and

central nervous system.71 However,

patients with NKX2.1 mutations

also may present in the newborn

period or during childhood with

isolated lung involvement as well

as with a spectrum of pulmonary

manifestations, including alveolar

proteinosis and severe neonatal

RDS, pulmonary fibrosis, PH, and

recurrent respiratory infections.72

Moreover, mutations within NKX2.1

may be associated with NEHI.48

Lung disease in this setting is

thought to result from decreased

amounts of several gene products

in combination or reduced amounts

of a key protein, particularly

SP-B or ABCA3, below a critical

level. Incidence and prevalence

of lung disease due to NKX2.1

haploinsufficiency are unknown. As

with other surfactant dysfunction

disorders, histologic abnormalities

include prominent alveolar type II

epithelial cell hyperplasia, thickening

of the interstitium by mesenchymal

cells, and accumulation of foamy

macrophages along with granular,

eosinophilic proteinaceous material

within the air spaces.7 Clinical

availability of genetic testing and

improved recognition of disease

patterns on imaging studies have

allowed many cases to be diagnosed

noninvasively. No specific therapies

have been demonstrated to be

effective in these disorders.

RECENT ADVANCES IN CHILD

Novel Genetic Entities

Integrin α3 Mutations

Integrins are transmembrane

αβ glycoproteins that connect

the extracellular matrix to the

8

FIGURE 5A, SP-C defi ciency in an 8-month-old girl presenting with RDS. CT scan shows extensive GGO. B, CT scan performed at the age of 18 months shows partial resolution of the ground glass abnormality. C, Follow-up CT scan performed at the age of 5 years shows further improvement of the parenchymal changes, although patchy GGO and fi ne septal thickening persist. All courtesy of Maurizio Zompatori, Bologna, Italy.



cytoskeleton. They are also

involved in signal transduction,

and cell survival, proliferation, and

differentiation.73, 74 Loss-of-function

mutations within the integrin α3

(ITGA3) gene have been associated

with a fatal recessive multiorgan

disorder consisting of congenital

nephrotic syndrome, early-onset

ILD, and skin fragility.75–77 Lung

involvement was the primary cause

of death in all cases, and lung biopsy

revealed abnormal alveolarization,

consistent with distorted

morphogenesis. ITGA3 mutations

are probably underrecognized, as

both the full spectrum of clinical

manifestations and genotype-

phenotype correlations are poorly

characterized. Nevertheless,

ITGA3 gene sequencing is strongly

recommended in newborns

presenting with severe RDS and/or

congenital nephrotic syndrome of

unknown etiology.

Filamin A Mutations

Loss-of-function mutations in filamin

A (FLNA), which encodes the actin

cross-linking protein FLNA, cause

X-linked periventricular nodular

heterotopia, one of the most common

brain malformations.78 However,

FLNA mutations also have been

associated with severe diffuse lung

disease (characterized on HRCT by

GGO, thickened interlobular septa,

atelectasis, areas of hyperinflation,

and cysts), tracheobronchomalacia,

and severe PH.79–81 Lung pathology

reveals alveolar simplification.

FLNA mutations are inherited in an

X-linked dominant manner, with

high perinatal mortality in affected

male patients, whereas in female

patients the prognosis depends

on the severity of the associated

cardiovascular abnormalities.82

In premature infants with diffuse

lung disease and respiratory course

atypical for chronic neonatal lung

disease in terms of timing, severity,

and response to treatment, FLNA

mutations should be suspected.

Humidifi er Disinfectant–Associated chILD

Humidifier disinfectant–

associated chILD is a unique chILD

syndrome caused by inhalation

of humidifier disinfectants in the

home environment. Humidifier

disinfectant–associated chILD,

outbreaks of which were

originally observed among Korean

children in spring 2006, 83–85 is

characterized by spontaneous

air leak, rapid progression, and

high mortality.86, 87 Radiologic

abnormalities include diffuse or

patchy GGO, dense consolidation,

and diffuse centrilobular nodules.

Lung biopsy reveals a temporally

homogeneous pathologic process

characterized by variable degrees

of bronchiolar injury associated

with bronchiolocentric acute lung

damage and relative sparing of the

lobular periphery, consistent with

an inhalation injury.86 Humidifier

disinfectant–associated chILD has

been eradicated on withdrawal of

humidifier disinfectants from the

market in November 2011. However,

thousands of potentially toxic

chemicals (to which children are far

more vulnerable than adults) are

used worldwide. Therefore, in cases

of unusually acute and progressive

disease, an environmental hazard

should be suspected.

Parent Experiences and Perspectives

A broader understanding of the

experiences and expectations of

families of children diagnosed with

ILD is crucial for improving current

delivery and future planning of

health care in this setting. A recent

Web-based survey conducted in the

United Kingdom identified a number

of areas for development, which

included feeding problems (an issue

previously not fully appreciated),

written information sharing,

written communication between

shared care hospitals, training for

less-experienced hospitals, and

psychological support.88 Some of

these issues will be addressed by

the currently ongoing FP-7 chILD

program, a European project, which

aims at increasing awareness of

chILD across Europe, setting up a

pan-European database and bio-bank

compatible with others worldwide,

increasing diagnostic accuracy

through international panels of

clinicians, radiologists, geneticists,

and pathologists, and implementing

evidence-based guidelines and

treatment protocols.89

American Thoracic Society Clinical Practice Guideline on chILD

The American Thoracic Society

has recently published a clinical

practice guideline that provides

a comprehensive approach to the

evaluation and management of chILD,

focusing on neonates and infants

<2 years of age.13 Some of the key

messages of the guideline can be

summarized as follows:

- Owing to their rarity, more common

causes of diffuse lung diseases

should be excluded before testing

for specific forms of chILD;

- Achieving a specific diagnosis is

critically important, as disease

behavior, management, and

outcomes are highly variable;

- Although many patients still require

tissue sampling, in the appropriate

clinical setting genetic testing

may obviate the need for lung

biopsy, 90 although the guideline

also emphasizes limitations of

current sequencing modalities

and challenges in interpretation

of results. Nevertheless, as

many as one-third of cases can

be classifiable based on clinical,

genetic, and/or radiographic

criteria without histologic

information91;

- Referral of patients to highly

specialized centers is highly

recommended, as multidisciplinary

discussion among pediatric

pulmonologists, radiologists,

and pathologists with expertise


SPAGNOLO and BUSH

in chILD greatly enhances the

likelihood of accurate diagnosis;

- Because no controlled clinical

trials of therapeutic interventions

have been performed for chILD,

recommendations on management

derive from observational

evidence and clinical experience.

Accordingly, the guideline

emphasizes the need for decisions

to be made on a case-by-case basis.

The chILD-EU Collaboration

ILD in children is rare and it has been

estimated that the average European

hospital will see no more than 5

cases per year.92 The chILD-EU

collaboration has brought together

centers from across Europe with the

aim of (1) creating a pan-European

registry, (2) peer reviewing all

potential diagnoses of child, (3)

collecting prospective longitudinal

data from well-defined groups of

patients, and (4) setting up and

performing the first randomized

controlled trial of treatment.29, 89

To achieve this, it is essential that

diagnostic and therapeutic approaches

be harmonized across Europe. To

this end, a sequence of diagnostic

procedures, along with standard

operating procedures for performing

such investigations, and therapeutic

interventions and protocols have

recently been proposed and agreed

on by using the Delphi methodology,

a consensus-building process among

experts through a series of carefully

designed questionnaires.29

SUMMARY AND CONCLUSIONS

Childhood ILD encompasses a large

spectrum of rare and heterogeneous

disorders, which differ substantially

from adult ILD. In the past

decade, genetic discoveries and

multicenter collaborative efforts

have resulted in the publication of

a guideline document that provides

systematic diagnostic approaches

and standardized nomenclature. In

addition, an increasing proportion of

cases can be diagnosed without lung

biopsy through chest CT patterns

and genetic testing. Yet, much work

remains to be done: relatively little

is known about the epidemiology,

natural history, and pathogenesis of

many chILDs; morbidity and mortality

associated with these disorders remain

substantial, and treatment is often

empirical and supportive. Ongoing

research and collaborative efforts are

expected to provide insights into the

molecular basis of chILD and identify

targets for therapeutic intervention,

thus allowing the establishment of

evidence-based therapies.

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10

ABBREVIATIONS

ABCA3: adenosine triphosphate

binding cassette family

member 3

ACDMPV: alveolar capillary

dysplasia associated

with misalignment of

pulmonary veins

BAL: bronchoalveolar lavage

chILD: childhood interstitial lung

disease

CT: computed tomography

DIP: desquamative interstitial

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FLNA: filamin A

GGO: ground glass opacity

HRCT: high-resolution CT

ILD: interstitial lung disease

ITGA3: integrin α3

NEHI: neuroendocrine

cell hyperplasia of

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NKX2.1: NK2 homeobox 1

NSIP: nonspecific interstitial

pneumonia

PH: pulmonary hypertension

PIG: pulmonary interstitial

glycogenosis

RDS: respiratory distress

syndrome

SP-B: surfactant protein B

SP-C: surfactant protein C

TTF-1: thyroid-transcription-

factor 1

Accepted for publication Dec 2, 2015

Address correspondence to Paolo Spagnolo, MD, PhD, Medical University Clinic, Canton Hospital Baselland, and University of Basel, Rheinstrasse 26, 4410 Liestal,

Switzerland. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2016 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have no fi nancial relationships relevant to this article to disclose.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential confl icts of interest to disclose.

FUNDING: Dr Bush was supported by the National Institute for Health Research Respiratory Disease Biomedical Research Unit at the Royal Brompton and

Harefi eld NHS Foundation Trust and Imperial College London, and the FP7 chILD-EU grant.



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DOI: 10.1542/peds.2015-2725 originally published online May 31, 2016; 2016;137;Pediatrics

Paolo Spagnolo and Andrew BushInterstitial Lung Disease in Children Younger Than 2 Years

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DOI: 10.1542/peds.2015-2725 originally published online May 31, 2016; 2016;137;Pediatrics

Paolo Spagnolo and Andrew BushInterstitial Lung Disease in Children Younger Than 2 Years

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