Children's Interstitial Lung Disease (ChILD) 

Updated: Feb 06, 2018
Author: James S Hagood, MD; Chief Editor: Girish D Sharma, MD, FCCP, FAAP 


Practice Essentials

Interstitial lung diseases (ILDs) in childhood are a diverse group of conditions that primarily involve the alveoli and perialveolar tissues, leading to derangement of gas exchange, restrictive lung physiology, and diffuse infiltrates on radiographs. Because ILDs can involve the distal airspaces as well as the interstitium, the term diffuse infiltrative lung disease has been suggested. This nomenclature may be more accurate than ILD, but children's interstitial lung disease (chILD) has become the preferred term. In 2004, the Rare Lung Diseases Consortium, a network of clinical and research centers and patient support organizations, was formed to accelerate clinical research in rare lung diseases, including chILD.[1]

As a result of the rarity of ILDs in children and the important differences between childhood ILD and ILDs that affect adults, a great deal of confusion surrounds their nomenclature, classification, and management. Idiopathic pulmonary fibrosis (IPF, also known as cryptogenic fibrosing alveolitis [CFA]), the most prominent adult ILD, mostly occurs after the fifth decade of life; this entity is not found in children. Unlike in adults, most ILDs in children are found to have an underlying cause. In addition, the clinical significance of the histologic classification differs significantly between children and adults.

For example, usual interstitial pneumonitis (UIP), the pattern associated with IPF in adults, is rarely described in children. Desquamative interstitial pneumonitis (DIP), which is associated with steroid responsiveness and a better prognosis in adults, has a very poor prognosis in children, particularly in infants. Neuroendocrine cell hyperplasia in infancy (NEHI) and pulmonary interstitial glycogenesis (PIG) are histologic patterns unique to children.

Management of ILD in children also differs from that in adults. Correct diagnosis is critical, requiring a comprehensive search for possible underlying causes. Case reports describing unique presentations and anecdotal responses to various therapeutic interventions abound. Definitive management of ILDs, particularly those of unknown etiology, is unclear at present. The recently formed consortium of centers, perhaps in collaboration with centers worldwide, may facilitate use of standardized diagnostic criteria and develop a network for clinical trials.


Childhood ILD is not a disease but a group of disorders (see Causes). However, most ILDs share a common pathophysiologic feature, namely, structural remodeling of the distal airspaces, leading to impaired gas exchange. In general, this remodeling has been believed to be the sequela of persistent inflammation; however, more recently, the paradigm has shifted away from inflammation to one of tissue injury with aberrant wound healing resulting in collagenous fibrosis. Until recently, most research in this field has been based on adult histopathology and data from animal models.

Wound healing and fibrosis are complex pathophysiologic processes that involve numerous cell types and cellular processes, such as adhesion; migration; proliferation; apoptosis; and a vast array of soluble mediators, extracellular matrix (ECM) molecules, and signaling intermediates. Detailed discussion of the pathophysiology of lung fibrosis can be found in several excellent reviews.[2, 3, 4] In chILD, these processes occur in an organ that is still developing, further complicating the pathophysiology.

Many types of ILD follow some type of injury to the distal airspaces, such as adenoviral infection or exposure to organic dust, resulting in damage to the epithelial or endothelial layers and the associated basement membrane. In an animal model of lung fibrosis using bleomycin, as well as in models of surfactant-dysfunction mutations (SDMs), apoptosis of the alveolar epithelium was demonstrated to be a key inciting event.

Fibroblasts, which are normally present in the attenuated interstitial spaces between alveoli and surrounding distal airways, play a key role in lung remodeling, which is characterized by proliferation and excessive elaboration of matrix molecules such as collagen. Fibroblasts also affect remodeling through production of proteases, protease inhibitors, cytokines, and chemokines. Recent data indicate alternate origins of fibroblasts, such as circulating precursors known as fibrocytes, which hone in on injured tissues, and transdifferentiation of other cells, such as epithelial-mesenchymal transition (EMT).

Inflammation is present in many types of ILD, and many forms of ILD are triggered by inflammatory events, such as infection or hypersensitivity. Neutrophils and lymphocytes are prominent in bronchoalveolar lavage (BAL) samples in many types of ILD. In DIP, the airspaces are filled with cells that were once believed to be desquamated epithelium but which are, in fact, activated macrophages. The mediators released by inflammatory cells, particularly IL-1 and transforming growth factor (TGF)-beta, are potent activators of fibroblast-mediated remodeling. Almost every type of inflammatory cell, including eosinophils and mast cells, have been described in various types of ILD and can interact with fibroblasts and other parenchymal cells. However, lung inflammation does not necessarily result in fibrotic remodeling, and fibrosis can occur in the absence of inflammation; therefore, inflammation has a prominent, but not a central, role in lung remodeling and fibrosis.

A large number of other pathophysiologic events are increasingly recognized as having clinically significant effects on lung remodeling. Markers of angiogenesis have been prominent in several animal models of ILD and substantially affect outcomes. The ECM is a complex, biologically active structure that signals cells either by direct means or by means of its soluble breakdown products and that binds, sequesters, and presents growth factors and other mediators to cells. The ECM is altered in ILDs, and alterations in the ECM may also have a causative role.

Resolution of fibrotic remodeling involves a complex series of orderly steps, including matrix breakdown and restructuring, reepithelialization, and apoptosis of fibroblasts and inflammatory cells.

Fibrotic remodeling is responsible for most of the morbidity and mortality associated with ILD. Remodeling of distal airspaces results in hypoxemia. Persistent hypoxemia results in pulmonary hypertension and vascular remodeling, leading to cor pulmonale. The increased work of breathing associated with reduced compliance results in increased energy expenditure, which, combined with the effects of inflammatory mediators, can result in cachexia. Portions of the lung may be replaced by fibrotic septae between dilated airspaces, the so-called honeycomb changes of endstage interstitial disease. Although the events described above are necessary for repair of the injured lung, excessive activation or failure of resolution of any of these pathways can result in disabling fibrosis.



United States

ILD is rare in children. Because of a lack (until recently) of consensus on case definition, the broad differential diagnosis, and the lack of organized reporting systems (eg, a national database), determining the precise incidence or prevalence of ILDs is impossible. Cases tend to cluster in infancy, and 10-16% appear to be familial.

Most of the literature is composed of case reports and small series. One of the largest reported series is a combined retrospective and prospective study by Fan et al performed over a 15-year period at a leading referral center for ILD.[5] The investigators reported 99 patients, in whom the case definition included respiratory symptoms lasting longer than one month, diffuse infiltrates depicted on chest radiography, and absence of known bronchopulmonary dysplasia (BPD), heart disease, malignancy, immunodeficiency, autoimmunity, cystic fibrosis (CF), aspiration, or acquired immunodeficiency syndrome (AIDS). A more recent retrospective study that attempted a relatively complete case ascertainment of children undergoing biopsy for ILD in 11 referral centers in the United States and Canada over a 5-year period (1999-2004) reported 187 cases in children younger than 2 years old.[6]


A national survey of cases of chronic ILD in immunocompetent children aged 0-16 years in the United Kingdom and Ireland over a three year period (1995-1998) yielded an estimated prevalence of 3.6 per million.[7]


The same factors that make estimating the incidence of ILD difficult make estimating its mortality rates difficult.

  • In the series of 99 patients discussed above, the probability of surviving 24, 48, or 60 months was 83%, 72%, and 64%, respectively.6 Mean survival interval from onset in this group of patients was 47 months.

  • Factors associated with poor outcome included pulmonary hypertension at the time of diagnosis and a final diagnosis of DIP or pulmonary vascular disease.

  • In general, accurate definitive diagnosis should be pursued before attempting to predict associated morbidity or mortality. Certain specific histologic diagnoses in newborns adversely influence prognosis; these include diffuse developmental disorders and patterns associated with certain surfactant protein mutations. Without lung transplantation, the prognosis for most of these conditions is poor.[6] However, for other types of ILD, such as NEHI, significant morbidity but no mortality has been reported.


No data are available in the pediatric literature concerning differences in racial incidence or prevalence.


There appears to be a slight male predominance (roughly 60:40) in reported cases of chILD.


Approximately 50% of chILD cases occur in infants, but presentation can occur throughout childhood and adolescence.

  • In one of the largest series, the mean age at onset was 43 months (range, 0-212 mo). The median age at onset was 8 months, but the median age at evaluation was 30 months. These data indicate that some clustering of ILD occurs in infancy, and that, as is seen in adults, the delay between the onset of symptoms and appropriate diagnostic evaluation is often lengthy.

  • Recently identified pediatric ILD syndromes unique to infancy, including NEHI, PIG, and chronic pneumonitis of infancy, may present at or shortly after birth. SDMs often cause severe symptoms during the newborn period (see Causes).




Diagnosing children's interstitial lung disease (ChILD) requires a high index of suspicion on the part of the physician. The delay between the onset of symptoms and ultimate diagnosis is often months to years. Respiratory symptoms can be subtle in infants and children, and clinicians often treat ILD as asthma. A delay in referral can lead to clinically significant remodeling of the lung before diagnosis.

The clinical history varies substantially by age. The onset of disease is often insidious, with caregivers or patients unsure when the illness actually began. Occasionally, patients present with relatively few symptoms but with abnormal findings on chest radiographs or pulmonary function tests (PFTs). Some patients, especially newborns with surfactant-dysfunction mutations (SDMs), may present with respiratory failure.

  • Tachypnea and/or dyspnea

    • Tachypnea is present in most patients (75%), particularly in infants.

    • Younger infants manifest retractions, difficulty in feeding, and diaphoresis with feeding. Cyanosis may be evident during feeding or at rest.

    • Exercise intolerance is often noted in older children

  • A cough that is described as dry and nonproductive is commonly present (75%) and can be the only symptom of ILD, even in the newborn.

  • Failure to thrive and weight loss are common symptoms that may result from anorexia, difficulty in feeding, and increased energy expenditure from increased work of breathing.

  • Hemoptysis may indicate the presence of a vasculitic process or a pulmonary hemorrhage syndrome.

  • Older children may report chest pain.

  • Fever may be present, suggesting infectious or inflammatory causes.

  • Wheezing occurs in 40% of patients, according to the history, and is present upon examination in as many as 20%.

  • A careful family history is critical because some forms of ChILD may have a genetic basis, which may be associated with neonatal deaths, unexplained childhood respiratory disease, or ILD in adults (see Causes).


See the list below:

  • General physical findings

    • Growth retardation, signs of weight loss, and/or failure to thrive may be evident.

    • Hypoxemia on room air is common (87% of patients with saturation below 90% in one series).

    • Desaturation may occur during sleep, during feeding (infants), or with exercise (eg, 6-minute walk test in older children and adolescents).

  • Auscultation may reveal normal findings or dry crackles that sound like Velcro being pulled apart; these are present only in a subset of patients.

  • Deformity of the chest has been reported and may indicate lung hypoplasia, as well the effects of prolonged illness. A recent study of 9 children with ABCA3 deficiency reported pectus excavatum as a frequent finding[8]

  • Signs of hyperinflation, such as increased chest diameter or palpable liver and spleen may be evident.

  • Signs consistent with pulmonary hypertension may be present. Examples include an active precordium, which signifies right ventricular hypertrophy and a loud pulmonary component to the second heart sound.

  • Cyanosis and clubbing are late manifestations of ILD.

  • Stigmata of collagen vascular diseases, vasculitides, and other systemic disorders should be carefully sought.


ILD in children can be classified in many ways.[9] In the largest reported clinical series in children, 19-27% of cases remain undetermined, with the rest classified into idiopathic disorders, those of known or suspected causes, and those associated with systemic diseases (see ILD associated with systemic diseases below).[10] Several important non-chILD disorders present with chronic respiratory symptoms and findings of diffuse radiographic infiltrates and must be considered in the differential diagnosis. ILD can also be classified based on histopathologic findings (see ILD classification systems below).

Different strains of mice and rats can be sensitive or resistant to experimental models of ILD. This fact, as well as the occurrence of familial IPF in humans, suggests both genetic and environmental determinants for ILD. A clinical classification of causes of childhood ILD is listed below. The numbers in parentheses indicate percentage of final diagnoses in the largest clinical series.[10]

Disorders with known causes

See the list below:

  • Infection (8-10%)

    • Viral infection (eg, adenoviral bronchiolitis obliterans [5%], cytomegalovirus [CMV] infection, infection with Epstein-Barr virus [EBV])

    • Bacterial infection (eg, pertussis or infection due to Legionella, Mycoplasma, Chlamydia, or Mycobacterium species)

    • Fungal infection (eg, infection due to Histoplasma, Aspergillus, or Pneumocystis species)

    • Parasitic infection (eg, visceral larva migrans)

  • Environmental conditions (13%)

    • Exposure to organic dusts (hypersensitivity pneumonitis [7-12%])

    • Exposure to inorganic particulates (eg, silica, asbestos, talc, zinc)

    • Exposure to chemical fumes (eg, sulfuric acid, hydrochloric acid, methyl isocyanate)

    • Exposure to gases (eg, oxygen, chlorine, nitrogen dioxide [silo-filler disease], ammonia)

    • Exposure to radiation

  • Drugs

    • Use of antineoplastic agents (eg, cyclophosphamide, nitrosoureas, methotrexate [MTX], azathioprine, cytosine arabinoside, 6-mercaptopurine [6-MP], vinblastine, bleomycin, busulfan)

    • Use of other drugs or elements (eg, penicillamine, nitrofurantoin, gold)

  • Previous lung injury

  • Chronic aspiration pneumonitis (4-5%)

  • Resolving acute respiratory distress syndrome (ARDS)

  • Bronchopulmonary dysplasia (BPD)

  • Lymphoproliferative disorders (10%)

  • Neoplasia (eg, lymphoma [1%], leukemia, Langerhans cell histiocytosis [LCH])

  • Metabolic disorders

  • Lysosomal storage disorders (eg, Gaucher disease, Niemann-Pick disease)

  • Degenerative disorders (eg, pulmonary microlithiasis [1%])

  • Immunodeficiency-associated ILD

Disorders with unknown causes

See the list below:

  • Undetermined (19-27%); also called nonspecific (but not nonspecific interstitial pneumonitis [NSIP]) cellular interstitial pneumonitis or chronic interstitial pneumonia)

  • Pulmonary hemorrhage syndromes (idiopathic pulmonary hemosiderosis [5-8%], capillaritis)

  • DIP (4-8%); correlates with SDMs in many cases

  • Lymphocytic interstitial pneumonitis (LIP [6%]) (Known AIDS cases are excluded; LIP is often associated with HIV infection or AIDS but can be idiopathic.)

  • UIP (2-4%) (The accuracy of this diagnosis in children is highly questionable; however, a recent study however demonstrated a usual interstitial pneumonitis [UIP] pattern in an adolescent with ABCA3 deficiency[11] )

  • Lymphangiomatosis (4%)

  • Nonadenoviral bronchiolitis obliterans (4%)

  • Sarcoidosis (2%)

  • Pulmonary alveolar proteinosis (PAP [2%]) (see below)

  • Eosinophilic syndromes (2%) (chronic eosinophilic pneumonia, pulmonary infiltrates with eosinophilia)

  • Idiopathic bronchiolitis obliterans organizing pneumonia (BOOP), also called cryptogenic organizing pneumonia (COP) (This is primarily a disease of adults that presents subacutely in the fifth or sixth decades, although rare idiopathic cases are reported in children.)

  • Bronchocentric granulomatosis (1%)

  • Nonspecific interstitial pneumonia (this pattern has been recently shown to correlate with SDMs, such as ABCA3 deficiency, in older children[8] )

  • Acute interstitial pneumonitis (AIP)

ILD associated with systemic diseases

See the list below:

  • Connective tissue diseases (2-4%) (juvenile rheumatoid arthritis [JRA], dermatomyositis/polymyositis, systemic sclerosis, systemic lupus erythematosus [SLE], ankylosing spondylitis, Sjögren syndrome, Behçet syndrome, mixed connective tissue disease)

  • Autoimmune diseases (antiglomerular basement membrane antibody disease)

  • Pulmonary vasculitis (polyarteritis nodosa, Wegener granulomatosis, Churg-Strauss syndrome)

  • Liver disease (chronic active hepatitis, primary biliary cirrhosis)

  • Bowel disease (2%) (eg, ulcerative colitis, Crohn disease)

  • Amyloidosis

  • Neurocutaneous disorders (tuberous sclerosis, neurofibromatosis, ataxia-telangiectasia)

  • Bronchiolitis obliterans: This may be the histologic pattern associated with connective tissue disorders or other chronic inflammatory disorders, such as inflammatory bowel disease. It may be seen as a noninfectious pulmonary complication of bone marrow transplantation (associated with graft vs host disease [GVHD]) or lung transplantation and may be seen in association with malignancies. Bronchiolitis obliterans syndrome (BOS) is a clinical term that refers to irreversible airway obstruction (defined as a decrease in forced expiratory volume in 1 second [FEV1] of >20% from baseline) after lung transplantation, in the absence of other causes.

Disorders with presenting features similar to those of ILD

See the list below:

  • Pulmonary veno-occlusive disorders (8-10%) (anomalous pulmonary venous return, pulmonary hemangiomatosis, hereditary hemorrhagic telangiectasia, alveolar capillary dysplasia, pulmonary venous stenosis/atresia)

  • Proliferative and congenital vascular disorders (alveolar capillary dysplasia and misalignment of pulmonary veins)

  • Heart disease (left ventricular failure, left-to-right shunts)

  • CF

  • Immunodeficiency

Forms of ILD most prevalent in infancy

See the list below:

  • Diffuse developmental disorders[12]

    • Acinar dysplasia

    • Congenital alveolar dysplasia

    • Alveolar capillary dysplasia with pulmonary vein misalignment (This is associated with a poor prognosis.)

  • Growth abnormalities

    • Pulmonary hypoplasia

    • Chronic neonatal lung diseases (prematurity-related BPD and acquired chronic lung diseases in term infants)

    • Structural pulmonary changes with chromosomal abnormalities (eg, trisomy 21)

    • Abnormalities associated with congenital heart disease in otherwise healthy children

  • Specific conditions with unknown etiology

    • PIG

    • NEHI

  • SDMs and related disorders

    • SFTPB genetic mutations (PAP as dominant histologic pattern; see below)

    • SFTPC genetic mutations

    • ABCA3 genetic mutations

    • Granulocyte-macrophage colony stimulating factor (GM-CSF) receptor mutations

Genetic and/or familial disorders

See the list below:

  • SDMs and related disorders

  • Familial hypocalciuric hypercalcemia

  • Lysinuric protein intolerance

  • Farber lipogranulomatosis

  • Hermansky-Pudlak syndrome

Pulmonary alveolar proteinosis

PAP is characterized by amorphous periodic acid-Schiff (PAS)-positive intra-alveolar lipoproteinaceous material. PAP can be associated with inherited abnormalities of surfactant metabolism that cause severe neonatal respiratory distress. Although most forms of PAP are either idiopathic or acquired, several conditions have been described in association with PAP, including lysinuric protein intolerance, congenital cellular immunodeficiency, AIDS, myeloid leukemias, sideroblastic anemia, and infections with Pneumocystis carinii, Nocardia species, and Histoplasma capsulatum.[13] Mutations in genes that encode for SFTPB, ABCA3, and the alpha and beta chains of the receptor for GM-CSF (CSF2RA and CSF2RB) have been found in neonatal and familial forms of PAP.

The 4 major surfactant proteins are A, B, C, and D. The lung collectins (SP-A and SP-D) function as opsonins for pathogens and also function as immunomodulators that regulate the inflammatory response in the alveolar space. Their levels are elevated in adults with IPF, in adults with ILD with collagen vascular disease, and in adults with PAP.[14] In children with ILD, SP-A and SP-D levels are correlated with some measures of disease severity.

SP-A deficiency was first described in animal models of BPD. Selman et al reported a significant association with SFTPA and SFTPB single nucleotide polymorphism and IPF.[3] However, so far, no human infants with SP-A deficiency have been identified.

SP-B deficiency is inherited in an autosomal recessive manner. When it is homozygous, it is highly lethal during newborn period. The radiologic appearance is similar to that of hyaline membrane disease. Patients do not respond to surfactant replacement therapy, and many of them require extracorporeal membrane oxygenation (ECMO). They eventually require lung transplantation. Heterozygous family members of infants with SP-B deficiency were free of pulmonary symptoms and had normal lung function.[15]

Recently, familial pulmonary fibrosis has been associated with mutations in the SFTPC gene. SP-C mutations can have variable clinical presentations, even in members of the same family.[16] ,[17] Its inheritance is autosomal dominant with variable penetrance. Patients can present with severe symptoms in the first few months of life, can present with symptoms of ILD in adulthood or they may remain asymptomatic. A recent study investigating a possible role of high-frequency SP-C variants in common pediatric disorders demonstrated that SP-C variants represent a risk factor for the development of severe respiratory syncytial virus (RSV) infection.[15]

Mutations of ABCA3, the gene that encodes for a transmembrane protein that transports substances across biologic membranes and that has been localized to the lamellar bodies, are inherited in an autosomal recessive fashion. Mutations in ABCA3 gene may be the most common genetic cause of neonatal interstitial lung disease.

In 2004, Shulenin et al described 21 infants with severe neonatal surfactant deficiency with an unknown etiology; mutations in ABCA3 were identified in 16 of 21 patients.[18] The exact function of the ABCA3 protein is unknown, but it is critical for the lipid transport into lamellar bodies and proper surfactant function.[19] The clinical picture in this condition varies; it might be lethal in newborns, but some patients have a more protracted course, and some are living as adolescents with ILD.[20, 21] A recent study reviewed the clinical, radiological and pathological features of ABCA3 mutations in 9 children, with symptom onset from birth to age 4 years. Histopathologic patterns included PAP, DIP and NSIP, and varied with age.[8]

The findings that the complete absence of ABCA3 function results in severe surfactant deficiency and that some mutations may result in milder lung disease in the neonatal period indicates that ABCA3 may be a candidate gene for more common lung diseases such as neonatal respiratory distress syndrome (RDS) in premature infants.[22]





Laboratory Studies

General diagnostic approach

The process and pace of evaluation depends on several factors and no single algorithm applies to the diverse clinical settings in which interstitial lung disease (ILD) can occur. Considerations influencing the diagnostic approach include age at presentation, immunocompetence, chronicity, severity of disease, duration of illness, family history, and trend toward improvement. For example, the full-term newborn with respiratory failure is approached differently from the young child with tachypnea of insidious onset and hypoxemia with feeding or sleep. As outlined below, some types of ILD may be diagnosed on the basis of genetic testing, and laboratory studies may provide clues for others, particularly in association with systemic disorders. Although chest CT patterns may suggest certain diagnoses, many forms of ILD require surgical lung biopsy for definitive diagnosis.

  • CBC count and differential: Anemia and reticulocytosis are seen in pulmonary hemorrhage. Polycythemia may be seen in chronic hypoxia. Peripheral eosinophilia suggests parasitic disease, hypersensitivity, eosinophilic syndromes, or other immune dysfunction.

  • Urinalysis may indicate coincident glomerulonephritis in patients with pulmonary-renal syndromes.

  • Stool hemoccult results may be positive in patients with idiopathic pulmonary hemorrhage or inflammatory bowel disease.

  • Sweat chloride test and cystic fibrosis (CF) genotyping may be required to exclude CF

  • Serologic testing for Mycoplasma pneumoniae may be used.

  • Fungal serologic testing may be used.

  • Respiratory viral studies may be used.

  • Markers of inflammation, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels, may be elevated in inflammatory disorders.

  • Workup for immunodeficiency includes testing for immunoglobulins, immunoglobulin G (IgG), IgG subclasses, specific antibodies to vaccine antigens (tetanus, diphtheria, polyvalent pneumococcal vaccine, and Haemophilus influenzae type B), complement (C3, C4, CH50), and lymphocyte subsets

    • Anergy skin test panel should be considered

    • Lymphocyte markers may be useful.

    • Immunoglobulin E (IgE) may be used to evaluate for parasitic disease, allergic bronchopulmonary aspergillosis (ABPA), and eosinophilic syndromes.

      • Human immunodeficiency virus (HIV) testing is indicated if LIP, P carinii pneumonia (PCP), or disseminated histoplasmosis is present.

      • Markers of rheumatic disorders, including rheumatoid factor (RF), antinuclear antibody (ANA)/anti–double-stranded DNA (anti-dsDNA) antibody, antineutrophil cytoplasmic antibodies (ANCAs), and anti–basement membrane antibodies, should be measured to determine connective tissue disease or autoimmune etiologies.

      • ACE levels and/or lysozyme may be elevated in patients with sarcoidosis, but these are neither sensitive nor specific.

      • Serum precipitin results may be positive in patients with hypersensitivity pneumonitis but do not prove disease causality.

      • Genetic testing for SFTPB and ABCA3 mutations should be performed in infants with unexplained severe neonatal respiratory distress, particularly if a family history of respiratory disease is known. Testing for SFTPC and ABCA3 mutations should be considered in infants and children with children’s interstitial lung disease (ChILD) syndrome, particularly if they exhibit digital clubbing, diffuse ground glass opacities, or "honeycomb" changes on high-resolution CT (HRCT) or if they have a family history of chronic lung disease. Clinical genetic testing for these disorders is available through Clinical Laboratories Improvement Act (CLIA)-certified diagnostic laboratories.

      • Serum and urine amino acids may be measured if metabolic conditions, such as lysinuric protein intolerance, are not suspected.

      • KL-6 is a high-molecular-weight protein produced by type II pneumocytes and bronchial epithelial cells, especially during their regeneration. Unfortunately, outside of Japan, testing is only available on a limited research basis.

      • KL-6 functions as a chemoattractant for fibroblasts

      • High levels of serum KL-6 reflect an active fibroblastic process affecting the pulmonary interstitium or bronchioles. Elevated serum KL-6 levels have been found in different types of ILD, bronchopulmonary dysplasia (BPD), severe measles pneumonia, and ILD associated with juvenile dermatomyositis.[23, 24]

      • KL-6 appears to have high sensitivity (93.9%) and high specificity (96.3%) for IDL in adults and correlates with disease severity.[25]

Imaging Studies

Chest radiography

Chest radiographs are often the first imaging study performed for evaluation of possible ILD. Although they rarely allow for a specific diagnosis, they can be useful in identifying other causes of respiratory symptoms that may present similarly to ILD.[26, 27] Findings on plain chest images may be normal in the presence of active disease and abnormal in the absence of symptoms. Numerous radiographic patterns are associated with ILD, including ground-glass opacities; reticular, nodular, or reticulonodular infiltrates; and honeycombing. The ground-glass appearance is consistent with active alveolitis, and honeycombing is consistent with advanced fibrosis.

Radiographic findings are usually described as interstitial infiltrates, although predominantly nodular (alveolar) and mixed reticulonodular patterns have been described, as have nonspecific findings (hyperinflation).

CT scanning

CT scanning, specifically high-resolution CT (HRCT), provides a noninvasive means for determining the patterns, extent and distribution of changes associated with ILD. The imaging appearance of diffuse abnormalities include ground-glass attenuation, a tree-in-bud appearance, lobular airtrapping, reticular attenuations, and centrilobular nodules.[28] CT is especially useful in demarcating the most appropriate areas for tissue biopsy.[29]

Disadvantages of HRCT include the need for sedation in uncooperative infants and the relatively high radiation exposure. Newer, more rapid acquisition algorithms have somewhat decreased these problems. Long and colleagues have developed a method by using combination of sedation and controlled ventilation with a face mask providing a controlled pause in respiration to allow scanning of the lung with 1-mm sections.[30] Without controlled ventilation, respiratory motion may mimic ground glass opacities, and dependent atelectasis may occur mimicking parenchymal changes. When possible, both inspiratory and expiratory images should be obtained, as expiratory images can be important to assess for air-trapping and to evaluate extent of ground-glass opacity. Whether serial HRCT provides any benefit in monitoring disease progression or response to therapy is unclear.

In a study of HRCT in 20 children with ILD, specific patterns were correlated with certain types of pathology, with little overlap.[31] Regions with hyperlucency, with or without bronchiectasis, were well correlated with airspace localizing diseases, such as bronchiolitis obliterans or bronchocentric granulomatosis. Septal thickening was correlated with lymphangiomatosis and pulmonary capillary hemangiomatosis. Ground-glass changes were seen in infiltrative ILD, such as DIP, hypersensitivity pneumonitis, and LIP. A characteristic CT pattern appears to be associated with NEHI (figure 3).[32] Consolidative patterns were seen in aspiration syndromes, BOOP (figure 5), and vasculitides. Characteristic thin-walled, heterogeneous cysts, alternating with small nodules, were seen only in patients with LCH.

In another study, investigators evaluated the ability of expert readers to correctly diagnose pediatric diffuse lung disease with HRCT.[27] The correct first-choice diagnosis of ILD was made in 61%, and the conditions correctly diagnosed with greatest frequency were alveolar proteinosis, idiopathic pulmonary hemosiderosis, and pulmonary lymphangiectasia.

Studies in a small number of patients with neuroendocrine cell hyperplasia of infancy (NEHI) or bronchiolitis obliterans suggest that characteristic HRCT patterns are often noted in these entities.[32, 33]

He et al used high-resolution computed tomography to classify cases of interstitial lung diseases in children. Sixty children with interstitial lung disease underwent high-resolution CT in supine position under free-respiratory conditions during scanning. Bronchovascular bundles were thick in 49 patients, and were both thick and stiff in 27 patients. Of the 41 infectious patients, 39 showed thickened bronchovascular bundles, and 26 showed thick and stiff bronchovascular bundles. Of the 19 noninfectious patients, bronchovascular bundles were thickened in 10 patients and were thick and stiff in 1 patient. Forty-one patients showed lobular ground-glass opacity (32 infectious, 9 noninfectious). Twenty-seven patients showed both bronchovascular bundle abnormality and lobular ground-glass opacity (20 infectious, 7 noninfectious). Eighteen patients showed patchy or mosaic ground-glass opacity (16 infectious, 2 noninfectious). Early in the course of disease, bronchovascular bundles were abnormal and complicated with lobular ground-glass opacity. Patchy ground-glass opacity was the most common manifestation and was difficult to resolve. Bronchiectasis indicated that the disease was irretrievable.[34]

Barium swallow studies

Barium swallow studies or radionuclide "milk" scans may demonstrate evidence of gastroesophageal reflux or aspiration.


Echocardiography should be included in the initial diagnostic workup. Special attention should be paid to depiction of all 4 pulmonary veins, because partial anomalous pulmonary venous return may be present in patients with respiratory distress and chest radiograph findings of interstitial infiltrates. Evidence of pulmonary hypertension (based on the tricuspid regurgitant jet velocity) and right ventricular hypertrophy may be evident.

Nuclear scintigraphy

Certain radionuclides (specifically 67Ga) accumulate preferentially in areas of active lung inflammation; therefore, they may be useful both in delineating areas of active inflammation and in monitoring disease progression. However, in adult IPF, results of 67Ga scanning are not correlated with disease activity or response to treatment.

Other Tests

Pulse oximetry

Decreased oxyhemoglobin saturation more often reflects ventilation-perfusion mismatching, rather than diffusion abnormalities, because of the remodeling of distal airspaces characteristic of most childhood ILD. In early stages of ILD, oxyhemoglobin saturation may be relatively normal at rest but may worsen dramatically with exercise or sleep.

Most children with more advanced ILD present with hypoxemia. In adults, the degree of arterial desaturation correlates with severity of fibrosis, pulmonary hypertension, and survival. In children, pulmonary hypertension is a more important predictor of poor prognosis than desaturation.

Pulmonary function testing

In children and adolescents who can perform spirometry and plethysmography, total lung capacity (TLC), forced vital capacity (FVC), and FEV1 are all reduced, consistent with restrictive physiology. Although TLC maybe reduced, functional residual capacity (FRC) and residual volume (RV) are often normal or elevated, resulting in increased FRC/TLC and RV/TLC ratios. Airflow limitation, as indicated by a reduced FEV1/FVC ratio, is present in as many as one half of children with ILD. Compliance of the respiratory system (Crs) is reduced.

Diffusing capacity for carbon monoxide is usually low, although this value often returns to normal when corrected for lung volume and hemoglobin. In pulmonary hemorrhage syndromes, diffusing capacity may be elevated because of the affinity of carbon monoxide for sequestered hemoglobin.

Infant PFTs can be safely performed in sedated infants at a large number of pediatric centers. Results of PFTs in infants, if available, usually show reduced Crs using both multiple occlusion and end inspiratory occlusion techniques, and PFTs have been used to monitor the response to treatment in some studies.

Results of arterial blood gas analysis may be normal, but typical changes include decreased arterial partial pressure of oxygen (PaO2) and respiratory alkalosis.

Exercise testing

In children old enough to cooperate, exercise testing may reveal exercise-related desaturation, even when oxyhemoglobin saturation is normal during rest. Exercise testing, or a 6-minute walk test, may provide an objective indicator of disease progression.

pH probe testing

pH or impedance probe testing may be required to demonstrate gastroesophageal reflux (GER), predisposing patients to aspiration. GER may occur as a secondary complication of ILD.


ECG readings may show evidence of cor pulmonale, specifically right atrial and ventricular enlargement, and right axis deviation.


Bronchoalveolar lavage

Bronchoscopy with BAL is useful in diagnosing certain conditions in the differential diagnosis of ILD, including alveolar proteinosis, aspiration syndromes, pulmonary hemosiderosis, and various infections. Occasionally, results of cytologic analysis may be diagnostic, for example, when Langerhans cells are present, indicating histiocytosis. Most authorities believe BAL should precede biopsy.

Problems with the use of BAL include the lack of a standardized methodology in children, the paucity of reference values for differential cell counts, the variability of BAL findings at different times in a disease course, and the lack of correlation between BAL and histologic findings.

Fluid should be sent for differential cell counts, culturing and special staining for bacteria (including mycobacteria) and fungi, cytologic analysis (including oil red O staining for lipid-laden macrophages and staining for hemosiderin), pepsin levels, and viral diagnostic studies. Analysis of lymphocyte markers in BAL is controversial in adults and has not been standardized in children.

BAL findings can be diagnostic of PAP, demonstrating cloudy or milky appearance of the fluid with periodic acid-Schiff (PAS)–positive amorphous debris. Increased eosinophils (>30% of total) are consistent with eosinophilic pneumonia syndromes, whereas predominant lymphocytosis can be associated with hypersensitivity pneumonitis. CD1a-positive cells are diagnostic for Langerhans' cell histiocytosis.[35]

A study by Griese et al looked to determine the value of quantitation of SP-B and SP-C levels in bronchoalveolar lavage fluid for the diagnosis of chILD and reported that low SP-C levels may point out diseases caused by mutations in TTF1, SFTPC, ABCA3, and in other genes involved in surfactant metabolism. SP-B levels may be used for screening for SP-B deficiency.[36]


Lung biopsy

Analysis of tissue obtained during lung biopsy is the best way to make a definitive diagnosis if it cannot be established by noninvasive means. Much of the classification of ILD, especially in disorders of unknown cause, is based on histopathology (see Histologic Findings). To maximize the diagnostic yield, a pediatric lung biopsy protocol has been developed and supported by the ChILD Pathology Cooperative Group.[37] However, a diagnosis is not reached in all patients, even after biopsy is performed.

The number of biopsy procedures performed and the method used (eg, open vs thoracoscopic) have little influence on diagnostic yield. The biopsy sample should be taken from a region of involvement: if diffuse involvement is found, any site except the tip of the right middle lobe or lingua is appropriate.

Open lung biopsy has been the traditional approach. Open biopsy allows for the collection of an optimal amount of tissue from areas most likely to enable a diagnosis. Diagnostic yield may be enhanced if HRCT is used to direct the biopsy sites. Communication between the clinician, surgeon, pathologist, and radiologist before biopsy is useful and appropriate for determining biopsy sites and prioritizing use of the tissue.

Compared with open lung biopsy, thoracoscopic biopsy shortens surgical time, duration of chest tube placement, and hospital stay without substantially altering the diagnostic yield. The choice between thoracoscopic and open approaches should be left to the consulting surgeon.

Transbronchial biopsy is increasingly performed in older pediatric patients because of its use after lung transplantation. Small pediatric bronchoscopes do not allow biopsy forceps to pass. Although this may be an option with newer models, tissue yield is less than that obtained with open or thoracoscopic lung biopsy, and, may not be sufficient for accurate diagnosis of chILD.[37] One group compared the diagnostic value of different techniques for lung biopsy. Specific diagnosis were made in 50%, 60%, and 53% of patients who underwent transbronchial, video-assisted, and open lung biopsy, respectively.[10, 5]

Regardless of the method used, biopsy samples should be processed for bacterial, fungal, and mycobacterial cultures and staining, including special staining, light microscopy, immunofluorescence, and electron microscopy. Immunostains, such as bombesin for NEHI and vimentin for PIG, may aid in the diagnosis of specific forms of ILD.[19]

Cardiac catheterization

This procedure should be considered in any child with noninvasive evidence of pulmonary hypertension but especially in children with a history of hemoptysis or absence of crackles on examination. These findings have been correlated with pulmonary venoocclusive disease.

Histologic Findings

Histologic findings on routine hematoxylin and eosin staining remain the criterion standard for the diagnosis and classification of many types of ILD and may indicate the underlying cause, if a cause is present, or may suggest associated systemic illnesses (eg, noncaseating granulomas characteristic of granulomatous infections or sarcoidosis). However, this area has been rife with confusion because of different classification schemes, inexact nomenclature, and important differences between children and adults. Consultation with pathologists experienced in chILD is critical and ideally should be sought before biopsy specimens are obtained.

ILD classification systems

Several classification systems have been developed for adults. The American Thoracic Society (ATS) classification of the differential diagnoses of IPF is as follows:[38]

  • UIP (required for IPF)

  • DIP


  • NSIP

  • AIP

  • BOOP

  • LIP

  • Pulmonary histiocytosis X

  • UIP pattern with likely underlying cause (eg, asbestosis, connective tissue disease, hypersensitivity pneumonitis)

  • Nonclassifiable

These are of questionable relevance to child, because particular patterns may have differing diagnostic and prognostic significance in adults and children. A classification system for infants with ILD based on a multicenter retrospective review of histopathology has recently been published, which divides child entities into "disorders more prevalent in infancy," "disorders not unique to infancy," and "unclassified disorders."[6] Most of the histologic patterns and associated clinical manifestations are described below.

Childhood Interstitial Lung Disease Syndromes That Manifest in Infancy

Neuroendocrine Cell Hyperplasia of Infancy (NEHI)

In 2005, Deterding et al reported a case series of 15 patients with a clinical picture of persistent tachypnea, crackles, and hypoxemia.[39] The clinical picture is consistent with what was previously termed persistent tachypnea of infancy. About 85% of the patients were born at full term, and none of those born prematurely had a history of chronic lung disease. In those infants, chest radiographs revealed hyperinflation; hyperinflation and a ground-glass appearance were revealed on HRCT. Lung biopsy did not reveal a characteristic histologic pattern, and interstitial involvement was minimal. They observed mild, nonspecific changes, including airway smooth muscle hyperplasia, increased alveolar macrophages, and increased airway clear cells. Immunostaining of the cells demonstrated strong staining for bombesin and serotonin, which identified these cells as pulmonary neuroendocrine cells (PNECs).

See the image below.

Neuroendocrine cell hyperplasia of infancy (NEHI) Neuroendocrine cell hyperplasia of infancy (NEHI) (A) Chest high-resolution CT (HRCT) scanning (at total lung capacity) in a 6-month-old infant with tachypnea, hypoxemia, and failure to thrive. Sharply defined areas of ground glass opacity are seen most prominent in the right middle lobe and lingual. Diffuse air-trapping was seen on expiratory images (not shown). No additional abnormalities were identified.(B) Hematoxylin and eosin staining of the lung biopsy reveals near-normal lung architecture. (C) Bombesin immunostaining reveals increased numbers of neuroendocrine cells.

Clinical improvement was inconsistent, but no pulmonary-related deaths were reported, suggesting that prognosis for children with NEHI is generally good. The authors suggested that NEHI and chronic idiopathic bronchiolitis of infancy might constitute the same entity.[39] ,[40]

Follicular bronchitis/bronchiolitis

In 2 case series similar to those described above, infants presented with tachypnea, fine crackles, and chronic cough by age 6 weeks.[41, 42] Lung biopsy findings demonstrated follicular lymphocytic infiltration surrounding and infiltrating the bronchial walls. All patients improved gradually over several years. See the image below.

Follicular bronchiolitis (A) Chest high-resolution Follicular bronchiolitis (A) Chest high-resolution CT (HRCT) scan from a 6-year-old infant with common variable immunodeficiency with history of anemia, thrombocytopenia, recurrent pneumonia, chronic cough, and exercise intolerance. Mosaic attenuation is present diffusely throughout the lungs. Extensive hilar and mediastinal lymphadenopathy is also present. Air-trapping was seen on expiratory images (not shown). (B) Lung histopathology demonstrates severe airway-centric lymphocytic inflammation with reactive follicles, which infiltrates and obscures most bronchioles.

In follicular bronchitis/bronchiolitis, the HRCT appearance is similar to that seen in NEHI, but biopsy findings differ because airway inflammation is not prominent or consistent in NEHI. In addition, PNECs are not described in follicular bronchiolitis.[40, 32]

Cellular interstitial pneumonitis/pulmonary interstitial glycogenosis (PIG)

Several case reports and small series have described infants with tachypnea since birth and diffuse lung infiltrates. Lung biopsy findings revealed interstitial proliferation of histiocytic type cells with minimal to no infiltration. In general, the clinical picture improved gradually.[40] In 2002, Canakis et al reported 7 neonates presenting with chronic ILD.[43] Lung biopsy findings demonstrated a histopathologic appearance similar to that of cellular interstitial pneumonitis, with spindle-shaped cells containing PAS-positive material. Electron microscopy demonstrated primitive interstitial cells with abundant cytoplasmic glycogen. The authors suggested that these cells represent a developmental abnormality. PIG is likely a more complete description of cellular interstitial pneumonitis.

Chronic pneumonitis of infancy

This is not to be confused with cellular interstitial pneumonitis. Several reports described infants with severe lung disease and chest radiographic findings including ground-glass opacities, volume loss, and hyperinflation. Biopsy findings revealed alveolar septal thickening, prominent pneumocyte hyperplasia, and alveolar exudates with numerous macrophages along with rare eosinophils and cholesterol clefts. This condition had a high mortality rate, and some cases were associated with genetic abnormalities of surfactant function.[44, 40]

Genetic abnormalities of surfactant function

The typical histologic pattern for SP-B deficiency is interstitial thickening, abundant type II cell hyperplasia, and eosinophilic PAS-positive granular material in the alveolar space. The eosinophilic granular material is typical of PAP. Immunohistochemical staining demonstrates absence of SP-B.[45, 20]

Adults with SP-C deficiency can have biopsy findings consistent with those of UIP, DIP, or NSIP.[40] ,[46] Studies suggest that a mutation in SFTPC gene may cause the production and accumulation of an abnormal protein, resulting in injury to the respiratory epithelium.[47] ,[20]

The histopathology of ABCA3 deficiency can widely vary and appears to be age-dependent, with infants manifesting patterns consistent with PAP, chronic pneumonitis of infancy or DIP, and older children manifesting features of NSIP.[8] The only well-documented case of UIP in a child was an adolescent with ABCA3 deficiency.[11]

Histologic Patterns of Interstitial Lung Disease not Limited to Children


In adults, DIP is a rare finding usually seen in cigarette smokers. The histologic pattern is uniform and diffuse. Alveoli are filled with accumulations of macrophages, which were originally believed to be desquamated alveolar epithelial cells, hence the name. DIP is associated with ground-glass changes on HRCT scans.

In children, DIP is not as rare a histologic pattern as it is in adults and is associated with ILD in the first year of life, sometimes with symptoms present at birth. This pattern is seen in some of the SDMs, such as ABCA3 deficiency. Unlike DIP in adults, in whom this pattern is associated with smoking history, steroid responsiveness and a favorable prognosis, DIP in children is one of the few specific ILD diagnoses associated with a significantly increased risk of death. In one large series from 1998, Fan et al reported a markedly increased mortality rate in patients with DIP compared with patients with other childhood ILDs.[48]


NSIP is a confusing term (a specific pattern despite the inclusion of “nonspecific”) for a microscopically homogeneous pattern of inflammation and fibrosis, although gross involvement may be patchy. Honeycomb changes are rare. Patchy ground-glass attenuations are depicted on HRCT scans. See the image below.

Nonspecific interstitial pneumonitis. (A) Chest hi Nonspecific interstitial pneumonitis. (A) Chest high-resolution CT (HRCT) scanning from a 10-year-old with systemic sclerosis and progressive exercise intolerance. (B) Lung biopsy showed multiple abnormalities including a relatively diffuse interstitial process with mild chronic inflammation, abundant fibroblastic tissue and patchy dense interstitial fibrosis. Accumulation of alveolar macrophages is seen in the airspaces, with rare foci of organizing pneumonia. Pulmonary arteries demonstrated focal intimal hyperplasia and medial hypertrophy, and the pleura contains patchy chronic inflammation. This overall constellation of findings is generally classified as mixed cellular and fibrotic nonspecific interstitial pneumonia (NSIP) and is a pattern most commonly seen in the setting of underlying collagen vascular disease.

In one series of 64 patients, 5 patients were younger than 20 years. This pattern is associated with improved survival rates. Severity appears to be associated with the extent of fibrosis seen on histologic analysis. NSIP can be associated with ABCA3 deficiency, with known or suspected connective tissue diseases, and with environmental exposures.


AIP is the pattern associated with the entity Hamman and Rich originally described in 1944.[49] The histologic pattern is one of diffuse active fibrosis (many proliferating fibroblasts, little collagen) with uniform alveolar septal thickening. Features of acute lung injury or diffuse alveolar damage (DAD) are present, such as hyaline membranes, acute inflammation, and bronchial epithelial atypia. The clinical picture is one of acute fulminant idiopathic ARDS. The mortality rate is high (60%), and progression is rapid (months). This clinical and histologic entity has been reported in children as young as 7 years.


BOOP is not technically an interstitial disease because the pathology is primarily intraluminal in distal airspaces, but BOOP may be difficult to clinically and radiographically distinguish from other ILDs. Upon histopathologic evaluation, BOOP appears as patchy areas of granulation tissue in conducting airways and alveolar ducts with inflammation (primarily macrophages) in the surrounding alveoli. In affected areas, the appearance is uniform without significant distortion of lung parenchyma. Buds of myofibroblasts in collagenous stroma (Masson bodies) may extend into adjacent airspaces, demonstrating a characteristic butterfly pattern. See the image below.

Bronchiolitis obliterans. (A) Chest CT scanning fr Bronchiolitis obliterans. (A) Chest CT scanning from an 8-year-old demonstrates irregular large mosaic regions of ground-glass opacity and air-trapping, as well as the presence of peribronchial thickening and bronchiectasis. (B) Pathology demonstrates focal areas of fibrosis with polypoid plugs of fibroblastic cells and fibrin filling distal bronchioles and airspaces (hematoxylin and eosin).

Organizing pneumonia may also be a secondary finding in other forms of ILD. Because the term BOOP is often misused, and because bronchiolar involvement is minimal in as many as one third of adults, COP is now the preferred term.


LIP is characterized by monotonous, diffuse, lymphoplasmacytic cell infiltrates in the interstitium and distal airspaces. Mononuclear cells and histiocytes are also seen. Occasionally, lymphoid aggregates are seen in a lymphatic or angiocentric distribution. LIP is often a pulmonary manifestation of AIDS in children. In addition, LIP is associated with Sjögren syndrome, chronic active hepatitis, and JRA. EBV-genomic DNA occasionally can be identified in LIP. Lymphoproliferative diseases, lymphomas, and underlying immunodeficiency must be considered.

Pulmonary LCH

LCH, or histiocytosis X, is predominantly interstitial on histologic analysis, with features of centrally scarred, stellate nodules with a polymorphic infiltrate containing characteristic Langerhans cells. The lungs are involved in approximately 10-40% of children with LCH, but few children present with isolated lung disease. In adults, pulmonary involvement is clearly related to smoking.


UIP is characterized by a heterogeneous appearance at low magnification, with alternating areas of normal lung, inflammation, fibrosis, and honeycomb changes, which are most prominent in the peripheral subpleural areas. Fibrotic areas contain dense collagenous deposits and characteristic foci of proliferating fibroblasts (fibroblastic foci), which have negative prognostic importance. There is only one well-characterized report of UIP in a child, and adolescent with ABCA3 deficiency.[11]

Nonclassifiable patterns

Clinical specimens that cannot be classified into one of the described patterns represent a substantial percentage of childhood ILD. Some of these may represent sampling error. Occasionally, important histologic information derived from portions of lung that may appear grossly normal. Remember that NSIP, despite its name, is a specific histologic pattern and distinct from nonclassifiable ILD.


No widely used staging system is available for ChILD, which is appropriate because the spectrum of possible final diagnoses is large.

In adults, a scoring system is available for IPF, based on clinical, radiographic, and pathologic findings (ie, CRP scoring system).

Fan devised a simple scoring system for ChILD. A score of 5 indicates the worst outcome, with a 38% survival rate at 60 months. A score of 2, 3, or 4 indicates a survival rate of 76%. Data from Cox proportional hazards modeling suggested a 140% increase in risk of death with each unit increase in score.

The Fan scoring system is as follows (1998):[48]

  1. Asymptomatic

  2. Symptomatic with normal oxyhemoglobin saturation

  3. Symptomatic with nocturnal or exercise-induced desaturation

  4. Desaturation at rest

  5. Pulmonary hypertension



Medical Care

The multiple possible diagnostic entities and lack of randomized clinical trials make offering specific recommendations regarding treatment of children’s interstitial lung disease (ChILD) impossible. If the process is secondary to an underlying condition, patients should be treated for the underlying disease.

The same principles that apply to all children with chronic pulmonary diseases apply to those with interstitial lung disease (ILD). These include meticulous attention to growth and nutrition, immunizations (including influenza and pneumococcal prophylaxis), and treatment of secondary infections.

  • Treatment with bronchodilators, inhaled steroids, or both may be appropriate if any component of airway reactivity is demonstrated on PFT. However, this therapy has not been proven to modify the clinical course of most types of ILD.

  • Oxygen therapy, either continuously or during sleep, may be necessary to provide symptomatic relief and to decrease the risk or halt the progression of pulmonary hypertension and cor pulmonale related to alveolar hypoxia.

  • Active and passive smoking should be avoided. Smoking cessation should be actively pursued for caregivers who smoke.

  • Many medications have been used to treat different forms of ILD. No therapeutic regimen has been subjected to the rigors of a randomized control trial in the pediatric population. Numerous broad treatment strategies have been attempted, including anti-inflammatory medications (eg, steroids, cytotoxic agents, immunosuppressive therapies), collagen synthesis inhibitors, antifibrotic agents, hydroxychloroquine, intravenous immunoglobulin (IVIG), antioxidants, and cytokine inhibitors.

  • Hypersensitivity pneumonitis is the most treatable condition among chILDs. Fan et al (2004) reported 86 cases of pediatric hypersensitivity pneumonitis that had an excellent response to steroids.[40] Other steroid-responsive conditions include NSIP, LIP, COP, eosinophilic pneumonia syndromes, sarcoidosis, pulmonary hemosiderosis, and ILD associated with connective tissue disease.[7]

  • Treatment of specific conditions resulting in ILD includes antiviral agents against CMV and EBV, antiretroviral therapy in addition to prednisolone for AIDS-associated LIP, surgical approach for lymphangiomatosis, therapeutic BAL for PAP, and PPI and Nissen fundoplication for GER-associated chronic aspiration. Reports indicate that infliximab (an inhibitor of tumor necrosis factor [TNF]-alpha) may be beneficial for ILD associated with rheumatoid arthritis.[50] Several studies have demonstrated successful use of subcutaneous treatments with GM-CSF in adults with PAP.[7]

  • In patients with associated PAH, sildenafil and/or anticoagulant therapy should be considered.

  • In patients with congenital PAP due to GM-CSF receptor mutation or acquired receptor dysfunction secondary to autoantibody formation, subcutaneous or inhaled GM-CSF treatment has been reported to be beneficial.[51] ,[52]

Surgical Care

See the list below:

  • Surgical consultation is usually sought for diagnostic biopsy (see Procedures).

  • Patients with end-stage idiopathic forms of ILD, severe lung disease associated with SFTPB or ABCA3 mutations, as well as some pulmonary veno-occlusive diseases, may be candidates for lung or heart/lung transplantation. These patients are considered on an individual basis at the few centers specializing in pediatric lung transplantation.

  • In children, the establishment of lung transplantation has been slower than in adults. Only 5% of all patients receiving transplants for this reason have been younger than 18 years. For some diseases, such as SP-B and ABCA3 deficiencies and alveolar capillary dysplasia, lung transplantation remains the only effective treatment.

  • Huddleston et al (2002) reported a 77% overall survival rate for the first year after transplantation in children.45 The 3- and 5-year survival declined to 63% and 54%, respectively. The authors observed no statistical relationship between pretransplantation diagnoses and long-term survival. The same authors reported 19 infants younger than 6 months who underwent lung transplantation: Seven had SP-B deficiency, 4 had PAP of other etiology, 3 had congenital interstitial pneumonitis, 2 had alveolar-capillary dysplasia, and 10 had pulmonary vascular disease.


See the list below:

  • Pediatric pulmonologist: All children with ILD should be treated in consultation with a pediatric pulmonologist.

  • Pediatric ILD specialist: In addition, referral to or telephone consultation with a center with clinicians specializing in childhood ILD is advised.

  • Pediatric cardiologist: As a result of the existence of cardiovascular diseases masquerading as ILD, all patients should see a pediatric cardiologist.

  • Pediatric rheumatologist: A pediatric rheumatologist should be involved in the management of ILD associated with connective tissue disease.

  • Pediatric radiologist: Consult a pediatric radiologist regarding interpretation of imaging studies.

  • In addition, consider consultation with the following specialists:

    • Infectious disease specialist

    • Immunologist

    • Rheumatologist

    • Transplantation specialist

  • Pathologist: Consultation with a pathologist is recommended before tissue is obtained to ensure that adequate specimens are collected and that they are correctly processed. Consider consultation with a pathologist knowledgeable about ChILD.


No specific diet is necessary. However, as with patients with any chronic disease, patients with ChILD should receive sufficient kilojoules to maintain adequate growth. Decreased lung compliance increases the work of breathing and energy expenditure. Energy supplementation should be undertaken with consideration to the added difficulty in handling high carbohydrate loads with chronic lung disease. Consult a nutritionist experienced in the management of chronic pulmonary conditions in children. Young infants with feeding difficulties resulting from dyspnea may require a transpyloric or gastrostomic feeding tube.


Activity may be limited by the patient's degree of dyspnea. Oxygen saturation during exercise should be measured. A prescribed, monitored, exercise program may be beneficial to prevent deconditioning in older children. Conditions that may exacerbate pulmonary symptoms (high levels of ozone or other environmental pollutants) should be avoided. Patients with hypersensitivity pneumonitis should be removed from exposure to the precipitating substances (eg, birds, organic dusts). Air travel or travel to high altitudes must be carefully planned in patients with arterial desaturation.



Medication Summary

Corticosteroids have been the mainstay of therapy in most children and adults with interstitial lung disease (ILD), despite little conclusive evidence of their efficacy. The theoretical basis for the use of corticosteroids is the assumption that the lung remodeling is in large part the result of persistent inflammation. This paradigm has recently been challenged in IPF (see Pathophysiology). Steroids may be administered daily or by pulse. Steroid responsiveness is often considered an important prognostic indicator. Data in adults indicate that the specific histopathologic pattern seen on biopsy specimens correlates with the degree of response to steroids. This has not been verified in children. Time to response is variable, but steroids should be continued for at least 8-12 weeks at full dose before therapy is deemed to have failed. Improvement may be seen in symptoms, physical signs, or chest radiographic appearance alone.


Class Summary

These agents elicit anti-inflammatory properties and cause profound and varied metabolic effects. They modify the immune response of the body to diverse stimuli. Suppression of immune-mediated alveolitis and repair mechanisms may reduce the progression of fibrosis. Data from small studies suggest that pulse administration with intravenous (IV) corticosteroids may improve survival and lessen toxicity compared with prolonged courses of oral steroids.

Prednisone (Deltasone, Meticorten, Orasone, Sterapred)

Most widely used agent, particularly for UIP, DIP, and hypersensitivity pneumonitis. May decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear (PMN) activity.

Methylprednisolone (Solu-Medrol)

Decreases inflammation by suppressing migration of PMN leukocytes and reversing increased capillary permeability. Can decrease frequency in patients with stable clinical course.

Immunomodulating and immunosuppressive agents

Class Summary

The use of hydroxychloroquine and chloroquine has been reported, with variable results. Hydroxychloroquine has been used most frequently as a corticosteroid sparing agent with anecdotal success in ILD and alveolar hemorrhage syndromes. The mechanism of action is unknown. Recent data suggest that the efficacy of these agents may be related in part to alkalization of macrophages, which may reduce the secretion of TNF-alpha and impair antigen presentation.

Rosen et al (2005) reported an infant with SP deficiency that was treated successfully with hydroxychloroquine.[53] They suggested that, in addition to its anti-inflammatory properties, hydroxychloroquine inhibits intracellular processing of the precursor of SP-C, which may be the mechanism of action in that disorder.

Azathioprine, MTX, cyclophosphamide, or penicillamine may be used as second-line therapy if response to corticosteroids has not occurred, if a steroid-sparing effect is desired, or as an adjunctive agent to steroids in severe or rapidly progressive disease. The mechanism of action is presumed to be immunosuppression by means of relative myelosuppression. The potential for pulmonary toxicity from MTX and cyclophosphamide has limited their use.

Hydroxychloroquine (Plaquenil)

Inhibits chemotaxis of eosinophils and locomotion of neutrophils and impairs complement-dependent antigen-antibody reactions. Hydroxychloroquine sulfate 200 mg equivalent to 155 mg hydroxychloroquine base and 250 mg chloroquine phosphate. Dose and duration not tested in controlled trials, but, case reports describe children receiving 5-10 mg/kg/d for years. In adults, usually discontinued if no clinical response after 6 months.

Chloroquine phosphate (Aralen)

Generally not used in young children who are unable to comply with thorough color-vision testing. Anti-inflammatory activity from lymphocyte transformation suppression. Dose and duration not tested in controlled trials, but case reports describe children receiving 5-10 mg/kg/d for years. In mostly uncontrolled case reports and small series of infants < 6 mo with ILD, mortality rates 66% with corticosteroids alone vs 16% with chloroquine. Most infants responded clinically within first 2 mo of treatment.

Azathioprine (Imuran)

Antagonizes purine metabolism and inhibits DNA, RNA, and protein synthesis. May decrease proliferation of immune cells, which lowers autoimmune activity.

Methotrexate (Rheumatrex)

Unknown mechanism of action in treatment of inflammatory reactions; may affect immune function.

Cyclophosphamide (Cytoxan)

Chemically related to nitrogen mustards. As an alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Penicillamine (Cuprimine)

Metal-chelating agent. Use in patients with ILD reported. Mechanism of action unknown.



Further Outpatient Care

See the list below:

  • A pediatric pulmonologist should regularly follow up patients with interstitial lung disease (ILD).

  • The patient's oxygen saturation, nutritional status, and incidence of adverse drug reactions should be monitored at each visit.

  • PFTs and imaging studies should be used to monitor disease progression and the patient's response to treatment.

  • Echocardiography should be repeated to assess for the development of pulmonary hypertension or cor pulmonale.

Further Inpatient Care

See the list below:

  • Admit patients to the hospital for diagnostic workup and initial therapy, pulse courses of IV corticosteroids, management of superimposed infections, and management of any serious adverse drug reactions.

Inpatient & Outpatient Medications

See the list below:

  • New therapies, particularly use of cytotoxic or immunosuppressive drugs, should be initiated in the hospital.

  • Long-term therapeutic agents are usually administered and monitored on an outpatient basis.


See the list below:

  • Transfer may be necessary for further diagnostic workup or lung transplantation.

  • Pretransplantation evaluation should be initiated before end-stage disease develops to allow sufficient time for evaluation and donor identification.


See the list below:

  • Superinfection can be life threatening, particularly if the patient is receiving immunosuppressive medications. Immunosuppressive drugs can mask signs and symptoms of infection. Prevention and careful monitoring are crucial.

  • Drug toxicity causes much of the morbidity associated with ILD. Again, prevention and monitoring are the keys to management.

  • Hemoptysis may occur in some types of ILD and suggests vasculitis or venoocclusive disease as possible underlying causes.

  • Death is usually the result of respiratory failure or cor pulmonale and right heart failure.


See the list below:

  • Mortality rates as high as 90% have been reported in children who develop ILD when younger than 1 year (predominantly DIP); other studies have reported much better survival with conservative management.

  • Fan and Kozinetz reviewed the outcomes of 99 children with ILD over 15 years.[5] Survival rates at 24, 48, and 60 months after the appearance of initial symptoms were 83%, 72%, and 64%, respectively. Patients with histopathologic DIP and pulmonary vascular disorders have a prognosis worse than this.

  • Familial IPF manifesting in the neonatal period is associated with a high mortality rate.

Patient Education

See the list below:

  • Stress the importance of compliance with medication and nutritional regimens, rehabilitation, and regular follow-up visits.

  • Carefully instruct patients and parents about the need to report possible adverse effects of medications and to monitor for signs and symptoms of superinfection.

  • Counsel patients and caregivers of patients with hypersensitivity pneumonitis to avoid precipitating exposures.

  • Strongly advise smoking cessation and prevention, and inform patients and caregivers about specific support programs.

  • Encourage involvement in support groups for rare disorders such as the Children’s Interstitial Lung Disease (chILD) Foundation

  • Caregivers and patients should receive education and counseling appropriate for families of children with chronic respiratory diseases, including financial counseling and transplantation preparedness.