eMedicine Specialties > Pediatrics: General Medicine > Pulmonology

Children's Interstitial Lung Disease (ChILD)

James S Hagood, MD, Director, Pediatric Pulmonary Center, Professor of Pediatrics, Cell Biology, Pathology and Biochemistry and Molecular Genetics, Department of Pediatrics, University of Alabama School of Medicine
Gulnur Com, MD, Pediatric Pulmonologist, University of Arkansas for Medical Sciences Children's Hospital; David J Vaughan, MBBCh, Consultant Pediatrician, Department of Pediatrics, Our Lady of Lourdes Hospital, Ireland; Daniel William Young, MD, FACR, Clinical Professor of Radiology, Clinical Professor of Pediatrics, University of Alabama School of Medicine; Active Staff, Department of Pediatric Imaging, Children's Hospital of Alabama; Vice-President, Pediatric Radiology Associates, PC; Elizabeth C Mroczek-Musulman, MD, Clinical Associate Professor of Pathology, Associate Pathologist, Department of Pathology, University of Alabama Schools of Medicine and Dentistry, The Children's Hospital of Alabama; Lisa R Young, MD, Assistant Professor, Pediatric Pulmonary Medicine and Pulmonary Critical Care and Sleep Medicine, University of Cincinnati; Director of Pediatric Rare Lung Diseases Program and Consulting Physician, Cincinnati Children's Hospital Medical Center; Consulting Physician, University Hospital, Cincinnati

Updated: Sep 11, 2009

Introduction

Background

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.
 
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.

Pathophysiology

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.^1,2,3 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.

Frequency

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.⁴ 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.⁵

International

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.⁶

Mortality/Morbidity

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.⁵  However, for other types of ILD, such as NEHI, significant morbidity but no mortality has been reported.

Race

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

Sex

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

Age

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).

Clinical

History

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).

Physical

• 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 finding⁷
• 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.

Causes

ILD in children can be classified in many ways. 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).⁸ 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.⁸  

Disorders with known causes

• 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

• 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 deficiency⁹ )
• 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 children⁷ )
• Acute interstitial pneumonitis (AIP)

ILD associated with systemic diseases

• 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

• 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

• Diffuse developmental disorders
  • 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

• 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.¹⁰ 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.¹¹ 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.² 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.¹²  

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.¹³ ,¹⁴ 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.¹²  

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.¹⁵ The exact function of the ABCA3 protein is unknown, but it is critical for the lipid transport into lamellar bodies and proper surfactant function.¹⁶ 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.^17,18 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.⁷

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.¹⁹

Differential Diagnoses

Other Problems to Be Considered

Other connective tissue disorders
Congenital heart disease
Pulmonary venoocclusive disorders
Immunodeficiency
Pediatric AIDS

Workup

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.^20,21
    • KL-6 appears to have high sensitivity (93.9%) and high specificity (96.3%) for IDL in adults and correlates with disease severity.²²

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.^23,24  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.²⁵ CT is especially useful in demarcating the most appropriate areas for tissue biopsy.
 
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.²⁶ 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.²⁷ 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).²⁸ 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.²⁴ 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.^28,29  
 
Barium swallow studies
 
Barium swallow studies or radionuclide "milk" scans may demonstrate evidence of gastroesophageal reflux or aspiration.

Echocardiography

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.
 
Electrocardiography

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

Procedures

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.³⁰
 
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.³¹ 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.³¹ 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.^8,4
 
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.¹⁶
 
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:³²

• UIP (required for IPF)
• DIP
• RBILD
• 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."⁵ 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)

(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.

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.

Histologic Patterns of Interstitial Lung Disease not Limited to Children

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.

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).

Staging

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):⁴²

1. Asymptomatic
2. Symptomatic with normal oxyhemoglobin saturation
3. Symptomatic with nocturnal or exercise-induced desaturation
4. Desaturation at rest
5. Pulmonary hypertension

Treatment

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.³⁴ Other steroid-responsive conditions include NSIP, LIP, COP, eosinophilic pneumonia syndromes, sarcoidosis, pulmonary hemosiderosis, and ILD associated with connective tissue disease.⁶
• 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.⁴⁴ Several studies have demonstrated successful use of subcutaneous treatments with GM-CSF in adults with PAP.⁶
• 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.⁴⁵ ,⁴⁶

Surgical Care

• 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.

Consultations

• 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.

Diet

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

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

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.

Glucocorticoids

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.

Dosing

Adult

Pediatric

2 mg/kg/d PO for 6-8 wk; not to exceed 60-80 mg/d; continue 8-12 wk at full dose, gradually taper or adjust dose to clinical response and PFT results; symptom relapse warrants return to maximum dosing

Interactions

Barbiturates, phenytoin, and rifampin increase clearance of corticosteroids; ketoconazole and troleandomycin decrease clearance of corticosteroids; increases clearance of salicylates; may impair vaccine or toxoid effectiveness; effects on anticoagulants varies; administration of live or live-attenuated vaccines is contraindicated in patients receiving immunosuppressive doses; coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; serious infection (ie, bacterial, viral, especially varicella, fungal)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Extensive adverse reactions associated with corticosteroids, mostly with long-term administration; fluid and electrolyte disturbances, hypertension, musculoskeletal problems (including osteoporosis), GI bleeding, neurologic disturbances, hypercoagulable states, endocrine disturbances (most notably adrenocortical suppression and growth impairment in children), and ophthalmic disturbances
Increased risk of disseminating infections (eg, chickenpox, measles); prophylaxis may be indicated if exposure to these infections cannot be avoided; may mask symptoms of serious infections; abrupt discontinuation of glucocorticoids may cause adrenal crisis

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.

Dosing

Adult

Pediatric

10-30 mg/kg/d IV for 3 d each month; in patients with stable clinical course, interval may be gradually increased

Interactions

Barbiturates, phenytoin, and rifampin increase clearance of corticosteroids; ketoconazole and troleandomycin decrease clearance of corticosteroids; increases clearance of salicylates; may impair vaccine or toxoid effectiveness; have variable effects on anticoagulants; administration of live or live-attenuated vaccines is contraindicated in patients receiving immunosuppressive doses; coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels; monitor patients for hypokalemia with concurrent administration with diuretics

Contraindications

Documented hypersensitivity; serious infections (ie, bacterial, viral, especially varicella and fungal)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Extensive adverse reactions associated with corticosteroids, mostly with long-term administration; fluid and electrolyte disturbances, hypertension, musculoskeletal problems (including osteoporosis), GI bleeding, neurologic disturbances, hypercoagulable states, endocrine disturbances (most notably adrenocortical suppression and growth impairment in children), and ophthalmic disturbances
Increased risk of disseminating infections, eg, chickenpox, measles; prophylaxis may be indicated if exposure to these infections cannot be avoided; may mask symptoms of serious infections; abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, hypokalemia, euphoria, psychosis, myopathy, and GI irritation or ulceration may be more likely in pulse administration

Immunomodulating and immunosuppressive agents

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.⁴⁷ 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.

Dosing

Adult

Pediatric

10 mg/kg/d PO hydroxychloroquine base; not to exceed 400 mg/d hydroxychloroquine sulfate

Interactions

Increases digoxin levels; cimetidine increases serum levels; magnesium trisilicate may decrease absorption; coadministration with gold increases risk of blood dyscrasias; may increase levels and toxicities of substrates (eg, metoprolol, opioid analgesics, tricyclic antidepressants [TCAs], antipsychotics) because is cytochrome P450 2D6 (CYP2D6) inhibitor

Contraindications

Documented hypersensitivity; psoriasis; porphyria; retinal and visual field changes attributable to 4-aminoquinolones

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Use in pregnancy should be avoided because of potential fetal ocular toxicity; numerous adverse effects reported and more likely in children than adults: neurotoxicity, ocular toxicity, muscle weakness, dermatologic changes, blood dyscrasias, and GI irritation; caution in hepatic disease, glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, psoriasis, and porphyria; long-term use not recommended in children; perform ophthalmologic examinations and blood counts at baseline and q3-6mo; periodically test for muscle weakness; abrupt or premature cessation associated with exacerbation of symptoms

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.

Dosing

Adult

Pediatric

5 mg/kg/d (as base) PO; not to exceed 300 mg/d (as base) PO; doses up to 10 mg/kg/d PO reported

Interactions

Cimetidine increases serum levels; magnesium trisilicate or kaolin may decrease absorption; coadministration with gold increases risk of blood dyscrasias; decreases gastric emptying and may decrease bioavailability of various drugs (eg, ampicillin, bacampicillin); increases thyroid-stimulating hormone (TSH) levels, decreasing effectiveness of levothyroxine; increases cyclosporine and penicillamine levels

Contraindications

Documented hypersensitivity; psoriasis; retinal and visual field changes attributable to 4-aminoquinolones

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Use in first trimester of pregnancy should be avoided because of potential fetal ocular toxicity; numerous adverse effects reported and more likely in children than adults: neurotoxicity, ocular toxicity, muscle weakness, dermatologic changes, blood dyscrasias, and GI irritation; caution in hepatic disease, G-6-PD deficiency, psoriasis, and porphyria; long-term use not recommended in children; perform ophthalmologic examinations and blood counts at baseline and q3-6mo; periodically test for muscle weakness; may cause auditory reactions (eg, tinnitus); abrupt or premature cessation associated with exacerbation of symptoms

Azathioprine (Imuran)

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

Dosing

Adult

Pediatric

1 mg/kg/d PO for 6-8 wk initially; increase by 0.5 mg/kg/d q4wk up to 2.5 mg/kg/d or until response

Interactions

Inhibits azathioprine metabolism by 30% (decrease azathioprine dose by 67-75%); concomitant cotrimoxazole or ACE inhibitors may exaggerate leukopenia; may decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine

Contraindications

Documented hypersensitivity; low levels of serum thiopurine S-methyltransferase (TPMT)

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Principal toxicities are hematologic (eg, leukopenia) and GI (eg, nausea, vomiting, hepatotoxicity); monitor blood counts frequently (eg, q1wk first month, q2wk second and third months, monthly thereafter); caution in liver or renal disease

Methotrexate (Rheumatrex)

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

Dosing

Adult

Pediatric

Specific dosing for ILD not standardized
In inflammatory conditions, such as JRA, 10 mg/m²/wk PO has been administered as single dose qwk; not to exceed 15 mg/wk

Interactions

Salicylates and NSAIDs may reduce tubular secretion and enhance toxicity; protein displacement by phenytoin, phenylbutazone, sulfonamides, and probenecid may increase toxicity; penicillins reduce renal clearance; concomitant retinoids can enhance hepatotoxicity; tetracycline and chloramphenicol decrease absorption; folic acid can decrease effectiveness, whereas folic acid deficiency can increase toxicity; decreases clearance of theophylline

Contraindications

Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia); renal insufficiency

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Folic acid usually prescribed concurrently as 1 mg/d; common adverse reactions are ulcerative stomatitis, leukopenia, nausea, malaise, and fatigue; risk of opportunistic infection increased; may elevate hepatic enzyme levels and persistent elevation may indicate hepatotoxicity or cirrhosis; monitor blood CBC counts at baseline and monthly; may cause pulmonary fibrosis but usually not at doses used for inflammatory conditions; reduce dose in patients with renal failure, ascites, or pleural effusions

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.

Dosing

Adult

Pediatric

5-10 mg/kg IV q2-3wk; not to exceed adult range of 500-1800 mg/dose

Interactions

Chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity

Contraindications

Documented hypersensitivity; severely depressed bone marrow function; active infection

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in impaired hepatic or renal function; nausea, vomiting, alopecia, and myelosuppression frequent; hemorrhagic cystitis and bladder fibrosis may occur; can impair fertility, sometimes irreversibly; pulmonary fibrosis reported; use antineoplastic handling and disposal; monitor CBC counts, urinalysis, electrolyte, and serum creatinine results

Penicillamine (Cuprimine)

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

Dosing

Adult

Pediatric

3 mg/kg/d PO for 3 mo, not to exceed 250 mg/d; then 6 mg/kg/d PO divided bid for 3 mo, not to exceed 500 mg/d; not to exceed final maximum dose of 10 mg/kg/d PO divided tid/qid

Interactions

Increases effects of immunosuppressants, phenylbutazone, and antimalarials; decreases digoxin effects; coadministration of zinc salts, antacids, gold, or iron may decrease effects

Contraindications

Documented hypersensitivity; renal insufficiency; previous penicillamine-related aplastic anemia; chronic lead poisoning

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Potential cross-sensitivity with penicillin allergy; many adverse effects reported; potential for severe hematologic and renal reactions; Goodpasture syndrome, obliterative bronchiolitis, myasthenia syndrome, and lupus-like syndrome reported; wound healing impaired; all patients should receive pyridoxine 25 mg/d; iron deficiency may develop; measure CBC counts q2wk for first 6 mo then monthly; advise patients to promptly report signs suggesting bone marrow failure (eg, bleeding, sore throat, fevers)

Follow-up

Further Inpatient Care

• 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.

Further Outpatient Care

• 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.

Inpatient & Outpatient Medications

• 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.

Transfer

• 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.

Complications

• 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.

Prognosis

• 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.⁴ 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

• 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.

Miscellaneous

Medicolegal Pitfalls

• Misdiagnosis of interstitial lung disease (ILD) symptoms as asthma
• Failure to recognize associated causative conditions
• Failure to monitor for and detect development of pulmonary hypertension
• Failure to monitor for drug toxicity

Multimedia

Media file 1: Interstitial lung disease (ILD) due to ABCA3 gene mutations.

(A) High-resolution CT (HRCT) scan from a 4-month-old infant with ABCA3 mutations. The CT scan was performed with controlled ventilation under general anesthesia. Diffuse bilateral ground glass opacities and thickened interlobular septae are present. This "crazy paving" pattern suggests alveolar proteinosis or ILD due to genetic mutations affecting surfactant function and metabolism.

(B) Histopathology (hematoxylin and eosin) shows diffuse alveolar septal thickening with uniform prominent type II cell hyperplasia. Accumulations of alveolar macrophages and granular proteinosis are also present in the alveolar spaces.

(C) Electron microscopy demonstrates abnormal lamellar bodies with dense inclusions (arrows).

Media file 2: Pulmonary interstitial glycogenosis (PIG).

(A) Lung histopathology from a 5-week-old infant shows diffuse interstitial widening and cellularity with bland-appearing vacuolated foamy cells that contain glycogen (periodic acid-Schiff [PAS] stain). These cells seen in PIG are strongly immunoreactive with vimentin (not shown). Pigmented alveolar macrophages were an additional finding in this infant with history of meconium aspiration.

(B) Electron microscopy demonstrates that these mesenchymal cells contain abundant monoparticulate glycogen.

Media file 3: 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.

Media file 4: 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.

Media file 5: 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).

Media file 6: 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.

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Keywords

children’s interstitial lung disease, ChILD, ILD, diffuse infiltrative lung disease, pulmonary disease, lung disease, interstitial disease, idiopathic pulmonary fibrosis, IPF, nonidiopathic interstitial pulmonary fibrosis, usual interstitial pneumonia, UIP, desquamative interstitial pneumonia, DIP, bronchiolitis obliterans with interstitial pneumonia, BIP, lymphoid interstitial pneumonia, lymphocytic interstitial pneumonia, LIP, giant cell interstitial pneumonia, giant-cell interstitial pneumonia, GIP, respiratory bronchiolitis interstitial lung disease, RBILD

nonspecific interstitial pneumonia, NSIP, bronchiolitis obliterans organizing pneumonia, BOOP, cryptogenic organizing pneumonia, COP, cryptogenic fibrosing alveolitis, CFA, pulmonary histiocytosis X, eosinophilic granuloma, Langerhans cell histiocytosis, LCH, acute interstitial pneumonia, AIP, idiopathic BOOP, nonclassifiable ILD, neuroendocrine cell hyperplasia of infancy, NEHI, pulmonary interstitial glycogenosis, PIG, idiopathic interstitial pneumonia, cryptogenic fibrosing alveolitis, chronic pneumonitis of infancy, cellular interstitial pneumonitis

Contributor Information and Disclosures

Author

James S Hagood, MD, Director, Pediatric Pulmonary Center, Professor of Pediatrics, Cell Biology, Pathology and Biochemistry and Molecular Genetics, Department of Pediatrics, University of Alabama School of Medicine
James S Hagood, MD is a member of the following medical societies: American Thoracic Society
Disclosure: Nothing to disclose.

Coauthor(s)

Gulnur Com, MD, Pediatric Pulmonologist, University of Arkansas for Medical Sciences Children's Hospital
Gulnur Com, MD is a member of the following medical societies: American Academy of Pediatrics, American Thoracic Society, and Cystic Fibrosis Foundation
Disclosure: Nothing to disclose.

David J Vaughan, MBBCh, Consultant Pediatrician, Department of Pediatrics, Our Lady of Lourdes Hospital, Ireland
David J Vaughan, MBBCh is a member of the following medical societies: American College of Chest Physicians, American Thoracic Society, and Society of Critical Care Medicine
Disclosure: Nothing to disclose.

Daniel William Young, MD, FACR, Clinical Professor of Radiology, Clinical Professor of Pediatrics, University of Alabama School of Medicine; Active Staff, Department of Pediatric Imaging, Children's Hospital of Alabama; Vice-President, Pediatric Radiology Associates, PC
Daniel William Young, MD, FACR is a member of the following medical societies: Alpha Omega Alpha, American College of Radiology, Radiological Society of North America, and Society for Pediatric Radiology
Disclosure: Nothing to disclose.

Elizabeth C Mroczek-Musulman, MD, Clinical Associate Professor of Pathology, Associate Pathologist, Department of Pathology, University of Alabama Schools of Medicine and Dentistry, The Children's Hospital of Alabama
Elizabeth C Mroczek-Musulman, MD is a member of the following medical societies: American Society for Clinical Pathology and College of American Pathologists
Disclosure: Nothing to disclose.

Lisa R Young, MD, Assistant Professor, Pediatric Pulmonary Medicine and Pulmonary Critical Care and Sleep Medicine, University of Cincinnati; Director of Pediatric Rare Lung Diseases Program and Consulting Physician, Cincinnati Children's Hospital Medical Center; Consulting Physician, University Hospital, Cincinnati
Lisa R Young, MD is a member of the following medical societies: American College of Chest Physicians, American Thoracic Society, Central Society for Clinical Research, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

Susanna A McColley, MD, Director of Cystic Fibrosis Center; Head, Division of Pulmonary Medicine; Associate Professor, Department of Pediatrics, Children's Memorial Medical Center of Chicago, Northwestern University
Susanna A McColley, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, American Sleep Disorders Association, and American Thoracic Society
Disclosure: Genentech Honoraria Speaking and teaching; Genentech Honoraria Consulting; Novartis Honoraria Consulting; Altus  Consulting fee Consulting; Axcan Scandi Consulting fee Consulting; Boston Scientific Consulting fee Consulting; Gilead  Speaking and teaching

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Heidi Connolly, MD, Associate Professor of Pediatrics and Psychiatry, University of Rochester; Director, Pediatric Sleep Medicine Services, Strong Sleep Disorders Center
Heidi Connolly, MD is a member of the following medical societies: American Academy of Pediatrics, American Thoracic Society, and Society of Critical Care Medicine
Disclosure: Nothing to disclose.

CME Editor

Mary E Cataletto, MD, Associate Director, Division of Pediatric Pulmonology, Winthrop University Hospital; Professor of Clinical Pediatrics, State University of New York at Stony Brook; Director of Children's Sleep Services, Winthrop University Hospital
Mary E Cataletto, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Chest Physicians
Disclosure: Shering Plough Pharmaceuticals Honoraria Consulting

Chief Editor

Michael R Bye, MD, Professor of Clinical Pediatrics, Division of Pulmonary Medicine, Columbia University College of Physicians and Surgeons; Attending Physician, Pediatric Pulmonary Medicine, Morgan Stanley Children's Hospital of New York Presbyterian, Columbia University Medical Center
Michael R Bye, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, and American Thoracic Society
Disclosure: Merck Honoraria Speaking and teaching

The authors are greatly indebted to the Rare Lung Disease Consortium, the members of the Children's Interstitial Lung Disease (chILD) collaborative, the chILD Foundation, and the children and families who struggle daily with interstitial lung disease (ILD).

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