AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

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

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Background

Interstitial lung diseases (ILDs) in childhood are a diverse group of conditions that primarily involve the alveoli and perialveolar tissues and that lead to derangement of gas exchange, restrictive lung physiology, and diffuse infiltrates as seen on radiographs. Because ILDs usually involve the distal airspaces and the interstitium, the term diffuse infiltrative lung disease has been suggested. This nomenclature is more accurate than ILD, but children's interstitial lung disease (chILD) has become the preferred term. In 2004, the Rare Lung Disease 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 and the important differences between childhood ILD and ILDs that affect adults, a great deal of confusion regarding their nomenclature, classification, and management is observed. Idiopathic pulmonary fibrosis (IPF, also known as cryptogenic fibrosing alveolitis [CFA]), the most prominent adult ILD, mostly occurs after the fifth decade of life and is almost never seen 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 between children and adults.

Usual interstitial pneumonitis (UIP), the pattern associated with IPF in adults, is rarely, if ever, described in children. Desquamative interstitial pneumonitis (DIP), which is associated with steroid responsiveness and a better prognosis in adults, has a 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 newly 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-protein (SP) abnormalities, apoptosis of the alveolar epithelium was demonstrated to be a key inciting event. Blood or plasma leaks into procoagulant-rich airspaces and clots, forming a provisional matrix that contains fibronectin, fibrin, and numerous mediators released from activated platelets and injured cells (the hyaline membranes of acute lung injury). This fibrinous exudate usually forms the base for subsequent repair and remodeling.

Fibroblasts, which are normally present in the attenuated interstitial spaces between alveoli and surrounding distal airways, are activated by exposure to plasma proteins and soluble mediators and migrate into the fibrinous wound matrix, where they proliferate and elaborate matrix molecules such as collagen. Fibroblasts also produce proteases, such as urokinase and collagenase (which degrade the matrix), and inhibitors of matrix degradation, such as tissue inhibitors of metalloproteinases (TIMPs).

Through production of cytokines and chemokines, such as interleukin (IL)-6, IL-8, and keratinocyte growth factor (KGF), fibroblasts signal inflammatory cells, endothelial cells, and type II pneumocytes, activating or modulating the other cellular events that follow lung injury. Recent data has indicated 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 most 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. Therefore, for some time, the degree or persistence of inflammation has been believed to dictate the degree of remodeling and fibrosis.

This inflammation hypothesis has recently been called into question for numerous reasons. Careful review of well-defined cases of UIP in adults has revealed little evidence of extensive inflammation. Numerous reports detail diseases with extensive airspace inflammation, such as hypersensitivity pneumonitis, that do not always progress to fibrosis. Animal models, particularly certain transgenic mice, have demonstrated that interstitial remodeling and fibrosis are possible without inflammation. Clinical markers of inflammation, such as BAL cellularity, scanning using gallium-67 citrate, and levels of circulating inflammatory mediators, have not been useful in determining disease activity or prognosis. 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. Injury or stress in epithelial cells, resulting in stress signaling or programmed cell death, may be the initiating factor in many types of fibrosis, such as that associated with surfactant protein abnormalities or viral infection. 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 ILD, 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. Proliferation of type II pneumocytes is seen in most types of ILD. The proliferation and migration of type II pneumocytes over the provisional wound matrix are believed to be crucial events in the resolution of fibrosis.

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 end-stage interstitial disease. Although the events described in the preceding paragraphs 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 of consensus on case definition (until recently), the broad differential diagnosis, and the lack of organized reporting systems (eg, a national database), determining the 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.

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.⁵

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.
• Data from small series suggest that patients with DIP, particularly infants, have a poor prognosis. This finding is in marked contrast to observations in adult ILD, in whom DIP diagnosed histologically indicates steroid responsiveness and an improved prognosis. Certain diagnosed conditions, such as SP-B deficiency, do not respond to any interventions. Without lung transplantation, the prognosis is poor.

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. A male predominance is observed in IPF in adults.

Age

Most cases of chILD 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.
• The mean age of onset of IPF (UIP) is 57 years. This particular entity likely does not occur in children at all.
• Recently identified pediatric ILD syndromes unique to infancy, including NEHI, PIG, and chronic pneumonitis of infancy, may present at or shortly after birth. Genetic abnormalities of SPs often cause severe symptoms during the newborn period (See Causes and Childhood ILD syndromes manifesting in infancy).

CLINICAL

Section 3 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

History

Diagnosing interstitial lung disease (ILD) 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 primary care providers 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).

• 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 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 children’s interstitial lung disease (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.
• 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.
• Deformity of the chest has been reported and may indicate lung hypoplasia, as well the effects of prolonged illness.

Causes

ILD in children can be classified into idiopathic disorders, those of known or suspected causes, and those associated with systemic diseases (see ILD associated with systemic diseases below). In the largest reported series in children, 19-27% of cases remain undetermined.⁶ Several important disorders present with chronic respiratory symptoms and findings of diffuse radiographic infiltrates and must be considered in the differential diagnosis.

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 located below. The numbers in parentheses indicate percentage of final diagnoses in the largest reported series.⁶

Disorders with known causes

• Infection (8-10%)
• • Viral infection (eg, adenoviral bronchiolitis obliterans[5%], cytomegaloviral [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) 
  • 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

• 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%])
• DIP (4-8%)
• 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.)
• 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
• Acute interstitial pneumonitis (AIP)

• 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)

Disorders with presenting features similar to those of ILD

• Pulmonary venoocclusive 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

• 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
• SP dysfunction mutations 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

• Mutations in genes for SP-B, SP-C, and ABCA3
• Familial hypocalciuric hypercalcemia
• Lysinuric protein intolerance
• Farber lipogranulomatosis
• Hermansky-Pudlak syndrome

The 4 major SPs 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 withPAP.⁸ 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.⁹

Recently, familial pulmonary fibrosis has been associated with mutations in the SFTPC gene. SP-C deficiency can have variable clinical presentations, even in members of the same family.^{10, 11} 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) infection⁹

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 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.¹³ The exact function of the ABCA3 protein is unknown, but it is critical for the lipid transport into lamellar bodies and proper surfactant function.¹⁴ 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.^{15, 16} 

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.¹⁷

DIFFERENTIALS

Section 4 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Other Problems to be Considered

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

WORKUP

Section 5 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Lab Studies

• 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, and eosinophilic syndromes.
• 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 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 may be elevated in patients with sarcoidosis.
• Serum precipitin results may be positive in patients with hypersensitivity pneumonitis.
• 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. 
• • 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 interstitial lung disease (ILD), BPD, severe measles pneumonia, and ILD associated with juvenile dermatomyositis.^{18, 19}
  • KL-6 appears to have high sensitivity (93.9%) and high specificity (96.3%) for IDL in adults and correlates with disease severity.²⁰

Imaging Studies

Chest radiography

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 pulmonary fibrosis, 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 end-stage 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).

Diagnostic accuracy based on chest radiograph appearances is 28-40%.

CT scanning

CT scanning, specifically HRCT, provides a noninvasive means for determining the extent and distribution of changes associated with pulmonary fibrosis. 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.²¹

Whether serial HRCT provides any benefit in monitoring disease progression or response to therapy is unclear. When possible, both inspiratory and expiratory images should be obtained. Expiratory images are important to assess for ground-glass attenuation. The imaging appearance of diffuse abnormalities include ground-glass attenuation, a tree-in-bud appearance, lobular airtrapping, reticular attenuations, and centrilobular nodules.²²

In a study of HRCT in 20 children with ILD, specific patterns were correlated with certain types of pathology, with little overlap.²³ 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.²⁴ Consolidative patterns were seen in aspiration syndromes, BOOP, 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.²⁵ 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.

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

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.

Results of PFTs in infants, if available, usually show reduced Crs by using both multiple occlusion and end-inspiratory occlusion techniques, and PFTs have been used to monitor the response to treatment in some studies.

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.

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 probe testing may be required to demonstrate gastroesophageal reflux (GER), predisposing patients to aspiration.

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), 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.²⁶

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). A pediatric lung biopsy protocol has been developed and supported by the ChILD Pathology Cooperative Group.²⁷ However, a diagnosis is not reached in a notable percentage of 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.²⁷

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.^{6, 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.¹⁴

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 ILD and may indicate the underlying cause, if a cause is present, or may suggest associated systemic illnesses. 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.

No systematic histologic classification of ILD is available for children. The scheme used for adult IPF is helpful, but the implications of particular patterns differ in important ways, and some classes are not considered in IPF. The chILD Consortium is currently revising classification systems on the basis of existing pathologic specimens at several centers.

ILD classification systems

Several classification systems have been developed.

Liebow provided the original classification of interstitial pneumonias in 1975, naming the following 5 patterns: (1) UIP, (2) DIP, (3) bronchiolitis obliterans with interstitial pneumonia (BIP), (4) LIP, and (5) giant-cell interstitial pneumonia (GIP).²⁸

In 1998, Katzenstein and Myers revised the classification in relation to IPF such that UIP remains the same as in the previous scheme, but DIP is combined with respiratory bronchiolitis ILD (RBILD) as DIP/RBILD, acute interstitial pneumonia (AIP), and nonspecific interstitial pneumonia (NSIP).¹ LIP and GIP were removed from the scheme because they are no longer considered idiopathic. BIP, currently more commonly termed BOOP, is not included because it predominantly involves airspaces; therefore, it is not technically interstitial.

In a 2000 international consensus statement, the American Thoracic Society (ATS) defined UIP as the histologic pattern necessary for a diagnosis of IPF (also termed CFA). The other patterns are classified as the pathologic differential diagnosis of UIP. 

The Liebow classification of interstitial pneumonias is as follows:²⁸

• UIP 
• DIP
• BIP
• LIP
• GIP

• UIP 
• DIP/RBILD
• AIP
• NSIP

• 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

Specific histologic patterns of ILD

UIP

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. Hypercellularity results from inflammatory cells (lymphocytes, plasma cells) and type II pneumocyte hyperplasia. Fibrotic areas contain dense collagenous deposits and characteristic foci of proliferating fibroblasts (fibroblastic foci), which have negative prognostic importance.

UIP is the histologic pattern of IPF; therefore, it is rarely seen in childhood ILD unless it is associated with a known or suspected underlying cause. UIP has been reported in children (possibly erroneously), but characteristic fibroblastic foci were not described in any of the reports. In addition, children with IPF often live much longer than adults with it, and they have a nonprogressive course, suggesting that they do not have UIP.³⁰

DIP

DIP is rare in adults and usually affects those who smoke cigarettes. The histologic pattern is uniform and diffuse, unlike UIP. 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. Unlike DIP in adults, in whom this pattern is associated with 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.³¹

RBILD

RBILD shares some histologic features with DIP, but its appearance is patchier and its distribution more bronchiolocentric, with macrophage accumulations in the lumens of respiratory bronchioles. Like DIP, RBILD is also associated with cigarette smoking in adults and has not been reported in childhood series.

NSIP

NSIP is a confusing term 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.

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 known or suspected connective tissue diseases and with environmental exposures. One problem is that the term nonspecific is often applied in patients in whom the histologic pattern or clinical diagnosis is unclear and not that of NSIP.

AIP

AIP is the pattern associated with the entity Hamman and Rich originally described in 1944.³² 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

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. 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. This entity has not been described in children.

LIP

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 and lymphomas 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.

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.

Childhood ILD syndromes that manifest in infancy

Persistent tachypnea of infancy and pulmonary NEHI

In 2005, Deterding et al reported a case series of 15 patients with a clinical picture of persistent tachypnea, crackles, and hypoxemia.³³ 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 demonstrate 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).

Most of the infants were treated with systemic steroids and bronchodilators, except for a few who treated with azathioprine and hydroxychloroquine. Clinical improvement was inconsistent, but no pulmonary-related deaths were reported. The authors suggested that NEHI and chronic idiopathic bronchiolitis of infancy might constitute the same entity.^{33, 30}

Follicular bronchitis/bronchiolitis

In 2 case series similar to those described above, infants presented with tachypnea, fine crackles, and chronic cough by 6 weeks of age.^{34, 35} Lung biopsy findings demonstrated follicular lymphocytic infiltration surrounding and infiltrating the bronchial walls. All patients improved gradually over several years.

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.^{30, 24}

Cellular interstitial pneumonitis/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.³⁰

In 2002, Canakis et al reported 7 neonates presenting with chronic ILD.³⁶ 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

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.^{37, 30}

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 alveolar PAP. Immunohistochemical staining demonstrates absence of SP-B.^{38, 15}

Adults with SP-C deficiency can have biopsy findings consistent with those of UIP, DIP, or NSIP.^{30, 39} Some have suggested that a mutation in SFTP-C gene may cause the production and accumulation of an abnormal protein, resulting in injury to the respiratory epithelium or complete absence of the functional protein.^{40, 15}

In several cases of ABCA3 deficiency, lung biopsy demonstrated proteinaceous material and interstitial thickening consistent with infantile PAP and DIP. In a recent report of ABCA3 deficiency, lung tissue obtained from 4 infants demonstrated abnormal lamellar bodies.¹³

In cases of PAP, lung biopsy often demonstrates foamy alveolar macrophages, epithelial-cell hyperplasia, and fibrosis associated with PAS-positive intraalveolar material. EM shows abnormal lamellar bodies in type II epithelial cells with absence of tubular myelin. Interstitial fibrosis complicates long-standing cases.

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):³¹

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

TREATMENT

Section 6 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

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.³⁰ Other steroid-responsive conditions include NSIP, DIP, LIP, COP, eosinophilic pneumonia syndromes, sarcoidosis, pulmonary hemosiderosis, and ILD associated with connective tissue disease.⁵ 
• 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.⁴¹ Several studies have demonstrated successful use of subcutaneous treatments with GM-CSF in adults with PAP.⁵
• After an initial report regarding the success of interferon (IFN) gamma-1b in adults with IPF, a phase 3 randomized double-blind placebo-controlled trial was completed.⁴² In it, 330 patients were randomly assigned either to receive placebo or IFN gamma-1b. Over a median of 58 weeks, IFN gamma-1b did not affect progression-free survival, pulmonary function, or quality of life. However, subsequent meta-analysis suggested that a subgroup of patients demonstrated some benefit from IFN-gamma1b, such that a large, phase III, multicenter study designed to further evaluate the potential survival benefit (International Study of Survival Outcomes in Idiopathic Pulmonary Fibrosis with IFN gamma-1b [INSPIRE]) is currently underway. 
• 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.^{43, 44}

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

Section 7 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

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.

Drug Category: 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.

Drug Category: 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.⁴⁶ 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.