Children's Interstitial Lung Disease (ChILD) Clinical Presentation

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

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).

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Physical

See the list below:

  • General physical findings

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

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

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

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

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

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

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

  • Cyanosis and clubbing are late manifestations of ILD.

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

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Causes

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

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

Disorders with known causes

See the list below:

  • Infection (8-10%)

  • Environmental conditions (13%)

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

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

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

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

    • Exposure to radiation

  • Drugs

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

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

  • Previous lung injury

  • Chronic aspiration pneumonitis (4-5%)

  • Resolving acute respiratory distress syndrome (ARDS)

  • Bronchopulmonary dysplasia (BPD)

  • Lymphoproliferative disorders (10%)

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

  • Metabolic disorders

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

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

  • Immunodeficiency-associated ILD

Disorders with unknown causes

See the list below:

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

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

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

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

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

  • Lymphangiomatosis (4%)

  • Nonadenoviral bronchiolitis obliterans (4%)

  • Sarcoidosis (2%)

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

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

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

  • Bronchocentric granulomatosis (1%)

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

  • Acute interstitial pneumonitis (AIP)

ILD associated with systemic diseases

See the list below:

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

  • Autoimmune diseases (antiglomerular basement membrane antibody disease)

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

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

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

  • Amyloidosis

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

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

Disorders with presenting features similar to those of ILD

See the list below:

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

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

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

  • CF

  • Immunodeficiency

Forms of ILD most prevalent in infancy

See the list below:

  • Diffuse developmental disorders [12]

    • Acinar dysplasia

    • Congenital alveolar dysplasia

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

  • Growth abnormalities

    • Pulmonary hypoplasia

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

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

    • Abnormalities associated with congenital heart disease in otherwise healthy children

  • Specific conditions with unknown etiology

    • PIG

    • NEHI

  • SDMs and related disorders

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

    • SFTPC genetic mutations

    • ABCA3 genetic mutations

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

Genetic and/or familial disorders

See the list below:

  • SDMs and related disorders

  • Familial hypocalciuric hypercalcemia

  • Lysinuric protein intolerance

  • Farber lipogranulomatosis

  • Hermansky-Pudlak syndrome

Pulmonary alveolar proteinosis

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

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

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

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

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

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

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

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

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