Interstital Lung Disease in Children

by Leland L. Fan, M.D.

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Introduction
Etiology and Pathogenesis
Usual Interstitial Pneumonitis (UIP)
Desquamative Interstitial Pneumonitis (DIP)
Lymphocytic Interstitial Pneumonitis (LIP)
Diagnostic Evaluation
Clinical Presentation
Exposure History
Chest Radiographic Pattern
Other Diagnostic Tests
Treatment

Introduction

Estimates of ILD incidence and prevalence in adults are imprecise, but some studies suggest ILD may account for as many as 100,000 hospital admissions annually. The diseases are more rare in children, but actual incidence remains unknown and curent knowledge is based largely on case reports and information obtained from small series of patients.

ILD poses a clinical challenge to physicians because the disease spectrum can range from mild disease that is responsive to medications to progressive loss of pulmonary function and death. Corticosteroids and cyclophosphamide result in clinical improvement in a subset of patients, but in other patient groups pharmacologic therapy remains largely empiric and unproven.

Clearly, progress is needed to improve understanding of ILD etiology, pathogenesis, diagnosis and treatment.

Etiology and Pathogenesis

In a minority of cases, ILD evolves from a known insult to the interstitium. A number of collagen vascular diseases have been associated ILD. Drug-induced lung injury also contributes a fair number of cases. Among other known causes of ILD, hypersensitivity pneumonitis, an immunologic response to organic dusts such as molds and bird antigens, is relatively common. Aspiration syndromes represent another common source of chronic lung disease in children. Infectious pneumonia may lead to chronic lung disease in either the immunocompetent or immunocompromised host, and previous, clinically unrecognized infection likely contributes to some ILD cases (See Tables 1 and 2).

The classic histologic patterns of idiopathic ILD are seen less often in children.

Despite the diversity of diseases that constitute ILD of known cause, the majority of patients have idiopathic disease. Among the most common forms of ILD in adults is idiopathic pulmonary fibrosis (IPF, also known as cryptogenic fibrosing alveolitis). A variety of etiologies have been proposed for the lung injury that leads to IPF, but to date none have been proved.

The conditions that make up ILD, whether of known or unknown origin, have in common an inflammatory process thought to be initiated by an injury to the alveolar wall. This inflammation, combined with the lungs' attempts to repair the injury, leads to distortion of the lung architecture and deposition of connective tissue. A number of inflammatory cells are thought to participate in the evolution of ILD, especially neutrophils and alveolar macrophages. T- and B-lymphocytes, monocytes, eosinophils, basophils and mast cells also have been implicated.

Several histologic descriptions are used to designate individual patterns on lung biopsy. This pathologic information is used along with clinical data to lead to a diagnostic categorization of the disease process.

The chest x-ray is a useful diagnostic tool for many types of ILD.

Usual Interstitial Pneumonitis (UIP)

Desquamative Interstitial Pneumonitis (DIP)

Lymphocytic Interstitial Pneumonitis (LIP)

LIP is characterized by a diffuse interstitial infiltrate with a predominance of lymphocytes, accompanied by plasma cells and histiocytes within the interstitial component of the alveolar wall and along lymphatic pathways. Resultant architectural changes typically consist of thickening of the bronchovascular bundles and interlobular septa. Small, noncleaved lymphocytes may accumulate to produce micronodules.

The classic histologic patterns of idiopathic ILD are seen less often in children. UIP has been described in a fair number of children, but the frequent ommission of lung biopsy results in most cases leaves the histologic diagnosis open to question. In the experience at National Jewish, true UIP has been unusual. DIP accounts for fewer pediatric cases of ILD, as the medical literature reflects about a 1:3 ratio of DIP to ILD in children. This ratio is higher than for adults, who have a 1:10 ratio. LIP in children is most commonly associated with with underlying autoimmune diseases and immunodeficiency states, especially AIDS. LIP occurs in almost a third of all children with perinatally acquired HIV infection, and the prevalence is likely to increase with the rising prevalence of pediatric AIDS.

Many children have diffuse interstitial inflammation that does not fit any specific histologic category. This observation is similar to that reported by other investigators.

Diagnostic Evaluation

Clinical Presentation

Signs of advanced disease include increased dyspnea and tachypnea, cyanosis and digital clubbing. Advanced disease in children may result in weight loss or failure to thrive.

Symptoms not confined to the chest can point toward ILD originating from a specific cause. For example, systemic lupus erythematosus may produce a characteristic malar rash; pitting of the fingertips may be a sign of scleroderma; joint tenderness and swelling may indicate rheumatoid arthritis.

While the clinical presentation may help guide the physician to a diagnosis of ILD, it must be combined with other aspects of the evaluation to generate a diagnosis.

Exposure History

A detailed drug history should focus on pharmaceutical agents that have a known association with ILD. The medical history should cover history of pulmonary diseases and infections, immune system disorders and immunodeficiency and conditions associated with ILD, such as collagen vascular diseases.

The link between HIV infection and ILD should not be underestimated. HIV infection predisposes a patient to LIP and to opportunistic infections associated with chronic lung disease. HIV should be high on the list of etiologic suspects in any patient who has diffuse interstitial infiltrates of unidentified origin. Given the typically long latency between exposure and emergence of the infection, the review of HIV risk factors should extend back as many years as necessary to rule out the possibility.

Supportive care remains an essential component in the treatment of adults and children.

Family history of ILD or chronic lung disease occasionally is a useful finding, as genetic factors contribute to the development of some types of ILD.

Chest Radiographic Pattern

Other Diagnostic Tests

Pulmonary function tests should be performed whenever ILD is suspected. The tests typically will reveal restrictive lung impairment. Forced vital capacity and forced expiratory volume at one second are reduced proportionally in most patients. Total lung capacity, functional residual capacity and residual volume all tend to be decreased in adults, but often vary in children.

Arterial blood gases reveal hypoxemia, with exercise or at rest, in a substantial number of patients (87% in the National Jewish pediatric series).

Laboratory tests should be used as indicated to help confirm or rule out specific etiologies. CBC, sedimentation and total eosinophil count are among the most common hematologic tests. Immunologic testing, screens for infectious disease (especially HIV), urinalysis and other tests may prove useful in specific patients.

At National Jewish, cardiac evaluation has proven useful in the workup of pediatric patients. More than 40% of the first 48 patients showed evidence of pulmonary hypertension by ECG, echocardiography and/or cardiac catheterization.

Bronchoalveolar lavage has been used in adults to predict response to therapy, narrow the differential diagnosis and gain insight into the pathophysiology of ILD. However, the procedure does not enjoy universal acceptance among physicians. The procedure's role in the evaluation of pediatric patients remains undefined, primarily because of a lack of comprehensive normal values for pediatric lavage fluid. Bronchoalveolar lavage has proven useful in diagnosing infection in immunocompromised and immunocompetent children.

Transbronchial lung biopsy has proven especially useful in the diagnosis of granulomatous ILD and sarcoidosis. The procedure is limited somewhat by the amount of tissue that can be obtained via fiberoptic bronchoscopy. In addition, transbronchial biopsy has been limited in children by the lack of a suitable flexible bronchoscope.

Though the most invasive diagnostic option, open lung biopsy remains the gold standard for ILD diagnosis. At National Jewish specific histologic diagnosis was made in 24 of 30 patients in whom biospies were obtained, a diagnostic yield comparable to those reported in published series.

Treatment

A few specific therapies exist for ILD, such as interferon alpha for pulmonary hemangiomatosis. By and large, however, pharmacologic therapy is somewhat empirical and unproven, due to the absence of controlled clinical trials.

Corticosteroids have emerged as primary pharmacologic therapy. Steroids have been used with varying degrees of success to treat UIP, DIP, LIP, hypersensitivity pneumonitis and other forms of ILD. About 40% of patients have responded to steroids in the National Jewish pediatric series. Other investigators have reported somewhat higher response rates. The true response rate remains unknown because steroids have not been evaluated in controlled trials of ILD. Both oral steroids and pulse therapy have been used.

A number of agents have been used as second-line therapy after corticosteroids. At National Jewish, hydroxychloroquine is used with some regularity in ILD, especially in pediatric patients, because of its relatively low toxicity. Among cytotoxic agents, cyclophosphamide, azathioprine and methotrexate are used most frequently. Although cyclophosphamide is often the drug of choice as adjunctive therapy to corticosteroids in adults, a higher than expected sterility rate limits its usefulness in children. In general, second-line pharmacologic therapies have not been evaluated in controlled clinical studies of ILD.

The Medical Scientific Update, a publication of the Office of Professional Education at National Jewish, provides information to physicians about our clinical and research programs in allergic, respiratory, and immune system disorders. The Web edition of the Medical Scientific Update published by the Gerald Tucker Memorial Medical Library.