Interstitial Lung Diseases

Interstitial lung diseases comprise a heterogeneous group of disorders that have in common the features of inflammation and fibrosis of the interalveolar septum, which represent a nonspecific reaction of the lung to injury of diverse cause. Some 130 disease entities share the manifestations of interstitial lung disease . In the majority of patients, no specific cause can be identified. In the remainder, drugs and a variety of inorganic and organic dusts are the predominant causes of the interstitial disease.

The pathogenesis of interstitial lung disease of unknown etiology is believed to be lung injury that leads to inflammation of the interalveolar septum (alveolitis). Persistent alveolitis may lead to eventual irreversible interstitial fibrosis.

Interstitial lung diseases share common clinical, physiologic, and radiographic features. Dyspnea and dry cough of insidious onset are the usual presenting symptoms. Chest examination is notable for fine inspiratory crackles at the bases of the lung. Digital clubbing is common. Pulmonary function testing reveals a restrictive ventilatory defect and a decreased diffusing capacity for carbon monoxide. Hypoxemia, especially with exercise, is common. Diffuse groundglass, nodular, reticular, or reticulonodular infiltrates that may progress to "honeycomb lung" are noted on chest x-ray. Infrequently, the chest x-ray is normal when lung biopsy demonstrates interstitial lung disease.

The history, physical examination, chest x-ray, and laboratory studies may provide evidence of a specific cause of interstitial lung disease. Sputum is usually minimal or nonexistent. Induced sputum is likely to yield useful diagnostic information only if pulmonary infection or malignancy is suspected. The role of lung biopsy (open or transbronchial), bronchoalveolar lavage, and gallium-67 (Ga 67) lung scanning in the diagnostic evaluation of patients with interstitial lung disease is controversial; histopathologic examination of lung tissue is frequently required for the definitive diagnosis of any interstitial lung disease.

Transbronchial biopsy using a fiberoptic broncho-scope is easily performed and is associated with a low morbidity rate, but the tissue specimens obtained are small, and sampling errors may result. Open lung biopsy produces large specimens but has a higher rate of complications. Transbronchial biopsies and washings may be adequate to permit the diagnosis of diseases such as sarcoidosis, histiocytosis X, Pneumocystis carinii pneumonia, miliary tuberculosis, pulmonary alveolar proteinosis, and lymphangitic carcinomatosis. On the other hand, patients who are rapidly deteriorating may be best served by definitive open lung biopsy rather than potentially nondiagnostic transbronchial biopsy. The choice between transbronchial biopsy and open lung biopsy depends on the following factors: (1) the probable diagnosis, (2) the patient's condition, (3) the operator's expertise in these biopsy procedures, (4) the risks of empiric therapy, and (5) the risk of biopsy procedures. It is probably reasonable to begin with transbronchial biopsy in most patients because of the low rate of complications associated with this procedure. If no specific diagnosis can be reached and the patient is a good candidate for surgery, open lung biopsy may then be performed.

Techniques to evaluate the progression of alveolitis have been devised in an attempt to identify patients suitable for anti-inflammatory therapy. These techniques include bronchoalveolarlavage,lung biopsy, and Ga 67 lung scanning.

Bronchoalveolar lavage is useful in the diagnosis of P carinii pneumonia and in selected patients with lung infection from other organisms (mycobacteria, fungi, cytomegalovirus, and Legionella species). It is occasionally employed for specific diagnosis of lung cancer, pulmonary alveolar proteinosis, histiocytosis X, beryllium-induced lung disease, amiodarone-induced pneumonitis, or pulmonary hemorrhage in thrombocytopenic patients. In ongoing studies, a very high percentage of T lymphocytes in bronchoalveolar lavage fluid suggests sarcoidosis or hypersensitivity pneumonitis; a predominance of neutrophils, eosinophils, and macrophages suggests idiopathic pulmonary fibrosis. Expertise in evaluation of lavage fluid is not widely available, limiting the application of this diagnostic tool. Lung scanning with Ga 67 is nonspecific and has no proved value in diagnosis or management of patients with interstitial lung disease.

Cryptogenic Fibrosing Alveolitis

(Idiopathic Pulmonary Fibrosis)

Cryptogenic fibrosing alveolitis is the most com-mon diagnosis among patients presenting with intersti-tial lung disease. Patients usually present in the sixth or seventh decade. The disease is more common in men than in women. A familial form of the disease (autosomal dominant trait with variable penetrance) has been described. Serologic tests for antinuclear antibody and rheumatoid factor are frequently positive (20-40% of cases). Symptoms, physical findings, and results on pulmonary function tests are typical of those of interstitial lung disease and are described above. Chest x-ray abnormalities are highly variable. Lower lung zone interstitial infiltrates of a reticular pattern are typical when the patient is first seen. High-resolution CT scan best demonstrates the extent of lung parenchymal fibrosis. Circulating immune complexes have been detected in patients with this disorder. However, the diagnosis is usually based on the clinical presentation and exclusion of other specific diagnoses, usually by means of bronchoalveolar lavage or lung biopsy. Histologic examination of lung tissue reveals a combination of cellular infiltration and fibrosis of the alveolar septum. Desquamated mononuclear cells, mainly macrophages, may be observed within alveoli; it is likely that fibrosis is pre-ceded by other histologic stages (desquamative interstitial pneumonitis, usual interstitial pneumonitis) in many of these patients. Open lung biopsy for the diagnosis of cryptogenic fibrosing alveolitis is helpful to exclude other specific causes of interstitial lung disease. Its routine use for this purpose is controversial.

High doses of oral corticosteroids (eg, prednisone, 40-80 mg daily) are the usual treatment. Cytotoxic drugs such as cyclophosphamide and azathioprine have also been used. Controlled clinical trials have not demonstrated any beneficial effect of therapy, but clinical experience with these drugs suggests that about 20% of patients will improve. The response to corticosteroids is better in patients with more in-flammation and less fibrosis noted on lung biopsy.

Relentless progression of the disease with eventual respiratory insufficiency is the rule, and the average survival time is about 4 years. Lung transplantation for highly selected patients with end-stage pulmonary fibrosis has been reported. It is important to distinguish cryptogenic fibrosing alveolitis from bronchiolitis obliterans organizing pneumonia (BOOP) because of the excellent response of the latter disorder to corticosteroid therapy.


Sarcoidosis is a systemic disease of unknown cause characterized by granulomatous inflammation that affects the lung in about 90% of patients. The incidence is highest in North American blacks and northern European whites; among blacks, women are more frequently affected than men. Onset of disease is usually in the third or fourth decade.

Patients may present with malaise, fever, and dyspnea of insidious onset. Alternatively, sarcoidosis may present with symptoms referable to the skin, eyes, peripheral nerves, liver, or heart. Some patients are asymptomatic and come to medical attention after abnormal findings on routine chest radiographs. Physical findings in the chest are typical of those associated with interstitial lung involvement, if the parenchyma is involved. Other findings may include skin rashes, erythema nodosum, parotid gland enlargement, hepatosplenomegaly, and lymphadenopathy.

Laboratory tests may show leukopenia, eosinophil-ia, an elevated erythrocyte sedimentation rate, and hypercalcemia (about 10% of patients) or hypercalciu-ria. Angiotensin-converting enzyme (ACE) levels may be elevated with active sarcoidosis, but this finding is neither sensitive nor specific enough to have diagnostic significance. ACE is derived from the cell membrane of epithelioid cells of the sarcoid granuloma. Its synthesis is controlled by T lymphocytes. Physiologic testing may reveal evidence of airflow obstruction, but decreased lung volumes and diffusing capacity are more common signs. Skin test anergy is present in 70%.

Radiographic findings are variable and include bilateral hilar adenopathy alone (stage I), hilar adenopathy and parenchymal involvement (stage II), or parenchymal involvement alone (stage III). Parenchymal involvement is usually manifested radiographically by diffuse reticular infiltrates, but focal infiltrates, nodules, and, rarely, cavitation may be seen. Pleural effusion is noted in fewer than 10% of patients.

The diagnosis of sarcoidosis generally requires histologic demonstration of noncaseating granulomas in biopsies from a patient with other typical associated manifestations. Other granulomatous diseases must be ruled out. If indicated, biopsy of easily accessible sites, eg, palpable lymph nodes, skin lesions, or salivary glands, is likely to provide positive findings. Transbronchial lung biopsy has a high yield of positive findings, especially in patients with radiographic evidence of parenchymal involvement. Most clinicians would agree that tissue biopsy is not necessary when stage I radiographic findings are detected in a clinical situation that strongly favors the diagnosis of sarcoidosis (eg, a young black female with erythema nodosum). Biopsy is essential whenever clinical and radio-graphic findings suggest the possibility of an alternative diagnosis such as lymphoma. Bronchoalveolar lavage is useful in following the activity of sarcoidosis in selected patients but does not provide a specific diagnosis.

Indications for treatment with corticosteroids include constitutional symptoms, hypercalcemia, iritis, arthritis, central nervous system involvement, granulomatous hepatitis, cutaneous lesions, and symptomatic pulmonary lesions. ACE serum levels usually fall with clinical improvement. About 20% of patients with lung involvement suffer irreversible lung impairment. The outlook is best for patients with hilar adenopathy alone; radiographic involvement of the lung parenchyma is associated with a worse prognosis. Death due to pulmonary insufficiency occurs in about 5% of patients.

Histiocytosis X

(Eosinophilic Granuloma)

Histiocytosis X is a generic term embracing 3 clinical syndromes that share a common histologic characteristic and are defined by age at onset, clinical course, and organ involvement. Letterer-Siwe disease is a rapidly fatal disseminated disorder occurring in children.

Hand-Schuller-Christian disease is a slowly progressive disorder occurring in children and adolescents that involves bone and the posterior pituitary and may be disseminated. Pulmonary histiocytosis X (pulmonary Langerhans cell granulomatosis, or eosinophilic granuloma) is characterized by bronchiolitis and small-vessel vasculitis that progresses to fibrosis and destruction of alveolar walls; bone and posterior pituitary are uncommonly involved.

Most patients present in the third or fourth decade. Nearly all are cigarette smokers. Symptoms may be absent or may include cough, dyspnea, chest pain, fever, and weight loss. Blood eosinophilia is not observed. Spontaneous pneumothorax occurs in about 10% of patients and may be bilateral.

Chest x-ray is characterized by finely nodular interstitial infiltrates mostly in the upper lung zones. A honeycomb pattern may evolve. Physiologic testing may reveal a restrictive defect, obstructive defect with hyperinflation, or a combination of these patterns.

The diagnosis is confirmed by the demonstration of characteristic pentalaminar structures (``X bodies") within histiocytosis X cells (mononuclear phagocytes, ie, alveolar macrophages, similar to Langerhans cells in normal skin).

These "X bodies" may be demonstrated by electron microscopic study of fluid obtained by bronchoalveolar lavage, thereby avoiding lung biopsy. The disease spontaneously stabilizes or improves in about half of patients and progresses to permanent loss of lung function in the other half. Corticosteroids are the usual form of therapy, although their efficacy has not been established.

Interstitial Lung Involvement in Other Diseases

Interstitial lung disease that clinically resembles cryptogenic fibrosing alveolitis has been described in a variety of rheumatic diseases. It also occurs with chronic active hepatitis, inflammatory bowel disease, biliary cirrhosis, autoimmune thrombocytopenia, and hemolytic anemia.

Although other manifestations of these diseases usually dominate the clinical picture, interstitial lung disease may be symptomatic and progress to respiratory insufficiency, in which case treatment with anti-inflammatory drugs similar to those used in cryptogenic fibrosing alveolitis should be started. Nonspecific interstitial pneumonitis characterized by diffuse alveolar damage but lacking evidence of infection has been reported to account for one-third of all episodes of clinical pneumonitis in patients with AIDS.

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