The interstitial lung diseases (ILDs) represent a variety of conditions that involve the alveolar walls (septa), perialveolar tissue, and other contiguous supporting structures.

The ILDs are nonmalignant and are not caused by any defined infectious agents. Although an acute phase of illness may occur, the onset is often insidious, and the disease is usually chronic in duration. The initial insult is injury to the epithelial surface causing inflammation in the air spaces and alveolar walls, creating an acute phase of intraluminal and mural alveolitis.

If the disease is chronic and smoldering, inflammation will spread to adjacent portions of the interstitium and vasculature and eventually produce interstitial fibrosis. The resultant scarring and distortion of lung tissue leads to significant derangement of gas exchange and ventilatory function. Inflammation also can involve the conducting airways, and bronchiolitis obliterans associated with an organizing pneumonia is now part of the spectrum of an ILD.

Although diverse, this group of diseases has many features in common, including similarity of symptoms, comparable appearance of chest imaging studies, consistent alterations in pulmonary physiology, and typical histologic features. Lung pathology is usually confined to several general patterns, showing a mixture of alveolar inflammatory infiltrates and fibrotic/scarred areas with cystic, honeycomb spaces evident in advanced stages, often called usual interstitial pneumonia. Recently, diffuse, temporally uniform, single-time-appearing reactions have defied customary classifications and are considered as nonspecific interstitial pneumonia/fibrosis. However, ILDs have been difficult to classify because approximately 150 known individual diseases are characterized by some interstitial lung involvement, either as primary disease or as a significant part of a multiorgan process, as may occur in the collagen vascular diseases.

The chest radiograph is of limited aid in classification because it can have a similar appearance in many of the ILDs as well as in other unrelated lung diseases; however, high-resolution computed tomography (HRCT) scanning of the chest has enhanced diagnostic accuracy. One useful approach for classification is to separate ILDs into two groups, those with known and unknown causes; each of these groups can be divided into subgroups according to the presence or absence of histologic evidence of granulomas in interstitial or vascular areas.

For each ILD there may be an acute phase, and there is usually a chronic one as well.

LUNG RESPONSE: Alveolitis, Interstitial Inflammation, and Fibrosis

KNOWN CAUSES

Asbestos Fumes, gases, Drugs (antibiotics) and chemotherapy drugs Radiation, Aspiration pneumonia, Residual of adult respiratory distress syndrome

UNKNOWN CAUSES

Idiopathic pulmonary fibrosis, Collagen vascular diseases,  Systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, systemic sclerosis, Sjögren's syndrome, polymyositis-dermatomyositis, Pulmonary hemorrhage syndromes,  Goodpasture's syndrome, idiopathic pulmonary hemosiderosis, Pulmonary alveolar proteinosis, Lymphocytic infiltrative disorders (lymphocytic interstitial pneumonitis associated with collagen vascular diseases) Eosinophilic pneumonias, Lymphangioleiomyomatosis, Amyloidosis

INHERITED DISEASES

 Tuberous sclerosis, neurofibromatosis, Niemann-Pick disease, Gaucher's disease, Hermansky-Pudlak syndrome Gastrointestinal or liver diseases (Crohn's disease, primary biliary cirrhosis, chronic active hepatitis, ulcerative colitis) Graft vs. host disease (bone marrow transplantation)

LUNG RESPONSE: AS ABOVE BUT WITH GRANULOMA Hypersensitivity pneumonitis (organic dusts) Inorganic dusts: beryllium silica Sarcoidosis Langerhans cell granulomatosis (eosinophilic granuloma) Granulomatous vasculitides  Wegener's granulomatosis, allergic granulomatosis of Churg-Strauss, lymphomatoid granulomatosis Bronchocentric granulomatosis   

Among the ILDs of known cause, the largest group comprises occupational and environmental inhalant exposures; these include diseases due to inhalation of inorganic dusts, organic dusts, and various irritative or noxious gases.

The number of ILDs of unknown cause is also very large. The major ones within this category are idiopathic pulmonary fibrosis (IPF), sarcoidosis, and the ILD often associated with collagen vascular disorders. ILD secondary to inorganic dust exposure usually can be recognized if the occupational history is pursued.

For the myriad of other diffuse ILDs, however, a precise diagnosis is obtained with difficulty, usually only after interpretation of an open-lung biopsy specimen; most of these diseases are relatively rare. The HRCT scan promises to improve diagnostic accuracy as further histologic-image correlations are perfected.

Although the initiating agent(s) or circumstances of the various ILDs may be multiple, and many are unknown, the immunopathogenic responses of lung tissue are limited, so the initial mechanisms of injury to the epithelial surface, the development of alveolitis, and the attempts at repair sometimes leading to fibrosis will have common features. IPF is discussed as the prototype ILD, since it is encountered relatively frequently and much of the recent research on mechanisms of inflammation and lung fibrosis has focused on this disease.

IDIOPATHIC PULMONARY FIBROSIS

Many patients who present with nonproductive cough, progressive dyspnea, a chest radiograph showing lower lung zone reticular or reticulonodular shadows, and pulmonary function tests showing a restrictive ventilatory pattern will be said to have IPF after the diagnostic evaluation is completed. This condition is also known as cryptogenic fibrosing alveolitis.

Although the terms idiopathic and cryptogenic mean that the etiologic agent is unknown, this is not a nebulous "wastebasket" diagnosis or just a diagnosis of exclusion but rather a well-defined clinical entity.

INTEGRATION OF THE PRESENTING CLINICAL PATTERN AND DIAGNOSTIC STUDIES

Patients with respiratory symptoms but a normal chest radiograph most commonly have diseases affecting the airways, such as asthma or chronic obstructive pulmonary disease. However, the latter diagnosis is also commonly associated with radiographic abnormalities, such as diaphragmatic flattening and attenuation of vascular markings.

Other disorders of the respiratory system for which the chest radiograph is normal include disorders of the respiratory pump (either the chest wall or the neuromuscular apparatus controlling the chest wall) and occasionally interstitial lung disease. Chest examination and pulmonary function tests are generally helpful in sorting out these diagnostic possibilities.

Obstructive diseases associated with a normal or relatively normal chest radiograph are often characterized by findings on physical examination and pulmonary function testing that are typical for these conditions. Similarly, diseases of the respiratory pump or interstitial diseases may also be suggested by findings on physical examination or by particular patterns of restrictive disease seen on pulmonary function testing.

When respiratory symptoms are accompanied by radiographic abnormalities, diseases of the pulmonary parenchyma or the pleura are usually present. Either diffuse or localized parenchymal lung disease is generally visualized well on the radiograph, and both air and liquid in the pleural space (pneumothorax and pleural effusion, respectively) are usually readily detected by radiography. Radiographic findings in the absence of respiratory symptoms often indicate localized disease affecting the airways or the pulmonary parenchyma. One or more nodules or masses can suggest intrathoracic malignancy, but they also can be the manifestation of a current or previous infectious process. Patients with diffuse parenchymal lung disease present on radiographic examination may be free of symptoms, as is sometimes the case with pulmonary sarcoidosis.

In approaching the patient with pulmonary disease, consideration must be given to the observation that substantial changes in the relative incidence of disease affecting the respiratory system have taken place in the United States during the past three decades.

The prevalence of chronic infectious disorders such as lung abscess and bronchiectasis has decreased. Tuberculosis declined only to undergo resurgence when two susceptible populations, patients with AIDS and immigrants from Southeast Asia, increased in number. Patients with chronic bronchitis and with emphysema now survive longer and form an increasing fraction of patients with chronic respiratory disease, as do patients with environmental lung disease and with drug-induced pulmonary disease.

Modern intercontinental travel has increased the appearance in the western world of parasitic infestations of the lung. Also, the reduction of immune competence that occurs in patients with AIDS and in diabetics as well as in patients being treated for a variety of malignancies and those receiving immunosuppressive drugs has led to an increasing incidence of opportunistic infections of the lungs with a variety of microorganisms that were rarely pathogenic in the past.

ILD Associated With Collagen Vascular Disorders

In these diseases, various pulmonary structures can be affected, especially the pleura, so that ILD is but one manifestation of intrathoracic involvement and is often a minor part of the multiorgan process. The same is true for fibrosis.

Systemic Lupus Erythematosus

About half of patients with systemic lupus erythematosus ultimately develop overt lung disease. Pleuritis, pleural effusion(s), and acute pneumonitis from pulmonary capillaritis causing alveolar hemorrhage are the most frequent forms of lung disease, while a chronic, progressive ILD is uncommon. It is important to exclude pulmonary infection. Although pleuropulmonary involvement may not be evident clinically, pulmonary function testing, particularly the diffusing capacity for carbon monoxide, reveals abnormalities in many patients. A lymphocytic alveolitis may occur, which usually indicates a better response to immunosuppressive therapy.

Rheumatoid Arthritis

A variety of pulmonary manifestations can occur, including pleural disease (pleural effusion and subpleural nodules), parenchymal nodular infiltrates associated with pneumoconiosis in miners (Caplan's syndrome), and diffuse interstitial fibrosis. The ILD can develop before joint disease becomes evident, particularly in men, and is accompanied by high titers of rheumatoid factor. Bronchiolitis obliterans with organizing pneumonia (BOOP) has been reported.

  The association between ILD and rheumatoid arthritis is frequent, but often confusing, especially when ILD precedes joint symptoms or if medications used to treat rheumatoid arthritis also happen to cause ILD (gold has been common in the past).

  In groups of patients with recent-onset rheumatoid arthritis, clinically significant ILD or changes consistent with, but not clinically significant, occurred in five of six (14 percent) and 16 of 36 (44 percent) groups, respectively; no lung abnormalities compatible with ILD were in 15 of 36.

  A marker to substantiate ILD in rheumatoid arthritis patients would be helpful. KL-6, a human MUC1 mucin, measured in serum was found increased in 8 of 9 patients with rheumatoid arthritis and active ILD, but only in one of 168 patients with rheumatoid arthritis but without active ILD. Patients with rheumatoid arthritis who are receiving treatment with methotrexate or gold may develop ILD that represents a drug hypersensitivity, which must be differentiated from a preexisting or developing ILD associated with the underlying disease. Penicillamine therapy in patients with rheumatoid arthritis has been implicated as a cause of bronchiolitis obliterans.

Ankylosing Spondylitis

Bilateral upper lobe fibrosis, which can be complicated by fibrocavitary disease, may develop late in the course.

Systemic Sclerosis

Radiographic evidence of lung involvement develops in a majority of patients, but its severity or progression is variable. Because distal esophageal motor dysfunction is present in many patients, reflux with regurgitation and chronic aspiration is common. Mast cells and their mediators in BAL fluid may be important in the alveolitis that develops. In addition, cutaneous scleroderma can involve the anterior chest wall and abdomen, causing restrictive lung function.

  Pulmonary artery pressure was measured in a series of 80 patients with systemic sclerosis. Pulmonary hypertension was present in 30 patients; it was attributable to pulmonary fibrosis in half and to a pulmonary arteriopathy in half (Murata et al, 1997).

SjöGren's Syndrome

General dryness and lack of airways secretions cause the major problems of hoarseness, cough, and bronchitis. Presence of an ILD in these patients may signify a lymphocytic infiltrate in lung tissue, which can behave as a low-grade lymphoma. As small terminal airways can be affected with bronchiolitis obliterans, lung hyperinflation on pulmonary function testing may be a clue (high residual volume to total lung capacity ratio).

Polymyositis And Dermatomyositis

Although ILD is reported to occur in only 5 to 10 percent of patients, its presence is more common in the subgroup of patients with an anti-Jo-1 antibody that is directed to histidyl tRNA synthetase. Weakness of respiratory muscles contributing to aspiration pneumonitis is a common occurrence.