Interstitial Lung Disease

The term interstitial lung disease (ILD) refers to a broad category of lung diseases rather than a specific disease entity.^1,² It includes a variety of illnesses with diverse causes, treatments, and prognoses. These disorders are grouped together because of similarities in their clinical presentations, plain chest radiographic appearance, and physiologic features.

Because there are more than 100 separate disorders, it is helpful to group them based on cause, disease associations, or pathology. An organizational scheme is presented in Figure 1. First, the diseases are broken down into those with known causes or associations and those of unknown cause. Diseases with known causes are further classified based on specific exposure, association with systemic disease, or association with a known genetic disorder. These groups are further divided into specific disease entities. Using this organizational scheme, one can perform a careful and complete history, working toward an accurate diagnosis and appropriate therapy.

Figure 1 Current organization of interstitial lung disease (ILD).

COP, cryptogenic organizing pneumonia; CTD, connective tissue disease; HPS, Hermansky-Pudlak syndrome; IBD, inflammatory bowel disease; IIP, idiopathic interstitial pneumonia; IPF, idiopathic pulmonary fibrosis; LAM, lymphangioleiomyomatosis; LIP, lymphocytic interstitial pneumonia; NSIP, nonspecific interstitial pneumonitis; PAP, pulmonary alveolar proteinosis.

PATHOPHYSIOLOGY

As the name implies, the histologic abnormalities that characterize ILD generally involve the pulmonary interstitium to a greater extent than the alveolar spaces or airways, although exceptions exist. The interstitium is the area between the capillaries and the alveolar space. In the normal state, this space allows close apposition of gas and capillaries with minimal connective tissue matrix, fibroblasts, and inflammatory cells such as macrophages. The interstitium supports the delicate relation between the alveoli and capillaries, allowing efficient gas exchange. When responding to any injury, whether from a specific exposure (e.g., asbestos, nitrofurantoin, moldy hay), an autoimmune-mediated inflammation from a systemic connective tissue disease (e.g., rheumatoid arthritis), or unknown injury (e.g., idiopathic pulmonary fibrosis), the lung must respond to the damage and repair itself. If the exposure persists or if the repair process is imperfect, the lung may be permanently damaged, with increased interstitial tissue replacing the normal capillaries, alveoli, and healthy interstitium.

These pathologic abnormalities can lead to profound impairment in lung physiology. Gas exchange is impaired due to ventilation-perfusion () mismatching, shunt, and decreased diffusion across the abnormal interstitium. Work of breathing is markedly increased because of decreased lung compliance. Together, these physiologic impairments lead to the exercise intolerance seen in all of the ILDs. Unfortunately, if the initiating injury or abnormal repair from injury is not halted, progressive tissue damage can lead to worsening physiologic impairment and even death.

CHARACTERISTICS

Clinical Signs and Symptoms

Many of the ILDs have similar clinical features and are not easily distinguished on examination. Symptoms are generally limited to the respiratory tract. Exertional breathlessness (dyspnea) and a nonproductive cough are the most common reasons patients seek medical attention. However, sputum production, hemoptysis, or wheezing are helpful in classifying the disease. If the patient also has prominent nonrespiratory symptoms, such as myalgia, arthralgia, or sclerodactyly, ILD might be the result of underlying connective tissue disease.

Physical Examination

Most patients with ILD have bilateral inspiratory fine crackles, which usually are most prominent at the lung bases. However, some diseases, such as sarcoidosis and lymphangioleiomyomatosis, have only decreased breath sounds without adventitious sounds despite markedly abnormal chest radiographs. Expiratory wheezing is relatively uncommon, and its presence suggests either airway involvement as part of the primary disease process or concomitant airways disease such as emphysema or asthma. Occasionally, wheezing is a clue to a particular diagnosis, such as sarcoidosis, which can involve the airways as well as the interstitium.

Signs of pulmonary arterial hypertension with right ventricular dysfunction, such as lower-extremity edema or jugular venous distention, can occur late in the course of any ILD and are not helpful in diagnosing a specific ILD.

Examination also can disclose features of underlying connective tissue disease, including active joint inflammation (synovitis), joint deformities, or skin rash.

Radiographic Features

There is considerable variability among the specific diseases in the character and distribution of radiographic abnormalities. However, for most ILDs, the plain chest radiograph reveals reduced lung volumes with bilateral reticular or reticulonodular opacities. The ready availability of high-resolution computed tomography (HRCT) has highlighted significant radiographic differences between diseases that have similar plain chest radiographic patterns.³ HRCT has the ability to better define the specific characteristics of lung parenchyma seen in each disease, increasing the chance of making a confident diagnosis.⁴

The plain chest radiograph and HRCT features of idiopathic pulmonary fibrosis (IPF) are important patterns to recognize because, next to sarcoidosis, IPF is the most common ILD, several other ILDs have a similar appearance, and IPF images are the prototypic pattern of fibrotic injury response in the lung. The plain radiograph and HRCT in IPF reveal bilateral, peripheral and basilar predominant disease with reticulonodular infiltrates, often with honeycomb, cystic changes. Figure 2 shows a plain radiograph with bibasilar reticulonodular infiltrates. Note the overall volume loss and poorly demarcated pleural-parenchymal borders along the hemidiaphragms and heart, indicating parenchymal abnormalities extending to the pleura. Figure 3 shows an HRCT image of IPF, with distortion of the lung architecture and traction bronchiectasis, especially at the lung bases. As predicted by the plain radiograph, the abnormalities are strikingly located in the subpleural and dependent areas of the lung. Ground glass abnormalities, increased attenuation of the lung tissue without distortion of the underlying blood vessels or bronchi, are absent or minimal in classic IPF. Pleural disease and significant lymphadenopathy are not seen, although up to two thirds of IPF patients have mild mediastinal adenopathy.⁵ As the burden of disease increases, the chest x-ray examination can reveal multiple tiny cysts in the most markedly involved regions. This cystic pattern, called honeycombing, reflects end-stage fibrosis and is a feature of many end-stage ILDs.

Figure 2 Plain chest radiograph of idiopathic pulmonary fibrosis.

Figure 3 High-resolution computed tomography scan of idiopathic pulmonary fibrosis.

In contrast to the fibrotic type of injury, some diseases cause an inflammatory abnormality with a much different radiographic image. In cellular nonspecific interstitial pneumonia, the predominant abnormality is ground glass without distortion of the lung architecture or loss of volume, as seen in Figure 4. In addition, the central and mid lung zone locations of abnormalities are distinct from IPF. Understanding these two patterns as ends of an extreme, we shall see how the clinician is able to evaluate other diseases in a similar context.

Figure 4 High-resolution computed tomography scan of ground glass opacity infiltrates.

Physiologic Features

Similar to the radiographic findings, among the specific diseases there can be considerable variability in the physiologic abnormalities seen. However, a restrictive physiologic impairment is the common finding.⁶ Thus, both forced expiratory volume in one second (FEV₁) and forced vital capacity (FVC) are diminished, and the FEV₁/FVC ratio is preserved or even supranormal. Lung volumes are reduced, as is the diffusing capacity of the lung for carbon monoxide (D_LCO). This reduction in diffusing capacity reflects a pathologic disturbance of the alveolar-capillary interface.

Although not commonly pursued, the compliance characteristics of the lungs can be evaluated with an esophageal balloon to measure intrathoracic pressure at various lung volumes. In almost all of the ILDs, the lungs have reduced compliance and require supranormal transpleural pressures to ventilate. This lack of compliance results in small lung volumes and increased work of breathing.

Less often, physiologic obstruction may be the pattern seen. This can be the result of the primary disease process (e.g., lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis; some sarcoid patients) or concomitant emphysema or asthma.⁷ Thus, if ILD develops in a patient with significant emphysema, the opposing physiologic effects of the two diseases can result in deceptively normal spirometry and lung volume measurements, as well as apparently normally compliant lungs. However, because both emphysema and ILD result in impaired gas exchange, the D_LCO is significantly decreased.

SELECT SPECIFIC TYPES

Exposure-Related Interstitial Lung Disease

Occupational Exposure

The three most common types of occupational ILD are asbestosis, chronic silicosis, and coal worker’s pneumoconiosis (CWP). Predictable clinical and radiographic abnormalities occur in susceptible patients who have been exposed to asbestos.⁸ These abnormalities include pleural changes (plaques, fibrosis, effusions, atelectasis, and mesothelioma), parenchymal scarring, and lung cancer. Asbestos exposure alone increases the risk of lung cancer only minimally (1.5-3.0 times). Asbestos exposure and cigarette smoking, however, act synergistically to greatly increase the risk of cancer.

Asbestos exposure also can result in benign asbestos pleural effusions (BAPE) or an entity known as rounded atelectasis. BAPE may be asymptomatic or may be associated with acute chest pain, fever, and dyspnea. Generally, lag time is shorter between the initial asbestos exposure and the development of BAPE (<15 years) than that seen with other manifestations of asbestos exposure. The effusions are characteristically exudative and are often bloody. In a patient with a history of asbestos exposure and a bloody pleural effusion, the major differential diagnostic concern is malignant pleural effusion, particularly associated with mesothelioma, another asbestos-related disease. The clinical course of BAPE is that of spontaneous resolution, often with recurrences, and treatment is drainage to alleviate symptoms. Rounded atelectasis typically manifests as a pleural-based parenchymal mass that may be mistaken for carcinoma. The characteristic computed tomography (CT) features, however, such as evidence of local volume loss, pleural thickening, and the comet tail appearance of bronchi and vessels curving into the lesion may be used to help distinguish rounded atelectasis from carcinoma.

The term asbestos-related pulmonary disease may be used to encompass all of these entities, and asbestosis is reserved for patients who have evidence of parenchymal fibrosis. Most patients with asbestosis have had considerable asbestos exposure many years before manifestation of the lung disease. Exposure is often associated with occupations such as shipbuilding or insulation work. Patients report very slowly progressive dyspnea on exertion ⁹ and have crackles on lung examination. Physiologic testing shows restrictive impairment, with reduced D_LCO. The chest x-ray examination reveals bilateral lower-zone reticulonodular infiltrates similar to those seen in IPF. With an appropriate exposure history, the presence of radiographic pleural plaques or rounded atelectasis can indicate asbestos as the cause of the ILD, although neither of these findings is required for establishing the diagnosis.

No medical therapy has been demonstrated to improve or decrease the progression of asbestosis. Unfortunately, severe impairment typically occurs 30 to 40 years after exposure, making almost all patients ineligible for lung transplantation because of age. Management of asbestosis is therefore supportive.

Chronic silicosis results from chronic exposure to inhaled silica particles. Occupations that commonly entail exposure to silica include mining, tunneling, sandblasting, and foundry work. The chest radiograph commonly shows upper lung zone–predominant abnormalities characterized by multiple small nodular opacities in the central lung tissue. These nodules can slowly coalesce into large masses known as progressive massive fibrosis (PMF). Enlargement and eggshell calcification of the hilar lymph nodes are common. Functional and physiologic impairments in chronic silicosis are quite variable. Some patients with abnormal chest radiographs report few, if any, symptoms and can have normal lung examination and pulmonary function tests. Unfortunately many patients are impaired and have mixed restrictive and obstructive impairments with reduced diffusion capacity. The physiologic impairment can remain stable or, if PMF occurs, can progress even in the absence of continued exposure. Symptoms are typically exertional dyspnea and variable mucus production.

It is important to recognize the association of silicosis with lung cancer and active tuberculosis.¹⁰ Patients with silicosis are at increased risk for lung cancer, and the risk is increased when combined with exposure to tobacco smoke, diesel exhaust, or radon gas. Silicosis patients develop active tuberculosis 2- to 30-fold more often than coworkers without silicosis. This association is especially important in societies with a high incidence of human immunodeficiency virus (HIV) infection, which markedly increases the risk of silicosis-associated active tuberculosis.

CWP develops as the result of chronic inhalation of coal dust. In the past, it was assumed that silica dust was responsible for the pulmonary disease seen among coal miners because the clinical and radiographic features are quite similar to those of chronic silicosis. However, it is now recognized that CWP and silicosis are the results of distinct exposures. Simple CWP, characterized by multiple small nodular opacities on the chest x-ray film, is asymptomatic. Cough and shortness of breath do not develop unless the disease progresses to PMF similar to that seen in silicosis.

There are no proven therapies for either silicosis or CWP other than eliminating future exposure. In patients with significant obstructive impairment or mucus production, inhaled bronchodilators and corticosteroids might relieve some symptoms. Exacerbations can be frequent and are treated with antibiotics and systemic corticosteroids.

Medication, Drug, and Radiation Exposure

Many drugs have been associated with pulmonary complications of various types, including interstitial inflammation and fibrosis, bronchospasm, pulmonary edema, and pleural effusions.¹¹ Drugs from many different therapeutic classes can cause ILD, including chemotherapeutic agents, antibiotics, antiarrhythmic drugs, and immunosuppressive agents (Box 1). There are no distinct physiologic, radiographic, or pathologic patterns of drug-induced ILD, and the diagnosis is usually made when a patient with ILD is exposed to a medication known to result in lung disease, the timing of the exposure is appropriate for the development of the disease, and other causes of ILD have been eliminated. Treatment is avoidance of further exposure and systemic corticosteroids in markedly impaired or declining patients.

Box 1 Drugs Associated with the Development of Interstitial Lung Disease

Data from Camus P: Drug induced infiltrative lung diseases. In Schwarz MI, King TE (eds): Interstitial lung disease, 4th ed. Hamilton, Ontario, BC Decker, 2003, pp 485-534.