Physical Examination

Most patients with ILD have bilateral fine inspiratory, crackles, which usually are most prominent at the lung bases. However, some diseases, such as sarcoidosis and lymphangioleiomyomatosis (LAM), may have only decreased breath sounds without adventitious sounds despite a markedly abnormal chest radiograph. Expiratory wheezing is uncommon, and its presence suggests either airway involvement as part of the primary disease process (LAM, sarcoidosis, respiratory bronchiolitis–associated interstitial lung disease [RB-ILD], desquamative interstitial pneumonitis [DIP], pulmonary Langerhans cell histiocytosis [PLCH]) or concomitant airways disease, such as emphysema or asthma. Signs of pulmonary arterial hypertension with right ventricular dysfunction, such as lower extremity edema or jugular venous distention, may occur late in the course of any ILD and are not helpful in the diagnosis of a specific ILD. Examination also may disclose features of underlying connective tissue disease, including synovitis, joint deformities, or skin rash.

Radiographic Features

ILDs manifest as abnormal lung parenchyma that cast abnormal radiographic shadows. For most ILDs, the chest radiograph reveals reduced lung volumes with bilateral reticular or reticulonodular opacities. However, the chest radiograph has limited value because the three-dimensional abnormalities are summed into a two-dimensional image with loss of spatial information. High-resolution cross-sectional imaging via computed tomography (CT) provides detailed images representing pulmonary pathology.³ High-resolution CT images allow noninvasive evaluation of ILDs and are a key element in making a confident diagnosis and managing ILD.⁴

Plain chest radiographs and high-resolution CT images of usual interstitial pneumonitis (UIP) show the prototypic fibrotic injury pattern. The chest radiograph (Figure 24-3, A) and high-resolution CT image (Figure 24-3, B) in UIP typically reveal a bilateral, patchy, peripheral (subpleural), and basilar predominant disease with reticulonodular infiltrates, often with honeycomb, cystic change. The lung architecture is distorted in patients with moderate or severe disease burden, with reduced lung volume and traction bronchiectasis, especially at the lung bases. Reticulogranular (ground-glass) abnormalities, increased attenuation of the lung tissue without distortion of the underlying blood vessels or bronchi, are absent or minimal in IPF. Pleural disease, air trapping, micronodules, and significant lymphadenopathy are not seen, although two-thirds of patients with IPF can have mild mediastinal adenopathy.⁵

As the burden of disease increases, the chest radiograph may 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. These fibrotic cysts represent irreversible destruction of normal alveoli; therapies are aimed at preserving the remaining normal parenchyma and reducing symptoms.

In contrast to UIP, cellular nonspecific interstitial pneumonitis is a pattern of injury dominated by inflammation and has imaging findings distinct from UIP. Reticulogranular (ground-glass) attenuation predominates and is found centrally and peripherally in the middle and lower lung zones. If the inflammation can be reduced, these abnormalities may improve. A mixed pattern of injury with fibrotic nonspecific interstitial pneumonitis can also be seen and is suggested by ground-glass attenuation in the presence of fibrotic changes.

Physiologic Features

Similar to the radiographic findings, there can be considerable variability among the specific diseases in the physiologic abnormalities seen. However, a restrictive physiologic impairment is the common finding.⁶ Both forced expiratory volume in 1 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 (DLCO). This reduction in diffusing capacity reflects a pathologic disturbance of the alveolus-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 ILDs, the lungs have reduced compliance and require supranormal transpleural pressures to ventilate (Figure 24-4). This lack of compliance results in small lung volumes and increased work of breathing.

Less frequently, a pattern of physiologic obstruction may be seen. This obstruction can be the result of the primary disease process (e.g., LAM, PLCH, or sarcoidosis in some patients) or concomitant emphysema or asthma.⁷ If ILD develops in a patient with significant emphysema, the opposing physiologic effects of the two diseases may result in deceptively normal spirometry and lung volume measurements and apparently normally compliant lungs. However, because both emphysema and ILD result in impaired gas exchange, DLCO is significantly decreased.

Drug-Related and Radiation-Related Interstitial Lung Disease

Many drugs have been associated with pulmonary complications of various types, including interstitial inflammation and fibrosis, bronchospasm, pulmonary edema, and pleural effusions. Drugs from many different therapeutic classes can cause ILD, most commonly chemotherapeutic agents, antibiotics, antiarrhythmic drugs, and immunosuppressive agents (Box 24-1). There are no distinct physiologic, radiographic, or pathologic patterns of drug-induced ILD, and the diagnosis is usually made when a patient 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. In addition to future drug exposure, bleomycin injury is accentuated by increased fractional inspired oxygen (FiO₂), even months after last drug exposure, and supplemental oxygen (O₂) should be used only if absolutely necessary in these patients.¹⁰

Exposure to therapeutic radiation in the management of cancer may result in ILD. Patients presenting within 6 months of radiation therapy generally have ground-glass abnormalities thought to represent acute inflammation. The ground-glass abnormalities can occur in both radiation-exposed tissue and unexposed tissue. Short-term systemic corticosteroid treatment can improve lung function. In contrast, radiographic abnormalities that develop more than 6 months after therapy typically appear as densely fibrotic tissue within the radiation port. On CT scan, a straight line indicating the margin of radiation is frequently evident as seen in Figure 24-8. These patients do not improve with corticosteroid therapy, and treatment is supportive.

Hypersensitivity Pneumonitis

Hypersensitivity pneumonitis (HP) is a cell-mediated immune reaction to inhaled antigens in susceptible persons.¹¹ Patients must be sensitized by an initial exposure, with subsequent reexposure leading to either acute HP usually after a brief but intense exposure or chronic HP from persistent exposure. Patients with acute HP present to medical attention with a history of a few days of shortness of breath, chest pain, fever, chills, malaise, and a cough that may be productive of purulent sputum. Patients who are chronically exposed to low levels of inhaled antigens may develop subtle interstitial inflammatory reactions in the lung that do not result in noticeable symptoms for months to years and can present with severe, impairing disease, which can be very difficult to distinguish from IPF.

Common organic antigens known to cause HP include bacteria and fungi, which may be found in moldy hay (farmer’s lung) or in the home environment, in particular, in association with central humidification systems (humidifier lung), indoor hot tubs, and animal proteins (e.g., bird breeder’s lung). Inorganic antigens from vaporized paints and plastics can also lead to HP. Numerous established antigens are listed in Table 24-3 along with the typical source of exposure and the associated syndrome.

Because the causal relationship between exposure and lung disease may not be obvious, a careful systematic occupational, environmental, and avocational history is crucial in evaluating patients with ILD. Elements that strongly suggest a diagnosis of HP are exposure to an appropriate antigen and the correct temporal relationship of symptoms to the exposure. Blood samples may be obtained to determine whether there has been an antibody response to certain antigens associated with HP (serum precipitins). However, the presence of such antibodies is insufficient to establish the diagnosis of HP because many individuals develop antibodies in the absence of disease. Likewise, the absence of detectable antibodies does not rule out the diagnosis of HP because the culprit may be an antigen that is not included in the blood analysis.¹²

Specific therapies for HP are strict antigen avoidance and immunosuppression with corticosteroids in patients with symptomatic or physiologically impairing disease. In acute HP, corticosteroids seem to hasten recovery but do not improve ultimate lung function.¹³ In chronic HP, patients with fibrosis on CT scan have a shorter survival, and it is unknown if long-term immunosuppression is beneficial.¹⁴

Occupational Interstitial Lung Disease

The three most common types of occupational ILD are asbestosis, chronic silicosis, and coal workers’ pneumoconiosis. Awareness of the associated risk and reduction in exposure has greatly reduced the incidence of these diseases in developed countries. However, they remain common in developing countries and emigrants from these countries.

Predictable clinical and radiographic abnormalities occur in susceptible patients who have been exposed to asbestos.¹⁵ These abnormalities include pleural changes (plaques, fibrosis, effusions, atelectasis, and mesothelioma) and parenchymal scarring and lung cancer. Asbestos exposure alone increases the risk of lung cancer only minimally (1.5 to 3.0 times). However, asbestos exposure and cigarette smoking act synergistically to increase greatly the risk of cancer. Asbestos exposure also may result in benign asbestos pleural effusions or an entity known as rounded atelectasis. Benign asbestos pleural effusions may be asymptomatic or may be associated with acute chest pain, fever, and dyspnea. Generally, a shorter lag time exists between initial asbestos exposure and the development of benign asbestos pleural effusions (<15 years) than is 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 from a mesothelioma. The clinical course of benign asbestos pleural effusions is characterized by spontaneous resolution, often with recurrences, and treatment is drainage to reduce symptoms. Rounded atelectasis typically manifests as a pleural-based parenchymal mass that may be mistaken for carcinoma. The characteristic CT features, such as local volume loss, pleural thickening, and the “comet tail” appearance of bronchi and vessels curving into the lesion, help distinguish rounded atelectasis from carcinoma.

The term asbestos-related pulmonary disease encompasses all of these entities, whereas asbestosis is reserved for patients who have evidence of parenchymal fibrosis. Most patients with asbestosis have had considerable airborne asbestos exposure many years before manifestation of the lung disease. Exposure frequently is associated with occupations such as shipbuilding or insulation work. Patients report very slowly progressive dyspnea on exertion¹⁶ and have crackles on lung examination. Physiologic testing shows restrictive impairment with reduced DLCO. The chest radiograph reveals bilateral lower zone reticulonodular infiltrates similar to infiltrates seen in IPF. With an appropriate exposure history, the presence of radiographic pleural plaques or rounded atelectasis indicates asbestos as the likely cause of ILD, although neither history nor radiographic findings is required for establishing the diagnosis. Differentiating indolent IPF from asbestosis can be difficult, and the presence of nonfibrotic pulmonary manifestation of asbestos exposure strongly argues for asbestosis, whereas indolent disease interrupted by rapid stair step decline usually occurs only in IPF. Surgical lung biopsy with asbestos body determination can establish a definitive diagnosis, but this is infrequently performed owing to the age and debility of these patients. No medical therapy has been shown to improve or decrease progression of asbestosis. 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 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 (simple silicosis) are asymptomatic and may never progress or cause symptoms. However, in susceptible individuals, the nodules coalesce into large midlung zone masses known as progressive massive fibrosis. Enlargement and eggshell calcification of the hilar lymph nodes are common in both types. Functional and physiologic impairment in chronic silicosis is quite variable. Some patients with abnormal chest radiographs report few, if any, symptoms and may have normal lung examination and pulmonary function testing. Many patients are impaired and have mixed restrictive and obstructive impairment with reduced diffusion capacity. The physiologic impairment may remain stable or, if progressive massive fibrosis occurs, may 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.¹⁷ Patients with silicosis are at increased risk of lung cancer, and the risk is increased when combined with exposure to tobacco smoke, diesel exhaust, or radon gas. Patients with silicosis develop active tuberculosis 2-fold to 30-fold more frequently than coworkers without silicosis. This association is especially important in societies with a high incidence of HIV infection, which markedly increases the risk of silicosis-associated active tuberculosis.

Coal workers’ pneumoconiosis 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 chronic silicosis. However, it is now recognized that coal workers’ pneumoconiosis and silicosis are the result of distinct exposures. Simple coal workers’ pneumoconiosis, characterized by multiple small nodular opacities on the chest radiograph, is asymptomatic. Cough and shortness of breath do not develop unless the disease progresses to progressive massive fibrosis similar to that seen in silicosis.

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

ILD is a well-known complication of various connective tissue diseases.¹⁸ The most commonly implicated disorders are scleroderma, rheumatoid arthritis, Sjögren syndrome, polymyositis/dermatomyositis, and systemic lupus erythematosus.

In any of these disorders, pulmonary involvement may remain undetected until significant impairment is present because these patients may be inactive owing to the underlying connective tissue disease. In addition, there is generally poor correlation between the severity of the pulmonary and nonpulmonary manifestations of these diseases. In some instances, the lung disease may overshadow or predate the other symptoms of the underlying disease. When symptoms develop, dyspnea and cough are common. On chest examination, rales, wheezing, or pleural rub may be heard because of the varied patterns of lung involvement in these disorders. Physiology is usually restrictive with decreased DLCO but may be obstructive depending on the anatomic location of the disease, especially with Sjögren syndrome because the collections of lymphocytes that define this disease are most frequent in the bronchioles.

High-resolution CT findings are variable and range from normal lung architecture to ground-glass abnormalities to reticular and fibrotic changes.¹⁹ The pathologic pattern of injury with these diseases is as equally diverse and correlates with the high-resolution CT findings. Inflammatory injury patterns are most commonly seen, such as nonspecific interstitial pneumonitis (NSIP) and organizing pneumonia (OP). The NSIP inflammatory injury pattern appears as ground-glass abnormalities on high-resolution CT scan, whereas OP is shown by patchy consolidated lung with air bronchograms. Both of these pathologic patterns can improve with aggressive immunosuppression. At the other end of the pathologic response spectrum is fibrotic injury, which manifests as UIP, which shows reticular fibrotic opacities and honeycomb cystic changes on high-resolution CT scan and typically does not improve with immunosuppression, although long-term controlled studies are lacking.

Specific treatment of connective tissue disease–associated ILD must be individualized. Patients with evidence of extrapulmonary inflammation, an inflammatory pathologic pattern such as NSIP or OP on high-resolution CT or biopsy, or rapidly progressive symptoms are usually treated with prolonged immunosuppressive agents such as cyclophosphamide, azathioprine, mycophenolate, or tacrolimus.20,21

More recent studies have begun to provide evidence-based therapy for these diverse patients. The Scleroderma Lung Study showed that 1 year of oral cyclophosphamide modestly improved lung function compared with modest decline in the control group.²⁰ The patients with the highest degree of fibrosis on high-resolution CT improved most, and ground-glass abnormalities or an inflammatory pattern on bronchoalveolar lavage were not predictive of benefit. After 1 year off immunosuppressive therapy, the patients treated with cyclophosphamide worsened and were indistinguishable from the untreated patients in the control group.²² Many clinicians hypothesize that to preserve any lung function gained by cyclophosphamide, continued immunosuppression may be necessary, and mycophenolate is most often used.

Polymyositis-associated ILD is being increasingly recognized as a common disease entity. Patients usually present with “mechanic’s hands” consisting of thickened skin and painful fingertip fissures, and 50% have Jo-1 antibodies on antinuclear antibody testing. Lung pathology is typically fibrotic NSIP or OP. As would be expected with these inflammatory patterns of injury, patients usually benefit from immunosuppression. Classic treatment is with cyclophosphamide, but tacrolimus and rituximab are emerging as salvage agents.

Sarcoidosis

Sarcoidosis is an idiopathic multisystem inflammatory disorder that commonly involves the lung.²³ It is the most common ILD in the United States. The tissue inflammation that occurs in sarcoidosis has a characteristic pattern in which the inflammatory cells collect in microscopic nodules called granulomas. In contrast to IPF, sarcoidosis is more common among young adults than among older adults. Sarcoidosis often follows a benign course of inflammation without symptoms or long-term consequences that spontaneously remits.

The most common manifestation of sarcoidosis is asymptomatic hilar adenopathy. Less frequently, the chest radiograph shows parenchymal opacities in the midlung zone that may be nodular, reticulonodular, or alveolar. When symptoms occur, cough, chest pain, dyspnea, and wheezing are most common. Pulmonary physiology may be normal, restrictive, obstructive, or mixed, all with reduced DLCO. Obstructive impairment may be related to endobronchial granulomatous inflammation or scarring.²⁴

Corticosteroids are commonly used in the management of sarcoidosis, but treatment usually is reserved for patients with marked symptoms or physiologic impairment attributable to the disease.²⁵ Although corticosteroids almost always reduce active sarcoid inflammation, long-term side effects should limit duration. For patients requiring long-term immunosuppression, alternative immunosuppressive agents such as methotrexate, azathioprine, leflunomide, or tumor necrosis factor-alpha inhibitors such as infliximab should be used.²⁶ Other organs that may require corticosteroid therapy include cardiac involvement, uveitis, and peripheral or central nervous system involvement with cranial nerve abnormalities. Disease activity is difficult to ascertain in many patients. Serum angiotensin-converting enzyme levels and gallium scans are not well correlated with disease activity, and their routine use is discouraged.²⁷

Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare disorder of abnormal smooth muscle tissue proliferating around small airways leading to severe obstruction and destruction of alveoli with resultant thin-walled cyst formation.²⁸ All patients are women, although both men and women with tuberous sclerosis complex can develop lung pathology identical to LAM that is called tuberous sclerosis complex LAM. This peculiar pathology is caused by abnormalities in the TSC-2 gene.²⁹

Dyspnea on exertion and an obstructive ventilatory impairment with reduced DLCO is almost always present except in very early disease. Disease progression is quite variable; some women having steadily worsening lung function during midlife, whereas some elderly women experience extremely slow decline over many years. Risk factors for worsening lung function include a significant bronchodilator response and possibly pregnancy. Other important disease manifestations include pneumothorax from a ruptured subpleural cyst. Unilateral or, less commonly, bilateral chylothorax is seen in about one-third of patients. This results from lymphatic obstruction by abnormal smooth muscle tissue. Treatment with a low-fat diet or blocking gut fat absorption is usually ineffective, and pleurodesis is required. Pleurodesis does not preclude subsequent lung transplantation.

Treatment is with inhaled bronchodilators and inhaled corticosteroids. Younger patients may ultimately require lung transplantation. Ongoing studies with rapamycin, which blocks the abnormal TSC-2 gene and inhibits LAM cell proliferation, may suggest the first disease-specific therapy for an ILD.

Despite a careful history, physical examination, and high-resolution CT scan, most patients are not found to have an exposure or systemic illness as a cause of ILD. These patients have a disorder isolated to the lung termed idiopathic interstitial pneumonia (IIP). Prognosis and potential therapies are completely dependent on the type of pathologic pattern of IIP.

Pulmonary Rehabilitation and Exercise Therapy

Pulmonary rehabilitation, a mainstay of treatment for obstructive lung disease, has also proven beneficial in the management of ILD. Pulmonary rehabilitation is important in building aerobic fitness, maintaining physical activity, and improving quality of life. When pulmonary rehabilitation is stopped, the benefits wane over a few months.⁵⁰ We encourage all of our patients to enroll in outpatient pulmonary rehabilitation and to continue maintenance therapy.

Vaccinations and Infection Avoidance

Because patients with ILD have increased consequences of respiratory infections, patients with ILD should receive a pneumococcal vaccine per U.S. Centers for Disease Control and Prevention guidelines and a yearly influenza virus vaccine. Additionally, we recommend that patients practice good hand hygiene (frequent handwashing). We do not recommend use of masks or special antibacterial products. Patients treated with prednisone in doses greater than 15 mg daily or with a steroid-sparing immunosuppressant should receive Pneumocystis prophylaxis.

Transplantation

The only therapy shown to prolong life in patients with end-stage, particularly fibrotic, ILD is lung transplantation.⁵¹ Transplantation has been performed successfully in the management of most ILDs. Enthusiasm for the procedure is tempered by the significant risk of mortality at 1 year (10% to 25%) and 5 years (50% to 60%). Many patients with ILD are older than the upper age limit of “physiologic” age 65. Additionally, comorbidities such as gastroesophageal reflux disease, which is common in many ILDs, preclude lung transplantation owing to the increased risk of chronic rejection and death.