Interstitial Lung Diseases

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[edit] Interstitial Lung Diseases

Donald P. Schlueter

More than 130 acute and chronic diseases can involve the interstitium of the lung either as a primary disorder or as a secondary manifestation of a systemic disease (Box 76-1). They constitute a heterogenous group of disorders in which often no cause can be identified. The interstitium of the lung includes the connective tissue of the pleura, blood vessels and bronchi, and the alveolar walls. Interstitial lung disease has been defined as an inflammatory process involving all the components of the alveolar wall that may heal completely or may result in excess connective tissue with gross distortion of the lung architecture.^[1] The initial event involves a focal or diffuse alveolitis caused by the accumulation in the alveolar walls of pulmonary macrophages, circulating lymphocytes, monocytes, and neutrophils that mediate acute and chronic inflammation. This inflammatory process results in the release of mediators that stimulate collagen production by fibroblasts and may eventually progress to interstitial pulmonary fibrosis, also known as fibrosing alveolitis. The clinical course depends on the pathologic diagnosis, and prognosis is quite variable. In some cases where a specific etiologic agent has been identified, simply removing the individual from exposure results in gradual recovery; others respond to steroid therapy, but in many patients the condition progresses despite treatment.

[edit] CLINICAL PRESENTATION

The most common presenting complaint of patients with interstitial lung disease is dyspnea.^[1] Initially it may be present only with exertion, but as the disease process progresses, it may occur at rest. Since the loss of lung function may be gradual (because substantial functional reserve exists in the lung), the disease may progress significantly before the patient seeks medical attention. A nonproductive, irritating cough frequently aggravated by exertion and deep breathing and a feeling of chest tightness or heaviness may be present, especially as the fibrosis develops and progresses. Wheezing, sputum production, anorexia, and weight loss are not usually seen until the disease is more advanced. However, systemic symptoms may be present in patients whose interstitial lung disease is secondary to another condition, such as a connective tissue disorder.

[edit] PATIENT EVALUATION

[edit] History

A thorough and accurate history is extremely important in the evaluation of a patient with interstitial lung disease. This should involve potential environmental exposures at work. The occupational history should include a detailed listing of all jobs held by the patient, the specific tasks performed, and materials used. Where potentially hazardous materials are used, the employer must provide the worker with the pertinent material safety data sheets (MSDS). This information should be helpful in considering the possible contribution of this source to the patient's problem. Since some exposures (e.g., asbestos) produce clinically apparent disease over a long latent period, usually 10 to 20 years, it may require considerable perseverance to obtain the appropriate information. The home environment should not be neglected, since contaminated humidifiers and air-conditioning systems can be a cause of interstitial lung disease in the form of hypersensitivity pneumonitis.^[2] Prolonged low-level exposure, as may be encountered with exposure to an organic dust in the home environment, may not produce sufficient acute symptoms to cause the patient to seek medical attention and therefore results in a delay in diagnosis. With the acute form of hypersensitivity pneumonitis, symptoms of malaise, fever, dyspnea, and cough develop 4 to 8 hours after exposure to the offending agent. Because of this delay, the patient often does not recognize the causal relationship. Early recognition is essential, since avoidance of further exposure can result in resolution or at least stabilization of the interstitial process. A number of drugs, particularly cancer chemotherapeutic agents and illicit street drugs, have been implicated as causative agents in this disease, and their use should be carefully evaluated. A geographic history may be helpful in suggesting or excluding a chronic infectious process. Symptoms consistent with a connective tissue or vascular disorder should be sought.

[edit] Physical Examination

In the early stages of interstitial lung disease the physical examination, including auscultation of the chest, may be entirely normal. As the disease process progresses and dyspnea develops, basilar crackles (Velcro rales) signal the presence of interstitial pulmonary fibrosis. However, the absence of crackles does not exclude the diagnosis. Later, cyanosis and, in about 10% to 15% of patients, finger clubbing develop. The latter is more common in patients with idiopathic pulmonary fibrosis (IPF) and asbestosis. With advanced disease, cardiac involvement is common, with pulmonary hypertension and right-sided heart failure. With the exception of sarcoidosis and the collagen vascular diseases, the physical findings are generally limited to the chest.

[edit] LABORATORY STUDIES AND DIAGNOSTIC PROCEDURES

The chest radiograph is the most important piece of information in the initial evaluation of a patient with suspected interstitial lung disease and may be abnormal in the absence of significant respiratory symptoms. Some patients with dyspnea and interstitial lung disease, however, may have a normal chest film; in one series, 13% of patients with IPF, 37% with hypersensitivity pneumonitis, and 10% with sarcoidosis had normal chest radiographs.^[3] The introduction of high-resolution computed tomography (HRCT) scanning of the lung has increased the sensitivity for detecting minimal interstitial disease not evident on conventional chest radiographs.^[4] Early in the disease process, radiographic changes may be limited to an increase in interstitial markings, more prominent in the lower lung fields. Every effort should be made to obtain any existing chest radiographs, since subtle changes may become more obvious when previous chest films are available for comparison. They may also provide information on disease onset and progression. Hilar and mediastinal lymphadenopathy is usually associated with sarcoidosis, silicosis, and some lymphomas. Pleural disease is uncommon in interstitial lung disease. Pleural effusion and pleural thickening may occur with collagen vascular disease, lymphoma, asbestos-related disease, and a small percentage of patients with sarcoidosis. As the disease progresses, a more clearly defined reticulonodular pattern becomes evident with a decrease in lung volume, as indicated by elevation of the diaphragms (Fig. 76-1).

Figure 76-1 Chest radiograph of 73-year-old woman showing diffuse linear opacities with honeycombing and early cor pulmonale. She had progressive dyspnea for 3 years, bilateral end-inspiratory crackles, and physiologic studies showing decreased vital capacity, very low single-breath diffusing capacity, and oxygen desaturation at rest that became more severe with exercise. Lung biopsy showed usual interstitial pneumonitis (UIP).

Pulmonary function studies reflect the structural changes that cause a stiff, noncompliant lung. All lung volumes are reduced, consistent with a restrictive ventilatory impairment. Spirometry shows a decrease in forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV₁) but a normal FEV₁/FVC ratio. Usually, flow rates are not significantly decreased unless the restriction is severe, although evidence for small airways obstruction has been reported in interstitial lung disease.^[5] Lung volume measurements show a decreased total lung capacity (TLC), functional residual capacity (FRC), and residual volume (RV), with a normal to low RV/TLC ratio. Most patients have a disturbance in gas exchange manifested by a significantly diminished single-breath diffusing lung capacity for carbon monoxide (DLco). Although arterial oxygenation may be normal at rest, arterial hypoxemia is usually present with exercise. Carbon dioxide (CO₂) retention does not occur, and despite hypoxemia, erythrocytosis and elevated hematocrits are uncommon.

Routine blood tests and serology may be helpful but relatively nonspecific, such as an increased erythrocyte sedimentation rate (ESR) or serum angiotensin-converting enzyme (ACE) level, which is elevated in about 29% to 93% of patients with active sarcoidosis. Serologic tests for collagen vascular disease are necessary to exclude these diagnoses, although low titers of antinuclear antibodies (ANAs) and rheumatoid factor (RF) have been reported in patients with IPF.^[6] Antineutrophil cytoplasmic antibody (ANCA) determinations appear helpful in diagnosing and assessing the activity of some of the necrotizing vasculitides.^[7] The demonstration of high titers of precipitating antibodies to organic dusts known to cause hypersensitivity pneumonitis, such as the thermophilic Actinomyces, may support this diagnosis when accompanied by an appropriate history. This is not a definitive diagnostic test for hypersensitivity pneumonitis, since 40% to 50% of exposed individuals may have antibodies in their serum without developing disease.^[8]

Bronchoalveolar lavage (BAL) provides a relatively simple and safe means of obtaining fluid samples for culture and cytologic evaluation in patients with interstitial lung disease.^[9] BAL has been particularly helpful in characterizing the inflammatory process in the lungs by providing viable cells for analysis of functional and secretory activity. Analysis of the cellular constituents has been suggested not only as a means for diagnosing the specific interstitial disease process, but also as guide for instituting and monitoring the effectiveness of therapy. A predominance of lymphocytes is found in sarcoidosis, hypersensitivity pneumonitis, and lymphoma, whereas polymorphonuclear neutrophils (PMNs) predominate in IPF, histiocytosis X, asbestosis, cigarette smokers, and infection. At present the use of BAL for diagnosing and staging of interstitial lung disease remains controversial, since the procedure is invasive, the technique is not standardized, and results show significant variability.

Radioactive gallium scanning has been used to evaluate patients with interstitial lung disease. Its role also remains somewhat controversial because of its nonspecificity; varied types of pulmonary inflammation as well as neoplasms can produce a positive result. Gallium is most likely taken up by activated alveolar macrophages or PMNs in the areas of inflammation, and the uptake may be a marker of alveolitis. This is supported by the finding of a better correlation of gallium uptake with the extent of inflammation on open lung biopsy compared with conventional chest radiographs. Gallium scanning has been used to follow the course of disease during treatment but has been disappointing in predicting responsiveness to corticosteroid or immunosuppressive therapy; only 10% to 30% of patients with increased uptake may respond to therapy.^[10] Favorable responses to therapy have been noted even when the gallium scans are normal. Gallium scanning may be helpful in planning a biopsy procedure by identifying areas of active inflammation and thus increasing the probability of a positive result.

Despite the large number of causes, a definitive diagnosis of interstitial disease can often be made on the basis of the history, clinical findings, and laboratory data. Some examples include pneumoconiosis, hypersensitivity pneumonitis, and drug-induced lung diseases. Sarcoidosis could be included, particularly if organs other than the lung are involved. In most patients with interstitial lung disease, however, histologic examination of lung tissue is the most effective method of obtaining a definitive characterization of the extent and pattern of disease and determining the presence or absence of organisms that might be responsible. Fiberoptic bronchoscopy with transbronchial biopsy is the initial procedure of choice when the suspected diagnosis includes sarcoidosis, hypersensitivity pneumonitis, pulmonary alveolar proteinosis, eosinophilic granuloma or histiocytosis X, and malignancy.

Open lung biopsy remains the gold standard for a histologic diagnosis when the transbronchial biopsy is nondiagnostic or with a suspected disease process that is not likely to yield a definitive result by this procedure. In addition, it excludes other etiologies and directly assesses the inflammatory and fibrotic lesions. It also provides enough tissue to perform a variety of special tests, including electron microscopy, energy-dispersive x-ray analysis, and immunofluorescence.^[11] Tissue can be obtained from several lobes and areas with different degrees of involvement. Video-assisted thoracoscopic lung biopsy can help in the diagnosis and staging of interstitial lung disease. This procedure involves two or three endoscopic trocars and instruments, with single-lung ventilation and collapse of the lung to be biopsied. Hospital stay and postoperative pain are reduced, and adequate tissue can be obtained in most patients.

[edit] ACUTE INTERSTITIAL PNEUMONIAS

Acute interstitial pneumonia, or diffuse alveolar damage, can result from a variety of insults to the lung. This response can be seen in viral pneumonias, adult respiratory distress syndrome (ARDS), toxic chemical exposures, antineoplastic drugs, active connective tissue diseases, radiation injury, and fat embolism syndrome. In most cases the pathologic changes of diffuse alveolar damage gradually resolve with minimal residual effect. In ARDS the chest radiograph shows a diffuse infiltrate consistent with pulmonary edema, whereas in the other conditions the infiltrates may be more patchy. The diagnosis usually can be suspected from the clinical setting; biopsy may be needed only when an infectious process is suspected. Treatment is supportive for most of these patients, but corticosteroids may accelerate recovery in those with acute interstitial pneumonia associated with connective tissue disorders or caused by chemical exposure, radiation therapy, or antineoplastic drugs.

[edit] CHRONIC INTERSTITIAL PNEUMONIAS

Idiopathic pulmonary fibrosis (IPF), or cryptogenic fibrosing alveolitis (a term preferred by the British), is one of the more common interstitial lung diseases of unknown etiology. IPF is a chronic progressive lung disorder associated with both inflammation and fibrosis of the lung parenchyma. Confusion has arisen concerning IPF and its relation to the morphologic classification of interstitial pneumonias, including desquamative interstitial pneumonitis (DIP) and usual interstitial pneumonitis (UIP).^[12] Some recommend that this terminology not be applied to IPF, even though lung tissue from patients with IPF may show morphologic changes typical of DIP or UIP, since these changes are nonspecific and found in other interstitial lung diseases; however, this suggestion has not been generally accepted.^[13] The distinction between DIP and UIP has some prognostic significance because patients with DIP are more likely to respond to corticosteroids. This has led to the conclusion that DIP is probably an early stage of UIP. In addition, certain subgroups of interstitial pneumonias are based on the types of predominant inflammatory cells in the lung biopsy, including lymphocytic interstitial pneumonia (LIP), giant cell interstitial pneumonia (GIP), and plasma cell interstitial pneumonia (PIP).

IPF typically occurs in people 50 to 80 years old but may affect all age groups and is more common in men and in smokers. It occurs with a prevalence rate of three to five cases per 100,000 population. In 1935 Hamman and Rich first described five patients with rapidly progressive dyspnea, diffuse infiltrates in chest radiographs, and death occurring in 6 months of presentation. Recent studies suggest that this more fulminant type of pulmonary fibrosis occurs more often in connective tissue diseases, particularly rheumatoid arthritis. Although the course of IPF is variable, progressive deterioration in pulmonary function and exercise capacity, increasing hypoxemia, and radiographic evidence of extensive fibrosis and honeycombing over 2 to 8 years are typical features. Periods of stabilization may occur, but spontanenous improvement is rarely seen. Mean survival ranges from 3 to 5 years, with mortality exceeding 40% within 5 years of onset of symptoms.^[14]

Patients with IPF typically present with a history of an insidious onset of progressive dyspnea on exertion and nonproductive cough. The cough often occurs with prolonged paroxysms and responds poorly to antitussives. Chest examination in most patients reveals bilateral late-inspiratory crackles (Velcro rales), predominantly over the lower lung fields. Wheezing is not a feature of IPF. Finger clubbing is relatively common, occurring in 40% to 75% of patients. Cardiac examination usually yields normal results, except in later stages of the disease, when signs of pulmonary hypertension and cor pulmonale may become evident. Cyanosis is also a late manifestation indicative of severe disease.

The chest radiograph is abnormal in the majority of patients with IPF, and these changes often alert the physician to the presence of interstitial lung disease. The most common abnormalities are a reticular or reticulonodular pattern diffusely involving the lower lung fields and volume loss. With advanced disease, multiple cystic or honeycombed areas may be seen. Although the correlation between the radiographic pattern and the stage of disease (clinical or histopathologic) is generally poor, chest radiographs and HRCT of the lungs are important in gauging progression or regression of disease in response to therapy. The HRCT may show the presence of interstitial fibrosis in a small percentage of patients with IPF who have a normal chest radiograph.

A variety of abnormal laboratory tests have been noted in IPF, including an elevated ESR, circulating immune complexes, RF, and ANAs. However, serologic parameters fail to correlate with activity of disease or predict responsiveness to therapy. Serum anticollagen antibodies may be a marker of IPF activity. The typical pulmonary function changes are consistent with a restrictive impairment, with reduction in all lung volumes, including FVC, FEV₁, TLC, FRC, and RV. Airways obstruction is not usually present unless there is complicating chronic obstructive lung disease. A major physiologic abnormality is a disturbance in gas exchange caused by ventilation/perfusion inequality and contraction of the pulmonary capillary volume. As a result the DLco is reduced, a change that may precede the reduction in lung volume. Although arterial oxygenation at rest may be normal, desaturation almost always can be demonstrated with exercise. Exercise testing is more sensitive in the detection of abnormalities in oxygen transfer and provides a more sensitive parameter for following the clinical course.

The clinical, physiologic, and radiographic manifestations of IPF are similar to those of other interstitial lung diseases; open lung biopsy is usually required to substantiate the diagnosis and exclude other etiologies. The lung biopsy in IPF shows a wide spectrum of histologic changes depending on the stage of the disease. The early stages involve an alveolitis characterized by an accumulation of mononuclear cells (lymphocytes, alveolar macrophages, and type II alveolar cells) in the alveolar spaces, with relative preservation of the alveolar walls (i.e., DIP). As the disease progresses, the alveolar walls are distorted with edema, mononuclear cell infiltration, and fibroblast proliferation (i.e., UIP). In advanced stages the alveolar walls are greatly thickened, and much of the alveolar architecture is destroyed and replaced by connective tissue and fibrosis.^[15] Large cystic spaces forming the honeycomb lung and minimal inflammatory cells represent the end stage of this disease. Because of the small amount of tissue obtained by transbronchial biopsy (TBB), it is difficult to assess the degree of inflammation and fibrosis, and therefore TBB provides little prognostic information. Thoracoscopic lung biopsy may provide a compromise between TBB and open lung biopsy by minimizing operative risks yet providing adequate tissue for diagnosis. BAL is not specific enough to provide a definitive diagnosis of IPF but may predict therapeutic responsiveness, since the presence of BAL lymphocytosis has been associated with a greater responsiveness to corticosteroid therapy.^[16]

The most effective treatment for IPF is corticosteroids, but response to therapy is inconsistent.^[17] In general, patients with the shortest duration of symptoms, with BAL fluid showing greater than 5% lymphocytes and less than 10% neutrophils, and with a lung biopsy demonstrating more inflammation with less fibrosis will most likely respond to corticosteroids and have a more favorable prognosis.^[18] Usually an initial dose of oral prednisone at 40 to 60 mg daily is given for several months, and if a favorable response is obtained, prednisone is tapered slowly to 15 to 20 mg daily or an equivalent alternate-day dosage. Corticosteroids should be continued for at least 1 year. If no response is observed in the initial therapeutic trial of corticosteroids, they should be rapidly tapered and discontinued. Cytotoxic agents, such as azathioprine and cyclophosphamide, are used as second-line drugs, usually in combination with oral corticosteroids; the efficacy of these treatments has not been definitively demonstrated, however, and they carry a considerably greater risk of adverse effects than corticosteroids alone. Colchicine has been suggested as a potentially useful agent in the treatment of IPF because of its antifibrotic properties.^[19] No controlled prospective clinical studies are available to evaluate the efficacy of this therapy. Finally, single-lung transplantation is a consideration for patients with end-stage pulmonary fibrosis refractory to medical therapy.^[20] Survival time has increased significantly since then, to more than 75% in some centers. Unfortunately, because of the shortage of donor organs, many patients with IPF die while awaiting transplantation.

[edit] HYPERSENSITIVITY PNEUMONITIS

Hypersensitivity pneumonitis, or extrinsic allergic alveolitis, is an immunologic-induced interstitial pneumonitis characterized by predominantly mononuclear cell inflammation of the pulmonary parenchyma, terminal bronchioles, and alveoli. The antigenic agents include organic dusts derived from fungal, bacterial, or serum protein sources, as well as some reactive organic chemicals^[21][22][23](Table 76-1).

Table 76-1 Occupational Hypersensitivity Pneumonitides

Because of the very small particle size, usually less than 5 μm, a large quantity of antigenic material can be delivered to the alveolar level. The clinical response to antigen exposure depends on the individual's immunologic reactivity, the nature of the dust or chemical, the size of the particles, and the intensity of the exposure, particularly whether it is regular or intermittent. The immunologic reactivity appears to be an important predisposing factor in the development of hypersensitivity pneumonitis, since large surveys of farmers and workers exposed to bagasse, the spent sugar cane after the sugar has been removed, and a number of organic chemicals reveal a high percentage with serum precipitating antibody against specific antigen, but a low incidence of lung disease. The immunologic hallmark of hypersensitivity pneumonitis is the presence of serum IgG and IgA precipitating antibody to the inhaled antigen, with precipitins present in more than 90% of patients.^[8] This finding of precipitating antibody in studies of farmer's lung disease suggested a hypersensitivity reaction. Subsequent investigations have shown that multiple immunologic reactions are involved predominantly with cell-mediated delayed hypersensitivity, with or without amplification by immune complexes, lymphokines, and other biologic modifiers. The predominance of CD8% T lymphocytes in BAL fluid in farmer's lung disease shifts toward the CD4% predominance after removal from exposure.

Although exposure in the workplace has most often been the focus of reports of hypersensitivity lung disease, more recently the home environment and even the family automobile have been implicated as a source of respiratory problems. Air-conditioning systems, furnace and room humidifiers, cold steamers, saunas, and hot tubs can cultivate a variety of organisms identified as etiologic agents in hypersensitivity pneumonitis.^[24] Alleviation of symptoms when away from home with recurrence on return, or changes in symptoms during the heating or cooling season, may also offer clues. Thus a patient's total environmental exposure must be considered when a hypersensitivity lung disease is suspected.

The clinical manifestations of hypersensitivity pneumonitis are similar, regardless of the organic dust or chemical inhaled; these diseases should be considered as a syndrome with a spectrum of clinical features. The patient with hypersensitivity pneumonitis may present with three different clinical pictures: acute, subacute, or chronic.

[edit] Acute Form

The classic and most readily recognized form of hypersensitivity pneumonitis results from intermittent exposure to antigen and resembles an acute viral or bacterial infection. Symptoms include chills, fever, malaise, headache, nonproductive cough, chest tightness, and dyspnea without wheezing. Symptoms develop 4 to 6 hours after exposure and resolve spontaneously in 12 to 24 hours but recur on reexposure. Fatigue and weight loss may follow frequent or severe episodes. Physical findings include fever, tachypnea, tachycardia, cyanosis, and bibasilar late-inspiratory crackles; wheezing is rarely heard. Laboratory studies reveal a leukocytosis without eosinophilia and elevated immunoglobulin levels. High titers of precipitating antibody against the offending antigen are characteristic. Because precipitins are also common in exposed individuals without disease, however, this finding is not sufficient to make a diagnosis of hypersensitivity pneumonitis.

The chest radiograph may be normal after a brief exposure. With an intense or more prolonged exposure, however, a diffuse pattern of small, somewhat discrete nodules or a diffuse, soft, stringy or patchy interstitial infiltrate may be seen. The typical physiologic change is restrictive, with a decrease in vital capacity and lung volumes without airways obstruction. Some patients, particularly with severe reactions, may demonstrate small airways obstruction. Bronchial hyperreactivity is found in a significant number of individuals, particularly after an acute attack. This enhanced responsiveness may be caused by mediators released in the inflammatory response. Hypoxia is usually present, and the DLco is invariably reduced, particularly at the height of the reaction. This abnormality may persist for some time after other parameters have returned to normal. Long-term follow-up studies in patients who continue to have only brief and infrequent exposure to the antigens usually do not show a significant decrement in pulmonary function.

[edit] Subacute Form

Subacute hypersensitivity pneumonitis is much less common than the acute form and tends to develop with more chronic exposure. Symptoms develop insidiously, with features of progressive chronic bronchitis, including productive cough, dyspnea, easy fatigue, anorexia, and weight loss. Typical acute attacks, although infrequent, can be precipitated by heavy exposure. The chest radiograph may show diffuse nodulation or change consistent with interstitial fibrosis, but normal radiologic findings are not unusual. Both restrictive and obstructive defects in pulmonary function are seen, with the former predominating. DLco is reduced, along with hypoxemia, at least with exercise if not at rest. Long-term avoidance of exposure and administration of corticosteroids usually result in reduced symptoms and physiologic abnormalities. This is the most difficult form of the disease to diagnose because of the insidious nature and nonspecific clinical findings.

[edit] Chronic Form

Recurrent intense exposure to antigen or prolonged low-level exposure can lead to the chronic form of hypersensitivity pneumonitis, with the gradual development of disabling respiratory symptoms and irreversible physiologic changes. Progressive dyspnea is the most common symptom, along with nonproductive cough and easy fatigue. Physical findings include tachypnea, bibasilar crackles (Velcro rales), and wheezing, which are heard in some patients with a predominantly obstructive profile. With advanced disease, signs of pulmonary hypertension and cor pulmonale may be present. The chest radiograph in this predominantly fibrotic phase shows contraction of the lungs, particularly in the upper lobes, more peripheral involvement, and development of a honeycomb appearance. Some nodulation may persist but probably does not represent active granulomatous disease. Avoidance of exposure for prolonged periods and administration of corticosteroids and bronchodilators afford only slight improvement.

[edit] Pathophysiology

The histologic pattern found in the lung in hypersensitivity pneumonitis depends at what stage of disease the biopsy is obtained. In the acute stage the primary process is an interstitial granulomatous pneumonitis with foreign body giant cells, large numbers of lymphocytes, and macrophages with abundant foamy cytoplasm. Eosinophilia may be seen in the perivascular areas; vasculitis is rare. In the subacute stage there is moderate interstitial thickening, with only slight fibrosis, along with changes consistent with chronic bronchitis. In the chronic stage, interstitial fibrosis is the predominant feature and may be focal or diffuse. Intraalveolar septa are infiltrated with lymphocytes, and collections of dust-laden macrophages may be seen in the alveolar spaces. Bronchiolitis obliterans, cystic changes, and honeycombing are found in association with densely fibrotic areas. Confluent fibrosis tends to occur predominantly in the upper lobes. Regardless of the disease stage, these changes are not specific for hypersensitivity pneumonitis and must be interpreted in the context of all the associated clinical information.

[edit] Diagnosis

The diagnosis of hypersensitivity pneumonitis requires a high index of suspicion, a thorough history focusing on potential exposures in both work and home environments, and the temporal relationship between development of symptoms and exposure. Familiarity with the variety of organic dusts and chemicals that can cause this disorder is helpful (see Table 76-1). Frequently a specific antigen is not readily identified, however, and environmental sampling and culturing are necessary to isolate the offending agent. This isolate can then be used to prepare an antigen to test the patient's serum for precipitating antibodies. The demonstration of precipitating antibody against a particular organic antigen reflects exposure and is not sufficient evidence alone to make a diagnosis of hypersensitivity pneumonitis. About 40% to 50% of exposed individuals may have antibodies present in their serum without developing disease. In addition, serum precipitins may disappear after exposure ceases. BAL studies show a predominance of lymphocytes, reflecting an active alveolitis, but this finding is not limited to hypersensitivity pneumonitis. The most specific diagnostic test at present, if the suspected antigen can be identified, is controlled inhalation challenge in the laboratory followed by serial pulmonary function tests and clinical response monitoring. In the sensitized patient the signs, symptoms, and physiologic changes are accurately reproduced.

[edit] Treatment

The major therapeutic approach to treatment is removal from exposure to the offending antigen. This could cause significant economic hardship, however, as in the case of an affected farmer. Efforts to reduce the intensity of antigen exposure by changes in work practices and use of personal protection with a respirator have been of some benefit. Cromolyn is capable of blocking the immediate and late reaction in some individuals, whereas corticosteroids block only the late reaction. It is not certain, however, that continued exposure to antigen and control of the symptoms with medication will prevent subsequent lung damage. In some patients, continued antigen exposure may not lead to clinical deterioration.^[25]

[edit] INORGANIC DUST DISEASE: PNEUMOCONIOSIS

The word pneumoconiosis literally means dust in the lungs; however, not all dusts deposited in the lungs cause disease. A more widely accepted definition is from the International Labor Organization (ILO): “pneumoconiosis is the accumulation of dust in the lungs and the tissue reaction to its presence.”^[26] Inorganic dusts that do not disrupt the alveolar architecture or produce fibrosis when retained in the lung are classified as inert dusts or nuisance particulates, provided that they are free from toxic impurities and contain less than 1% quartz. These dusts ordinarily do not cause respiratory symptoms or functional abnormalities and may be cleared from the lung over time with avoidance of exposure; the term benign pneumoconiosis has been applied to this condition (Box 76-2). The most common example is siderosis, occurring primarily in welders and in workers mining and crushing iron ores. The inhalation of inorganic dusts that elicit a response in the lungs, eventually leading to irreversible fibrosis and structural and functional alterations, causes fibrosing, or collagenous, pneumoconiosis. The most important etiologic agents are silica and asbestos.^[27]

[edit] Silicosis

Silicosis is a chronic fibrotic disease of the lungs resulting from prolonged and intense exposure to free crystalline silica. Industrial sources of free silica include mining, quarrying and tunneling, foundry work, sandblasting, stone cutting and polishing, glass manufacturing, ceramics, and vitreous enameling. Several different clinical forms of silicosis are seen. The most common type is chronic classic silicosis, which occurs with moderate exposure over 20 to 45 years, usually involving respirable dust with less than 30% quartz. The lesions are usually nodular with a predominance in the upper lobes, probably due to better clearance of dust from the lower lobes. This simple stage of silicosis is associated with nodules generally 5 mm or less and usually normal pulmonary function. However, silicosis may be complicated by coalescence of the nodular lesions into conglomerate or confluent lesions, called massive fibrosis, usually in the upper lobes (progressive massive fibrosis, PMF) (Fig. 76-2). High quartz content apparently is the primary factor in the pathogenesis of massive fibrosis in silicosis.

Figure 76-2 Chest radiograph of coal worker 2 weeks before his death. Appearance is classic for progressive massive fibrosis (PMF), with larger conglomerate masses in both lung fields. (Courtesy JC Wagner.)

Accelerated silicosis occurs most frequently in sandblasters and silica flour workers. It results from moderately high exposure to dust containing 40% to 80% quartz and appears 5 to 15 years after the initial exposure. The nodular lesions tend to be smaller than in chronic silicosis, and the massive fibrosis favors the midzones of the lungs.

Acute silicosis (silicoproteinosis) is a rare form of silicosis occurring in workers with intense exposure to dust with very high concentrations of silica. It has been reported primarily in sandblasters. The disease develops over 1 to 3 years and progresses rapidly to death from respiratory failure. The characteristic histopathologic finding is a lipid-proteinaceous material filling the alveoli, which gives a strongly positive reaction to periodic acid–Schiff reagent, similar to that in idiopathic pulmonary alveolar proteinosis. Since acute silicosis is frequently associated with occupations in which freshly fractured crystalline silica of respirable size is generated, fracture-generated silicon-based radicals may play a significant role in the pathogenesis of this disease.

[edit] Pathogenesis.

Inhalation of silica particles small enough to reach the alveolar level induces a series of events resulting in the activation and persistence of inflammatory cells, with the alveolar macrophage playing a central role in the development of pulmonary inflammation. Earlier studies in the pathogenesis of silicosis suggested that ingestion of silica particles by the macrophages resulted in an interaction of silica-containing phagosomes with lysozymes releasing enzymes, which caused rupture of the phagosome and freed the silica particles in the cell cytoplasm. This process eventually leads to death of the cell due to the release of lysosome enzymes. The cycle of cell destruction is perpetuated by ingestion of the silica particles by other macrophages. However, more recent studies have shown that silica-laden macrophages can maintain normal viability but may be activated to produce proinflammatory mediators such as cytokines, interleukin-1 (IL-1), and tumor necrosis factor alpha (TNF-α) that can participate in numerous inflammatory processes. Repeated inhalation of silica and slow clearance of silica-laden macrophages would keep the inflammatory mediators chronically activated and would perpetuate the inflammatory process, resulting in the development of granulomatous inflammation and fibrosis in the lung. Alveolar macrophages have also been shown to produce fibronectin and macrophage-derived growth factor (MDGF), which would also contribute to the subsequent progressive fibrosis.

The typical lesion of silicosis is the silicotic nodule. These well-circumscribed nodules consist of whorled zones of acellular hyalin surrounded by a moderately cellular collagenous capsule. The majority of the silica particles are found in the outer layers of the nodules. The silica can be demonstrated as birefringent particles when the tissue sections are viewed under polarized light. The nodules are usually associated with adjoining parenchymal fibrosis.

[edit] Clinical Features.

Silicosis is a disease with a long latent period and usually requires 15 to 20 years of exposure before the chest film shows significant abnormality, except where very intense exposure has occurred. With simple silicosis, although a nodular infiltration may be seen on the chest radiograph, the worker is usually asymptomatic, and no functional impairment is evident. With progression of disease to a more advanced stage, shortness of breath with exertion is the major symptom. Often, poor correlation exists between the radiographic findings and the degree of functional impairment. Cough and sputum may develop, especially in smokers, as the disease progresses, but wheezing is not usually present. With development of PMF, normal lung structure is distorted from contraction of the upper lobes, and emphysematous changes occur in the lower lobes, resulting in airways obstruction. Silicosis is the only pneumoconiosis that predisposes to the development of tuberculosis and is most likely to occur after age 50 in association with moderate to severe silicosis. Incidence of atypical mycobacteriosis is also increased, primarily from Mycobacterium avium-intracellulare complex (MAC), which can be difficult to treat because of resistance to most antituberculosis drugs.

Physical findings in simple silicosis are nonspecific unless complicated by heart or other lung disease, such as congestive heart failure, chronic obstructive pulmonary disease, and tuberculosis. With complicated silicosis there are signs of fibrotic or obstructive lung disease. Finger clubbing is not a feature of this disease, even though significant hypoxemia may be present.

[edit] Lung Function.

In simple nodular silicosis, lung function is usually normal. With progression of disease, a restrictive impairment gradually increases, with a reduced FVC, FEV₁, and TLC. DLco gradually decreases, and although hypoxemia may be absent at rest, it usually can be demonstrated during exercise. In the absence of PMF, hypoxemia at rest is rare. Associated airways obstruction may also be present, particularly in smokers with advanced disease. The latter suggests a synergistic effect between silica dust exposure and cigarette smoke.

[edit] Diagnosis.

With an occupational history of significant silica exposure and a chest radiograph showing a discrete nodular infiltrate, a diagnosis of simple silicosis can be made with reasonable certainty. Obtaining previous chest films is helpful in establishing the stability and progression of the disease. Although a restrictive impairment and abnormal DLco may be demonstrated in some patients at this stage, pulmonary function studies are usually normal. A lung biopsy is rarely indicated to make a diagnosis. When the diagnosis is in question, a biopsy may be used to rule out a potentially treatable disease. If tissue is available, it can be examined under light and electron microscopy; examination under polarized light can identify birefringent foreign material. Spectroscopy and x-ray diffraction have been used for the qualitative and quantitative analysis of lung tissue, but these techniques require considerable lung tissue. Energy-dispersive x-ray analysis (EDXA) permits simultaneous multielemental analysis while examining the tissue in the scanning electron microscope (SEM) without destruction of the tissue sample.

[edit] Treatment.

No specific treatment exists for silicosis. When a diagnosis has been made, the worker should be removed from further silica exposure. Although even simple silicosis may progress in the absence of further exposure, it is more likely to do so if exposure continues. Selected workers may continue working with the use of an external air–supplied airstream helmet, which does offer excellent dust protection. With advanced disease, treatment is supportive with oxygen, bronchodilators, cardiac medications, and antibiotics for infections.

[edit] Asbestos-related Disease

The term asbestos is given to a group of naturally occurring fibrous silicates with the unique property of great resistance to heat and chemical destruction. Asbestos was seldom used commercially until the Industrial Revolution, when the need arose to insulate the steam engine. Between 1877 and 1967 the world production of asbestos increased from 50 tons to 4 million tons per year. Of the various types of asbestos fibers, only chrysotile, crocidolite, and amosite are of economic importance. More than 90% of all asbestos used in the United States is chrysotile. With the wide use of asbestos, an estimated 2.5 million U.S. workers had potential exposure to asbestos by 1976.^[28]

Asbestosis is a pneumoconiosis resulting from the inhalation of asbestos fibers and is characterized by diffuse interstitial fibrosis of the lung. These parenchymal changes may be associated with pleural fibrosis and parietal pleural plaques. The first detailed epidemiologic study of asbestos workers in the United States was undertaken by the Public Health Service in 1937. This study^[28] demonstrated a relationship between the extent of exposure and clinical symptoms, prompting the recommendation of an exposure limit of 5 million particles per cubic foot of air. In 1965 Selikoff and colleagues^[29] published a landmark survey of 1500 asbestos insulation workers. They found that nearly half of those examined had asbestosis and concluded that asbestosis and its complications were significant hazards among insulation workers. This was subsequently corroborated by other investigators.

[edit] Pathogenesis.

Deposition of inhaled particles, in this case asbestos fibers, depends on the aerodynamic behavior of the fibers, the dimensions of the respiratory tract entered, and the pattern of breathing. Since the fibers tend to align with the airstream, large fibers (even greater than 50 μm) can reach peripheral locations. Longer fibers are retained and eventually gain access into the interstitium of the lung. Smaller fibers are cleared by the alveolar macrophages. Exposure to asbestos results in the accumulation of macrophages in the area of deposition, which may serve a protective role. Because alveolar macrophages can release mediators capable of injuring alveolar walls and stimulating fibroblast proliferation, however, the alveolar macrophage may play the central role in the production of fibrosis and asbestosis. Studies in animals and in humans exposed to asbestos using BAL have demonstrated an inflammatory process (alveolitis) preceding the development of pulmonary fibrosis. Alveolar macrophages contribute to the alveolitis and fibrosis by the direct release of tissue-destructive metabolites, release of growth factors (e.g., MDGF, fibronectin) that stimulate fibroblasts to replicate and synthesize collagen, and release of neutral proteases.^[30] Active alveolitis appears predictive of disease progression and can be evaluated by BAL or gallium scan. Despite a clear understanding of the mechanisms involved in the development of lung fibrosis resulting from asbestos exposure, it is not clear why individuals with similar exposure may have very different responses in terms of the fibrotic process.

[edit] Pathophysiology.

In the early stages of asbestosis, only microscopic changes are observed, manifested by fibrosis at the level of the respiratory bronchiole. As the disease evolves, the fibrosis extends peripherally, resulting in diffuse interstitial fibrosis most prominent in the lower lobes. Fibrous wall cysts may form, giving the lung a honeycomb appearance. Pleural fibrosis and circumscribed pleural plaques, involving the parietal pleura with or without calcification, may be present. Asbestos bodies are an indicator of asbestos exposure that differentiates it from other forms of lung fibrosis. They are considered an essential feature for the histologic diagnosis of asbestosis. Asbestos bodies tend to form a yellow-brown structure on the larger fibers that measures 20 to 150 μm in length. These bodies result from the deposition of an iron-protein complex on the core fiber by alveolar macrophages. Asbestos body content has been quantitated by counting asbestos bodies in tissue sections, by digesting lung tissue and extracting the bodies, and more recently by examination of BAL fluid. By employing a combination of ultrastructural morphology, electron microscopy, and EDXA, it is possible to identify almost every asbestos fiber found in the lung. From a medicolegal standpoint the number of fibers present would provide some estimate of the asbestos exposure, and data on the fiber type might allow identification of a source of exposure if the worker was thought to have been exposed to a specific type of asbestos.

[edit] Clinical Features.

Asbestosis develops insidiously many years after the initial exposure, so the association may not be recognized. Symptoms and signs are not specific for asbestosis, since they do not differ from those found in diffuse interstitial fibrosis from a variety of other causes. The most common symptom is shortness of breath, particularly with exertion, which slowly progresses to breathlessness at rest. The dyspnea may be out of proportion to the radiographic abnormality, and cough is often present and may be productive, especially among smokers, due to coexisting chronic bronchitis. The most characteristic physical sign is bibasilar inspiratory crackles, which may be an early finding in asbestosis. Finger clubbing has been noted in 20% to 84% of patients. With advancing disease, cyanosis may become apparent, with signs of pulmonary hypertension and cor pulmonale.

[edit] Lung Function.

A characteristic functional change in asbestosis is restrictive lung disease. All lung volumes are reduced, particularly the vital capacity, inspiratory capacity, and TLC. Lung compliance is reduced because of the pulmonary fibrosis. Airways obstruction is uncommon, except in cigarette smokers. However, varying degrees of small airways obstruction have been demonstrated in nonsmoking asbestos workers, attributable to distortion of the small airways with bronchiolar fibrosis.^[31] The diffusing capacity is frequently reduced, and although hypoxemia may be absent at rest, it may first become evident only under the stress of exercise. In general the effects of asbestos on lung function are dose related, but functional abnormalities can be demonstrated in some asbestos-exposed individuals in the absence of definite radiologic change.

The radiographic appearance is characterized by linear and irregular opacities predominant in the lower half of the lung fields, as opposed to the nodular changes seen in silicosis and coal worker's pneumoconiosis. The early changes of asbestosis consist of linear shadows of varying thickness, between 1 and 3 mm, most marked in the lower lung fields. As these lesions increase in profusion, the cardiac and diaphragmatic borders are gradually obscured. Irregular opacities may be seen, but discrete rounded opacities are not a feature of asbestosis. As the fibrotic process progresses, the linear and irregular opacities become thicker and spread into the middle zones but rarely reach the upper zones. Lung volume gradually decreases. The basilar fibrotic changes are bilateral, and although they tend to be more prominent in one side, they are never unilateral.

[edit] Diagnosis.

A clinical diagnosis of asbestosis depends on a history of asbestos exposure and one or more of the following: radiographic changes of parenchymal/pleural fibrosis, basilar crackles, dyspnea on exertion, and abnormal pulmonary function that demonstrates restrictive impairment, low diffusing capacity, and hypoxemia at rest or with exercise. With all criteria present the diagnosis would be certain, but a history of exposure and a chest film consistent with asbestosis usually are sufficient. A lung biopsy is rarely indicated, but the pathologist cannot make a definite diagnosis of asbestosis in cases that show characteristic fibrosis in the absence of asbestos bodies or other evidence of asbestos fibers.

[edit] Treatment.

Asbestosis has no specific treatment, although corticosteroids have been used with some symptomatic improvement but without evidence that they affect the course of disease. Removal from further exposure to asbestos is an accepted approach; eliminating further asbestos burden on the lungs at an early stage would favor arresting the disease. Despite removal from further exposure, however, disease can continue to progress slowly.

[edit] Pleural Disease.

See Chapter 79 .

[edit] Lung Cancer.

The association between lung cancer and asbestos exposure was reported as early as 1935 and firmly established in 1964.^[32] The effects of smoking and asbestos are multiplicative and result in a cancer risk over 50 times greater for a smoking asbestos worker compared with a nonsmoker with no asbestos exposure. The risk for nonsmokers exposed to asbestos is also slightly increased. Epidemiologic surveys indicate that the risk of lung cancer is dose related. Lung cancers tend to arise in relation to areas of fibrosis and therefore occur chiefly in the lower lobes and periphery. All major tumor cell types are seen, but adenocarcinoma is predominant. In the absence of asbestosis it is difficult to establish an asbestos etiology for the lung cancer, particularly in a smoker.

Clinical findings are those of the underlying asbestosis. A rapid increase in respiratory symptoms, appearance of hemoptysis, loss of appetite, and weight loss should alert the physician to the possibility of lung cancer. Chest radiographs should be taken and compared to previous radiographs. Since the changes of asbestosis progress slowly, any abrupt change should prompt further studies to include sputum cytology and a diagnostic bronchoscopy and biopsy. Once the cell type has been determined, appropriate therapy can be instituted. The most effective measure is to convince the worker to discontinue cigarette smoking.

[edit] Mesothelioma.

The incidence of mesothelioma in the United States is estimated at 12 cases per 1 million population per year. The association of pleural mesothelioma and asbestos exposure was first demonstrated in 1960.^[33] The latency period from first exposure to diagnosis is long, ranging from 20 to 40 years, with a mean of about 35 years. Although a dose-effect response has been shown in some groups, there is no threshold below which asbestos exposure is safe with regard to mesothelioma. In addition, mesothelioma may occur without radiologic evidence of asbestosis. In contrast to bronchogenic carcinoma, cigarette smoking does not play a synergistic role in the development of mesothelioma. Fiber type appears to be important, since a much higher mesothelioma death rate is seen in those individuals exposed to crocidolite.

A diagnosis of mesothelioma can be difficult for the pathologist, not only to recognize that the tumor is a mesothelioma, but also to distinguish it from metastatic adenocarcinoma or sarcoma. A thoracotomy and open biopsy are invariably required to obtain an adequate specimen for histologic evaluation.The major presenting symptoms in patients with mesothelioma is chest pain of insidious onset. The pain is nonpleuritic, aching, and persistent and may be referred to the upper abdomen or shoulder. Progressive shortness of breath and cough may accompany the pain. The chest pain gradually becomes an incapacitating symptom, with dyspnea, anorexia, and weight loss. Physical findings vary with the stage of disease, but patients usually present with signs of fluid in the involved hemithorax; the fluid often is hemorrhagic. A chest film may show a pleural effusion and thickened pleura on the affected side. A CT scan may be helpful in determining the extent of the disease and separating fluid from tissue densities.

Most patients with mesothelioma die within 12 to 15 months from the onset of symptoms. Radical surgery, chemotherapy, and megavolt therapy have minimally improved survival and have not been curative.

[edit] REFERENCES