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Raed A.
Dweik, MD

Peter J.
Mazzone, MD

Department of
Pulmonary & Critical
Care Medicine

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Exposure to dust in the workplace is associated with a variety of pulmonary and systemic illnesses. The term "pneumoconiosis" is derived from Greek and simply means "dusty lungs." In current medical practice, the term is reserved for the permanent alteration of lung structure caused by inhalation of a mineral dust and the reaction of the lung tissue to this dust. The reactions that occur within the lungs vary with the size of the dust particle and its biologic activity. While some dusts (like barium, tin, and iron) do not result in a fibrogenic reaction in the lungs, others can evoke a variety of tissue responses. Such responses include nodular fibrosis (silicosis), diffuse fibrosis (asbestosis), and macule formation with focal emphysema (coal worker's disease). Still others (like beryllium) can evoke a systemic response and induce a granulomatous reaction in the lungs. Pneumoconioses can appear and progress after the exposure has ceased. Regression does not occur, and treatment is mostly symptomatic and supportive.

As we move well into the 21st century, and due to improvements in industrial hygiene practices and dust control measures, we will probably be seeing less of the traditional pneumoconioses in the industrialized countries. We will, however, start seeing more of the immunologically mediated disorders related to more modern technologies like hard metal disease and chronic beryllium disease. We will discuss a few of the traditional dust exposures (asbestos, silica, coal, and hard metals) and the illnesses they produce. Special emphasis will be given to beryllium-induced lung disease because of its emerging role and the need for increased awareness to recognize individuals at risk based on recent advances in our understanding of its pathophysiology.

ASBESTOS-RELATED
LUNG DISEASE

Pleural Diseases

Asbestosis

Asbestos as a Carcinogen

Silicosis

Mycobacterial Disease

Exposure to asbestos occurs during its mining, milling, and transporting, as well as during the manufacture and application of asbestos-containing products. The most common industries in which exposure occurs are the construction and shipbuilding industries. The most common occupations are plumbing, pipefitting, insulating, and electricians. This exposure can lead to a variety of lung diseases including pleural diseases and the pneumoconiosis asbestosis. Asbestos is also a known carcinogen.^1-4

Four forms of pleural disease related to asbestos exposure have been described: pleural plaques, benign asbestos pleural effusions, pleural fibrosis, and malignant mesotheliomas.

Pleural plaques are the most common manifestation of asbestos exposure. They are smooth, white, raised, irregular lesions found on the parietal pleura, commonly located in the lateral and posterior midzones and over the diaphragms (Figure 1). They are frequently asymptomatic and are recognized only on chest imaging. Macroscopic calcification is common. Plaques are not associated with the development of a malignant mesothelioma. They are, however, markers of asbestos exposure, and thus individuals with pleural plaques are at risk of developing pulmonary fibrosis, mesothelioma, and lung cancer.

Computed tomography of the chest demonstrating pleural plaques due to asbestos exposure.

Figure 1

Benign asbestos pleural effusions may be silent or present with pain, fever, and shortness of breath. They are an early manifestation of asbestos exposure, occurring within 15 years of the initial exposure. The diagnosis of this condition is one of exclusion. It requires known asbestos exposure, the finding of an exudative, bloodstained, lymphocyte-predominant effusion, the lack of tumor development over a 3-year follow-up, and no evidence of another cause of the effusion. Frequently a thoracoscopy with biopsy is performed to exclude other causes. A benign asbestos pleural effusion is usually transient but requires close follow-up. It is not associated with the development of a malignant mesothelioma.

Pleural fibrosis typically occurs in individuals who have had a remote exposure to asbestos (more than 20 years before) that was short-lived and heavy in intensity. It can occur as a focal or diffuse process. The fibrosed pleura may surround the lung, leading to a trapped lung, or fold in on itself, encasing a portion of the parenchyma. The masslike lesion that results is known as rounded atelectasis. All forms of pleural fibrosis are difficult to distinguish from malignancy, and frequently require biopsies to ensure benignity. The presence of pleural fibrosis indicates an increased risk of pulmonary fibrosis.

Asbestos exposure is responsible for most cases of malignant mesothelioma. The presentation is typically the insidious onset of nonpleuritic chest wall pain, 20 to 40 years after the initial exposure. The pain can radiate to the upper abdomen or shoulder and is often associated with dyspnea and systemic symptoms. The mass typically involves both the parietal and visceral pleura. Local invasion is common, with symptoms stemming from the organs invaded. Chest imaging frequently reveals an effusion ipsilateral to the pleural disease and may show pleural plaques in the contralateral hemithorax. Open biopsy is required for the diagnosis. Treatment options are unsatisfactory. There is no synergy between smoking and asbestos exposure for the development of a malignant mesothelioma.

The term “asbestosis” refers to pulmonary fibrosis secondary to asbestos exposure. Risk factors for the development of asbestosis include increased levels and duration of exposure, younger age at initial exposure, and exposure to the amphibole fiber type. It is not associated with smoking.

Common symptoms include progressive shortness of breath and a nonproductive cough. Chest pain may be reported. On examination, inspiratory crackles on lung auscultation and digital clubbing are present with variable frequency.

The parenchymal fibrotic changes are most prominent in the lower lobes and subpleural areas. Pulmonary function testing reveals restrictive lung disease with a decreased diffusing capacity for carbon monoxide. Thus, radiographic and physiologic testing findings can be indistinguishable from those of other causes of pulmonary fibrosis. The presence of concomitant pleural disease and the finding of asbestos or ferruginous bodies (Figures 2a, and 2b) in pathologic samples help to support the diagnosis.

Asbestosis may appear and progress long after exposure has ceased. It may remain static or progress over time. There is no known effective therapy. The number of reported deaths from asbestosis has increased over time, related to the use of asbestos in a time-delayed manner (Figure 3).

Asbestos is a known carcinogen. The risk of developing lung cancer in an individual exposed to asbestos is enhanced in a multiplicative fashion by concomitant cigarette smoking. Lung cancer more commonly occurs in individuals who also have asbestosis. All cell types are associated with exposure. The lag time to the development of lung cancer is usually more than 20 years. Treatment follows the principles of lung cancer therapy in individuals without prior asbestos exposure. Comorbid lung disease may limit the treatment options.

Exposure to crystalline silica occurs when silica-containing rock and sand are encountered. This most commonly occurs in occupations associated with construction, mining, quarrying, drilling, and foundry work. A variety of conditions have been associated with the inhalation of crystalline silica, including silicosis, tuberculosis, obstructive lung disease, and lung cancer.^1,3-6

Inhalation of crystalline silica can lead to a fibronodular parenchymal lung disease known as silicosis. This most commonly occurs in a form known as chronic or simple silicosis. Individuals with chronic silicosis typically have had more than 20 years of silica exposure. They are frequently without symptoms although shortness of breath and cough can develop. Their disease is thus recognized radiographically with multiple small nodules with an upper lobe predominance (Figure 4). Hilar adenopathy with “eggshell” calcification can be seen. Pulmonary function abnormalities do not invariably occur. Pathologically, the nodules are recognized as silicotic nodules.

The pulmonary nodules seen with chronic silicosis can become progressive. They may be seen to conglomerate and be accompanied by fibrosis, which has been termed “conglomerate silicosis and progressive massive fibrosis.” Shortness of breath and cough can become debilitating. Pulmonary function testing often shows a mixed obstructive and restrictive defect with a reduction in the diffusing capacity. Death due to silicosis continues to occur (Figure 5).

Acute and accelerated forms of silicosis are more rapidly progressive, typically associated with intense exposure to silica. Acute silicosis can develop within months of exposure, and resembles acute airspace disease on radiographs. Pathology mimics alveolar proteinosis with proteinaceous material in the alveoli, but interstitial involvement and early nodule formation can be seen. Rapid progression to acute respiratory failure is common. Accelerated silicosis occurs after 5 to 15 years of exposure. Patients are usually symptomatic and often progress to respiratory failure and death. They are recognized by the development of upper zone nodules and fibrosis on radiographs and numerous nodules with interstitial fibrosis on pathology.

Mycobacterial disease is known to occur with increased frequency in individuals with silicosis. Individuals with chronic silicosis have an incidence of mycobacterial tuberculosis that is three times greater than that of age-matched controls. Those with acute and accelerated silicosis have the highest incidence of mycobacterial disease. Others exposed to silica but without silicosis may have an excess risk of developing tuberculosis.

Given the high incidence of tuberculosis, it is recommended that individuals with silicosis or long-term exposure to crystalline silica should receive a tuberculin skin test. If the reaction is 10 mm or greater and there is no evidence of active tuberculosis, tuberculosis chemoprophylaxis should be administered. If symptoms or radiographic changes suggest the possibility of mycobacterial disease, routine or induced sputum should be obtained and bronchoscopy considered. If active tuberculosis is confirmed, standard tuberculosis therapy, with a regimen containing rifampin, should be administered. Similarly, if a nontuberculous mycobacterium is identified, standard therapy for that organism should be administered.

Exposure to crystalline silica has been associated with the development of obstructive lung disease, chronic bronchitis, and emphysema. These associations are more prominent in those with silicosis. The intensity of dust exposure appears to affect the development of obstructive lung diseases. Tobacco smoking may cause an additive effect.

According to the International Agency for Research on Cancer, there is sufficient evidence to classify silica as carcinogenic in humans. Available studies are complicated by multiple confounders and selection biases. Despite this, the bulk of the evidence supports an increased risk for lung cancer in tobacco smokers with silicosis. The relationship is less clear for never-smokers and for individuals exposed to silica who do not have silicosis.

Evidence suggests a relation between appreciable silica exposure and the development of scleroderma. Less evidence is available to support an association with rheumatoid arthritis or systemic lupus erythematosis. Similarly, reports of renal disease associated with silica exposure require further evidence to confirm a link.

The deposition of coal dust in the lungs can lead to lung disease. Coal mining is the major source of exposure. The tissue reaction to coal dust inhalation is the development of a coal macule. Focal emphysema may form around the macule. This combination is termed a coal nodule and is the characteristic lesion of simple coal worker’s pneumoconiosis (CWP). In addition to CWP, coal dust exposure is also related to the development of airflow limitation, chronic bronchitis, and emphysema. Silica exposure frequently occurs in combination with coal dust exposure; thus, the above-described silica-related illness may also be seen.^1,3

Simple CWP is usually without symptoms. The presence of shortness of breath or a productive cough is often related to the presence of chronic bronchitis or airflow obstruction. Progressive massive fibrosis (PMF) can occur, more frequently when there has also been exposure to silica. Symptoms advance as the PMF worsens (Figure 6). Deaths from CWP continue to occur (Figure 7).

Given the frequent absence of symptoms, simple CWP is often a radiographic diagnosis. Chest imaging reveals small nodules with upper and posterior zone predominance. Hilar lymph node enlargement is not uncommon although eggshell calcification does not generally occur. When PMF occurs, these small nodules coalesce, forming opacities larger than 1 cm. These lesions are odd-shaped, usually bilateral, progressive, and may cavitate or become calcified. Care must be taken since lesions diagnosed radiographically as PMF are often shown later to have been tumors, tuberculosis scars, or Caplan’s nodules (see below).

Simple CWP tends to have little effect on lung function. Airflow limitation, restriction, and a reduction in diffusing capacity can all be seen when PMF develops. Pulmonary hypertension may develop in advanced disease.

Complications of CWP include a higher incidence of mycobacterial disease (though not as high as with silicosis), and an increased risk of stomach cancer. Tuberculin skin testing, chemoprophylaxis, and treatment of active tuberculosis are as recommended in silicosis. Caplan’s syndrome is a nodular form of CWP seen in individuals with rheumatoid arthritis. The nodules are multiple, tend to be larger than typical coal nodules, develop over short periods of time, and more frequently cavitate. These findings usually occur concomitantly with the joint manifestations, active arthritis, and the presence of circulating rheumatoid factor.

Hard metal, or cemented tungsten carbide, is found in tools for high-speed cutting, drilling, grinding, or polishing of other metals or hard materials. The consensus is that the agent responsible for the disease is the cobalt used as a catalyst to promote the binding of tungsten to carbon rather than the tungsten carbide itself. Workers in industries that manufacture cutting tools, drills, and the like are at highest risk. However, users of such tools (eg, dental laboratories, sharpeners of saws, and diamond polishers) may also be exposed.

Work-related illness in hard metal disease includes asthma and interstitial lung disease. The disease may present acutely with rapidly progressing dyspnea after relatively short exposure, or more insidiously, and usually after long exposure. An acquired hypersensitivity may play a role in the development of a hypersensitivity bronchitis or asthma-like picture in a small percentage of workers in hard metal. The interstitial fibrosis is characterized by a fibrosing alveolitis, interstitial pneumonitis, and the presence of multinucleated giant cells (Figure 8) also recovered from the bronchoalveolar lavage. Both interstitial and area disease may of course occur in the same individual. Diagnosis is based on an exposure history, a compatible clinical presentation, and pathologic findings. Treatment is mostly supportive. Corticosteroids have been used to treat cases with acute presentation.^7,8

Figure 8

Beryllium is an extremely light metal with a high modulus of elasticity (stiffness), low coefficient of thermal expansion, high thermal and electrical conductivity, and a high melting point. Because of these unique properties, beryllium is used in many industries (Table 1). Pure beryllium metal is useful in the nuclear industry as a moderator of neutrons, increasing the effectiveness of the chain reaction. More frequently, it is formulated as an alloy or an oxide.^9,10

Historically, acute toxicity was associated with occupational exposures to concentrations of soluble beryllium salts greater than 100 µg/m3. With the advent of industrial control measures to minimize air levels, acute pulmonary syndromes have virtually disappeared.

Individuals who work with beryllium continue to be at risk for developing chronic beryllium disease (CBD or berylliosis). This is a granulomatous lung disease similar to sarcoidosis that is caused by a delayed-type hypersensitivity reaction in which there is proliferation of beryllium-specific T cells.¹¹ About 10% of exposed individuals will develop beryllium hypersensitivity, and about 5 % of those exposed will develop CBD (Figure 9). The most significant exposure is in the occupational setting. Occupations with the highest potential for exposure are those involved with primary production, metal machining, and reclaiming scrap alloys. Other high-exposure areas are in the nuclear power, aerospace, and electronic industries (Table 2).^12,13

In addition to environmental exposure, genetic predisposition seems to have a major role in the development of CBD. A variant of the human leukocyte antigen (HLA-DPb1 [Glu69]) is found in 80% to 97% of patients with CBD and in only 30% of controls.^14,15

The lung is the primary organ affected by CBD. Other organs can also be affected including the extrapulmonary lymph nodes, skin, salivary glands, liver, spleen, kidney, bone, myocardium, and skeletal muscle. Symptoms are usually nonspecific and occur late in the course of the disease. Dyspnea is the most common symptom, but patients may also present with cough, chest pain, arthralgia, fatigue, and weight loss. Physical signs, like symptoms, occur late in the course of disease and include inspiratory crackles on pulmonary auscultation, lymphadenopathy, skin lesions, and hepatosplenomegaly. Pulmonary function testing reveals an obstructive pattern in 39% and a restrictive pattern in 20% of patients with CBD. DLCO ( the lung diffusion capacity for carbon monoxide) also declines over time in 36% of individuals. However, the most sensitive test would be abnormalities in gas exchange during exercise. A chest radiograph is normal in about one-half the patients with documented CBD. Abnormal findings in the other half include hilar adenopathy and/or increased interstitial markings. High-resolution CT (HRCT) of the chest is more sensitive than chest radiography. Typical findings on HRCT are ground-glass opacification (Figure 10), parenchymal nodules, or septal lines. HRCT, however, may show negative results in up to 25% of patients with documented CBD.^9,10,16,17

The diagnosis of CBD is based on the presence of:

• History of beryllium exposure
• A positive blood or bronchoalveolar lavage beryllium-specific lymphocyte proliferation test
  (BeLPT; see below)
• The presence of non-necrotizing granuloma on
  lung biopsy

The blood BeLPT is currently the screening test of choice to identify beryllium workers who develop beryllium sensitization or CBD. It involves exposing peripheral blood mononuclear cells in vitro to beryllium salts at varying concentrations for variable time intervals, looking for cell proliferation. This test is performed only in selected, specialized laboratories around the country (Table 3).^18,19 Patients who have a positive blood BeLPT but no lung pathology are considered to be sensitized to beryllium but do not have CBD. They remain, however, at a lifelong risk for developing CBD.

There are many similarities between CBD and sarcoidosis (Table 4). Without a suspicion of beryllium exposure, almost all cases of CBD will be diagnosed as sarcoidosis. For the same reason, all patients with sarcoidosis should have a detailed occupational history obtained to exclude history of exposure to beryllium.^9,10

Flexible fiberoptic bronchoscopy with bronchoalveolar lavage and transbronchial biopsy is usually necessary to confirm a suspected diagnosis of CBD. Bronchoscopy is also helpful in excluding other possible etiologies with similar presentations such as hypersensitivity pneumonitis or mycobacterial or fungal infection. The presence of non-necrotizing granulomas on transbronchial biopsy is the hallmark of CBD and is diagnostic in the appropriate clinical and epidemiologic setting. The granulomas in CBD are indistinguishable from sarcoid granulomas (Figure 11). This is why exposure to beryllium (confirmed by occupational history, a positive BeLPT test, or beryllium in the tissue) is an integral part of the diagnosis of CBD. Patients with CBD usually have lymphocytosis (more than 20% lymphocytes in fluid from broncheoalveolar lavage. The BeLPT can also be performed on mononuclear cells from broncheoalveolar lavage fluid. An open lung biopsy is rarely needed but could be resorted to if the transbronchial biopsy was negative and the suspicion for CBD remained high. Although the diagnostic yield is slightly higher than in transbronchial biopsy, the risk is also significantly higher. Serum levels of angiotensin-converting inhibitors may be high in CBD as in other granulomatous diseases, but this has no diagnostic value.^9,10,12,18

All patients with CBD should be advised to avoid any further beryllium exposure. Although there is no proof that cessation of exposure to beryllium will improve the disease or halt its progression, it is prudent to avoid further exposure due to the immune-mediated nature of the disease. There is currently no cure for CBD, and no controlled studies for CBD are available. However, based on anecdotal reports and on the pathogenesis of the disease (immune mediated), and because of the similarities with sarcoidosis, CBD is treated with corticosteroids. Since therapy is not curative and has significant side effects, it is recommended only in patients who are symptomatic or demonstrate decline in their pulmonary function. In patients in whom corticosteroids fail or who develop significant side effects, methotrexate may be considered. In endstage cases, lung transplant may be considered.^9,10

In summary, chronic beryllium disease (CBD, berylliosis) is an occupationally acquired granulomatous lung disease similar to sarcoidosis. It is caused by exposure to beryllium in genetically susceptible individuals. CBD should be suspected in individuals with beryllium exposure who present with pulmonary symptoms or have a positive screening blood BeLPT.

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2. Asbestos Standard for the Construction Industry. OSHA 3096, US Department of Labor, 2002 (Revised).

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14. Richeldi L, Sorrentino R, Saltini C. HLA-DPB1 glutamate 69: a genetic marker of beryllium disease. Science. 1993;262:242-244.

15. Saltini C, Richeldi L, Losi M, et al. Major histocompatibility locus genetic markers of beryllium sensitization and disease. Eur Respir J. 2001;18:677-684.

16. Saber W, Dweik RA. A 65-year-old factory worker with dyspnea on exertion and a normal chest x-ray. Cleve Clin J Med. 2000;67:791-800.

17. Berlin JM, Taylor JS, Sigel JE, Bergfeld WF, Dweik RA. Beryllium dermatitis. J Am Acad Dermatol. 2003;49:939-941.

18. Rossman MD, Kern JA, Elias JA, et al. Proliferative response of bronchoalveolar lymphocytes to beryllium. A test for chronic beryllium disease. Ann Intern Med. 1988;108:687-693.

19. Barna BP, Culver DA, Yen-Lieberman B, Dweik RA, Thomassen MJ. Clinical application of beryllium lymphocyte proliferation testing. Clin Diagn Lab Immunol. 2003;10:990-994.

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