When should you suspect asbestos-related pulmonary disease?

The potential respiratory effects of asbestos exposure include asbestosis (chronic, diffuse, interstitial pulmonary fibrosis), pleural plaques, diffuse pleural thickening, mesothelioma, and lung cancer. In some respects, the diagnosis of asbestos-related respiratory diseases has become increasingly difficult. Generally, levels of asbestos exposure are much lower than they were in the past and, for a number of reasons, it can be quite difficult to assess a patient's exposure history.

In this article, I will review the respiratory effects of asbestos and the approach to evaluating the patient.

BACKGROUND

Asbestos is a naturally occurring silicate mineral that is found worldwide. According to analysis of the polar ice caps, humans have been exposed to asbestos in the environment for several thousand years. However, determining whether a specific exposure was hazardous is a complex process that must take into account the duration and intensity of exposure and the type of asbestos fiber involved. The respiratory diseases that have been associated with asbestos exposure are shown in Table 1.

Exposure to asbestos is classified according to the concentration of respirable fibers multiplied by the duration of exposure multiplied by the intensity of exposure.¹ Based on their molecular structure, asbestos fibers may be classified as amphibole or serpentine. Of the 5 subtypes of amphiboles, 3 (tremolite, actinolite, and anthophyllite) may also exist as nonfibrous forms. The only serpentine asbestos of clinical importance is chrysotile. Although all types of asbestos can cause asbestos-related illnesses, chrysotile (white asbestos) is important from a public health perspective because it was widely used commercially.

The specific type of asbestos fiber is critical in determining whether exposure causes a specific respiratory disease (Table 2). For example, crocidolite is 500 times more likely to cause mesothelioma than chrysotile is, whereas chrysotile is 10 times less likely to cause asbestosis than crocidolite is.²

Other factors that influence the sequelae of asbestos exposure are the size of the fiber and the duration and intensity of exposure. As a cause of mesothelioma, only exposure to long, thin fibers with a length of 8 µm or more and a diameter of less than 0.25 µm is significant.

Among workers who are exposed to asbestos, the prevalence of pleural changes ranges from 22.1% in Ontario cement workers to 79% in British applicants for workers' compensation.^3,4 Pleural plaques are very common in some countries, such as Finland, because of environmental exposure to amphibole asbestos such as anthophyllite. Pleural plaques were found in 58% of all autopsies of men in Helsinki who had died suddenly.⁵

Anthophyllite asbestos has a strong propensity to cause pleural plaques but a low propensity to cause mesothelioma. This difference is thought to reflect the larger diameter of anthophyllite fibers compared with other commercial amphiboles.

The effect of amphibole asbestos exposure has been most dramatic in workers exposed to pure crocidolite. Among crocidolite miners in western Australia, diffuse pleural thickening was observed much more frequently than were pleural plaques, particularly within the first 5 to 15 years after exposure.⁶ Interestingly, after the first 15 years of exposure, the level of crocidolite exposure had no effect on the rate of onset of diffuse pleural thickening. Eventually, 56% of workers had diffuse pleural thickening, and about 70% had pleural plaques or diffuse pleural thickening.⁶

In contrast, exposure to pure chrysotile asbestos is less likely to lead to the development of pleural plaques, diffuse pleural thickening, or mesothelioma. Among 6529 workers who were heavily exposed to chrysotile asbestos during mining operations in Quebec, pleural thickening was observed in only 3.8%; pleural calcifications, in only 2.5%; and obliteration of the costophrenic angle, in 5.8%.⁷ The prevalence of pleural thickening and pleural calcification increased with both the age of the worker and the total exposure to dust.⁷

Among the Quebec miners, the likelihood of pleural abnormalities developing appeared to be associated with the degree of contamination of chrysotile asbestos with tremolite.⁷ Among workers at the Thedford mines in Quebec, the prevalence of pleural abnormalities was 6.4%; it was 3.2% at the Asbestos, Quebec, mines. Moreover, as was demonstrated in Russia and South Africa, where there is no significant contamination of chrysotile by tremolite, exposure to chryso-tile contaminated with very small amounts of tremolite is associated with a very low incidence of pleural disease.^8,9

The causal role of various asbestos fibers in respiratory disease, particularly pleural disease and mesothelioma, may have to be assessed in certain circumstances. In one study, tissue analysis in 11 of 13 patients with diffuse pleural disease revealed asbestos fiber counts that were increased to the range seen with pleural plaques and minimal asbestosis.¹⁰ All 13 patients had been exposed to commercial amphibole asbestos products. Of these 11 patients, 3 had extremely high fiber counts.¹⁰ The 2 patients who did not have increased fiber counts of amphibole asbestos were thought to have diffuse pleural disease that was not related to asbestos.

In the lung parenchyma of these 13 patients, the levels of chrysotile fibers were at background level in all but 1 patient, who also had elevated levels of amphibole asbestos. However, in the pleural specimens, the fibers were almost exclusively short chrysotile fibers.

These findings have been interpreted by some authorities as suggesting that chrysotile fiber levels in pleura are a better measure of true chrysotile exposure than they are in the parenchyma, because in lung parenchyma, most chrysotile fibers are eventually dissolved. Unlike amphibole asbestos fibers, which are stable in acidic environments, chrysotile fibers are not acid-stable.^11,12

Chrysotile asbestos easily breaks longitudinally into smaller fibrils. Most experts attribute the ease with which chrysotile fibers are deposited in the subpleural lymphatics and tissues to their small size. In these locations, the fibrils are relatively safe from lysosomal destruction.

Most epidemiologic studies have found that only fiber counts of amphiboles (such as tremolite, crocidolite, and amosite) in lung parenchyma were correlated with the risk of mesothelioma. Pleural tissue levels of asbestos fibers are not correlated with lung parenchymal tissue levels or other historical measures of exposure and are not valuable in establishing causation from asbestos exposure in patients who have mesothelioma.

PATIENT EVALUATION

Because asbestosis is relatively rare, it is important that the more common causes of interstitial lung disease (ILD) be considered. Respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) should also be considered in the differential diagnosis of a patient with chronic dyspnea. Most patients who have been most heavily exposed to asbestos are now aged 65 to 85 years. This age group is at increased risk for other respiratory problems--such as COPD--that can cause pulmonary function changes that are difficult to distinguish from those associated with asbestosis.

Tables 3 and 4 present the findings associated with asbestosis according to specificity and sensitivity. Some of the confounding factors in making the diagnosis are shown in Table 5.

The exposure history

Patient histories are frequently unreliable in assessing exposure because definite information about the degree of exposure and identification of the types of asbestos are lacking. Patients may associate exposure with visible dust, but injurious asbestos fibers are not perceptible to the naked eye. Workers may also attribute a pulmonary problem to work exposure or assume that any exposure to asbestos is hazardous.

The history can also be inaccurate because of poor patient recall, especially given the long latency between exposure and the development of disease, and because of a desire for workers' compensation. Information about the friability of the product, industrial process, fiber size, fiber type, fiber counts in the respiratory zone (the air immediately surrounding the worker), and the degree of exposure to bystanders in the workplace is not usually available. Yet such information is critical in evaluating the degree of exposure.

Rarely is there enough information to accurately assess cumulative asbestos exposure to specific products, industrial processes, and fiber type. Therefore, most information about exposure is based on speculation about details such as a job title or description--for example, "I worked in a shipyard for 5 years."

However, the potential for exposure to asbestos in a shipyard may vary more than 1000-fold. If the position involved new construction after the decline of the use of asbestos products in the mid-1970s, the degree of exposure would be much less than that in a position that involved retrofitting older steam-powered vessels before the introduction of strict asbestos-containment procedures. Other factors that affect the degree of exposure include the type of work and the physical location of the work in the shipyard.

Occupational histories tend to grossly overestimate the degree of asbestos exposure as a factor in the etiology of diseases such as lung cancer.¹³ Epidemiologic studies have demonstrated that occupational histories do not correlate well with lung-fiber analysis. Therefore, bronchoalveolar lavage (BAL), with a count of asbestos bodies, and fiber analysis of a lung biopsy specimen are the only ways of assessing the extent of asbes- tos exposure with any degree of certainty.¹³

It is important to remember that asbestos-related diseases have very long latency from the time of exposure. This long latency further compromises the patient's ability to recall exposure information, a situation that also may be influenced by legal considerations. The latency between time of exposure and the development of an asbestos-related disease depends on the total cumulative exposure. The cumulative required exposures of the asbestos-related disorders--and hence, the latency periods--in ascending order of exposure are:

• Asbestos-related pleural plaques.

• Mesothelioma.

• Asbestos corns (small, hard nodules under the skin).

• Asbestos-related diffuse pleural disease (including asbestos-related pleural effusions, pericardial effusions, diffuse pleural thickening, and rounded atelectasis).

• Asbestosis.

• Asbestos-related lung cancer.

Originally, the latency period for asbestos-related diffuse pleural disease and pleural effusions was thought to be relatively short--about 5 to 10 years.¹⁴ More recent information indicates that asbestos-related diffuse pleural disease may not occur until more than 30 to 50 years after exposure.¹⁵

This obvious discrepancy may simply be a reflection of the greater exposures that were reported in the earlier historical cohorts. With the exception of asbestos-related pleural plaques and mesothelioma, total exposure plays a major role in determining the latency from the time of first exposure to the development of clinical disease. As a result, patients occasionally are found to have asbestosis or diffuse pleural disease 50 years after the initial exposure. Historically, because of a history of relatively low exposure and a long latency period, these patients would have been thought to be at very low risk for asbestosis or diffuse pleural disease.¹⁶

Physical examination

One of the more consistent findings in patients with diffuse ILD, such as asbestosis, is the presence of dry rales. Rales are an early and specific finding in patients who have ILD. In various studies, rales have been reported in 71% to 95% of patients with different forms of pulmonary fibrosis and are frequently detected before the chest radiographic abnormalities become significant.¹⁷

Most patients with asbestos- related respiratory disorders are asymptomatic until the disease is moderately advanced. Pleural plaques generally cause no symptoms. Patients with asbestos-related pleural effusions or pericarditis may complain of pleuritic chest pain, but they are more commonly asymptomatic. Effusions that are large or that progress to significant diffuse pleural disease cause dyspnea.

Asbestosis develops silently over many years, and patients may have chest radiographic or high-resolution CT (HRCT) changes for many years before they have significant deficits in lung function and dyspnea. Chronic cough is a late symptom in nonsmokers who have asbestosis and is seen in moderate to advanced disease.

The onset of pleuritic chest pain warrants a thorough evaluation in asbestos-exposed persons, since it may be caused by mesothelioma. Patients may present with what appears to be a benign, recurrent asbestos-related pleural effusion, but the true diagnosis is not discovered until several months later when a thorascopic procedure is performed.

Radiographic and imaging studies

• Pleural disease: Traditionally, surveillance for asbestos-related diseases has relied on a standard posteroanterior (PA) chest radiograph. However, chest radiographs have very low sensitivity and specific- ity for asbestos-related pleural plaques, diffuse pleural disease, and early asbestosis.¹⁷ Once the asbestos-related condition has become more advanced, the specificity and sensitivity increase, but at this point, the diagnosis has usually been confirmed by other tests, such as HRCT (Figure 1).

HRCT offers greatly increased sensitivity and specificity for asbestos-related pleural disease and neoplasms, but the increased cost makes large-scale surveillance generally unaffordable. Moreover, there is considerable inter-observer variability in interpretation, as shown by a study of CT scans of persons who had been exposed to asbestos for 10 or more years.¹⁸

Whether the patient has pleural plaques is not helpful because this finding is not correlated with the intensity and duration of exposure. Also, in some patients with asbestosis, pleural plaques may be absent.¹⁹ Generally, pleural plaques are not associated with pulmonary function abnormalities, whereas diffuse pleural thickening may have significant functional consequences.

The problem of correlating CT findings of diffuse pleural thickening with pulmonary function was addressed in a study of 50 patients with CT-identified pleural disease who had undergone pulmonary function testing within the previous 3 months.²⁰ Of 5 different methods used for quantifying the extent of pleural disease, a simple method of CT evaluation that was applicable to clinical practice was found to have the best inter-observer agreement as well as the best functional-morphologic correlation.²⁰

To determine whether the degree of exposure correlated with radiographic abnormalities, the chest radiographs and CT scans of 103 patients who had lung cancer and exposure to asbestos were reviewed for pleural and parenchymal abnormalities.²¹ Asbestos exposure was quantified with use of an exposure index based on reported time and intensity of exposure. CT scans were more sensitive than PA chest radiographs in detecting pleural and parenchymal abnormalities. Only an exposure index score of greater than 10 was associated with pleural or parenchymal abnormalities detected by CT.²¹

• Asbestosis: The positive predictive value of the standard PA chest radiograph in diagnosing minimal or mild asbestosis varies with the prevalence of disease in the population being screened. In a population in which the prevalence of asbestosis is 3%, the positive predictive value may be as low as 28%.¹⁷

Although HRCT is better than standard radiography for detecting asbestosis, the pattern of asbestosis, or ILD, seen on HRCT is nonspecific (Figure 2).¹⁷ This pattern closely resembles that of biopsy-proven usual interstitial pneumonia, but differs markedly from that of biopsy-proven nonspecific interstitial pneumonia.²² In an older patient, ILD is more likely to be idiopathic pulmonary fibrosis or to be secondary to a variety of conditions, such as chronic aspiration, an adverse reaction to a medication, or rheumatoid arthritis.

Until recently, the specificity of HRCT in the diagnosis of asbestosis has been compromised by a lack of consensus on the meaning of low-level abnormalities and the paucity of data on an age-matched, non-asbestos-exposed reference population. Both cigarette smoking and increased exposure to dust and fumes are known to cause increased interstitial abnormalities on standard chest radiographs, but populations exposed to these substances have not been the subject of extensive HRCT surveillance.

Among patients whose chest radiographs are classified by International Labour Organization (ILO) criteria as 1/0 (minimal disease), there are numerous false-negative and false-positive results. However, relatively few false-positive results are found with ILO 1/1 (mild disease), and the statistical certainty of asbestosis is relatively high. At lower levels of profusion on the ILO scale, HRCT is more sensitive than radiography. Studies using the rigid criteriahave suggested relatively good inter- and intra- observer agreements.^17,18,21-23

The problem of interpreting HRCT scans has been solved in part by a group of Finnish investigators,²³ who proposed a grading system that takes into account the lack of specificity for minor changes associated with ILD and the increased specificity for major changes, such as honeycombing. In this scoring system, fibrosis is graded from class 0 to class V. This system recognizes that the CT confirmation of asbestosis is not an all-or-nothing diagnosis. The sensitivity and specificity of the diagnostic study increases with increasing severity of disease.

One study compared the accuracy of ILO B-Reader interpretation of 421 chest radiographs with autopsy findings and confirmed that the accuracy of radiographic interpretation is limited.²⁴ The specificity ranged from 59% with a liberal definition (67% sensitivity) to 98% with very strict definition of true positivity (9% sensitivity).²⁴ The use of ILO standard films has been compromised by asbestos- related legal proceedings in which some plaintiff attorneys have relied on reports from a few B-Readers whose reports are unreliable.^25,26

Radiographic findings that may be confused with asbestosis but that are frequently seen in diffuse pleural disease include septal lines, intralobular lines, parenchymal bands, rounded atelectasis, and ground-glass abnormalities. Fortunately, in patients with diffuse pleural disease, these changes are usually unilateral.¹⁹

Figure 3 demonstrates the HRCT findings in a patient with asbestos-related lung cancer.

Pulmonary function tests

In the evaluation of suspected asbestos-related lung disease, pulmonary function tests include measurement of lung compliance or stiffness as well as measurement of lung volumes to determine whether a restrictive ventilatory defect is present. The diffusing capacity of a lung is highly dependent on the integrity of the very small airways of the lungs, the alveolar ducts, the alveoli, and the associated microcirculation. At this level of gas exchange, interstitial fibrosis distorts the ventilation-perfusion match.

The carbon monoxide-diffusing capacity (DlCO) is an exquisitely sensitive test. A reduced DlCO has been observed in 71% to 97% of patients with interstitial fibrosis.¹⁷ The DlCO is commonly reduced in patients with asbestosis. However, DlCO is commonly reduced in the asbestos-exposed population as a result of smoking-related emphysema and needs to be corrected for carbon monoxide back-pressure caused by current cigarette smoking.

Recently, some authors have raised the possibility of clinically significant asbestos-related obstructive lung disease. There is no question that asbestos causes fibrosis in the small airways; however, most experts have not found evidence of clinically significant airflow obstruction that is not explained by other causes (predominantly cigarette smoking).²⁷

Abnormal pulmonary function must be interpreted within the context of the history, physical findings, and other diagnostic tests.²⁸ The resting PaO₂ and the exercise PaO₂ are not reduced until very late in the course of asbestosis, when the disease is advanced and the diagnosis is obvious. Therefore, measuring arterial blood gases is of no practical value in making the diagnosis.²⁹ However, exercise testing with analysis of expired gas helps determine the level of exercise impairment and associated problems such as heart disease.³⁰

BAL and lung biopsy

When in doubt, the diagnosis of asbestosis can be confirmed by evidence of high exposure either by BAL or a count of asbestos fibers in lung tissue.^31,32 The use of BAL for mineralogic analysis has been largely neglected.³³ Both asbestos-fiber concentration and asbestos-body concentrations in BAL fluid correlate well with exposure history and parenchymal asbestosis. The BAL fiber count can be considered a reliable biomarker of past asbestos exposure, even many years after the end of exposure.

If a patient has true bibasilar interstitial fibrosis, BAL for the detection of asbestos bodies would be reasonable. If, in the presence of interstitial fibrosis, the asbestos-body count in BAL fluid is increased to at least 5/mL, the diagnosis of asbestosis can be made with reasonable certainty.

In patients who have diffuse interstitial fibrosis, asbestosis can be diagnosed with certainty only by the microscopic identification of diffuse interstitial fibrosis associated with visible asbestos bodies on hematoxylin and eosin-stained tissue sections. The classic case, which is now seen infrequently, is that of an asbestos insulation worker.

As a result of government regulation of the use of asbestos beginning in 1972, fewer patients in the United States will be found to have asbestosis. Most of the patients who will receive a diagnosis of asbestosis within the next decade will have had relatively low levels of exposure.

References:

REFERENCES

1. Kohyama N. Airborne asbestos levels in non-occupational environments in Japan.

IARC

Sci Pub.

1989;90:262-276.
2. Hodgson JT, Darnton A. The quantitative risks of mesothelioma and lung cancer in relation to asbestos exposure.

Ann Occup Hyg.

2000;44: 565-601.
3. Finkelstein MM, Vingilis JJ. Radiographic abnormalities among asbestos-cement workers. An exposure-response study.

Am Rev Respir Dis.

1984;129:17-22.
4. Soutar CA, Simon G, Turner-Warwick M. The radiology of asbestos-induced disease of the lungs.

Br J Dis Chest.

1974;68:235-252.
5. Karjalainen A, Karhunen PJ, Lalu K, et al. Pleural plaques and exposure to mineral fibres in a male urban necropsy population.

Occup Environ Med.

1994;51:456-460.
6. de Klerk NH, Cookson WO, Musk AW, et al. Natural history of pleural thickening after exposure to crocidolite.

Br J Ind Med.

1989;46: 461-467.
7. Rossiter CE, Bristol LJ, Cartier PH, et al. Radiographic changes in chrysotile asbestos mine and mill workers of Quebec.

Arch Environ Health.

1972;24:388-400.
8. Shcherbakov SV, Kashansky SV, Domnin SG, Nolan RP. The health effects associated with mining and milling chrysotile asbestos in the Urals Region of the Russian Federation.

Canadian Mineralogist

. 2001;special publication 5: 187-198.
9. Rees D, Phillips JI, Garton E, Pooley FD. Asbestos lung fibre concentrations in South African chrysotile mine workers.

Ann Occup Hyg.

2001; 45:473-477.
10. Gibbs AR, Griffiths DM, Stephens M, et al. Asbestos-related diffuse pleural fibrosis. Presented at: the VIIth International Pneumoconioses Conference; 1988; Pittsburgh. DHHS (NIOSH) publication 90-108. 1990:915-918.
11. Suzuki Y, Yuen SR. Asbestos tissue burden study on human malignant mesothelioma.

Ind Health.

2001;39:150-160.
12. Suzuki Y, Yuen SR. Asbestos fibers contributing to the induction of human malignant mesothelioma.

Ann N Y Acad Sci.

2002;982: 160-176.
13. Bianchi C, Brollo A, Ramani L, Zuch C. Asbestos exposure in lung carcinoma: a necropsy-based study of 414 cases.

Am J Ind Med.

1999;36:360-364.
14. Epler GR, McLoud TC, Gaensler EA. Prevalence and incidence of benign asbestos pleural effusion in a working population.

JAMA.

1982; 247:617-622.
15. Miller A, Miller JA. Diffuse thickening superimposed on circumscribed pleural thickening related to asbestos exposure.

Am J Ind Med.

1993;23:859-871.
16. Gevenois PA, de Maertelaer V, Madani A, et al. Asbestosis, pleural plaques and diffuse pleural thickening: three distinct benign responses to asbestos exposure.

Eur Respir J.

1998;11:1021-1027.
17. Ross RM. The clinical diagnosis of asbestosis in this century requires more than a chest radiograph.

Chest.

2003;124:1120-1128.
18. De Raeve H, Verschakelen JA, Gevenois PA, et al. Observer variation in computed tomography of pleural lesions in subjects exposed to indoor asbestos.

Eur Respir J.

2001;17:916-921.
19. Smith DD. Asbestos-related pleural disease: questions in need of answers.

Clin Pulm Med.

1994;1:289-300.
20. Copley SJ, Wells AU, Rubens MB, et al. Functional consequences of pleural disease evaluated with chest radiography and CT.

Radiology.

2001;220:237-243.
21. Schaeffner ES, Miller DP, Wain JC, Christiani DC. Use of an asbestos exposure score and the presence of pleural and parenchymal abnormalities in a lung cancer case series.

Int J Occup Environ Health.

2001;7:14-18.
22. Copley SJ, Wells AU, Sivakumaran P, et al. Asbestosis and idiopathic pulmonary fibrosis: comparison of thin-section CT features.

Radiology.

2003;229:731-736.
23. Huuskonen O, Kivisaari L, Zitting A, et al. High-resolution computed tomography classification of lung fibrosis for patients with asbestos-related disease.

Scand J Work Environ Health.

2001;27:106-112.
24. Frumkin H, Pransky G, Cosmatos I. Radiologic detection of pleural thickening.

Am Rev Respir Dis.

1990;142(6 pt 1):1325-1330.
25. Janower ML, Berlin L. "B" Readers' radiographic interpretations in asbestos litigation: is something rotten in the courtroom?

Acad Radiol.

2004;11:841-842.
26. Gitlin JN, Cook LL, Linton OW, Garrett-Mayer E. Comparison of "B" readers' interpretation of chest radiographs for asbestos-related changes.

Acad Radiol.

2004;11:843-856.
27. Smith DD. Does asbestos exposure cause obstructive airways disease?

Chest.

2004;126: 1000-1001.
28. Smith DD. Pulmonary impairment/disability evaluation: controversies and criticisms.

Clin Pulm Med.

1995;2:334-343.
29. Smith DD, Agostoni PG. The discriminatory value of abnormalities of the P(A-a)O

₂

during exercise in the detection of asbestosis in asbestos exposed workers.

Chest.

1989; 95:52-55.
30. Agostoni P, Smith DD, Schoene RB, et al. Evaluation of breathlessness in asbestos workers. Results of exercise testing.

Am Rev Respir Dis.

1987;135:812-816.
31. De Vuyst P, Karjalainen A, Dumortier P, et al. Guidelines for mineral fibre analyses in biological samples: report of the ERS Working Group. European Respiratory Society.

Eur Resp J.

1998; 11:1416-1426.
32. Magnani C, Mollo F, Paoletti L, et al. Asbestos lung burden and asbestosis after occupational and environmental exposure in an asbestos cement manufacturing area: a necropsy study.

Occup Environ Med.

1998;55:840-846.
33. Sartorelli P, Scancarello G, Romeo R, et al. Asbestos exposure assessment by mineralogical analysis of bronchoalveolar lavage fluid.

J Occup Environ Med.

2001;43:872-881.