Screening for Chronic Beryllium Disease
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《美国医学杂志》
Over two decades have passed since the declaration that chronic beryllium disease (CBD) had disappeared (1) and recognition, almost simultaneously, that a silent epidemic of the disease smoldered among the hundreds of thousands exposed to the metal in the nuclear, aerospace, electronics, and other metal-using industries (2, 3). In an historic collaboration of bench researchers, translational scientists, and epidemiologists, hundreds of cases have been identified, most previously misdiagnosed as idiopathic sarcoidosis. A test was also developed—the beryllium lymphocyte proliferation test or BeLPT—first on bronchoalveolar lavage, then whole blood, with the capability both of differentiating CBD from sarcoidosis and identifying, among asymptomatic individuals formerly or presently exposed, a state of "beryllium sensitization" (4, 5). Knowledge of the dire prognosis of cases followed in the beryllium case registry in the '40s, '50s, and '60s (6), and the prospect that early recognition might ameliorate the outlook, led to widespread adoption of the BeLPT blood test as a screening test for exposed men and women, despite absence of proof of efficacy and limitations of the test itself—inaccessibility of labs, intralab variability, and the vexing problem of "transitory" positives (7). As a consequence, we now know that as many as 10% or slightly more of the most heavily exposed workers are repeatedly positive in almost every work setting studied (7–10), a not inconsiderable epidemic if, as anticipated, many subsequently develop CBD.
In this issue of the Journal (pp. 54–60), Newman and colleagues have extended our knowledge of the value of the test (11)—blood BeLPT has now met the first of three critical challenges for any new screening test: that those testing positive, i.e., that "beryllium sensitized" subjects have a high likelihood of developing CBD. The data presented fail to refute completely the possibility that some who appear to have "progressed" to CBD, by virtue of granulomas or lymphocytic infiltrates on transbronchial biopsy, may have been missed on initial evaluation. But for most of the 17 cases diagnosed in the follow-up period, pathologic changes reported are convincingly new.
There are two large scientific hurdles that remain for the BeLPT before we can be certain that exposed workers should be screened. Although historic data, relying on the follow-up reports of clinically recognized cases, may have obscured this possibility, there is a growing awareness that some subjects meeting pathologic criteria for CBD have none of the historically associated clinical manifestations (12, 13). Hence, there is a need to demonstrate that some significant portion of cases detected by screening not only develop pathologic changes characteristic of CBD, but also clinically manifest disease. Failure to establish such a link has led recently to reevaluation of the utility of the PSA screening test for prostate cancer, because many, if not most, of the detected cases now appear, based on epidemiologic inference, destined not to have clinical manifestations, even if untreated. Perhaps ironically, the report from Newman in this issue, although good news for the patients, serves to underscore this concern. Although the data are not presented in a form sufficiently transparent to address this entirely, it still appears from what is presented that among the 55 patients followed an average of 4.8 years, no more than a handful have developed significant clinical manifestations; only one is reported to be under treatment with steroids (11). Although the prognosis was certainly poor (6) for clinically recognized cases of CBD in the era of high exposure, before institution of control measures in the 1950s (1), it remains premature, based on available information, to apply this prediction uncritically to those less heavily exposed and recognized asymptomatically by screening. If anything, available data suggest a much more indolent course, at least for some. Given the potential for significant negative psycho-social and economic impact on those having a positive test, evidence that only a small fraction of those identified become sick would sharply alter the risk–benefit ratio for screening, possibly undermining its rationale.
There remains, too, a third, as yet unresolved burden for the test, namely scientific verification that some intervention made after a positive test has the potential to change the natural history, whatever it is. Up until now it has been presumed that removal from exposure among those still working with beryllium constitutes just such an intervention. Its value has been taken for granted in practice, although not all patients have complied for personal or financial reasons. Because it is unlikely that employers or doctors will waver from that commonsense advice, and numbers progressing rapidly are too few to allow a clinical trial, knowledge of what, if anything, can actually alter the natural history will have to be gleaned from continued observation of BeLPT-positive subjects, in the hope that some behavioral, environmental, or medical factor or factors can be discerned that distinguish between those who do well and those who deteriorate. Genetic differences, or risks conferred by previous exposure, may be vital for primary preventive efforts to control CBD, but do little to enhance the value of screening per se. In this regard we are most fortunate for the prodigious efforts of Newman and his colleagues who have assembled large numbers of subjects, follow and study them meticulously, and report their observations.
Pending the outcome of these further observations, many may continue to advocate using the test for the very reasons it was originally adopted. It would be difficult to fault such a posture so long as renewed efforts are made to ensure that those administering and interpreting the test, as well as those being tested, understand that neither the clinical implication of a positive test nor the benefit of any action advised as a result is based on strong scientific evidence, other than the need for a full baseline pulmonary evaluation and regular follow-up care.
FOOTNOTES
Conflict of Interest Statement: M.R.C. has received a grant from Brush-Wellman, a beryllium manufacturer, to conduct a follow-up study of sensitized ex-workers and is a Medical Advisor to Alcoa who supervises screening of beryllium-exposed workers, interprets test results, advises on compensation, and helps set up corporate policy regarding use of beryllium.
REFERENCES
Eisenbud M, Lisson J. Epidemiologic aspects of beryllium induced nonmalignant lung disease: a 30 year update. J Occup Med 1983;25:196–202.
Balmes J, Cullen MR, Robins JM. Epidemic chronic beryllium disease in a scrap metal refining plant. In: Gee JBL, Morgan WKC, Brooks S, editors. Occupational lung disease. New York: Raven Press; 1984. p. 225.
Cullen MR, Kominsky JR, Rossman MD, Cherniack MG, Rankin JA, Balmes JR, Kern JA, Daniele RP, Palmer L, Naegel GP, et al. Chronic beryllium disease in a precious metal refinery: clinical epidemiologic and immunologic evidence for continuing risk from exposure to low level beryllium fume. Am Rev Respir Dis 1987;135:201–208.
Rossman MD, Kern JA, Elias JA, Cullen MR, Epstein PE, Preuss OP, Markham TN, Daniele RP. Lung proliferation to beryllium: a diagnostic test for chronic beryllium disease. Ann Intern Med 1988;108:687–692.
Mroz MM, Kreiss K, Lezotte DC, Campbell PA, Newman LS. Reexamination of the blood lymphocyte transformation test in the diagnosis of chronic beryllium disease. J Allergy Clin Immunol 1991;88:54–60.
Freiman DG, Hardy HL. Beryllium disease: the relation of pulmonary pathology to clinical course and progrnosis based on a study of 130 cases from the US beryllium Case Registry. Hum Pathol 1970;1:25–44.
Kreiss K, Wasserman S, Mroz MM, Newman LS. Beryllium disease screening in the ceramics industry: blood lymphocyte test performance and exposure-disease relations. J Occup Med 1993;35:267–274.
Kreiss K, Mroz MM, Newman LS, Martyny J, Zhen B. Machining risk of beryllium disease and sensitization with median exposures below 2 μg/m3. Am J Ind Med 1996;30:16–25.
Kreiss K, Mroz MM, Zhen B, Wiedemann H, Barna B. Risks of beryllium disease related to work processes at a metal, alloy, and oxide production plant. Occup Environ Med 1997;54:605–612.
Kreiss K, Mroz MM, Zhen B, Martyny J, Newman LS. Epidemiology of beryllium sensitization and disease in nuclear workers. Am Rev Respir Dis 1993;148:985–991.
Newman LS, Mroz MM, Balkisson R, Maier L. Beryllium sensitzation progresses to chronic beryllium disease: a longitudinal study of disease risk. Am J Respir Crit Care Med 2005;171:54–60.
Kreiss K, Newman LS, Mroz MM, Campbell PA. Screening blood test identifies subclinical beryllium disease. J Occup Med 1989;31:603–608.
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.(Mark R. Cullen, M.D.)
In this issue of the Journal (pp. 54–60), Newman and colleagues have extended our knowledge of the value of the test (11)—blood BeLPT has now met the first of three critical challenges for any new screening test: that those testing positive, i.e., that "beryllium sensitized" subjects have a high likelihood of developing CBD. The data presented fail to refute completely the possibility that some who appear to have "progressed" to CBD, by virtue of granulomas or lymphocytic infiltrates on transbronchial biopsy, may have been missed on initial evaluation. But for most of the 17 cases diagnosed in the follow-up period, pathologic changes reported are convincingly new.
There are two large scientific hurdles that remain for the BeLPT before we can be certain that exposed workers should be screened. Although historic data, relying on the follow-up reports of clinically recognized cases, may have obscured this possibility, there is a growing awareness that some subjects meeting pathologic criteria for CBD have none of the historically associated clinical manifestations (12, 13). Hence, there is a need to demonstrate that some significant portion of cases detected by screening not only develop pathologic changes characteristic of CBD, but also clinically manifest disease. Failure to establish such a link has led recently to reevaluation of the utility of the PSA screening test for prostate cancer, because many, if not most, of the detected cases now appear, based on epidemiologic inference, destined not to have clinical manifestations, even if untreated. Perhaps ironically, the report from Newman in this issue, although good news for the patients, serves to underscore this concern. Although the data are not presented in a form sufficiently transparent to address this entirely, it still appears from what is presented that among the 55 patients followed an average of 4.8 years, no more than a handful have developed significant clinical manifestations; only one is reported to be under treatment with steroids (11). Although the prognosis was certainly poor (6) for clinically recognized cases of CBD in the era of high exposure, before institution of control measures in the 1950s (1), it remains premature, based on available information, to apply this prediction uncritically to those less heavily exposed and recognized asymptomatically by screening. If anything, available data suggest a much more indolent course, at least for some. Given the potential for significant negative psycho-social and economic impact on those having a positive test, evidence that only a small fraction of those identified become sick would sharply alter the risk–benefit ratio for screening, possibly undermining its rationale.
There remains, too, a third, as yet unresolved burden for the test, namely scientific verification that some intervention made after a positive test has the potential to change the natural history, whatever it is. Up until now it has been presumed that removal from exposure among those still working with beryllium constitutes just such an intervention. Its value has been taken for granted in practice, although not all patients have complied for personal or financial reasons. Because it is unlikely that employers or doctors will waver from that commonsense advice, and numbers progressing rapidly are too few to allow a clinical trial, knowledge of what, if anything, can actually alter the natural history will have to be gleaned from continued observation of BeLPT-positive subjects, in the hope that some behavioral, environmental, or medical factor or factors can be discerned that distinguish between those who do well and those who deteriorate. Genetic differences, or risks conferred by previous exposure, may be vital for primary preventive efforts to control CBD, but do little to enhance the value of screening per se. In this regard we are most fortunate for the prodigious efforts of Newman and his colleagues who have assembled large numbers of subjects, follow and study them meticulously, and report their observations.
Pending the outcome of these further observations, many may continue to advocate using the test for the very reasons it was originally adopted. It would be difficult to fault such a posture so long as renewed efforts are made to ensure that those administering and interpreting the test, as well as those being tested, understand that neither the clinical implication of a positive test nor the benefit of any action advised as a result is based on strong scientific evidence, other than the need for a full baseline pulmonary evaluation and regular follow-up care.
FOOTNOTES
Conflict of Interest Statement: M.R.C. has received a grant from Brush-Wellman, a beryllium manufacturer, to conduct a follow-up study of sensitized ex-workers and is a Medical Advisor to Alcoa who supervises screening of beryllium-exposed workers, interprets test results, advises on compensation, and helps set up corporate policy regarding use of beryllium.
REFERENCES
Eisenbud M, Lisson J. Epidemiologic aspects of beryllium induced nonmalignant lung disease: a 30 year update. J Occup Med 1983;25:196–202.
Balmes J, Cullen MR, Robins JM. Epidemic chronic beryllium disease in a scrap metal refining plant. In: Gee JBL, Morgan WKC, Brooks S, editors. Occupational lung disease. New York: Raven Press; 1984. p. 225.
Cullen MR, Kominsky JR, Rossman MD, Cherniack MG, Rankin JA, Balmes JR, Kern JA, Daniele RP, Palmer L, Naegel GP, et al. Chronic beryllium disease in a precious metal refinery: clinical epidemiologic and immunologic evidence for continuing risk from exposure to low level beryllium fume. Am Rev Respir Dis 1987;135:201–208.
Rossman MD, Kern JA, Elias JA, Cullen MR, Epstein PE, Preuss OP, Markham TN, Daniele RP. Lung proliferation to beryllium: a diagnostic test for chronic beryllium disease. Ann Intern Med 1988;108:687–692.
Mroz MM, Kreiss K, Lezotte DC, Campbell PA, Newman LS. Reexamination of the blood lymphocyte transformation test in the diagnosis of chronic beryllium disease. J Allergy Clin Immunol 1991;88:54–60.
Freiman DG, Hardy HL. Beryllium disease: the relation of pulmonary pathology to clinical course and progrnosis based on a study of 130 cases from the US beryllium Case Registry. Hum Pathol 1970;1:25–44.
Kreiss K, Wasserman S, Mroz MM, Newman LS. Beryllium disease screening in the ceramics industry: blood lymphocyte test performance and exposure-disease relations. J Occup Med 1993;35:267–274.
Kreiss K, Mroz MM, Newman LS, Martyny J, Zhen B. Machining risk of beryllium disease and sensitization with median exposures below 2 μg/m3. Am J Ind Med 1996;30:16–25.
Kreiss K, Mroz MM, Zhen B, Wiedemann H, Barna B. Risks of beryllium disease related to work processes at a metal, alloy, and oxide production plant. Occup Environ Med 1997;54:605–612.
Kreiss K, Mroz MM, Zhen B, Martyny J, Newman LS. Epidemiology of beryllium sensitization and disease in nuclear workers. Am Rev Respir Dis 1993;148:985–991.
Newman LS, Mroz MM, Balkisson R, Maier L. Beryllium sensitzation progresses to chronic beryllium disease: a longitudinal study of disease risk. Am J Respir Crit Care Med 2005;171:54–60.
Kreiss K, Newman LS, Mroz MM, Campbell PA. Screening blood test identifies subclinical beryllium disease. J Occup Med 1989;31:603–608.
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.(Mark R. Cullen, M.D.)