Commentaries Chronic Beryllium Disease: Uncommon Disease, Less Common Diagnosis Dannie C. Middleton Health Investigations Branch, Division of Health Studies, Agency for Toxic Substances and Disease Registry, Atlanta, GA 30333 USA Chronic beryllium disease (CBD) is typically considered only when occupational exposure to beryllium is a certainty; however, CBD has also occurred in occupational and environmental set- tings where exposure was uneected. When the etiology of a case of granulomatous pulmonary disease is not determined, sarcoidosis is the "diagnosis of exclusion." This diagnosis does not coum cate much information about the patient's prognosis, the disease's etiology, or even what disease iologies were specific excluded. Some cass of CBD have been called sarcoido- sis, allowing exposure to continue for the patient and (at times) other individuals. The granulo- matous changes of sarcoidosis are thought to result from an abnormal une response. Whie the etiologic agents that can initiate this response are la unknown, the io pathogenesis of CBD has been well decribed and laboratoy methods are available in a fw. centers that can (if used) identify berylihum .hyerenity The potential for exposure .andisse to be widely separated in time and location rtant for health-care and l hea pro fesionas to be aware of these new diagostic. methods. Ky w b , eryllium, granu- lomatous, hypersensitive, lrmphocyte, pulmonary, sarcoidosis. Environ Health Perspect 106:765-767 (1998). [Online 2 November 1998] hbrp:/ /ehbpnetl.nieXs.nib.govldoc/19,98/106p765-767middton/labstracb.hr Beryllium-induced lung diseases can usually be categorized as either an acute or a chronic disease process. After briefly reviewing acute beryllium disease (ABD), this paper reviews chronic beryllium disease (CBD) and explores state-of-the-art diagnostic advances. Acute Beryllium Disease Inhaling high concentrations of beryllium can lead to acute chemical pneumonitis with dyspnea, cough, and chest pain. Physical examination of these patients reveals tachypnea with inspiratory rales and tachycardia. Pulmonary infiltrates are usual- ly seen on the chest X ray, and arterial blood gases typically reveal hypoxemia (1). This acute process has occasionally resulted in death; if the patient survives the acute ill- ness, recovery is typically complete. The first cases of ABD in the United States were reported in 1943; the exposures occurred while workers were extracting beryllium oxide from beryllium ore. The physicians reporting these cases were initially unsure about the role of beryllium, condud- ing that the chemical pneumonia in three workers was due to "chemical compounds formed outside or inside the respiratory tract during the processing of the ore" (2). By the time of a follow-up report in 1945 (3), this group of researchers had seen 170 cases of acute beryllium poisoning. In these cases, the symptom complexes includ- ed dermatitis, chronic skin ulcers, and pneu- monitis; five of these workers had died. With advances in industrial hygiene, ABD has been virtually eliminated in the United States: there were 53 acute cases reported in 1947, 28 in 1948, and 1 in 1949 (4). A committee of experts was assembled in 1950 by the Atomic Energy Commission to recommend safe levels of beryllium in air (4). Other than rare cases resulting from accidental exposures, ABD is no longer a problem in the United States. Chronic Beryllium Disease While ABD is mostly of historical signifi- cance in this country (5), cases of CBD continue to occur. The inflammatory process of CBD is characterized by the for- mation of noncaseating granulomas that contain predominantly epithelioid cells and lymphocytes. While case reports have included other organ systems, the lungs are the primary site of involvement. An unknown number of CBD cases are not properly diagnosed (6). Most cases of CBD result from pro- longed or multiple ambient exposures to beryllium. When exposure is uncertain, it is sometimes possible to demonstrate excess beryllium in biopsy specimens from the lung using laser microprobe mass spectrographic analysis. The symptoms that cause the patient to seek medical evaluation can include arthralgias, chest pain, cough, or (most commonly) dyspnea with relatively mild exertion. Physical examination may reveal hepatosplenomegaly, inspiratory rales, and lymphadenopathy. The chest X ray typical- ly reveals diffuse infiltrates and frequently reveals hilar lymphadenopathy. Computed tomography can accurately characterize the extent of disease, but cannot reliably differ- entiate between CBD and sarcoidosis (7). Pulmonary functioning (especially exercise tolerance) eventually becomes abnormal, although air flow patterns can be restrictive, obstructive, or even normal with a reduced diffusing capacity (8). CBD is a progressive disease that often requires treatment with corticosteroids for life. Preventing additional exposure is an important aspect of therapy, but does not arrest the disease process in most patients. In one sense, exposure continues: beryllium deposited in the patient's lungs provides per- sistent antigenic stimulation over time ($l. Epidemiology of CBD. The first cases of CBD in the United States were reported in 1946; these exposures occurred while work- ers were manufacturing fluorescent lamps. The U.S. Beryllium Case Registry (currently inactive) was established in 1952 at the Massachusetts Institute of Technology and maintained after 1978 by the National Institute for Occupational Safety and Health (NIOSH). This registry contains approxi- mately 900 cases of CBD; entering a case into the registry required documentation of beryllium exposure, either by history or by demonstration of excess beryllium in biolog- ic specimens, plus any three of the clinico- pathologic criteria summarized below (10): 1. Clinical symptoms of a lower respiratory tract disorder 2. Reticulonodular infiltrates on chest radi- ography 3. Restrictive or obstructive impairment of pulmonary function or a depressed diffus- ing capacity for carbon monoxide 4. Histologic demonstration of noncaseating granulomas and/or mononuclear cell inter- stitial infiltrates on lung biopsy specimens. The number of CBD cases that could meet the definition, but were not identified and added to the registry is unknown. There is evidence that sarcoidosis is diag- nosed without adequately excluding CBD (6). Also, researchers using modern labora- tory methods have shown that some patients who do not meet the registry crite- ria do have CBD (11). After taking a thor- ough exposure history, the clinical diagnosis Address correspondence to D.C. Middleton, Health Investigations Branch, Division of Health Studies, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road MS E31, Atlanta, GA 30333 USA. I thank Mary C. White and Myron G. Schultz for advice and encouragement during the preparation of this manuscript. Received 15 May 1998; accepted 16 July 1998. Environmental Health Perspectives * Volume 106, Number 12, December 1998 765 Commentaries * Middleton of CBD can be adequately supported by demonstrating both pulmonary granulomas and immune responsiveness to beryllium. Besides occupational cases of beryllium, the registry also contains 65 nonoccupa- tional (environmental) cases reported before 1960: 23 cases resulted from expo- sure to dust brought home on work clothes and 42 cases resulted from off-site air pol- lution. With improvements in industrial hygiene, environmental cases of CBD were thought to have disappeared. However, Newman and Kreiss (12) recently reported a case that resulted from what appeared to be a brief, low-level exposure; this report suggested that although environmental cases are rarely diagnosed, they do occur. Immunology of CBD. The early health studies of beryllium were difficult to inter- pret because the dose that produced disease appeared to vary considerably, disease severity did not correlate with tissue levels, and the latency period was often long (13,14). These characteristics lead (as early as 1951) to the postulation of an immune mechanism (15); however, because berylli- um has a very low molecular weight, this ability to induce an immune response was unexpected. Much of the research on CBD has focused on understanding this immune response and developing a reliable test for beryllium hypersensitivity (16). In 1951, cutaneous hypersensitivity to beryllium was described and a patch test developed; a positive test at 72 hr was con- sidered evidence of beryllium hypersensi- tivity and of CBD in patients with granu- lomatous lung disease (17,18). However, cutaneous hypersensitivity developed in 8 of 16 previously unexposed controls, and at least one fatality was associated with the patch test (19). The patch test was never widely used and is rarely used today because of safety concerns and the test's proven ability to induce hypersensitivity. Two in vitro tests have been developed to test for hypersensitivity to beryllium: the migratory inhibitory factor (MIF) test and the lymphocyte proliferation test (LPT). MIF is secreted by activated T lymphocytes during antigenic stimulation to keep macrophages from migrating. In theory, identifying hypersensitive people by incu- bating lymphocytes from the blood or bron- choalveolar fluid with beryllium and testing for MIF should be possible. In practice, this test is technically difficult and gives results that are both insensitive (even to well-estab- lished CBD) and difficult to reproduce (20). The MIF test is no longer used. The current test for beryllium hyper- sensitivity is the LPT (20). In the LPT, lymphocytes are taken from the peripheral blood or from bronchoalveolar fluid (21) 766 and exposed in vitro to beryllium sulfate. If the patient is hypersensitive, T lympho- cytes will proliferate. Typically, a stimula- tion index is determined by comparing proliferation among lymphocytes incubat- ed with and without beryllium sulfate. Rossman et al. (22) looked at the sensi- tivity and specificity of the LPT in a small series of cases and controls; bronchoalveo- lar lymphocytes were exposed in vitro to beryllium sulfate; a positive proliferative response was defined as a stimulation index greater than 5 on two separate determina- tions. The 23 beryllium workers evaluated in the study included 14 patients who clearly met the registry case definition for CBD (described above). For these 14 patients, the sensitivity of the proliferation test was 100%. The 22 controls selected included 16 patients with sarcoidosis and 6 normal volunteers; none of the controls had positive proliferative tests (100% speci- ficity for these 22 controls). When the pro- liferation tests were repeated with lympho- cytes from peripheral blood, the sensitivity for CBD was lower. Kreiss et al. (23) demonstrated the util- ity of screening the peripheral blood of exposed workers using the LPT. The test identified several new cases of CBD among nuclear workers and in the ceramics indus- try (24,25). The "predictive value positive" of a confirmed test in the ceramics workers was 100%, but two cases of CBD initially identified by chest X ray did not have con- sistently abnormal blood tests. In other words, while a positive blood test can con- firm CBD, a negative blood test (alone) does not exclude it. Genetics of CBD. CBD is an immune hypersensitivity disorder caused by an interaction between beryllium and sensi- tized helper (CD4+) T lymphocytes. For this interaction to occur, the small berylli- um molecules must first be bound to a car- rier protein. The antigen (a beryllium/pro- tein complex) is then processed and pre- sented to T lymphocytes by a major histo- compatibility complex Class II molecule. This molecule consists of an a-chain and a 3-chain that interact to bind the antigen. Because the substitution of a single amino acid can determine what antigen is bound, Richeldi et al. (26) recently studied the genes that encode the 1-chain in 33 cases (exposed workers with CBD) and 44 con- trols (exposed workers without CBD). These researchers found that 97% (32/33) of the cases exhibited the amino acid gluta- mate (rather than lysine) at position 69 of a cell-surface glycoprotein involved in anti- gen recognition. This marker (Glu69) was present in only 30% (13/44) of the con- trols, suggesting a significant genetic role in the immune process leading to CBD. This finding could have relevance for counseling in certain occupational settings (26). Differential Diagnosis of CBD The known causes of granulomatous dis- ease (with examples in parentheses) are bacterial (brucellosis, leprosy, salmonel- losis, and tuberculosis), fungal (blastomy- cosis, coccidiomycosis, and histoplasmosis), viral (cat scratch fever and lymphogranulo- ma venereum), helminthic (schistosomiasis, trichinosis, filariasis, and capillariasis), or metallic (beryllium and zirconium). The causes of some granulomatous diseases (sar- coidosis, Crohn's disease, and Wegener's granulomatosis) are unknown (27). Sarcoidosis is the granulomatous disease that is clinically the most similar to CBD. A careful occupational and environmental history can be helpful, but even well-docu- mented exposure to beryllium does not eliminate the possibility of sarcoidosis. Clinical findings that are (when present) more characteristic of sarcoidosis include extensive hilar adenopathy, spontaneous remission, and the presence of extrapul- monary manifestations (e.g., erythema nodosum, parotid involvement, bone changes). Certain findings (variably present in sarcoidosis) have never been reported in a patient with CBD, including uveitis, uveoparotid fever, cranial or peripheral nerve involvement, and cystic bone lesions. None of these clinical features is ade- quately sensitive or specific to reliably distin- guish between sarcoidosis and CBD in indi- vidual patients. Though not part of the orig- inal beryllium registry case definition, the LPT is extremely useful in identifying indi- viduals who have developed beryllium hypersensitivity. Most notably, the LPT was used to identify a cluster of CBD in a metal refinery after one worker questioned the diagnosis of sarcoidosis given to him and several co-workers (6). This test is now avail- able at a handful of medical centers in the United States. A number of medical tests (other than the LPT) are also useful in the quest to iden- tify the cause of a patient's granulomatous pulmonary disease and assess the physiologic impact of the disease. The tests selected to evaluate a new patient would typically include 1) measurement of angiotensin-con- verting enzyme, a nonspecific marker of dis- ease activity; 2) chest radiograph to assess the extent of chest disease; 3) immune para- meters and lymphocyte proliferative responses to assess the immune system and test for hypersensitivity to beryllium; 4) liver function tests to assess liver involvement; 5) review of biopsy slides for evidence of infec- tion, malignancy, suppurative processes, and Volume 106, Number 12, December 1998 * Environmental Health Perspectives Commentaries * Chronic beryllium disease granulomatous processes; and 6) cultures and microscopic examination of bron- choalveolar lavage (BAL) fluid for evidence of infection, malignancy, or hypersensitivity. Summary CBD has historically been a difficult diag- nosis to make with certainty; the diagnosis has typically required physicians to docu- ment beryllium exposure by history or by demonstrating excess beryllium in biologic specimens, and to meet certain clinical and pathologic criteria for chronic granuloma- tous pulmonary disease, criteria that are also present in other granulomatous dis- eases such as sarcoidosis. In routine medical practice, the lack of a known (typically occupational) exposure has usually precluded active consideration of CBD in patients with granulomatous disease. If no other etiology is found, sar- coidosis has been the diagnosis of exclusion. This approach has rested upon unstated assumptions that 1) the only significant exposures are occupational; 2) the worker and employer know about the exposure; 3) the exposure is disclosed to the physician; and 4) the physician understands the clini- cal implications of beryllium exposure. The validity of these assumptions has not been tested, and in some recent cases it is demonstrably false. When the clinical find- ings are consistent with granulomatous dis- ease, CBD can now be diagnosed (or exclud- ed) by assessing the immune response to beryllium (28). This specialized testing requires a priori coordination with an appro- priate laboratory. The best time to consider CBD is dur- ing the initial evaluation of patients with granulomatous pulmonary disease because a diagnostic bronchoscopy is usually per- formed. An LPT using BAL lymphocytes is the gold standard for diagnosing or exclud- ing CBD; while a positive LPT using peripheral blood lymphocytes can also sup- port the diagnosis, a negative test does not exclude it. Recommendations The state of the art for beryllium-related biomedical testing has advanced significant- ly, and reliable testing is available in a few centers. The following proposed guidelines are intended to encourage physicians to con- sider testing in the presence of uncertainty about the potential for beryllium exposure: 1. A careful environmental and occupa- tional history should be taken on every new patient with granulomatous pul- monary disease. 2. If beryllium exposure is documented, T lymphocytes should be collected during the initial bronchoscopy for the LPT; it is also appropriate (but less sensitive) to test lymphocytes from peripheral blood for hypersensitivity to beryllium. 3. If beryllium exposure is not documented (but cannot be excluded), collection of T lymphocytes for the LPT should be con- sidered during the initial bronchoscopy; it is also appropriate (but less sensitive) to test lymphocytes from peripheral blood for hypersensitivity to beryllium. 4. If beryllium exposure can be excluded with reasonable confidence, the patient is unlikely to benefit from beryllium-relat- ed biomedical testing. (Testing for beryllium hypersensi- tivity requires a priori coordination with an appropriate laboratory; a listing of laboratories that perform the LPT is maintained by the Beryllium Support Group, P.O. Box 2021, Broomfield, CO 80038-2021 USA.) To illustrate, a patient who once worked at or lived by a foundry processing metals from a variety of sources may have beryllium exposure that has not been docu- mented; thus, some uncertainty remains and testing can reasonably be considered. Uncertainties about beryllium exposure can also be affected by a physician's knowl- edge of industry; two physicians might appropriately make different decisions about testing in similar situations. The fol- lowing points are offered to support the consideration of testing when the patient's potential for exposure is uncertain: 1) chronic granulomatous disease is potential- ly a life-threatening condition; 2) manage- ment decisions and prognosis are clarified by recognizing CBD; 3) the diagnostic test (LPT) is very specific for beryllium hyper- sensitivity when performed by an experi- enced laboratory; 4) exposure and disease can be widely separated in time and loca- tion; 5) exposure histories are not always reliable; and 6) a case of CBD can have public health significance as a sentinel case. REFERENCES AND NOTES 1. Meyer KC. Beryllium and lung disease. Chest 106:942-946 (1994). 2. van Ordstrand HS, Hughes R, DeNardi JM, Carmody MG. Chemical pneumonia in workers extracting beryllium oxide: report of three cases. Cleve Clin Q 10:10-18 (1943). 3. van Ordstrand HS, Hughes R, DeNardi JM, Carmody MG. Beryllium poisoning. JAMA 129:1084-1090 (1945). 4. Aronschick JM. Chronic beryllium disease. Occupational lung disease. Radiol Clin North Am 30(6):1209-1217 (1992). 5. Eisenbud M. Origins of the standards for control of beryllium disease 11947-19491. Environ Res 27:79-88 (1982). 6. Cullen MR, Kominsky JR, Rossman MD, Cherniack MG, Rankin JA, Balmes JR, Kern JA, Daniele RP, Palmer L, Naegel GP, et al. Clinical epidemiologic and immunologic evidence for continuing risk from expo- sure to low level beryllium fume. Am Rev Respir Dis 135:201-208 (1987). 7. Harris KM, McConnochie K, Adams H. The computed tomographic appearances in chronic berylliosis. Clin Radiol 47:26-31 (1993). 8. Pappas GP, Newman LS. Early pulmonary physiologic abnormalities in beryllium disease. Am Rev Respir Dis 148:661-666 (1993). 9. Haley PJ. Mechanisms of granulomatous lung dis- ease from inhaled beryllium: the role of antigenicity in granuloma formation. Toxicol Pathol 19(4, Part 1):514-525 (1991). 10. Sprince NL. Beryllium disease. In: Occupational Respiratory Diseases (Merchant JA, ed). DHHS (NIOSH) Publication No 86-102. Washington, DC:National Institute for Occupational Safety and Health, 1986:385-399. 11. Newman LS, Kreiss K, King TE, Seay S, Campbell PA. Pathologic and immunologic alterations in early stages of beryllium disease. Re-examination of dis- ease definition and natural history. Am Rev Respir Dis 139:1479-1486 (1989). 12. Newman LS, Kreiss K. Nonoccupational beryllium disease masquerading as sarcoidosis: identification by blood lymphocyte proliferative response to berylli- um. Am Rev Respir Dis 145:1212-1214 (1992). 13. Hardy HL. Beryllium disease: a clinical perspective. Environ Res 21:1-9 (1980). 14. Eisenbud M, Lisson J. Epidemiological aspects of beryllium-induced nonmalignant lung disease: a 30- year update. J Occup Med 25(3):196-202 (1993). 15. Sterner JH, Eisenbud M. Epidemiology of beryllium intoxication. Arch Indust Hyg Occup Med 4:123-157 (1951). 16. Deodhar SD, Barna BP. Immune mechanisms in beryllium lung disease. Cleve Clin J Med 58(2):157-60 (1991). 17. Curtis GH. Cutaneous hypersensitivity due to berylli- um: a study of 13 cases. Arch Dermatol Syphilol 64:470-382 (1951). 18. Curtis GH. The diagnosis of beryllium disease, with special reference to the patch test. Arch Ind Health 19:150-153 (1959). 19. Sneddon IB. Berylliosis: a case report. Br Med J 1:1488-1489 (1955). 20. Williams WR, Williams WJ. Comparison of lympho- cyte transformation and macrophage migration inhi- bition tests in the detection of beryllium hypersensi- tivity. J Clin Pathol 35:684-687 (1982). 21. Daniele RP, Elias JA, Epstein PE, Rossman MD. Bronchoalveolar lavage: role in the pathogenesis, diagnosis, and management of interstitial lung dis- ease. Ann Intern Med 102(1:93-108 (1985). 22. Rossman MD, Kern JA, Elias JA, Cullen MR, Epstein PE, Preuss OP, Markham TN, Daniele RP. Proliferative response of bronchoalveolar lymphocytes to berylli- um. Ann Intern Med 108:687-93 (1988). 23. Kreiss K, Newman LS, Mroz MM, Campbell PA. Screening blood test identifies subclinical beryllium disease. J Occup Med 31(7):603-608 (1989). 24. Kreiss K, Mroz MM, Zhen B, Martyny JW, Newman LS. Epidemiology of beryllium sensitization and dis- ease in nuclear workers. Am Rev Respir Dis 148:985-991 (1993). 25. Kreiss K, Wasserman S, Mroz MM, Newman LS. Beryllium disease screening in the ceramics industry. J Occup Med 35(3):267-274 (1993). 26. Richeldi L, Sorrentino R, Saltini C. HLA-DPB1 Glutamate 69: a genetic marker of beryllium disease. Science 262:242-244 (1993). 27. Newman LS. To Be2+ or not to Be2+: immunogenetics and occupational exposure. Science 262(5131)197-198 (1993). 28. Mroz MM, Kreiss K, Lezotte DC, Campbell PA, Newman LS. Reexamination of the blood lymphocyte transformation test in the diagnosis of chronic berylli- um disease. J Allergy Clin Immunol 88:54-60 (1991). 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