A Reconsideration of Acute Beryllium Disease
A Reconsideration of Acute Beryllium Disease
Context: Although chronic beryllium disease (CBD) is clearly an immune-mediated granulomatous reaction to beryllium, acute beryllium disease (ABD) is commonly considered an irritative chemical phenomenon related to high exposures. Given reported new cases of ABD and projected increased demand for beryllium, we aimed to reevaluate the pathophysiologic associations between ABD and CBD using two cases identified from a survey of beryllium production facility workers.
Case Presentation: Within weeks after exposure to beryllium fluoride began, two workers had systemic illness characterized by dermal and respiratory symptoms and precipitous declines in pulmonary function. Symptoms and pulmonary function abnormalities improved with cessation of exposure and, in one worker, recurred with repeat exposure. Bronchoalveolar lavage fluid analyses and blood beryllium lymphocyte proliferation tests revealed lymphocytic alveolitis and cellular immune recognition of beryllium. None of the measured air samples exceeded 100 μg/m, and most were < 10 μg/m, lower than usually described. In both cases, lung biopsy about 18 months after acute illness revealed noncaseating granulomas. Years after first exposure, the workers left employment because of CBD.
Discussion: Contrary to common understanding, these cases suggest that ABD and CBD represent a continuum of disease, and both involve hypersensitivity reactions to beryllium. Differences in disease presentation and progression are likely influenced by the solubility of the beryllium compound involved.
Relevance to Practice: ABD may occur after exposures lower than the high concentrations commonly described. Prudence dictates limitation of further beryllium exposure in both ABD and CBD.
In 2004, South Korean investigators reported nine cases of a disease thought to have been eliminated decades before: acute beryllium disease (ABD) (Kim et al. 2004). The recognition of new cases, the projected growth in worldwide demand for beryllium for applications including nuclear energy production (U.S. Department of Energy 2008) and national defense (Business Wire 2005), and advances in the understanding of chronic beryllium disease (CBD) led us to reconsider the pathogenesis of ABD. The resulting reconceptualization has implications for prevention, diagnosis, and case management in the global beryllium industry.
Textbooks and review articles have stated that exposure to beryllium may result in two distinct respiratory conditions. ABD is considered to be an irritative chemical phenomenon, whereas CBD is recognized as an immune-mediated granulomatous process (Balmes 2005; Becklake and Cowie 2000; Churg and Green 1998; Williams 1988). This conceptualization began > 50 years ago, with the assertions that ABD followed a traditional exposure–response pattern and was associated with airborne beryllium concentrations > 100 μg/m, whereas CBD could occur at much lower levels, indicating an immune phenomenon (Sterner and Eisenbud 1951). Although the description of ABD has remained essentially static, the understanding of CBD has evolved greatly in recent decades. It is now well established that sensitization to beryllium, as measured by the beryllium lymphocyte proliferation test (BeLPT), reflects cellular immune recognition of beryllium and confers a higher risk of subsequent development of CBD (Kreiss et al. 2007; Mroz et al. 1991; Newman et al. 2005; Sawyer et al. 2002). CBD can be detected at a subclinical stage by bronchoalveolar lavage (BAL) and biopsy (Cordeiro et al. 2007; Maier 2001). Lymphocyte predominance and abnormal BeLPT on BAL fluid analysis are findings consistent with CBD.
Acute respiratory and dermal reactions to beryllium exposure were first reported in the United States in the 1940s, observed among workers in the beryllium extraction and processing industry (DeNardi et al. 1949; Van Ordstrand et al. 1945). A relationship with exposure to soluble beryllium salts (sulfate and fluoride) and soluble forms of the oxide was noted by early investigators (Eisenbud 1982; Eisenbud et al. 1948). During that era, daily weighted average (DWA) exposures to beryllium were known to exceed 1,000 μg/m in certain operations (Eisenbud 1982).
In 1949, the U.S. Atomic Energy Commission recommended two different occupational exposure limits to their contractors: 25 μg/m as a maximum permissible peak exposure, to prevent ABD, and 2 μg/m as a DWA over a quarterly period, to prevent CBD (Eisenbud 1982). These limits were subsequently adopted in the United States by various professional organizations and the Occupational Safety and Health Administration, and regulatory bodies in many other countries also recognize the 2 μg/m limit (Eisenbud 1982, 1998). Over time, average exposures have decreased from hundreds of micrograms per cubic meter in the 1940s and 1950s to ≤ 1 μg/m in the 1980s and 1990s (National Research Council 2008).
Beryllium fluoride is intentionally formed during the production of beryllium metal. In the initial step, ammonium beryllium fluoride is heated in a fluoride furnace to drive off ammonium fluoride gas and yield beryllium fluoride (Kroschwitz and Howe-Grant 1992; White and Burke 1955). The beryllium fluoride then is transferred to an adjacent reduction furnace and reacted with magnesium to yield beryllium metal. In this article, we describe two cases of acute respiratory and dermal illness that occurred in workers involved in beryllium metal production. The extensive diagnostic evaluations that they underwent provide details on pathogenesis that were not available in earlier reports of ABD. In light of these cases and a review of the historical literature, we suggest that rather than being two distinct clinical entities, ABD and CBD represent points on a continuum of hypersensitivity reactions to beryllium.
Abstract and Introduction
Abstract
Context: Although chronic beryllium disease (CBD) is clearly an immune-mediated granulomatous reaction to beryllium, acute beryllium disease (ABD) is commonly considered an irritative chemical phenomenon related to high exposures. Given reported new cases of ABD and projected increased demand for beryllium, we aimed to reevaluate the pathophysiologic associations between ABD and CBD using two cases identified from a survey of beryllium production facility workers.
Case Presentation: Within weeks after exposure to beryllium fluoride began, two workers had systemic illness characterized by dermal and respiratory symptoms and precipitous declines in pulmonary function. Symptoms and pulmonary function abnormalities improved with cessation of exposure and, in one worker, recurred with repeat exposure. Bronchoalveolar lavage fluid analyses and blood beryllium lymphocyte proliferation tests revealed lymphocytic alveolitis and cellular immune recognition of beryllium. None of the measured air samples exceeded 100 μg/m, and most were < 10 μg/m, lower than usually described. In both cases, lung biopsy about 18 months after acute illness revealed noncaseating granulomas. Years after first exposure, the workers left employment because of CBD.
Discussion: Contrary to common understanding, these cases suggest that ABD and CBD represent a continuum of disease, and both involve hypersensitivity reactions to beryllium. Differences in disease presentation and progression are likely influenced by the solubility of the beryllium compound involved.
Relevance to Practice: ABD may occur after exposures lower than the high concentrations commonly described. Prudence dictates limitation of further beryllium exposure in both ABD and CBD.
Introduction
In 2004, South Korean investigators reported nine cases of a disease thought to have been eliminated decades before: acute beryllium disease (ABD) (Kim et al. 2004). The recognition of new cases, the projected growth in worldwide demand for beryllium for applications including nuclear energy production (U.S. Department of Energy 2008) and national defense (Business Wire 2005), and advances in the understanding of chronic beryllium disease (CBD) led us to reconsider the pathogenesis of ABD. The resulting reconceptualization has implications for prevention, diagnosis, and case management in the global beryllium industry.
Textbooks and review articles have stated that exposure to beryllium may result in two distinct respiratory conditions. ABD is considered to be an irritative chemical phenomenon, whereas CBD is recognized as an immune-mediated granulomatous process (Balmes 2005; Becklake and Cowie 2000; Churg and Green 1998; Williams 1988). This conceptualization began > 50 years ago, with the assertions that ABD followed a traditional exposure–response pattern and was associated with airborne beryllium concentrations > 100 μg/m, whereas CBD could occur at much lower levels, indicating an immune phenomenon (Sterner and Eisenbud 1951). Although the description of ABD has remained essentially static, the understanding of CBD has evolved greatly in recent decades. It is now well established that sensitization to beryllium, as measured by the beryllium lymphocyte proliferation test (BeLPT), reflects cellular immune recognition of beryllium and confers a higher risk of subsequent development of CBD (Kreiss et al. 2007; Mroz et al. 1991; Newman et al. 2005; Sawyer et al. 2002). CBD can be detected at a subclinical stage by bronchoalveolar lavage (BAL) and biopsy (Cordeiro et al. 2007; Maier 2001). Lymphocyte predominance and abnormal BeLPT on BAL fluid analysis are findings consistent with CBD.
Acute respiratory and dermal reactions to beryllium exposure were first reported in the United States in the 1940s, observed among workers in the beryllium extraction and processing industry (DeNardi et al. 1949; Van Ordstrand et al. 1945). A relationship with exposure to soluble beryllium salts (sulfate and fluoride) and soluble forms of the oxide was noted by early investigators (Eisenbud 1982; Eisenbud et al. 1948). During that era, daily weighted average (DWA) exposures to beryllium were known to exceed 1,000 μg/m in certain operations (Eisenbud 1982).
In 1949, the U.S. Atomic Energy Commission recommended two different occupational exposure limits to their contractors: 25 μg/m as a maximum permissible peak exposure, to prevent ABD, and 2 μg/m as a DWA over a quarterly period, to prevent CBD (Eisenbud 1982). These limits were subsequently adopted in the United States by various professional organizations and the Occupational Safety and Health Administration, and regulatory bodies in many other countries also recognize the 2 μg/m limit (Eisenbud 1982, 1998). Over time, average exposures have decreased from hundreds of micrograms per cubic meter in the 1940s and 1950s to ≤ 1 μg/m in the 1980s and 1990s (National Research Council 2008).
Beryllium fluoride is intentionally formed during the production of beryllium metal. In the initial step, ammonium beryllium fluoride is heated in a fluoride furnace to drive off ammonium fluoride gas and yield beryllium fluoride (Kroschwitz and Howe-Grant 1992; White and Burke 1955). The beryllium fluoride then is transferred to an adjacent reduction furnace and reacted with magnesium to yield beryllium metal. In this article, we describe two cases of acute respiratory and dermal illness that occurred in workers involved in beryllium metal production. The extensive diagnostic evaluations that they underwent provide details on pathogenesis that were not available in earlier reports of ABD. In light of these cases and a review of the historical literature, we suggest that rather than being two distinct clinical entities, ABD and CBD represent points on a continuum of hypersensitivity reactions to beryllium.
