Beryllium Lymphocyte Proliferation Test Research Articles

Beryllium disease among construction trade workers at Department of Energy nuclear sites: A follow-up.

Construction workers at U.S. Department of Energy (DOE) nuclear weapons facilities are screened to identify DOE-related occupational illnesses, including beryllium sensitization (BeS) and chronic beryllium disease (CBD). The study objectives were to estimate beryllium disease risks and the CBD claims acceptance rate in the energy workers' benefits program. Workers diagnosed with BeS via beryllium lymphocyte proliferation test (BeLPT) included in screening examinations were interviewed about subsequent diagnosis of CBD. We estimated the proportion who developed CBD based on the ratio of CBD cases, based on self-reported compensation claim status, to all workers with BeS interviewed. We used stratified analyses to explore trends in disease frequency by age, race, sex, DOE employment duration, site, trade group, and cigarette smoking history. Between 1998 and 2020, 21,854 workers received a BeLPT; 262 (1.20%) had BeS (two abnormals or one abnormal plus one borderline test); 212 (0.97%) had a single abnormal BeLPT. Of 177 BeS workers interviewed, 35 (19.8%) reported an accepted CBD compensation claim. The claims acceptance rate among BeS workers increased with years of DOE employment, from 8.4% with <5 years to 33.3% for >25 or more years. Five of 68 interviewed workers with a single positive BeLPT reported CBD claim acceptance; an additional CBD case was confirmed by chart review (8.8%). Years of DOE work predict the risk of developing CBD among those sensitized and getting a claim for CBD accepted. Ongoing surveillance and increased awareness of the risk of beryllium exposure and CBD as an occupational disease among construction workers are needed.

Sarcoidosis and berylliosis

Sarcoidosis and berylliosis (chronic beryllium disease, CBD) are granulomatous diseases and are phenocopies which cannot be differentiated based on the clinical presentation. Whereas for sarcoidosis the eliciting agent is unknown, for berylliosis an exposure to beryllium (mostly as occupational exposure) can be confirmed that therefore induces asensitization against beryllium. The diagnosis is generally made in patients with a typical clinical presentation, the histological proof of a non-necrotizing granuloma and the exclusion of other diseases causing granulomas. In most cases, granulomas can be detected in the lungs and/or (intrathoracic) lymph nodes. The proof of sensitization to beryllium for the differential diagnosis can be performed with aso-called beryllium lymphocyte proliferation test in peripheral mononuclear blood cells or cells from a bronchoalveolar lavage. The objectives of treatment are avoidance of functional organ impairment and symptom control. Immunosuppressive therapy (initially mostly with corticosteroids) and supportive measures can prove beneficial; however, in many cases clinical observation can be sufficient because of stable disease or spontaneous resolution. In addition, further beryllium exposure must be avoided, which mostly necessitates a change of the workplace.

Standard beryllium lymphocyte proliferation test vs CFSE assay to detect beryllium sensitization, a comparative pilot study in dental technicians

Standard beryllium lymphocyte proliferation test vs CFSE assay to detect beryllium sensitization, a comparative pilot study in dental technicians

A Cluster of Beryllium Sensitization Traced to the Presence of Beryllium in Concrete Dust

Chronic beryllium disease (CBD), a granulomatous disease with similarities to sarcoidosis, arises only in individuals exposed to beryllium. Inhaled beryllium can elicit a T-cell-dominated alveolitis leading nonnecrotizing granulomata. CBD can be distinguished from sarcoidosis by demonstrating beryllium sensitization in a lymphocyte proliferation test. Beryllium exposure usually occurs in an occupational setting. Because of the diagnosis of CBD in a patient without evident beryllium exposure, we performed a beryllium-lymphocyte proliferation test (BeLPT) among his work colleagues. This field study investigated a cohort of work colleagues without obvious beryllium exposure. Twenty-one of 30 individuals were assessed in our outpatient clinic for beryllium sensitization. Therefore, BeLPT was performed with freshly collected peripheral blood mononuclear cells. Data were extracted from clinical charts, including geographical data. Beryllium content in dust samples collected at the workplace was measured by graphite-furnace atomic absorption spectroscopy and was compared with samples from different areas of Germany. For the initial patient, the diagnosis of sarcoidosis was reclassified as CBD based on two positive BeLPT results. Assessment of his workplace did not identify a source of beryllium. However, BeLPTs performed on his workmates demonstrated beryllium sensitization in 5 of 21 individuals, suggesting a local beryllium source. Concrete dust obtained from the building yard, the workplace of the index patient, contained high amounts of beryllium (1138 ± 162 μg/kg), whereas dust from other localities (control samples) showed much lower beryllium content (range, 147 ± 18-452 ± 206 μg/kg). Notably, the control dust collected from different places all over Germany exhibit different beryllium concentrations. We describe a cluster of beryllium-sensitized workers from an industry not related to beryllium caused by environmental exposure to beryllium-containing concrete dust, which exhibited markedly elevated beryllium content. Importantly, analyses of dust samples collected from different localities showed that they contain markedly different amounts of beryllium. Thus, besides workplace-related exposure, environmental factors also are capable of eliciting a beryllium sensitization.

Difficultés diagnostiques de la bérylliose pulmonaire chronique en France

The epidemiology of chronic beryllium disease (CBD) in France is poorly understood. The aim of this study was to determine the number of prevalent cases of CBD in France between 2010 and 2014. We conducted a national survey using a specific questionnaire distributed by the professional pathology services. In total, 33 CBD cases were reported in France, with a diagnosis established between 1982 and 2014. 85% (28/33) of CBD cases resulted from professional exposure and mostly concerned foundry workers (39%). A definite diagnosis defined by the association of an abnormal beryllium lymphocyte proliferation test and of a granulomatous inflammatory response in the lung, was obtained in 29/33 cases (88%). The other cases were probable CBD, defined by a granulomatous lung disease with a beryllium exposure, but without evidence of beryllium sensitisation. The diagnosis of granulomatous disease was confirmed a mean of 4 years after the end of exposure. The median delay between diagnosis of a granulomatous disease and diagnosis of CBD was 2 years (range 0-38 years). A genetic predisposition was found in 14 of 17 tested patients (82%). In this study, we report 33 cases of CBD followed in France between 2010 and 2014. The poor understanding of CBD and the exposure leading to it, the late development after the end of exposure, the complexity of the diagnosis and the similarities with sarcoidosis may explain the small number of cases reported.

As an Occupational Medicine Provider, What Are the Basics That I Need to Know About the Beryllium Lymphocyte Proliferation Test?

Conflicts of interest: RAM—None declared. DLC does not receive any direct financial reimbursement. She is the director of the ORISE beryllium lab, which receives funds on a per-test basis from customers. She also reviews and interprets LPTs as an employee of ORAU. SEH receives funding to her employer by the Building Trades Medical Screening Program to provide medical surveillance supervision for evaluation of former construction workers employed at Department of Energy sites who undergo testing for beryllium sensitization. LAM does not receive any direct financial reimbursement, but does see beryllium patients in the clinic and interpret LPTs as an employee of National Jewish Health.

Yield of Low-Dose Computerized Tomography Screening for Lung Cancer in High-Risk Workers: The Case of 7189 US Nuclear Weapons Workers.

To determine the lung cancer screening yield and stages in a union-sponsored low-dose computerized tomography scan program for nuclear weapons workers with diverse ages, smoking histories, and occupations. We implemented a low-dose computerized tomography program among 7189 nuclear weapons workers in 9 nonmetropolitan US communities during 2000 to 2013. Eligibility criteria included age, smoking, occupation, radiographic asbestos-related fibrosis, and a positive beryllium lymphocyte proliferation test. The proportion with screen-detected lung cancer among smokers aged 50 years or older was 0.83% at baseline and 0.51% on annual scan. Of 80 lung cancers, 59% (n = 47) were stage I, and 10% (n = 8) were stage II. Screening yields of study subpopulations who met the National Lung Screening Trial or the National Comprehensive Cancer Network Group 2 eligibility criteria were similar to those found in the National Lung Screening Trial. Computerized tomography screening for lung cancer among high-risk workers leads to a favorable yield of early-stage lung cancers. Public Health Implications. Health equity and efficiency dictate that screening high-risk workers for lung cancer should be an important public health priority.

Clinical and laboratory factors contributing to uninterpretable beryllium lymphocyte proliferation tests (BeLPT).

The beryllium lymphocyte proliferation test (BeLPT), has become the principal clinical test for detecting beryllium sensitization and chronic beryllium disease. Uninterpretable BeLPT results can occur in a small but significant proportion of tests from poor lymphocyte growth (PG) or over proliferation of lymphocytes (OP). The clinical and laboratory causes of uninterpretable results are not known. BeLPT data from the US Department of Energy-supported Former Worker Screening Program were analyzed for a 10-year period. Drivers of uninterpretable BeLPTs were investigated using multivariable models and classification techniques. Three participant attributes were significantly associated with PG, while OP showed no significant associations. Serum lot for the lymphocyte growth medium accounted for 21% of the variation in PG and 16% in OP. Serum lots influence the likelihood of having uninterpretable BeLPT. To better understand uninterpretable results and possibly reduce their occurrence, additional laboratory-related factors should be addressed.

Identification of metal sensitization in sarcoid-like metal-exposed patients by the MELISA® lymphocyte proliferation test — a pilot study

BackgroundPulmonary function is often affected by the inhalation of metal particles. The resulting pathology might trigger various lung diseases, e.g., parenchymal lung fibrosis and granulomatous lung disorders. We previously demonstrated that 6 % of tissue-proven sarcoid patients had a positive beryllium lymphocyte proliferation test (BeLPT), thus correcting the diagnosis to chronic beryllium disease. The aim of this study was to examine if MEmory Lymphocyte Immnuno Stimulation Assay (MELISA®), currently used for non-pulmonary diseases, can identify metals other than beryllium that can also trigger sensitization and induce granulomatous disease.MethodsThis pilot study included 13 sarcoid-like patients who underwent MELISA®. Eleven patients also underwent BeLPT. Biopsy samples were tested for metal content by scanning electron microscope. Eleven study patients had been exposed to metals at the workplace and 2 had silicone implants.ResultsTwo patients who had undergone BeLPT were positive for beryllium. MELISA® detected 9 patients (9/13, 69 %) who were positive for at least one of the tested metals: 4 reacted positively to nickel, 4 to titanium, 2 to chromium, 2 to beryllium, 2 to silica, and one each to palladium, mercury and lead.ConclusionIt is proposed that MELISA® can be exploited to also identify specific sensitization in individuals exposed to inhaled particles from a variety of metals.

An official American Thoracic Society statement: diagnosis and management of beryllium sensitivity and chronic beryllium disease.

Beryllium continues to have a wide range of industrial applications. Exposure to beryllium can lead to sensitization (BeS) and chronic beryllium disease (CBD). The purpose of this statement is to increase awareness and knowledge about beryllium exposure, BeS, and CBD. Evidence was identified by a search of MEDLINE. The committee then summarized the evidence, drew conclusions, and described their approach to diagnosis and management. The beryllium lymphocyte proliferation test is the cornerstone of both medical surveillance and the diagnosis of BeS and CBD. A confirmed abnormal beryllium lymphocyte proliferation test without evidence of lung disease is diagnostic of BeS. BeS with evidence of a granulomatous inflammatory response in the lung is diagnostic of CBD. The determinants of progression from BeS to CBD are uncertain, but higher exposures and the presence of a genetic variant in the HLA-DP β chain appear to increase the risk. Periodic evaluation of affected individuals can detect disease progression (from BeS to CBD, or from mild CBD to more severe CBD). Corticosteroid therapy is typically administered when a patient with CBD exhibits evidence of significant lung function abnormality or decline. Medical surveillance in workplaces that use beryllium-containing materials can identify individuals with BeS and at-risk groups of workers, which can help prioritize efforts to reduce inhalational and dermal exposures.

A Novel Alternative to Environmental Monitoring to Detect Workers at Risk for Beryllium Exposure-Related Health Effects

The purpose of this study was to describe a methodology for surveillance and monitoring of beryllium exposure using biological monitoring to complement environmental monitoring. Eighty-three Israeli dental technicians (mean age 41.6 ± 1.36 years) and 80 American nuclear machining workers (54.9 ± 1.21 years) were enrolled. Biological monitoring was carried out by analyzing particle size (laser technique) and shape (image analysis) in 131/163 (80.3%) induced sputum samples (Dipa Analyser, Donner Tech, Or Aquiva, Israel). Environmental monitoring was carried out only in the United States (Sioutas impactor, SKC, Inc., Eighty Four, Pa.). Pulmonary function testing performance and induced sputum retrieval were done by conventional methods. Sixty-three Israeli workers and 37 American workers were followed up for at least 2 years.Biological monitoring by induced sputum indicated that a >92% accumulation of <5 μm particles correlated significantly to a positive beryllium lymphocyte proliferation test result (OR 3.8, 95% CI 1.2–11.4, p = 0.015) among all participants. Environmental monitoring showed that beryllium particles were <1 μm, and this small fraction (0.1–1 μ) was significantly more highly accumulated in nuclear machining workers compared to dental technicians. The small fractions positively correlated with induced sputum macrophages (r = 0.21 p = 0.01) and negatively correlated with diffusion lung carbon monoxide single breath (DLCO-SB r = 0.180 p = 0.04) in all subjects. Years of exposure were positively correlated to the number of accumulated particles 2–3 μ in diameter (r = 0.2, p = 0.02) and negatively correlated to forced expiratory volume in one second/forced vital capacity findings (r = −0.18, p = 0.02). DLCO was decreased in both groups after two years of monitoring.Biological monitoring is more informative than environmental monitoring in the surveillance and monitoring of workers in beryllium industries. Induced sputum is a feasible and promising biomonitoring method that should be included in the surveillance of exposed workers.

Beryllium BioBank: 2. Lymphocyte proliferation testing.

To incrementally improve the use of beryllium lymphocyte proliferation test (LPT) results. Beryllium BioBank data were analyzed for 532 subjects in three groups: beryllium-exposed, sensitized, or chronic beryllium disease. Predictor variables were LPT stimulation index (SI) at the date of the earliest available data and at the study entry date. Cross-sectionally, LPT SI magnitude does not distinguish among the three groups. The likelihood of progression from sensitization to disease is associated with the absolute value of SI, but LPT SI interpreted by traditional cut point criteria was not predictive. Updating the criteria for interpreting beryllium LPT data should be considered. Prediction of progression to chronic beryllium disease may be improved by changing the cut point for interpretation or by using the SI as a continuous variable.

Sarcoidosis and chronic beryllium disease: similarities and differences.

Chronic beryllium disease (CBD) is a granulomatous lung disease that may be pathologically and clinically indistinguishable from pulmonary sarcoidosis, except through use of immunologic testing, such as the beryllium lymphocyte proliferation test (BeLPT). Similar to sarcoidosis, the pulmonary manifestations of CBD are variable and overlap with other respiratory diseases. Definitive diagnosis of CBD is established by evidence of immune sensitization to beryllium and diagnostic bronchoscopy with bronchoalveolar lavage and transbronchial biopsy. However, the diagnosis of CBD can also be established on a medically probable basis in beryllium-exposed patients with consistent radiographic imaging and clinical course. Beryllium workers exposed too much higher levels of beryllium in the past demonstrated a much more fulminant disease than is usually seen today. Some extrapulmonary manifestations similar to sarcoidosis were noted in these historic cohorts, although with a narrower spectrum. Extrapulmonary manifestations of CBD are rare today. Since lung-predominant sarcoidosis can very closely resemble CBD, CBD is still misdiagnosed as sarcoidosis when current or past exposure to beryllium is not recognized and no BeLPT is obtained. This article describes the similarities and differences between CBD and sarcoidosis, including clinical and diagnostic features that can help physicians consider CBD in patients with apparent lung-predominant sarcoidosis.

Biological Exposure Metrics of Beryllium-Exposed Dental Technicians

ABSTRACT Beryllium is commonly used in the dental industry. This study investigates the association between particle size and shape in induced sputum (IS) with beryllium exposure and oxidative stress in 83 dental technicians. Particle size and shape were defined by laser and video, whereas beryllium exposure data came from self-reports and beryllium lymphocyte proliferation test (BeLPT) results. Heme oxygenase-1 (HO1) gene expression in IS was evaluated by quantitative polymerase chain reaction. A high content of particles (92%) in IS >5 μ in size is correlated to a positive BeLPT risk (odds ratio [OR] = 3.4, 95% confidence interval [CI]: 0.9–13). Use of masks, hoods, and type of exposure yielded differences in the transparency of IS particles (gray level) and modulate HO1 levels. These results indicate that parameters of size and shape of particles in IS are sensitive to workplace hygiene, affect the level of oxidative stress, and may be potential markers for monitoring hazardous dust exposures.

Long‐Term Efficacy of a Program to Prevent Beryllium Disease

In 2000, a manufacturer of beryllium materials and products introduced a comprehensive program to prevent beryllium sensitization and chronic beryllium disease (CBD). We assessed the program's efficacy in preventing sensitization 9 years after implementation. Current and former workers hired since program implementation completed questionnaires and provided blood samples for the beryllium lymphocyte proliferation test (BeLPT). Using these data, as well as company medical surveillance data, we estimated beryllium sensitization prevalence. Cross-sectional prevalence of sensitization was 0.7% (2/298). Combining survey results with surveillance results, a total of seven were identified as sensitized (2.3%). Early Program workers were more likely to be sensitized than Late Program workers; one of the latter was newly identified. All sensitization was identified while participants were employed. One worker was diagnosed with CBD during employment. The combination of increased respiratory and dermal protection, enclosure and improved ventilation of high-risk processes, dust migration control, improved housekeeping, and worker and management education showed utility in reducing sensitization in the program's first 9 years. The low rate (0.6%, 1/175) among Late Program workers suggests that continuing refinements have provided additional protection against sensitization compared to the program's early years.

Alternative screening assay to beryllium lymphocyte proliferation test for identification of beryllium sensitization – Pilot study

Sarcoidosis is a rare interstitial lung disorder of unknown aetiology. In contrast, chronic beryllium disease (CBD), which is clinically indistinguishable from sarcoidosis, is induced by occupational beryllium exposure. In both disorders the primarily affected organ is the lung. The only applicable hallmark to differentiate sarcoidosis from CBD is the presence of beryllium specific T cells defined as beryllium sensitization (BeS) which is a prerequisite for clinical manifestation of CBD. To date the only assay to detect BeS is the beryllium lymphocyte proliferation test (Be-LPT) which measures the capability of T cell lymphocytes in peripheral blood or bronchoalveolar lavage to proliferate ex-vivo in response to beryllium. Since this cumbersome Be-LPT harbours a huge number of technical parameters critical for the final result interpretation the Be-LPT is performed only in a limited number of expert laboratories world wide. We think a robust, cheap and simple assay for detection of BeS is needed to cover the increasing demand for appropriate occupational surveillance in referring occupational settings. To develop an alternative assay we measured beryllium induced IFN-gamma concentrations in supernatants of cultivated peripheral blood cells of beryllium exposed and unexposed individuals after defined time intervals and compared the results with those of simultaneously performed Be-LPTs. Up to date we included 37 assays which had been performed at two independent laboratories in Borstel and Freiburg following an identical work flow. Simultaneous performance of the alternative assay and the Be-LPT revealed consistent findings 76.9%. To date 23.1% of the findings differed between the tests compared. Of interest is the result that individuals with a positive Be-LPT show significantly increased IFN-gamma levels compared with those with a negative finding. This was true for all Beryllium concentrations included and time intervals tested. In conclusion the data presented in this pilot study are promising. However, the numbers of tests have to be increased significantly to improve the statistical power of this study.

Search for Chronic Beryllium Disease Among Sarcoidosis Patients in Ontario, Canada

Chronic beryllium disease (CBD) is clinically similar to other granulomatous diseases such as sarcoidosis. It is often misdiagnosed if a thorough occupational history is not taken. When appropriate, a beryllium lymphocyte proliferation tests (BeLPT) need to be performed. We aimed to search for CBD among currently diagnosed pulmonary sarcoidosis patients and to identify the occupations and exposures in Ontario leading to CBD. Questionnaire items included work history and details of possible exposure to beryllium. Participants who provided a history of previous work with metals underwent BeLPTs and an ELISPOT on the basis of having a higher pretest probability of CBD. Among 121 sarcoid patients enrolled, 87 (72%) reported no known previous metal dust or fume exposure, while 34 (28%) had metal exposure, including 17 (14%) with beryllium exposure at work or home. However, none of these 34 who underwent testing had positive test results. Self-reported exposure to beryllium or metals was relatively common in these patients with clinical sarcoidosis, but CBD was not confirmed using blood assays in this population.

Prevalence of Beryllium Sensitization Among Department of Defense Conventional Munitions Workers at Low Risk for Exposure

To estimate the prevalence of beryllium sensitization among former and current Department of Defense workers from a conventional munitions facility. Participants were screened by using Beryllium Lymphocyte Proliferation Test. Those sensitized were offered clinical evaluation for chronic beryllium disease. Eight (1.5%) of 524 screened workers were found sensitized to beryllium. Although the confidence interval was wide, the results suggested a possibly higher risk of sensitization among workers exposed to beryllium by occasional resurfacing of copper-2% beryllium alloy tools compared with workers with the lowest potential exposure (odds ratio = 2.6; 95% confidence interval, 0.23-29.9). The findings from this study suggest that Department of Defense workers with low overall exposure to beryllium had a low prevalence of beryllium sensitization. Sensitization rates might be higher where higher beryllium exposures presumably occurred, although this study lacked sufficient power to confirm this.

Interpreting borderline belpt results

The beryllium lymphocyte proliferation test (BeLPT) identifies persons sensitized to beryllium (BeS) and thus at risk for chronic beryllium disease (CBD). BeLPT test results are abnormal (AB), borderline (BL), or normal (NL). This manuscript addresses the predictive value and interpretation of BL BeLPT results. The various three-result combinations that meet or exceed a nominal referral criteria of 1 AB + 1 BL are assessed with probability modeling and compared. At 2% prevalence, the three-result combinations that meet or exceed this referral criteria and associated probabilities of BeS are: (a) 1 AB + 1 BL + 1 NL (72%); (b) 3 BL (91%); (c) 2 AB + 1 NL (95%); (d) 1 AB + 2 BL (99%); (e) 2 AB + 1 BL (100%); and (f) 3 AB (100%). These results suggest that BL results are meaningful and that three BL results predict BeS across a broad range of population prevalences. An analysis of longitudinal BeLPT results and clinical findings from an actual surveillance program is warranted to confirm the model's predictions.

Prevalence of beryllium sensitization among aluminium smelter workers

Beryllium exposure occurs in aluminium smelters from natural contamination of bauxite, the principal source of aluminium. To characterize beryllium exposure in aluminium smelters and determine the prevalence rate of beryllium sensitization (BeS) among aluminium smelter workers. A population of 3185 workers from nine aluminium smelters owned by four different aluminium-producing companies were determined to have significant beryllium exposure. Of these, 1932 workers participated in medical surveillance programmes that included the serum beryllium lymphocyte proliferation test (BeLPT), confirmation of sensitization by at least two abnormal BeLPT test results and further evaluation for chronic beryllium disease in workers with BeS. Personal beryllium samples obtained from the nine aluminium smelters showed a range of <0.01-13.00 μg/m(3) time-weighted average with an arithmetic mean of 0.25 μg/m(3) and geometric mean of 0.06 μg/m(3). Nine workers were diagnosed with BeS (prevalence rate of 0.47%, 95% confidence interval = 0.21-0.88%). BeS can occur in aluminium smelter workers through natural beryllium contamination of the bauxite and further concentration during the refining and smelting processes. Exposure levels to beryllium observed in aluminium smelters are similar to those seen in other industries that utilize beryllium. However, compared with beryllium-exposed workers in other industries, the rate of BeS among aluminium smelter workers appears lower. This lower observed rate may be related to a more soluble form of beryllium found in the aluminium smelting work environment as well as the consistent use of respiratory protection.