Chronic Beryllium Disease: Update on a Moving Target.

Beryllium exposure remains an ongoing occupational health concern for workers worldwide. Since the initial Occupational Safety and Health Administration (OSHA) ruling on a permissible exposure limit (PEL) for beryllium in 1971, our understanding of the risks of beryllium sensitization and chronic beryllium disease (CBD) has evolved substantially. A new OSHA ruling released in early 2017 and implemented in late 2018 reduced the PEL for beryllium, increased requirements for medical screening and monitoring, and may ultimately enhance worker protection. This review highlights advances in our understanding of the pathway from beryllium exposure to sensitization and progression to CBD that guided the development of this OSHA ruling. Screening workers exposed to beryllium and management of CBD will also be discussed. Finally, we will discuss the role of beryllium as a cause of morbidity and mortality among exposed workers in this potentially preventable occupational lung disease.

Effect of inhaled corticosteroids on lung function in chronic beryllium disease.

BACKGROUND: The clinical effects of inhaled corticosteroids (ICS) on chronic beryllium disease (CBD) are unknown. Although frequently used for symptoms or disease not requiring systemic therapy, the clinical course of patients on ICS has not been evaluated. METHODS: In a retrospective cohort study, forty-eight subjects with CBD, diagnosed by granulomas on lung biopsy and treated with inhaled corticosteroids, were matched to sixty-eight subjects with CBD who were not treated. Pulmonary function testing, exercise tolerance, blood BeLPT, BAL cell count, and symptoms were evaluated. RESULTS: Treated patients showed no significant change over time in pulmonary function, when compared to controls, by forced vital capacity (FVC, p = 0.28) or diffusion capacity (DLCO, p = 0.45) or in exercise tolerance testing. However, symptoms of cough significantly improved in 58% (compared to 17% in controls) and dyspnea improved in 26% after ICS treatment (compared to 0 in controls). Symptoms of cough were improved in patients with a lower baseline FEV1 and FEV1/FVC ratio. Subgroup analysis showed significant lung function response in cases with lower baseline FEV1/FVC and higher residual volume (RV). CONCLUSION: Although FVC and DLCO did not improve in the ICS treated group, we saw no difference in decline compared to matched controls. Symptoms of dyspnea and cough improved with ICS especially in those with obstruction and air trapping suggesting that these should be considered an indication of ICS use in CBD patients.

Interstitial pneumonia in a glassblower: think to chronic beryllium disease!

Chronic beryllium disease (CBD) is an occupational illness with varying severity. In this report, we describe a 27 year old man, glassblower, who developed a fatal CBD after six months of unknown Beryllium's exposure. The diagnosis was suspected on histological examination and then consolidated by confirmation of Beryllium's exposure at the working area. Physicians should be aware of the potential risk to develop CBD in glassblowers. These workers should benefit from early medical surveillance using the Beryllium lymphocyte proliferation test (BeLPT) and therefore from suitable management.

Beryllium-induced lung disease exhibits expression profiles similar to sarcoidosis.

A subset of beryllium-exposed workers develop beryllium sensitisation (BeS) which precedes chronic beryllium disease (CBD). We conducted an in-depth analysis of differentially expressed candidate genes in CBD.We performed Affymetrix GeneChip 1.0 ST array analysis on peripheral blood mononuclear cells (PBMCs) from 10 CBD, 10 BeS and 10 beryllium-exposed, nondiseased controls stimulated with BeSO4 or medium. The differentially expressed genes were validated by high-throughput real-time PCR in this group and in an additional group of cases and nonexposed controls. The functional roles of the top candidate genes in CBD were assessed using a pharmacological inhibitor. CBD gene expression data were compared with whole blood and lung tissue in sarcoidosis from the Gene Expression Omnibus.We confirmed almost 450 genes that were significantly differentially expressed between CBD and controls. The top enrichment of genes was for JAK (Janus kinase)-STAT (signal transducer and activator of transcription) signalling. A JAK2 inhibitor significantly decreased tumour necrosis factor-α and interferon-γ production. Furthermore, we found 287 differentially expressed genes overlapped in CBD/sarcoidosis. The top shared pathways included cytokine-cytokine receptor interactions, and Toll-like receptor, chemokine and JAK-STAT signalling pathways.We show that PBMCs demonstrate differentially expressed gene profiles relevant to the immunnopathogenesis of CBD. CBD and sarcoidosis share similar differential expression of pathogenic genes and pathways.

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.

Occupational exposure to beryllium and cancer risk: a review of the epidemiologic evidence.

There is controversy on whether occupational exposure to beryllium causes lung cancer. We conducted a systematic review of epidemiologic studies on cancer among workers exposed to beryllium, including a study of seven U.S. production plants which has been recently updated, a study of patients with beryllium disease (largely overlapping with the former study) and several smaller studies. A small excess mortality from lung cancer was detected in the large cohort, which was partially explained by confounding by tobacco smoking and urban residence. Other potential confounders have not been addressed. The excess mortality was mainly among workers employed (often for a short duration) in the early phase of the manufacturing industry. There was no relation with duration of employment or cumulative exposure, whereas average and maximum exposure were associated with lung cancer risk. The use of lagged exposure variables resulted in associations with lung cancer risk; however, these associations were due to confounding by year of birth and year of hire. The studies of beryllium disease patients do not provide independent evidence and the results from other studies do not support the hypothesis of an increased risk of lung cancer or any other cancer. Overall, the available evidence does not support a conclusion that a causal association has been established between occupational exposure to beryllium and the risk of cancer.

Long-term complications and prognosis of chronic beryllium disease.

BACKGROUND: Chronic beryllium disease (CBD) is a rare disease, and there are no previous reports that have followed CBD patients over several decades. Thus, the long-term complications and prognosis of this illness still remain unclear. OBJECTIVE: The aim of this study was to investigate long-term complications and prognosis of CBD patients. STUDY DESIGN AND METHODS: This was a retrospective study based on the medical records of all CBD patients diagnosed at Kyoto University Hospital between the period 1973 to the present day. Ultimately, ten patients whose diagnoses had been made during the period 1973 to 1977 were included. Long-term physiological and radiological change, complications and prognosis of these patients were investigated. RESULTS: Three patients completely remitted, and one died of cor-pulmonale. Among the remaining six patients, four have been followed up for more than thirty years in our institute. The majority developed mixed patterns of lung function impairment, cavity lesions of the lung, pneumothorax, and respiratory infections. CONCLUSIONS: Long-term prognosis of CBD was poor with several complications due to chronic parenchymal and airway lesions.

Induced sputum and occupational diseases other than asthma.

PURPOSE OF REVIEW: Induced sputum noninvasively provides information on cellular and soluble material from airways. It has been successfully applied for assessing airway inflammation in asthma and chronic obstructive pulmonary disease, producing reliable results comparable to biopsy and bronchoalveolar lavage. Induced sputum research in the field of occupational medicine has mainly focused upon occupational asthma, and less to other types of occupational diseases. RECENT FINDINGS: Particulate size distribution in induced sputum samples points to accumulation over time, leading to the consideration that this measurement may serve as a time-dependent marker for biological monitoring. Qualitative analysis of chemical composition of induced sputum particles is well correlated to the chemical elements spectrum in bronchoalveolar lavage lung cells and in biopsy thin sections. T cell subsets in induced sputum can be used as a marker of granulomatosis in chronic beryllium disease. Cytokines retrieved from induced sputum samples in exposed workers show a differential pattern compared to nonexposed workers. SUMMARY: Induced sputum is a well tolerated, noninvasive technique that is opening a new window in the field of occupational diseases of the lung and can be integrated into the well established criteria for diagnosing and monitoring these diseases, especially when invasive techniques are clinically contraindicated or impractical.

Beryllium sensitization and lung function among former workers at the Nevada Test Site.

BACKGROUND: Beryllium use at the Nevada Test Site (NTS) was not acknowledged until the late 1990's. Subsequently, the ongoing U.S. DOE funded medical screening program, which began in 1998, started testing former workers of the NTS for beryllium sensitization (BeS) in 2001 to identify individuals who may be at higher risk of developing chronic beryllium disease (CBD). METHODS: An observational study was conducted to identify work-related factors associated with the odds of having BeS. Work history questionnaires were administered and principal components analysis was used to identify categories of related tasks associated with BeS. RESULTS: Of the 1,786 former workers tested for BeS, 23 had a confirmed positive result. An increased risk of BeS was found among workers who performed cleanup (OR = 2.68, 95% CI: 1.10, 6.56) and those who worked in Building B where beryllium parts were machined (OR = 2.52, 95% CI: 1.02, 6.19), though no significant increased risk was found when categories of related tasks were used. Additionally, the number of years worked at the NTS was associated with increased risk of BeS. There was no difference in pulmonary function, chest X-ray abnormalities, or respiratory symptoms between those who were sensitized and normal. CONCLUSIONS: The prevalence of BeS among former workers of the NTS who participated in our screening program was 1.3%. Former workers who performed specific job tasks may be at greater risk of developing BeS.

Immunology of chronic beryllium disease.

PURPOSE OF REVIEW: This review discusses the immunology of chronic beryllium disease. It addresses the importance of the interaction between class II molecules and the T cells that recognize beryllium, along with the subsequent immune response that results in sensitization and disease, and genetic factors leading to variation in this response. RECENT FINDINGS: HLA-DPB1 with a glutamic acid at amino acid position 69 (Glu69) confers increased risk of beryllium sensitization and is not specific for chronic beryllium disease. The degree of negative surface charge of the molecule may increase risk of chronic beryllium disease but not sensitization. In the absence of Glu69, HLA-DRB1 alleles may function in beryllium presentation, increasing the risk of chronic beryllium disease. The T-cell response as assessed by the beryllium lymphocyte proliferation test is dependent on central memory T-cells, while Th1 cytokine secretion leading to granulomatous inflammation and chronic beryllium disease is dependent on the activity of effector memory T cells. Polymorphisms in cytokine genes, such as the TGF-beta1 gene, also affect the risk of chronic beryllium disease and more severe disease. SUMMARY: The current diagnostic criteria for sensitization and chronic beryllium disease rely on the beryllium lymphocyte proliferation test. By understanding the novel immunologic mechanisms and genetic factors associated with sensitization and chronic beryllium disease, we may improve our ability to detect beryllium health effects with new diagnostics, and hopefully refine therapies for disease.

Recent chronic beryllium disease in residents surrounding a beryllium facility.

RATIONALE: Between 1948 and 1969, cases of community-acquired chronic beryllium disease (CA-CBD) were reported in neighborhoods surrounding beryllium facilities. Further surveillance was not performed in these communities, and additional cases have not been reported. OBJECTIVES: To increase awareness of recently diagnosed cases of CA-CBD in residents surrounding a beryllium facility. METHODS: Medical records were reviewed from individuals in a community surrounding a beryllium manufacturing facility in Reading, Pennsylvania. Definite cases of CBD required (1) an abnormal beryllium lymphocyte proliferation test in blood or bronchoalveolar lavage and (2) biopsy evidence of granulomatous inflammation. Probable cases of CBD either displayed an abnormal blood test to beryllium and radiographic evidence consistent with disease, or met epidemiologic criteria for CBD based on the Beryllium Case Registry criteria. Cases with occupational or potential paraoccupational exposure were excluded. MEASUREMENTS AND MAIN RESULTS: Sixteen cases of potential community-acquired CBD were evaluated. From these, eight cases of community-acquired CBD were identified (five definite and three probable). The cases' initial year of residence began between 1943 and 1953 and continued until 1956-2001. Six of the eight cases required medical treatment and three of the cases died since diagnosis. CONCLUSIONS: Cases of CBD meeting current immunologic diagnostic criteria and attributable to industry-associated environmental exposure were detected among residents of a community surrounding a beryllium manufacturing facility. Most were diagnosed years after exposure cessation. The frequency and extent of beryllium disease in this community are unknown. We anticipate that not only have cases been misdiagnosed in this community but that more cases of CBD will be diagnosed in the future.

Metal-induced diffuse lung disease.

The number of metals that are associated with the development of diffuse parenchymal lung disease continues to expand. In addition to lung fibrosis, inhalation of metal particulates can induce a wide range of lung pathology, including reactive airways disease and cancer. This article focuses on diffuse parenchymal diseases resulting from the inhalation of beryllium and cobalt. More is known regarding the immunopathogenesis of beryllium-induced disease than is known for disease induced by any other metal. Chronic beryllium disease (CBD) is a granulomatous lung disorder caused by beryllium exposure in the workplace and is characterized by the accumulation of beryllium-specific CD4 (+) T cells in the bronchoalveolar lavage. Genetic susceptibility markers associated with increased risk have been identified for both CBD and hard metal lung disease. The mechanism for the genetic susceptibility of CBD lies in the ability of certain human leukocyte antigen (HLA)-DP molecules to bind and present beryllium to pathogenic CD4 (+) T cells. Whether the same is true for hard metal lung disease is unknown. In contrast, no HLA allelic association has been identified in nickel allergic subjects. The study of metal-induced lung disease allows the investigation of the relationship between environmental exposure and genetic susceptibility. These studies will enhance our understanding of the immunopathogenesis of metal-induced disease and how exposure to these metals results in irreversible lung fibrosis.

[State of broncho-pulmonary system in berylliosis patients on distant follow-up period].

The article presents results concerning evaluation of bronchopulmonary system in berylliosis patients on distant follow-up period. In accordance with work conditions, the authors defined two forms of berylliosis: granulomatous and interstitial. Granulomatous one was characterized by progressive course at early stages, with complications resulting in cardio-pulmonary failure. Interstitial one was benign in nature.

Comparative analysis between CFSE flow cytometric and tritiated thymidine incorporation tests for beryllium sensitivity.

BACKGROUND: In this study, we evaluated alternative possibility for CFSE beryllium flow cytometric test against beryllium blood lymphocyte proliferation test (BeLPT) as a standard radioactive clinical screening method to identify sensitization to beryllium. METHODS: Delta PD (the ratio of divided cell population to the total number of cells with subtracted counts of unstimulated cells) of specific beryllium-induced pathogenic CD3+ CD4+ T-lymphocytes and stimulation index (SI) in CFSE proliferation test was compared with delta counts per minute (mean test CPM minus mean control CPM) and SI in radioactive blood BeLPT. RESULTS: Comparison analysis of CFSE and BeLPT demonstrated excellent agreement between delta PD and delta CPM (kappa = 0.845, P << 0.0001). We determined 6.8% positive subjects in the beryllium-exposed, Be-LPT-negative group. The decreased mean difference of these indexes to percentage of average and the long tail in the plot reflects increased sensitivity. CFSE/CD4+ T-cell proliferation assay has 100% specificity, significantly higher sensitivity and efficiency than BeLPT. CONCLUSIONS: Both delta PD, measured by the precursor frequencies method in CFSE assay and delta CPM, defined by tritiated thymidine in BeLPT, can be used for the enumeration of beryllium specific CD4+ T-cell proliferation and may substantially improve the quality of the early diagnosis of beryllium hypersensitivity.

Beryllium sensitization progresses to chronic beryllium disease: a longitudinal study of disease risk.

The blood beryllium lymphocyte proliferation test is used in medical surveillance to identify both beryllium sensitization and chronic beryllium disease. Approximately 50% of individuals with beryllium sensitization have chronic beryllium disease at the time of their initial clinical evaluation; however, the rate of progression from beryllium sensitization to chronic beryllium disease is unknown. We monitored a cohort of beryllium-sensitized patients at 2-year intervals, using bronchoalveolar lavage and repeated transbronchial lung biopsies to determine progression to chronic beryllium disease as evidenced by granulomatous inflammation in lung tissue. Fifty-five individuals with beryllium sensitization were monitored with a range of 2 to 5 clinical evaluations. Disease developed in 17 sensitized individuals (31%) within an average follow-up period of 3.8 years (range, 1.0-9.5 years). Thirty-eight of the 55 (69%) remained beryllium sensitized without disease after an average follow-up time of 4.8 years (range, 1.7-11.6 years). Progressors were more likely to have worked as machinists. We found no difference in average age, sex, race or ethnicity, smoking status, or beryllium exposure time between those who progressed to chronic beryllium disease and those who remained sensitized without disease. We conclude that beryllium sensitization is an adverse health effect in beryllium-exposed workers and merits medical follow-up.

Variable response to long-term corticosteroid therapy in chronic beryllium disease.

OBJECTIVES: Chronic beryllium disease (CBD) shares many of its characteristics with sarcoidosis and is often treated with corticosteroids. There is limited available literature regarding the effect of long-term corticosteroid therapy on the natural history of CBD. METHODS AND MATERIALS: We conducted an observational retrospective study of six patients with CBD who received prolonged corticosteroid treatment with a mean pulmonary function test follow-up period of 10.1 years. Five of the six patients were exposed to beryllium at the same workplace. The diagnosis in four of the six cases was confirmed by a positive beryllium lymphocyte proliferation test result on blood or BAL fluid. Periodic pulmonary function tests were analyzed in relation to removal from beryllium exposure and treatment with corticosteroids. MEASUREMENTS AND RESULTS: Two broad patterns of response were noted in these patients. The first pattern seen in two patients showed no improvement in FVC or diffusion capacity of the lung for carbon monoxide (Dlco) with corticosteroids. However, a significant improvement in these parameters was noted on cessation of beryllium exposure in one of the two patients. The second pattern showed an initial improvement in FVC and Dlco with corticosteroids, which was not sustained. An improvement was noted on stopping beryllium exposure. CONCLUSIONS: The response to long-term corticosteroids in CBD, quite like that in sarcoidosis, is variable. Significant lung function improvement may be seen following cessation of beryllium exposure.

Analysis of differentially regulated mRNAs in monocytic cells induced by in vitro stimulation with Kveim-Siltzbach test reagent.

Sarcoidosis is a granulomatous disorder of unknown origin. The sarcoid spleen-derived Kveim-Siltzbach test reagent (KSTR) elicits a sarcoid-specific, granulomatous response and was used to diagnose sarcoidosis. The active component and the pathomechanism by which KSTR induces granuloma are still unknown. This study investigated the KSTR-associated gene expression pattern in cells of patients with sarcoidosis or chronic beryllium disease (CBD). The monocytic-like cell line U937, alveolar macrophages of sarcoidosis patients, and peripheral blood monocytes of patients with CBD were stimulated with KSTR and other granuloma-associated stimuli. The KSTR-associated gene expression pattern was analyzed by means of differential display reverse transcription-polymerase chain reaction in combination with a multiple comparison of expressed sequence tags induced in response to KSTR and other granuloma-associated stimuli. Depending on the origin of cells tested, 3.7% to 14.6% of the analyzed sequence tags showed differential regulation induced by granuloma-associated stimuli. Alterations restricted to KSTR stimulation could be observed in 1.2% for the cell line U937, in 2.8% for blood monocytes of patients with CBD, and 1.3% for alveolar macrophages of sarcoidosis patients. These data are comparable to those achieved for the other granuloma-associated stimuli tested in this study. Therefore, it can be assumed that KSTR induces pathomechanisms for granuloma formation in sarcoidosis as beryllium in CBD.

Beryllium-induced tumor necrosis factor-alpha production by CD4+ T cells is mediated by HLA-DP.

Beryllium (Be) presentation to CD4+ T cells from patients with chronic beryllium disease (CBD) results in T cell activation, and these Be-specific CD4+ T cells undergo clonal proliferation and T-helper 1-type cytokine production. In exposed workers, genetic susceptibility to this granulomatous disorder is associated with particular HLA-DPB1 alleles. We hypothesized that these HLA-DP molecules could mediate Be-stimulated tumor necrosis factor-alpha (TNF-alpha) messenger RNA (mRNA) and protein production. Using intracellular cytokine staining, we found that treatment with an anti-HLA-DP, but not anti-HLA-DR, monoclonal antibody inhibited Be-stimulated TNF-alpha expression in lung CD3+ CD4+ T cells. This monoclonal antibody also blocked Be-specific T cell proliferation, increased production of TNF-alpha mature-mRNA transcripts, and increased TNF-alpha protein production by Be-stimulated CBD peripheral blood mononuclear cells and bronchoalveolar lavage (BAL) cells. The Be-stimulated upregulation of TNF-alpha mature-mRNA levels with TNF-alpha protein production was a unique property of CBD BAL cells, and did not occur in BAL cells from Be-sensitized patients without CBD, or sarcoidosis BAL cells. This study identifies HLA-DP as a regulatory component in the activation of T cell receptors on Be-specific CD4+ T cells from CBD patients resulting in proliferation and proinflammatory cytokine production.

Electrostatic potential on human leukocyte antigen: implications for putative mechanism of chronic beryllium disease.

The pathobiology of chronic beryllium disease (CBD) involves the major histocompatibility complex class II human leukocyte antigen (HLA). Although occupational exposure to beryllium is the cause of CBD, molecular epidemiologic studies suggest that specific (Italic)HLA-DPB1(/Italic) alleles may be genetic susceptibility factors. We have studied three-dimensional structural models of HLA-DP proteins encoded by these genes. The extracellular domains of HLA-DPA1*0103/B1*1701, *1901, *0201, and *0401, and HLA-DPA1*0201/B1*1701, *1901, *0201, and *0401 were modeled from the X-ray coordinates of an HLA-DR template. Using these models, the electrostatic potential at the molecular surface of each HLA-DP was calculated and compared. These comparisons identify specific characteristics in the vicinity of the antigen-binding pocket that distinguish the different HLA-DP allotypes. Differences in electrostatics originate from the shape, specific disposition, and variation in the negatively charged groups around the pocket. The more negative the pocket potential, the greater the odds of developing CBD estimated from reported epidemiologic studies. Adverse impact is caused by charged substitutions in positions 55, 56, 69, 84, and 85, namely, the exact same loci identified as genetic markers of CBD susceptibility as well as cobalt-lung hard metal disease. These findings suggest that certain substitutions may promote an involuntary cation-binding site within a putatively metal-free peptide-binding pocket and therefore change the innate specificity of antigen recognition.