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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

[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.

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.

Chronic beryllium disease: uncommon disease, less common diagnosis.

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 settings where exposure was unexpected. When the etiology of a case of granulomatous pulmonary disease is not determined, sarcoidosis is the "diagnosis of exclusion." This diagnosis does not communicate much information about the patient's prognosis, the disease's etiology, or even what disease etiologies were specifically excluded. Some cases of CBD have been called sarcoidosis, allowing exposure to continue for the patient and (at times) other individuals. The granulomatous changes of sarcoidosis are thought to result from an abnormal immune response. While the etiologic agents that can initiate this response are largely unknown, the immunopathogenesis of CBD has been well described, and laboratory methods are available in a few centers that can (if used) identify beryllium hypersensitivity. The potential for exposure and disease to be widely separated in time and location makes it important for health-care and environmental health professionals to be aware of these new diagnostic methods.

Skin as a route of exposure and sensitization in chronic beryllium disease.

Chronic beryllium disease is an occupational lung disease that begins as a cell-mediated immune response to beryllium. Although respiratory and engineering controls have significantly decreased occupational beryllium exposures over the last decade, the rate of beryllium sensitization has not declined. We hypothesized that skin exposure to beryllium particles would provide an alternative route for sensitization to this metal. We employed optical scanning laser confocal microscopy and size-selected fluorospheres to demonstrate that 0.5- and 1.0- micro m particles, in conjunction with motion, as at the wrist, penetrate the stratum corneum of human skin and reach the epidermis and, occasionally, the dermis. The cutaneous immune response to chemical sensitizers is initiated in the skin, matures in the local lymph node (LN), and releases hapten-specific T cells into the peripheral blood. Topical application of beryllium to C3H mice generated beryllium-specific sensitization that was documented by peripheral blood and LN beryllium lymphocyte proliferation tests (BeLPT) and by changes in LN T-cell activation markers, increased expression of CD44, and decreased CD62L. In a sensitization-challenge treatment paradigm, epicutaneous beryllium increased murine ear thickness following chemical challenge. These data are consistent with development of a hapten-specific, cell-mediated immune response following topical application of beryllium and suggest a mechanistic link between the persistent rate of beryllium worker sensitization and skin exposure to fine and ultrafine beryllium particles.

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.

Indirect and direct gas exchange at maximum exercise in beryllium sensitization and disease.

STUDY OBJECTIVES: To determine whether pulse oximetry accurately estimates arterial blood gas measurements during exercise in the assessment of chronic beryllium disease (CBD) and beryllium sensitization (BeS). DESIGN: Participants underwent maximal exercise physiology testing in a clinical-practice setting. Oxygen saturation in the blood was measured through an indwelling arterial line and by pulse oximetry. SETTING: All exercise physiology tests were performed in the pulmonary physiology unit of the National Jewish Medical and Research Center (NJMRC) between December 1985 and November 1998. PATIENTS: We analyzed the exercise physiology data for 168 individuals who were referred to NJMRC for evaluation of possible CBD and underwent exercise testing. On evaluation, they subsequently received diagnoses of either CBD or BeS. RESULTS: In BeS subjects, the percentage of oxygen saturation as measured by pulse oximetry (SpO(2)) often underestimated the percentage of arterial oxygen saturation (SaO(2)) (mean [+/- SD] underestimation, 0.88 +/- 4.6%) at maximum exercise and showed no significant correlation (r = -0.13; p = 0.3). The use of SpO(2) misclassified 14.9% of BeS subjects as having abnormal gas exchange levels (< 90%) that were normal by arterial blood gas measurement. In contrast, SpO(2) and SaO(2) values correlated at maximum exercise in CBD subjects (r = 0.55 [corrected]; p = 0.0001) without exhibiting SpO(2) underestimation of SaO(2), and misclassification occurred in only 5.9%. CONCLUSIONS: These data suggest that pulse oximetry cannot be used reliably to distinguish between CBD and BeS and, thus, is not an adequate substitute for arterial blood gas analysis with exercise.

Chronic beryllium disease: a model interaction between innate and acquired immunity.

Beryllium (Be) is a lightweight and durable metal useful to a variety of manufacturing processes. With the use of Be in industrial settings, a number of health effects were noted including acute pneumonitis, sensitization to Be, interstitial lung disease and dermatological disease. Interstitial mononuclear cell inflammation and granuloma formation are the primary processes that occur in the lungs of Be-exposed workers, resulting in chronic beryllium disease (CBD). Recent studies have begun to describe the role of Be in the pathogenesis of CBD. These studies reveal that the host's response to Be involves components of the innate immune system or inflammatory responses. Inflammatory responses to Be can establish a state of acquired, Be antigen-specific, cell-mediated immunity. Despite triggering both the innate and acquired immune responses, Be is not eliminated from the host. Rather, it establishes pathways leading to chronic granulomatous inflammation. We will examine recent studies describing the host's cellular and molecular responses to Be, responses that promote granuloma formation.

Beryllium disease.

Berylliosis is an environmental chronic inflammatory disorder of the lung caused by inhalation of insoluble beryllium (Be) dusts and characterized by the accumulation of CD4+ T cells and macrophages in the lower respiratory tract. In response to Be inhalation, noncaseating granuloma formation and, eventually, fibrosis. The immunopathogenic process is maintained by Be-specific lung CD4+ T-lymphocytes. Consistent with the disease immunopathology, these Be-specific T cells have a T-helper 1 phenotype producing interleukin-2 and interferon-gamma, the macrophage-activating cytokine driving the granulomatous reaction. Previous studies have demonstrated that the glutamic acid in position 69 of the human leukocyte antigen class II b chain is strongly associated with increased susceptibility to Be in exposed workers, suggesting that human leukocyte antigen gene markers may be used as epidemiological probes to identify population groups at higher risk.