Multisystemic Beryllium Disease: An Exceptional Case Revealed by a Urinary Tract Granulomatosis.

Chronic beryllium disease (CBD), or berylliosis, is an interstitial lung disease caused by the chronic inhalation of finely particulate beryllium, frequently mistaken for sarcoidosis. It is rarely associated with skin nodular lesions, asymptomatic granulomatous hepatitis or calcium nephrolithiasis. To date, it has never been reported as a diffused multi-organ granulomatous disease. A 60-year-old Pakistani man, a former excavation worker with ancient history of suspected sarcoidosis, underwent a left nephroureterectomy for suspected papillary kidney carcinoma. The histopathological analysis showed a benign non-necrotic granulomatous infiltration of the renal pelvis and ureter. Six months later, he suffered from two consecutive episodes of acute kidney failure. Bladder biopsies found similar noncaseous granulomatosis and kidney biopsies showed interstitial nephritis. Known for suspected asthma, sleep apnea, and usual interstitial pneumonia, the patient would regularly consult for episodes of pyrexia, chills, nocturnal coughing, and wheezing. As kidney function gradually worsened, he ultimately started hemodialysis and was transferred to our facility. A positive blood beryllium lymphocyte proliferation test confirmed the diagnosis of CBD. This original report is the first description of multi-organ berylliosis with diffused urothelial granulomatosis and pseudo-tumor. The patient's pulmonary disease is minimal compared with renal and urinary tract involvement, eventually responsible for end-stage kidney disease. Berylliosis usually responds to glucocorticoids. This case report highlights the importance of evoking the diagnosis of CBD in the presence of any granulomatosis, even extra-thoracic, especially if associated with pulmonary symptoms, however atypical.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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%). CONCLUSIONS: 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]. / Sarkoidose und Berylliose.

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 a sensitization 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 a so-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.

Genomic biomarkers in chronic beryllium disease and sarcoidosis.

Background Previous gene expression studies have identified genes IFNγ, TNFα, RNase 3, CXCL9, and CD55 as potential biomarkers for sarcoidosis and/or chronic beryllium disease (CBD). We hypothesized that differential expression of these genes could function as diagnostic biomarkers for sarcoidosis and CBD, and prognostic biomarkers for sarcoidosis. Study Design/Methods We performed RT-qPCR on whole blood samples from CBD (n = 132), beryllium sensitized (BeS) (n = 109), and sarcoidosis (n = 99) cases and non-diseased controls (n = 97) to determine differential expression of target genes. We then performed logistic regression modeling and generated ROC curves to determine which genes could most accurately differentiate: 1) CBD versus sarcoidosis 2) CBD versus BeS 3) sarcoidosis versus controls 4) non-progressive versus progressive sarcoidosis. Results CD55 and TNFα were significantly upregulated, while CXCL9 was significantly downregulated in CBD compared to sarcoidosis (p < 0.05). The ROC curve from the logistic regression model demonstrated high discriminatory ability of the combination of CD55, TNFα, and CXCL9 to distinguish between CBD and sarcoidosis with an AUC of 0.98. CD55 and TNFα were significantly downregulated in sarcoidosis compared to controls (p < 0.05). The ROC curve from the model showed a reasonable discriminatory ability of CD55 and TNFα to distinguish between sarcoidosis and controls with an AUC of 0.86. There was no combination of genes that could accurately differentiate between CBD and BeS or sarcoidosis phenotypes. Interpretation CD55, TNFα and CXCL9 expression levels can accurately differentiate between CBD and sarcoidosis, while CD55 and TNFα expression levels can accurately differentiate sarcoidosis and controls.

[Management of occupational health for adverse health effects of beryllium and its compounds in workplaces - Recent trends and issues in Japan].

OBJECTIVES: Beryllium is primarily used in its metallic form, in alloys, or in beryllium oxide ceramics. Its physical and mechanical properties make it useful for many applications across a range of industries. Because beryllium is recognized as a sensitizing and carcinogenic agent, the management of occupational health for workers who may be occupationally exposed to beryllium has long been an important issue in the world. Under these circumstances, the U.S. Occupational Safety and Health Administration (OSHA) had published a rule in January 2017, to prevent the development of chronic beryllium disease and lung cancer. This rule strengthens the regulations governing the use of beryllium and its compounds. With the announcement of the OSHA rule in January 2017, the purpose of this study is to gain insight into the health problems and industrial hygiene associated with the use of beryllium and share the issues related to the management of occupational health for persons working with beryllium in Japan. METHODS: We collected information regarding the beryllium industry, beryllium exposure, beryllium-induced health disorders, OSHA rule of January 2017, and regulations for beryllium use in Japan. After reviewing them, we discussed the issues concerning occupational health management of workers exposed to beryllium in Japan. RESULTS: It has been reconfirmed that in recent years, the most serious health problem due to beryllium exposure is chronic beryllium disease caused by beryllium sensitization. Management of occupational health that emphasizes reduction of beryllium sensitization and early detection of beryllium-sensitized workers is important. CONCLUSIONS: It was suggested that the following should be considered as the issues of management of occupational health of workers exposed to beryllium in Japan: (1) Collect epidemiologic data on health hazards from beryllium exposure in Japan. (2) Review the diagnostic items of special medical check-ups. (3) Review the definition of beryllium and its compounds in the Ordinance on Prevention of Hazards due to Specified Chemical Substances.

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

BACKGROUND: 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. RESEARCH QUESTION: 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. STUDY DESIGN AND METHODS: 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. RESULTS: 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. INTERPRETATION: 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.

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.

[Diagnostic difficulties of chronic pulmonary berylliosis in France]. / Difficultés diagnostiques de la bérylliose pulmonaire chronique en France.

INTRODUCTION: 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. METHODS: We conducted a national survey using a specific questionnaire distributed by the professional pathology services. RESULTS: 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%). CONCLUSION: 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.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

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.

Thoracic lymphadenopathy in benign diseases: A state of the art review.

Lymphadenopathy is a common radiological finding in many thoracic diseases and may be caused by a variety of infectious, inflammatory, and neoplastic conditions. This review aims to describe the patterns of mediastinal and hilar lymphadenopathy found in benign diseases in immunocompetent patients. Computed tomography is the method of choice for the evaluation of lymphadenopathy, as it is able to demonstrate increased size of individual nodes, abnormalities of the interface between the mediastinum and lung, invasion of surrounding fat, coalescence of adjacent nodes, obliteration of the mediastinal fat, and hypo- and hyperdensity in lymph nodes. Intravenous contrast enhancement may be needed to help distinguish nodes from vessels. The most frequent infections resulting in this finding are tuberculosis and fungal disease (particularly histoplasmosis and coccidioidomycosis). Sarcoidosis is a relatively frequent cause of lymphadenopathy in young adults, and can be distinguished from other diseases - especially when enlarged lymph nodes are found to be multiple and symmetrical. Other conditions discussed in this review are silicosis, drug reactions, amyloidosis, heart failure, Castleman's disease, viral infections, and chronic obstructive pulmonary disease.

CpG promoter methylation status is not a prognostic indicator of gene expression in beryllium challenge.

Individuals exposed to beryllium (Be) may develop Be sensitization (BeS) and progress to chronic beryllium disease (CBD). Recent studies with other metal antigens suggest epigenetic mechanisms may be involved in inflammatory disease processes, including granulomatous lung disorders and that a number of metal cations alter gene methylation. The objective of this study was to determine if Be can exert an epigenetic effect on gene expression by altering methylation in the promoter region of specific genes known to be involved in Be antigen-mediated gene expression. To investigate this objective, three macrophage tumor mouse cell lines known to differentially produce tumor necrosis factor (TNF)-α, but not interferon (IFN)-γ, in response to Be antigen were cultured with Be or controls. Following challenges, ELISA were performed to quantify induced TNFα and IFNγ expression. Bisulfate-converted DNA was evaluated by pyrosequencing to quantify CpG methylation within the promoters of TNFα and IFNγ. Be-challenged H36.12J cells expressed higher levels of TNFα compared to either H36.12E cells or P388D.1 cells. However, there were no variations in TNFα promoter CpG methylation levels between cell lines at the six CpG sites tested. H36.12J cell TNFα expression was shown to be metal-specific by the induction of significantly more TNFα when exposed to Be than when exposed to aluminum sulfate, or nickel (II) chloride, but not when exposed to cobalt (II) chloride. However, H36.12J cell methylation levels at the six CpG sites examined in the TNFα promoter did not correlate with cytokine expression differences. Nonetheless, all three cell lines had significantly more promoter methylation at the six CpG sites investigated within the IFNγ promoter (a gene that is not expressed) when compared to the six CpG sites investigated in the TNFα promoter, regardless of treatment condition (p < 1.17 × 10(-9)). These findings suggest that, in this cell system, promoter hypo-methylation may be necessary to allow expression of metal-induced TNFα and that promoter hyper-methylation in the IFNγ promoter may interfere with expression. Also, at the dozen CpG sites investigated in the promoter regions of both genes, beryllium had no impact on promoter methylation status, despite its ability to induce pro-inflammatory cytokine expression.

Accelerator mass spectrometry detection of beryllium ions in the antigen processing and presentation pathway.

Exposure to small amounts of beryllium (Be) can result in beryllium sensitization and progression to Chronic Beryllium Disease (CBD). In CBD, beryllium is presented to Be-responsive T-cells by professional antigen-presenting cells (APC). This presentation drives T-cell proliferation and pro-inflammatory cytokine (IL-2, TNFα, and IFNγ) production and leads to granuloma formation. The mechanism by which beryllium enters an APC and is processed to become part of the beryllium antigen complex has not yet been elucidated. Developing techniques for beryllium detection with enough sensitivity has presented a barrier to further investigation. The objective of this study was to demonstrate that Accelerator Mass Spectrometry (AMS) is sensitive enough to quantify the amount of beryllium presented by APC to stimulate Be-responsive T-cells. To achieve this goal, APC - which may or may not stimulate Be-responsive T-cells - were cultured with Be-ferritin. Then, by utilizing AMS, the amount of beryllium processed for presentation was determined. Further, IFNγ intracellular cytokine assays were performed to demonstrate that Be-ferritin (at levels used in the experiments) could stimulate Be-responsive T-cells when presented by an APC of the correct HLA type (HLA-DP0201). The results indicated that Be-responsive T-cells expressed IFNγ only when APC with the correct HLA type were able to process Be for presentation. Utilizing AMS, it was determined that APC with HLA-DP0201 had membrane fractions containing 0.17-0.59 ng Be and APC with HLA-DP0401 had membrane fractions bearing 0.40-0.45 ng Be. However, HLA-DP0401 APC had 20-times more Be associated with the whole cells (57.68-61.12 ng) than HLA-DP0201 APC (0.90-3.49 ng). As these findings demonstrate, AMS detection of picogram levels of Be processed by APC is possible. Further, regardless of form, Be requires processing by APC to successfully stimulate Be-responsive T-cells to generate IFNγ.

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

RATIONALE: Beryllium continues to have a wide range of industrial applications. Exposure to beryllium can lead to sensitization (BeS) and chronic beryllium disease (CBD). OBJECTIVES: The purpose of this statement is to increase awareness and knowledge about beryllium exposure, BeS, and CBD. METHODS: Evidence was identified by a search of MEDLINE. The committee then summarized the evidence, drew conclusions, and described their approach to diagnosis and management. MAIN RESULTS: 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 ß 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. CONCLUSIONS: 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.

Beryllium BioBank: 2. Lymphocyte proliferation testing.

OBJECTIVE: To incrementally improve the use of beryllium lymphocyte proliferation test (LPT) results. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Beryllium Biobank 3: considerations for improving chronic beryllium disease screening.

OBJECTIVE: To optimize beryllium worker screening. METHODS: Beryllium-exposed persons are classified as beryllium-exposed, beryllium-sensitized (BeS), or chronic beryllium disease. Implications of defining BeS by two or more positive lymphocyte proliferation tests (LPTs) were investigated with a simple binomial model. The potential effect of adjusting the interval for repeated intensive testing to detect chronic beryllium disease among persons with BeS was assessed with a Markov model. RESULTS: Accuracy of properly identifying BeS is reduced as the number of repeated tests increases. Markov simulation illustrates that adjusting second-stage screening intervals on the basis of personal risk may significantly affect cost-effectiveness. CONCLUSIONS: The criteria for classification as BeS should be adjusted depending on the number of LPTs performed. Modifying the interval for repeated intensive testing on the basis of each worker's data can improve cost-effectiveness.