Beryllium Disease Research Articles

Beryllium coordination chemistry and its implications on the understanding of metal induced immune responses.

The inhalation of beryllium and its compounds can cause the development of chronic beryllium disease in susceptible individuals. This is caused by a distinct autoimmune process. Here, beryllium coordination compounds with biomimetic ligands are discussed, which are used to understand the coordination of Be2+ in the body and its effect on biomolecules. The advances in the development of precursors for the directed synthesis of these coordination complexes are presented as well as the potential use of non-aqueous solvents for these investigations.

Associations of Metrics of Peak Inhalation Exposure and Skin Exposure Indices With Beryllium Sensitization at a Beryllium Manufacturing Facility.

Peak beryllium inhalation exposures and exposure to the skin may be relevant for developing beryllium sensitization (BeS). The objective of this study was to identify risk factors associated with BeS to inform the prevention of sensitization, and the development of chronic beryllium disease (CBD). In a survey of short-term workers employed at a primary beryllium manufacturing facility between the years 1994-1999, 264 participants completed a questionnaire and were tested for BeS. A range of qualitative and quantitative peak inhalation metrics and skin exposure indices were created using: personal full-shift beryllium exposure measurements, 15 min to 24 h process-specific task and area exposure measurements, glove measurements as indicator of skin exposure, process-upset information gleaned from historical reports, and self-reported information on exposure events. Hierarchical clustering was conducted to systematically group participants based on similarity of patterns of 16 exposure variables. The associations of the exposure metrics with BeS and self-reported skin symptoms (in work areas processing beryllium salts as well as in other work areas) were evaluated using correlation analysis, log-binomial and logistic regression models with splines. Metrics of peak inhalation exposure, indices of skin exposure, and using material containing beryllium salts were significantly associated with skin symptoms and BeS; skin symptoms were a strong predictor of BeS. However, in this cohort, we could not tease apart the independent effects of skin exposure from inhalation exposure, as these exposures occurred simultaneously and were highly correlated. Hierarchical clustering identified groups of participants with unique patterns of exposure characteristics resulting in different prevalence of BeS and skin symptoms. A cluster with high skin exposure index and use of material containing beryllium salts had the highest prevalence of BeS and self-reported skin symptoms, followed by a cluster with high inhalation and skin exposure index and a very small fraction of jobs in which beryllium salts were used. A cluster with low inhalation and skin exposure and no workers using beryllium salts had no cases of BeS. Multiple pathways and types of exposure were associated with BeS and may be important for informing BeS prevention. Prevention efforts should focus on controlling airborne beryllium exposures with attention to peaks, use of process characteristics (e.g. the likelihood of upset conditions to design interventions) minimize skin exposure to beryllium particles, and in particular, eliminate skin contact with beryllium salts to interrupt potential exposure pathways for BeS risk.

Protective role of B cells in sterile particulate-induced lung injury.

Susceptibility to chronic beryllium (Be) disease is linked to HLA-DP molecules possessing a glutamic acid at the 69th position of the β-chain (βGlu69), with the most prevalent βGlu69-containing molecule being HLA-DP2. We have previously shown that HLA-DP2 transgenic (Tg) mice exposed to Be oxide (BeO) develop mononuclear infiltrates in a peribronchovascular distribution and a beryllium-specific, HLA-DP2-restricted CD4+ T cell response. In addition to T cells, B cells constituted a major portion of infiltrated leukocytes in the lung of BeO-exposed HLA-DP2 Tg mice and sequester BeO particles within ectopic lymphoid aggregates and granulomas. B cell depletion was associated with a loss of lymphoid aggregates and granulomas as well as a significant increase in lung injury in BeO-exposed mice. The protective role of B cells was innate in origin, and BeO-induced B cell recruitment to the lung was dependent on MyD88 signaling. Similar to BeO-exposed HLA-DP2 mice, B cells also accumulate in the lungs of CBD subjects, located at the periphery and surrounding the granuloma. Overall, our data suggest a novel modulatory role for B cells in the protection of the lung against sterile particulate exposure, with B cell recruitment to the inflamed lung occurring in an antigen-independent and MyD88-dependent manner.

BeO-exposure induces B cell-mediated Noninfectious Granuloma Formation in the Lung

Abstract Susceptibility to chronic beryllium disease (CBD)is linked to HLA-DP molecules possessing a glutamic acid at the 69thposition of the β-chain (βGlu69), with the most prevalent βGlu69-containing molecule being HLA-DP2. We have previously shown that exposure of HLA-DP2 transgenic mice to beryllium oxide (BeO) results in the development of mononuclear infiltrates in a peribronchovascular distribution and a beryllium-specific, HLA-DP2-restricted CD4+T cell response. In addition to T cells, B cells constituted a major portion of infiltrated leukocytes in the lung of BeO-exposed HLA-DP2 Tg mice and were localized within ectopic lymphoid aggregates and granulomas. B cell depletion had no effect on the development of Be-specific CD4+T cells. However, B cell depletion was associated with a loss of lymphoid aggregates and granulomas as well as a significant increase in lung injury in BeO-exposed mice compared to the isotype-treated group. Furthermore, B cell recruitment to the lung was independent of antigen and dependent on MyD88 signaling through the secretion of CXCL13. Adoptively-transferred WT B cells into BeO-exposed μMT mice significantly reduced lung injury. B cells also surrounded granulomas in transbronchial biopsies from CBD patients, confirming a role for B cells in CBD. Overall, our data suggest a novel modulatory role for B cells in the formation of granulomas and lymphoid aggregates, resulting in the protection of the lung against sterile particulate exposure.

New insight in beryllium toxicity excluding exposure to beryllium-containing dust: accumulation patterns, target organs, and elimination.

There is much contradiction between different experimental studies on beryllium (Be) toxicity. The majority of studies focus on occupational pathologies, caused by the exposure to Be dust. However, Be pollution may affect wide population groups through other exposure routes. The discrepancies between experimental studies may be attributed to the lack of adequate Be toxicity model since conventional administration routes are hampered by high acidity and low solubility of Be compounds. This study was aimed to develop a novel way to implement Be toxicity avoiding side effects, related to high acidity or low solubility of Be salts. Intraperitoneal injection of Be-glycine composition (containing BeSO4, glycine, purified water, pH adjusted to 5.5 with NaOH) was tested in the dose range 238-7622 µmolBekg-1 (body weight, b/w) in full-grown Wistar male rats. The model provided reliable uptake of Be from the peritoneum into general circulation for at least 48h. LD50 was found to be 687 µmolBekg-1 (b/w). The established LD50 value differed from previous data on gastrointestinal, intramuscular or intravenous administration of Be compounds. The liver was found to act as a primary elimination route for Be and related to the highest Be content in the animal. However, it had no signs of morphological damage, which was observed only in the testes (deterioration of germinal epithelium). At the same time, the lungs, stated as a primary target tissue for Be in the models of chronic beryllium disease, did not show strong Be accumulation nor morphological changes. Survived animals showed behavioral changes, including increased motor activity and aggressive reactions in some cases, and complete spasticity in other. The obtained data show the applicability of the established modeling protocol and testified for the independence of chronic beryllium disease on Be2+ ion toxicity per se.

Occupational exposure to beryllium in French industries

Beryllium (Be) is a metal mainly used in the form of alloys, with copper (Cu) and aluminium (Al) in the metal industry. Be is an extremely toxic element which must be handled under strictly controlled conditions to avoid health hazards to workers. Exposure to Be can be responsible for Chronic Beryllium Disease, a pulmonary disease preceded by sensitization to the element, and for lung cancer. The goals of the current study were to investigate Be exposure in France, to determine the airborne Be occupational exposure levels, the associated impregnation of employees through their urinary Be levels and the factors that might affect them, and finally to study a possible relation between biomonitoring and airborne data. Seventy-five volunteer subjects were thus atmospherically and biologically monitored in five French companies involved in Cu or Al casting, Al smelting, CuBe machining or AlBe general mechanical engineering. Airborne exposure was quite low with only 2% of measurements above the current French Occupational Exposure Limit (2 µg/m3); the population potentially most exposed was foundry workers. Impregnation with Be was also low with only 10% of quantified urinary Be measurements above the current German BAR value (0.05 µg/L). Using a Bayesian statistical modelling approach, the mean subject-specific urinary excretion of Be was found to increase significantly with the mean subject-specific exposure to airborne Be. From this relationship, and based on the current French OEL-8 hr, a Biological Limit Value of 0.08 µg/L (= 0.06 µg/g creatinine) could be proposed.

Interstitial Lung Diseases in Developing Countries.

More than 100 different conditions are grouped under the term interstitial lung disease (ILD). A diagnosis of an ILD primarily relies on a combination of clinical, radiological, and pathological criteria, which should be evaluated by a multidisciplinary team of specialists. Multiple factors, such as environmental and occupational exposures, infections, drugs, radiation, and genetic predisposition have been implicated in the pathogenesis of these conditions. Asbestosis and other pneumoconiosis, hypersensitivity pneumonitis (HP), chronic beryllium disease, and smoking-related ILD are specifically linked to inhalational exposure of environmental agents. The recent Global Burden of Disease Study reported that ILD rank 40th in relation to global years of life lost in 2013, which represents an increase of 86% compared to 1990. Idiopathic pulmonary fibrosis (IPF) is the prototype of fibrotic ILD. A recent study from the United States reported that the incidence and prevalence of IPF are 14.6 per 100,000 person-years and 58.7 per 100,000 persons, respectively. These data suggests that, in large populated areas such as Brazil, Russia, India, and China (the BRIC region), there may be approximately 2 million people living with IPF. However, studies from South America found much lower rates (0.4–1.2 cases per 100,000 per year). Limited access to high-resolution computed tomography and spirometry or to multidisciplinary teams for accurate diagnosis and optimal treatment are common challenges to the management of ILD in developing countries.

DNA Methylation Changes in Lung Immune Cells Are Associated with Granulomatous Lung Disease.

Epigenetic marks are likely to explain variability of response to antigen in granulomatous lung disease. The objective of this study was to identify DNA methylation and gene expression changes associated with chronic beryllium disease (CBD) and sarcoidosis in lung cells obtained by BAL. BAL cells from CBD (n = 8), beryllium-sensitized (n = 8), sarcoidosis (n = 8), and additional progressive sarcoidosis (n = 9) and remitting (n = 15) sarcoidosis were profiled on the Illumina 450k methylation and Affymetrix/Agilent gene expression microarrays. Statistical analyses were performed to identify DNA methylation and gene expression changes associated with CBD, sarcoidosis, and disease progression in sarcoidosis. DNA methylation array findings were validated by pyrosequencing. We identified 52,860 significant (P < 0.005 and q < 0.05) CpGs associated with CBD; 2,726 CpGs near 1,944 unique genes have greater than 25% methylation change. A total of 69% of differentially methylated genes are significantly (q < 0.05) differentially expressed in CBD, with many canonical inverse relationships of methylation and expression in genes critical to T-helper cell type 1 differentiation, chemokines and their receptors, and other genes involved in immunity. Testing of these CBD-associated CpGs in sarcoidosis reveals that methylation changes only approach significance, but are methylated in the same direction, suggesting similarities between the two diseases with more heterogeneity in sarcoidosis that limits power with the current sample size. Analysis of progressive versus remitting sarcoidosis identified 15,215 CpGs (P < 0.005 and q < 0.05), but only 801 of them have greater than 5% methylation change, demonstrating that DNA methylation marks of disease progression changes are more subtle. Our study highlights the significance of epigenetic marks in lung immune response in granulomatous lung disease.

TLR9 and IL-1R1 Promote Mobilization of Pulmonary Dendritic Cells during Beryllium Sensitization.

Metal-induced hypersensitivity is driven by dendritic cells (DCs) that migrate from the site of exposure to the lymph nodes, upregulate costimulatory molecules, and initiate metal-specific CD4+ T cell responses. Chronic beryllium disease (CBD), a life-threatening metal-induced hypersensitivity, is driven by beryllium-specific CD4+ Th1 cells that expand in the lung-draining lymph nodes (LDLNs) after beryllium exposure (sensitization phase) and are recruited back to the lung, where they orchestrate granulomatous lung disease (elicitation phase). To understand more about how beryllium exposures impact DC function during sensitization, we examined the early events in the lung and LDLNs after pulmonary exposure to different physiochemical forms of beryllium. Exposure to soluble or crystalline forms of beryllium induced alveolar macrophage death/release of IL-1α and DNA, enhanced migration of CD80hi DCs to the LDLNs, and sensitized HLA-DP2 transgenic mice after single low-dose exposures, whereas exposures to insoluble particulate forms beryllium did not. IL-1α and DNA released by alveolar macrophages upregulated CD80 on immature BMDC via IL-1R1 and TLR9, respectively. Intrapulmonary exposure of mice to IL-1R and TLR9 agonists without beryllium was sufficient to drive accumulation of CD80hi DCs in the LDLNs, whereas blocking both pathways prevented accumulation of CD80hi DCs in the LDLNs of beryllium-exposed mice. Thus, in contrast to particulate forms of beryllium, which are poor sensitizers, soluble or crystalline forms of beryllium promote death of alveolar macrophages and their release of IL-1α and DNA, which act as damage-associated molecular pattern molecules to enhance DC function during beryllium sensitization.

A comparative evaluation of the effectiveness of wipe sampling materials to remove beryllium from differently textured surfaces using zinc oxide as a surrogate

Wipe sampling is a commonly used method for testing a surface for beryllium or other metal particle contamination. Existing wipe sampling methods have only been validated for smooth surfaces. On rough surfaces contaminant particles may be located behind surface projections where they would not be collected by the wipe. This could lead to an underestimate of surface contamination levels. Worker exposure to surfaces contaminated with beryllium could contribute to beryllium sensitization leading to chronic beryllium disease. Likewise, exposure to surfaces contaminated with other toxic metals could have their own health effects. This study investigated the efficiency of collecting 1–5 μm diameter zinc oxide particles by five commercially available wipe materials (SKC Smear Tabs, Whatman® 41 filter paper, Kimtech Prep* ScottPure* Critical Task Wipers, Ghost Wipes, and Hygenall LeadOff wipes) from surfaces of different roughness (sandpaper of 60–6,000 grit). Zinc oxide was used as a surrogate for beryllium because of its much lower toxicity. Overall, the wipes were most efficient at collecting particles from the fine grits and poor at collecting particles from the coarse grits. The Smear Tabs and Whatman filters performed poorly in both durability and particle collection efficiency. In both respects, the superior performers were the Ghost Wipes and LeadOff wipes. However, even in the best case, the wipe still left behind 20% of the particles. These results indicate that underestimating metal particle contamination levels is a serious possibility when conducting wipe sampling on textured surfaces.

Polymorphism of FCGR3A gene in chronic beryllium disease.

Previously we showed that alveolar macrophages(AMs) from patients with chronic beryllium disease(CBD) and beryllium sensitization(BeS) demonstrated significantly greater cell surface CD16(encoded by the FCGR3A gene) than controls. We hypothesized that these differences were related to polymorphisms in the FCGR3A gene. This study was to determine the association between FCGR3A polymorphisms in CBD, BeS versus controls as well as clinical data, providing potential information about disease pathogenesis, risk and activity. 189 CBD/154 BeS /150 controls (92 Be-exposed-non-diseased and 58 healthy controls) were included in this study. Sequence specific primers polymerase chain reaction(PCR-SSP) was used to determine FCGR3A 158V/F polymorphisms. We found significantly higher frequencies of the 158V allele (OR:1.60 (CI: 1.17-2.19),p=0.004) and 158VV homozygotes (OR:2.97 (CI:1.48-5.97) p=0.007) in CBD versus controls. No differences were found in the frequencies of FCGR3A alleles or genotypes between BeS versus controls and CBD versus BeS. Average changes in exercise testing maximum workload(Wlm),maximum oxygen consumption(VO2m) and diffusion capacity of carbon monoxide(DLCO) demonstrated greater decline over time in those CBD cases with the 158VV gene, modelled between 10 and 40 years from first beryllium exposure. The FCGR3A V158F polymorphism is associated with CBD compared to BeS and controls and may impact lung function in CBD.

A Pilot Study Assessing the Ability of 5-Aminosalicylic Acid to Modulate the Immune Response in Chronic Beryllium Disease

Chronic beryllium disease is a granulomatous lung disease, characterized by the accumulation of macrophages and beryllium-specific CD4+ T-cells that proliferate and produce T-helper cell type 1 cyt...

Immunologic Effects of Beryllium Exposure.

Metal-induced hypersensitivity is driven by T-cell sensitization to metal ions. Although numerous metals are associated with the development of diffuse parenchymal lung disease, beryllium-induced hypersensitivity is the best-studied to date. This review focuses on the interaction between innate and adaptive immunity that leads to the development of chronic beryllium disease. After beryllium exposure, activation of the innate immune system occurs through the engagement of pattern-recognition receptors. This activation leads to cell death, release of alarmins, and activation and migration of dendritic cells to lung-draining lymph nodes. These events culminate in the development of an adaptive immune response that is characterized by beryllium-specific, T-helper type 1-polarized, CD4+ T-cells and granuloma formation in the lung. The unique ability of beryllium to bind to human leukocyte antigen-DP molecules that express a glutamic acid at position 69 of the β-chain alters the charge and conformation of the human leukocyte antigen-DP-peptide complex. These changes induce post-translational modifications that are recognized as non-self. In essence, the ability of beryllium to create neoantigens underlies the genesis of chronic beryllium disease, and demonstrates the similarity between beryllium-induced hypersensitivity and autoimmunity.

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.

Measuring the Psychosocial Effects of Beryllium Sensitization and Chronic Beryllium Disease in Current and Retired Workers

Current and former workers from the U.S. Department of Energy complex were surveyed to measure the psychosocial effects of beryllium sensitization (BeS) and chronic beryllium disease (CBD). Questionnaires were administered to measure uncertainty in illness, psychosocial adjustment to illness, and health quality of life. Hypotheses were tested and relationships between variables determined. There were 126 participants; 52 with CBD and 74 with BeS. The health quality of life survey indicated participants with CBD had significantly different physical component summary scores than those with BeS. Mental component summary scores were similar. Psychosocial adjustment scores were also significantly different. Uncertainty scores were approximately equal. Moderate to strong correlations were found between the three variables. As uncertainty increased, health quality of life decreased unless the effects were mediated by psychosocial adjustments to the illness. It was concluded that BeS may have as much impact on mental health as CBD. If true, this adds an important new component to the spectrum of CBD that has implications for treatment and workers compensation.

Conceptual Model of the Psychosocial Effects of Beryllium Sensitization and Chronic Beryllium Disease

The objective of this research was to develop a theoretical model that describes the psychosocial effects of beryllium sensitization (BeS) and chronic beryllium disease (CBD). The medical, nursing, health education, and psychological literature was reviewed to identify theories that might support the development of a psychosocial model of BeS and CBD. A proposed model was synthesized based upon elements from multiple academic disciplines. The conceptual model is based on three prominent psychological theories: 1) health, stress, and coping, 2) uncertainty and illness, and 3) psychosocial adjustment to illness. The model hypothesizes that workers who are diagnosed with BeS or CBD experience a great deal of uncertainty that has a detrimental effect on their health quality of life. The focal relationship in this model is between the independent variable uncertainty and the dependent variable health quality of life. It is further hypothesized that the relationship between these two variables is affected by an intermediate variable, the ability to make psychosocial adjustments to disease. Creating this model is a step toward filling a void in our understanding of the natural history of CBD. Once validated it will establish a foundation for future research, interventions and program evaluations and may lead to changes in the psychological, social, financial, and disease management support provided to this population.

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

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. 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. 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). 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.

Clinical tool for disease phenotyping in granulomatous lung disease.

BackgroundExposure to beryllium may lead to granuloma formation and fibrosis in those who develop chronic beryllium disease (CBD). Although disease presentation varies from mild to severe, little is known about CBD phenotypes. This study characterized CBD disease phenotypes using longitudinal measures of lung function.MethodsUsing a case-only study of 207 CBD subjects, subject-specific trajectories over time were estimated from longitudinal pulmonary function and exercise-tolerance tests. To estimate linear combinations of the 30-year values that define underlying patterns of lung function, we conducted factor analysis. Cluster analysis was then performed on all the predicted lung function values at 30 years. These estimates were used to identify underlying features and subgroups of CBD.ResultsTwo factors, or composite measures, explained nearly 70% of the co-variation among the tests; one factor represented pulmonary function in addition to oxygen consumption and workload during exercise, while the second factor represented exercise tests related to gas exchange. Factors were associated with granulomas on biopsy, exposure, steroid use and lung inflammation. Three clusters of patients (n = 53, n = 59 and, n = 95) were identified based on the collection of test values. Lower levels of each of the factor composite scores and cluster membership were associated with baseline characteristics of patients.ConclusionsUsing factor analysis and cluster analysis, we identified disease phenotypes that were associated with baseline patient characteristics, suggesting that CBD is a heterogeneous disease with varying severity. These clinical tools may be used in future basic and clinical studies to help define the mechanisms and risk factors for disease severity.

5-Aminosalicylic Acid Modulates the Immune Response in Chronic Beryllium Disease Subjects.

Chronic beryllium disease (CBD) is characterized by accumulation of macrophages and beryllium-specific CD4+ T cells that proliferate and produce Th1 cytokines. 5-Amino salicylic acid (5-ASA) is currently used to treat inflammatory bowel disease and has both antioxidant and anti-inflammatory actions. We hypothesized that 5-ASA may be a beneficial therapeutic in CBD. Seventeen CBD patients were randomized 3:1 to receive 5-ASA 500-mg capsules or placebo four times daily for 6weeks orally. Primary study endpoints included changes in beryllium lymphocyte proliferation (BeLPT). Secondary endpoints included changes in bronchoalveolar lavage (BAL) fluid, cells, serum, and blood cell glutathione (GSH) levels, BAL cell TNF-α levels, lung function, and quality of life measures. 5-ASA decreased BAL cell BeLPT by 20% within the 5-ASA treatment group. No significant changes were observed in serum, PBMCs, BALF, or BAL cell GSH levels in either the 5-ASA or placebo treatment group. 5-ASA treatment decreased ex vivo Be-stimulated BAL cell TNF-α levels within the 5-ASA group and when compared to placebo. Significant improvements were noted in quality of life measurements with 5-ASA treatment. 5-ASA's ability to decrease BAL cell BeLPT and Be-stimulated BAL cell TNF-α levels suggests that 5-ASA may impact the beryllium-specific immune response in CBD. 5-ASA use in other non-infectious granulomatous lung diseases, such as sarcoidosis, may prove to be a useful alternative treatment to corticosteroids for those with mild to moderate disease.

Clinical Course of Sarcoidosis in World Trade Center-Exposed Firefighters

Sarcoidosis is believed to represent a genetically primed, abnormal immune response to an antigen exposure or inflammatory trigger, with both genetic and environmental factors playing a role in disease onset and phenotypic expression. In a population of firefighters with post-World Trade Center (WTC) 9/11/2001 (9/11) sarcoidosis, we have a unique opportunity to describe the clinical course of incident sarcoidosis during the 15 years postexposure and, on average, 8 years following diagnosis. Among the WTC-exposed cohort, 74 firefighters with post-9/11 sarcoidosis were identified through medical records review. A total of 59 were enrolled in follow-up studies. For each participant, the World Association of Sarcoidosis and Other Granulomatous Diseases organ assessment tool was used to categorize the sarcoidosis involvement of each organ system at time of diagnosis and at follow-up. The incidence of sarcoidosis post-9/11 was 25 per 100,000. Radiographic resolution of intrathoracic involvement occurred in 24 (45%) subjects. Lung function for nearly all subjects was within normal limits. Extrathoracic involvement increased, most prominently joints (15%) and cardiac (16%) involvement. There was no evidence of calcium dysmetabolism. Few subjects had ocular (5%) or skin (2%) involvement, and none had beryllium sensitization. Most (76%) subjects did not receive any treatment. Extrathoracic disease was more prevalent in WTC-related sarcoidosis than reported for patients with sarcoidosis without WTC exposure or for other exposure-related granulomatous diseases (beryllium disease and hypersensitivity pneumonitis). Cardiac involvement would have been missed if evaluation stopped after ECG, 48-h recordings, and echocardiogram. Our results also support the need for advanced cardiac screening in asymptomatic patients with strenuous, stressful, public safety occupations, given the potential fatality of a missed diagnosis.