Inhalation of beryllium (Be) has been associated with two pulmonary syndromes, which are an acute chemical pneumonitis and a granulomatous lung disease known as chronic beryllium disease (CBD), or berylliosis. In acute beryllium disease, the metal acts as a direct chemical irritant, causing a nonspecific inflammatory reaction (acute chemical pneumonitis). Due to improved industrial hygiene measures, acute beryllium disease virtually has disappeared and is not discussed in this article.
CBD continues to occur in industries where beryllium is manufactured and processed, and workers are exposed to beryllium fumes or dust. It is clinically similar to other granulomatous diseases such as sarcoidosis.[1] Signs and symptoms of CBD can include shortness of breath, an unexplained cough, fatigue, weight loss, fever, and night sweats. Some workers may develop severe symptoms very quickly, while others may not experience signs and symptoms until months or years after their exposure to beryllium. CBD can continue to progress even after exposure has been removed. Beryllium sensitization (BeS) is affected by both exposure and genetic characteristics and only individuals with BeS are at risk for developing CBD. Cross-sectional studies of workers in various U.S. industries have found that the prevalence of BeS ranged from 0.9% to 14.6%, and the prevalence of CBD ranged from 0.0% to 7.8%.[2]
Due to the use of the beryllium lymphocyte proliferation test (BeLPT) to screen workers exposed to beryllium, many cases now are diagnosed very early in the course of the disease, before radiographic or physiologic changes are observed and before symptoms or physical signs develop. Patients with a positive finding on blood BeLPT but no lung pathology are considered sensitized to beryllium, but they do not have CBD. To make the diagnosis of CBD, the following criteria need to be satisfied: (1) evidence of sensitization to beryllium by positive findings on blood or bronchoalveolar lavage beryllium lymphocyte proliferation test (BeLPT) (see Workup) and (2) the presence of compatible lung pathology (usually nonnecrotizing granulomas on lung biopsy).
The current indications for therapy include the presence of symptoms, abnormal pulmonary function test results, or a decline in pulmonary function over time.[2] In the absence of any of these criteria, no therapy is recommended. Close monitoring of symptoms and follow-up pulmonary function testing is recommended.
In patients with unclear or uncertain history of exposure to beryllium, a positive finding on BeLPT can be used as evidence of prior exposure.
The key to the pathogenesis of chronic beryllium disease (CBD) is a delayed-type hypersensitivity reaction in which beryllium most likely functions as a hapten and acts as a class II restricted antigen, stimulating local proliferation and accumulation in the lung of beryllium-specific T cells.
Beryllium exposure occurs primarily by inhalation of beryllium fumes or dust and contact through broken skin. Most beryllium is excreted in the urine, and the pulmonary half-life ranges from several weeks to 6 months. Relatively insoluble chemical forms of beryllium may be retained for years. Following inhalation of beryllium, large numbers of CD4+ lymphocytes accumulate in the lungs. These helper T cells demonstrate a marked proliferative response on exposure to beryllium.[3]
A study by Van Dyke et al found that a genetic factor, a glutamic acid at position 69 (E69), and exposure to beryllium contribute to the odds of developing chronic beryllium disease and beryllium sensitization.[4]
Beryllium not only has antigen-specific effects but also acts in nonspecific inflammatory ways to promote the cellular events leading to granuloma formation. It may induce changes in lung permeability and production of proinflammatory cytokines and growth factors that lead to granuloma formation and maintenance.
As the disease progresses, the granulomas become organized and eventually form small, fibrous nodules; progressive impairment of pulmonary function occurs. Inhaled beryllium is solubilized in the lungs and distributed primarily to bone, liver, and kidneys. However, other organs can be involved, including extrapulmonary lymph nodes, skin, salivary glands, myocardium, and skeletal muscle.
Chronic beryllium disease (CBD), or berylliosis, is an occupationally acquired lung disease caused by exposure to beryllium, primarily by inhalation and contact through broken skin. Although BeS is required for the development of CBD, not all individuals with BeS progress to CBD. Both genetic factors and higher exposure contribute to risk of CBD, but only genetic factors appear to be associated with BeS.[5]
In 1993, a variant of the major histocompatibility complex HLA-DPB1(Glu 69) was found in 97% of patients with CBD and only in 30% of controls. In this genetic variant, glutamine is expressed instead of lysine at position 69 of the beta region of class II of the major histocompatibility complex.[6] All Glu69 alleles do not confer equal risk, as those with greater negative surface charge (ie, greater binding affinity) are related to increased risk of CBD.[5]
As of 2016, 630 known DNA sequence variants of HLA-DPB1 have been identified, of which 204 are Glu69 alleles (coded as E69). Presence of one copy of the most common E69 allele, HLA-DPB1*02:01, confers an odds ratio of 2 for CBD compared with workers having no E69 alleles; but having any two E69 alleles or having one of the E69 alleles with a −9 (most electronegative) charge on the surface of the molecule is associated with much higher odds ratios, up to 30.8 for CBD, compared with workers with no E69 allele. The subset of HLA-DPB1*E69 alleles with −9 surface charge includes *93:01, *37:01, *29:01, *17:01, *16:01, *10:01, *09:01, *08:01, and *06:01.[7]
The genotype associated with the highest CBD prevalence (72.7%) contains the most common E69 allele (−7-charged) paired with an E69 −9-charged allele, HLA-DPB1*02:01:02/DPB1*17:01. The genotype associated with the second highest CBD prevalence (53.3%) is HLA-DPB1*04:01/DPB1*10:01—a non-E69 −3-charged allele paired with an E69 −9-charged allele. The genotype HLA-DPB1*02:01:02/HLA-DPB1*02:01:02 (homozygous for the most common E69 allele) has a 33.3% CBD prevalence.[7]
Longitudinal studies of defined cohorts showed that 1.0-16.2% of exposed workers developed beryllium sensitization over time, and 0.0-11.0% developed chronic beryllium disease. Usually the attack rate is highest in areas of highest exposure. Longitudinal studies of workers hired after a comprehensive preventive program showed lower levels of beryllium sensitization.[2]
Although strong evidence of genetic susceptibility exists, no racial preference has been shown and males and females are affected equally. chronic beryllium disease is reported in all age groups, from children (due to secondary exposure) to elderly people. Because this is mostly an occupationally acquired disease, the most commonly affected age group is adults.
Due to the persistence of beryllium in the lung years after exposure cessation, the natural history of chronic beryllium disease is characterized by a gradual decline in lung function, with one-third of untreated patients historically progressing to end-stage respiratory insufficiency.[5]
Certain individuals with beryllium sensitization or chronic beryllium disease may be eligible for government benefits and compensation under the Energy Employees Occupational Illness Compensation Program Act. More information is available at Claims for Compensation Under the Energy Employees Occupational Illness Compensation Program Act.
The most significant exposure to beryllium occurs in the occupational setting. Obtaining a good occupational history is critical to effective diagnosis.[8] Occupations with the highest potential for exposure to beryllium are those involved with primary production, metal machining, and reclaiming scrap alloys. Other high-exposure occupations are in the nuclear power, aerospace, and electronics industries. The number of industries that use beryllium is continuously expanding and the above list should not be viewed as exclusive.
Beryllium has been used in a wide variety of products, including some bicycles and golf clubs. Individuals using end products that contain beryllium are currently not considered at risk for sensitization or disease. Only if the beryllium component is handled in a way that generates beryllium dust or particles (eg, sanding) would there be a risk.
Due to the use of BeLPT testing to screen workers exposed to beryllium, many cases now are diagnosed very early in the course of the disease, before radiographic or physiologic changes are observed and before symptoms or physical signs develop. Dyspnea, usually of insidious onset, is the most common symptom. Other symptoms include cough, chest pain, arthralgia, fatigue and weight loss. Physical signs include inspiratory crackles on pulmonary auscultation, lymphadenopathy, rash (dermatitis)[9] and hepatosplenomegaly.
Blood BeLPT currently is the test of choice to identify beryllium workers who develop beryllium sensitization or chronic beryllium disease (CBD).[10, 11, 12, 2, 13] Blood BeLPT has an integral role in reaching a diagnosis of CBD. The test involves exposing peripheral blood mononuclear cells in vitro to beryllium salts at varying concentrations for variable time intervals. Cell proliferation in the presence of beryllium indicates a positive test result.
The beryllium lymphocyte proliferation test (BeLPT) is used for both medical surveillance and diagnosis of BeS and CBD. A BeLPT is considered abnormal if two or more of the six stimulation indices exceed the normal range. A test is typically considered borderline if only one of the six stimulation indices exceeds the normal range.[2]
BeLPT is only performed in selected specialized laboratories, including the following:
Cleveland Clinic
Respiratory Institute
9500 Euclid Avenue
Cleveland, OH 44195-0001
(216) 444-6503
National Jewish Health
Division of Environmental & Occupational Health Sciences
Findings on chest radiography are normal in about half of the patients with documented chronic beryllium disease (CBD). Abnormal findings include hilar adenopathy and/or increased interstitial markings.
High-resolution CT (HRCT) scanning of the chest is more sensitive than chest radiography.[14] Typical findings on HRCT scanning are ground glass opacification (see the image below), parenchymal nodules, or septal lines. Findings on HRCT scanning are negative in 25% of patients with documented CBD.
View Image
Berylliosis. A high-resolution CT scan of the chest showing the typical ground glass appearance in a patient with chronic beryllium disease, or beryll....
Diffusing capacity of lung for carbon monoxide (DLCO)
Arterial blood gases
Cardiopulmonary exercise
With disease progression, spirometry may show evidence of obstruction, restriction, or both. In an early study in 40 patients with advanced chronic beryllium disease, an obstructive pattern was observed in 39% of patients, a restrictive pattern in 20%, and a low DLCO in 36%. The DLCO declines over the course of the disease.[15]
The most sensitive test is abnormalities in gas exchange during exercise.
Laser microprobe mass spectrometry (LAMMS) can be used to detect beryllium in histologic sections from lung biopsy specimens. This test is not necessary for the diagnosis and is not widely available.
Flexible fiberoptic bronchoscopy with BAL and transbronchial biopsies (TBBX) usually is the first invasive step necessary to confirm a suspected diagnosis of chronic beryllium disease (CBD). Patients with CBD usually have BAL lymphocytosis (>20% lymphocytes). The BeLPT test also can be performed on BAL cells. Transbronchial biopsies are sent for histology. A minimum of six high-quality biopsies should be obtained to optimize the yield. If TBBX results are negative but the suspicion for CBD remains high (eg, a positive result on BeLPT and/or a high percentage of lymphocytes in the BAL specimens), consider repeat bronchoscopy.
Open lung biopsy may need to be performed if repeat bronchoscopy findings still are negative.
The hallmark of chronic beryllium disease is the presence of nonnecrotizing granulomas on lung biopsy (see the image below). These granulomas are histopathologically indistinguishable from sarcoid granulomas.
View Image
Berylliosis. A histopathology slide (hematosin and eosin stain) showing the typical well-formed granuloma of chronic beryllium disease, or berylliosis....
The natural history of the disease is not clear in patients who have granulomas on TBBX but who are asymptomatic and have no physiologic or radiographic abnormalities. The current indications for therapy include the presence of symptoms, abnormal pulmonary function test results, or a decline in pulmonary function over time.[2] In the absence of any of these criteria, no therapy is recommended. Close monitoring of symptoms and follow-up pulmonary function testing is recommended.
No controlled studies for chronic beryllium disease (CBD) therapy are available. Based on the pathogenesis of the disease (immune-mediated) and due to the similarities with sarcoidosis, CBD is treated with corticosteroids. When corticosteroid therapy fails or in patients who develop significant adverse effects, methotrexate (MTX) may be considered. Supportive and preventive therapies are administered as needed, similar to the management of other types of interstitial lung disease. Lung transplantation has been used in a few patients with end-stage CBD, but its effectiveness is unknown.
A team approach involving industrial hygiene, occupational health, and pulmonary specialists is necessary for prevention, screening, early diagnosis, and appropriate treatment of CBD.
On January 9, 2017, the US Department of Labor Occupational Safety and Health Administration (OSHA) published its ruling on Occupational Exposure to Beryllium and Beryllium Compounds. The ruling reduced the permissible exposure limit (PEL) for beryllium to an 8-hour time-weighted-average (TWA) of 0.2 micrograms per cubic meter of air (μg/m3). The final rule also established a new short-term exposure limit of 2.0 μg/m3 over a 15-minute sampling period. The new 8-hour exposure limit represents a ten-fold decrease from the previous PEL and is expected to reduce the risk of disease among approximately 62,000 beryllium-exposed workers.[16]
Although no proof exists that cessation of exposure to beryllium improves the disease course or slows the progression, advising all patients with chronic beryllium disease to avoid any further exposure to beryllium is prudent.
The American Thoracic Society (ATS) has released an official clinical statement on the diagnosis and management of beryllium sensitivity and chronic beryllium disease. The ATS notes that medical surveillance identifies individuals with BeS and at-risk groups of workers, which can help prioritize the efforts to reduce inhalation and dermal exposures. Because individuals with beryllium exposure who do not have BeS at the time of initial evaluation remain at future risk, periodic BeLPTs are beneficial. Other key recommendations included the following[2] :
A diagnosis of BeS can be based on two abnormal blood BeLPTs, one abnormal and one borderline blood BeLPT, or one abnormal bronchoalveolar lavage (BAL) BeLPT.
Workers identified as having BeS should be evaluated for CBD.
Pulmonary function testing (PFT) and chest imaging (either a chest radiograph or chest CT scan) are performed on any patient whose BeLPT is diagnostic of BeS.
In the absence of contraindications, bronchoscopy should be considered in patients with evidence of pulmonary function and chest imaging abnormalities
The diagnosis of CBD is based on the demonstration of both BeS and granulomatous inflammation on lung biopsy. Probable CBD can be diagnosed based on differing combinations of diagnostic criteria, including a clinical presentation consistent with CBD, a history of beryllium exposure, evidence of BeS (e.g., abnormal BeLPT), radiographic findings, lung histology, BAL findings, and PFT abnormalities.
Periodic evaluation (every 1–3 yr) should be performed to determine if an individual with BeS has progressed to CBD. It includes a symptom review, physical examination, and PFT, followed by a chest computed tomography scan if pulmonary function has deteriorated and bronchoscopy in select cases.
Corticosteroid therapy is initiated for CBD when there is significant lung function decline. If significant side effects occur, steroid-sparing agents should be considered.
The OSHA final ruling on Occupational Exposure to Beryllium and Beryllium Compounds includes provisions for screening and medical surveillance of workers. In response to the information gained through medical surveillance, workers are able to take actions to improve their health, such as making job choices to reduce exposures, requesting a powered-air purifying respirator for extra protection, or making personal lifestyle or health decisions, such as quitting smoking. OSHA requires employers to offer medical surveillance within 30 days to workers with one of the following triggers[16] :
Is or is expected to be exposed to beryllium above a level of 0.1 µg/m3 for 30 days in a year
Show signs or symptoms of CBD
Were exposed to beryllium during an emergency
Have received a recommendation for continued medical surveillance from a physician or other licensed health care professional (PLHCP) from the most recent exam
Continued medical surveillance should be offered at least every two years thereafter to workers who continue to meet criteria above.
Medical surveillance must include[16] :
Medical and work history with emphasis on past and present airborne exposure to or dermal contact with beryllium
Smoking history
History of respiratory system dysfunction
Physical examination with emphasis on the respiratory system
Physical examination for skin rashes
Pulmonary function tests
BeLPT1
Any other test deemed appropriate by the PLHCP (including low-dose CT scan2)
If the worker is confirmed positive for beryllium sensitization or diagnosed with CBD they should be referred to a CBD Diagnostic Center for further evaluation.
Corticosteroids are the treatment of choice for chronic beryllium disease (CBD). No consensus on the dose or duration of corticosteroid therapy exists. A starting dose of 20-40 mg of oral prednisone daily or every other day usually is used. After an initial 4-6 weeks of therapy, prednisone is tapered, depending on the clinical response.
Methotrexate may be considered in patients who do not respond to corticosteroids or in patients who develop significant adverse effects on corticosteroid therapy.
Clinical Context:
Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production. A 3-phase approach is suggested.
Have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.
Clinical Context:
Unknown mechanism of action in treatment of inflammatory reactions. May affect immune function. Ameliorates symptoms of inflammation (eg, pain, swelling, stiffness). Adjust dose gradually to attain satisfactory response.
Raed A Dweik, MD, MBA, FACP, FRCPC, FCCP, FCCM, FAHA, Professor of Medicine, Cleveland Clinic Lerner College of Medicine;
Chairman, Respiratory Institute, Cleveland Clinic
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
Zab Mosenifar, MD, FACP, FCCP, Geri and Richard Brawerman Chair in Pulmonary and Critical Care Medicine, Professor and Executive Vice Chairman, Department of Medicine, Medical Director, Women's Guild Lung Institute, Cedars Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine
Disclosure: Nothing to disclose.
Acknowledgements
Gregg T Anders, DO Medical Director, Great Plains Regional Medical Command , Brooke Army Medical Center; Clinical Associate Professor, Department of Internal Medicine, Division of Pulmonary Disease, University of Texas Health Science Center at San Antonio
Disclosure: Nothing to disclose.
Oleh Wasyl Hnatiuk, MD Program Director, National Capital Consortium, Pulmonary and Critical Care, Walter Reed Army Medical Center; Associate Professor, Department of Medicine, Uniformed Services University of Health Sciences
Oleh Wasyl Hnatiuk, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and American Thoracic Society
Berylliosis. A high-resolution CT scan of the chest showing the typical ground glass appearance in a patient with chronic beryllium disease, or berylliosis.
Berylliosis. A histopathology slide (hematosin and eosin stain) showing the typical well-formed granuloma of chronic beryllium disease, or berylliosis.
Berylliosis. A high-resolution CT scan of the chest showing the typical ground glass appearance in a patient with chronic beryllium disease, or berylliosis.
Berylliosis. A histopathology slide (hematosin and eosin stain) showing the typical well-formed granuloma of chronic beryllium disease, or berylliosis.
){kind=link}
){kind=link}