Berylliosis, also known as chronic beryllium disease (CBD), is a granulomatous disease caused by exposure to beryllium. CBD has a variable clinical course with cough, fever, night sweats, and fatigue being the most common symptoms. A definitive diagnosis of berylliosis is based on occupational history, positive blood or bronchoalveolar lavage (BAL) beryllium lymphocyte proliferation test (BeLPT), and granulomatous inflammation on lung biopsy. The current Occupational Safety and Health Administration (OSHA) guidelines reduce the permissible exposure limit for beryllium to .2 mcg/m3 averaged over 8 hours or less than 2 mcg/m3 over a 15 minute period. It is an incurable occupational lung disease, but symptoms can be treated with glucocorticoids and immunosuppressive agents.
CBD is more likely to develop in individuals who work in industries that manufacture and process beryllium. Overall, there is nothing unique about berylliosis; it is similar to many other granulomatous lung disorders.
Exposure to beryllium is the underlying causative factor. Heavy beryllium-using industries include metal machine shops, electronics, defense industries, and beryllium extraction companies. Other industries include ceramic, automotive, aerospace, jewelry making, dental/alloy appliance, and computer. It appears that some people may have a genetic predisposition towards developing severe CBD.
Beryllium exposure tends to occur via inhalation of beryllium fumes or dust, but it can also be absorbed following skin exposure. The organic forms of beryllium are rapidly excreted, but the insoluble inorganic particles can remain in the body for many years.
CBD is a hypersensitivity granulomatous disease that occurs in 2 to 5% of beryllium-exposed workers. Stopping exposure to beryllium has not been shown to stop the progression to CBD. Unless an individual lives very close to an industrial site, the general population is unlikely to develop acute or CBD because ambient air levels of beryllium are normally very low (< 0.03 ng/m3).
Exposure to beryllium can lead to a cell-mediated immune response where T-cells become sensitized to beryllium. Each subsequent exposure leads to an immune response involving macrophages and CD4+ helper T-lymphocytes accumulating in the lungs. As this response proceeds, macrophages, CD+4 T-lymphocytes, and plasma cells aggregate to form noncaseating granulomas that evolve to cause fibrosis of the lung. Studies have revealed there is a genetic component to beryllium sensitivity. Specifically, those beryllium-exposed workers with a mutation at the HLA-DPB1 Glu69 position have increased the prevalence of beryllium sensitization and CBD. The HLA-DPB1 gene is important for MCH class II molecule function on antigen-presenting cells. Beryllium and beryllium compounds are category 1 carcinogens and carcinogenic to both animals and humans.
The key feature on histopathology is the nonnecrotizing granulomas in the lung; which mimic those seen in sarcoidosis.
The clinical manifestations of CBD are nonspecific. The latency period between beryllium exposure and the onset of symptoms varies from three months to 30 years. Common symptoms include fever, night sweats, weight loss, dry cough, and fatigue. Continued exposure causes noncaseating inflammatory granulomas. They also see granulomas in other chronic diseases, such as tuberculosis and sarcoidosis. CBD leads to restrictive lung disease (a decrease in diffusion capacity). Rarely, granulomas occur in other organs, such as the liver.
The physical exam may reveal lymphadenopathy, crackles, rash, and hepatosplenomegaly.
A definitive diagnosis of berylliosis is based on the history, positive blood or bronchoalveolar lavage (BAL) beryllium lymphocyte proliferation test (BeLPT), and granulomatous inflammation on lung biopsy. Establishing beryllium sensitivity is the first step, and this is determined by the beryllium lymphocyte proliferation test (BeLPT). The test is performed by acquiring either peripheral blood or fluid from a bronchial alveolar lavage and culturing lymphocytes with beryllium sulfate. Cells are then counted, and they consider those with an elevated number of cells abnormal. Those exposed persons with two abnormal BeLPTs with peripheral blood or one abnormal and one borderline result are beryllium sensitized. Also, those with one abnormal BeLPT with fluid from a bronchial alveolar lavage is considered sensitized. For patients with positive BeLPT, bronchoscopy with bronchoalveolar lavage (BAL) is performed to obtain cell counts. Lastly, a tissue biopsy is obtained from bronchoscopy to fulfill the last criterion for CBD diagnosis. 
Chest radiography findings of berylliosis are non-specific. Early in the disease, radiography findings are usually normal. In later stages, interstitial fibrosis, pleural irregularities, hilar lymphadenopathy, and ground-glass opacities have been reported. Findings on CT are not specific for berylliosis. Findings that are common in CT scans of people with berylliosis include parenchymal nodules in early stages. One study found that ground-glass opacities were more commonly seen on CT scan in berylliosis than in sarcoidosis. In later stages, hilar lymphadenopathy, interstitial pulmonary fibrosis, and pleural thickening are found.
Other tests include:
The goals when treating berylliosis are to reduce symptoms and slow the progression of the disease as no cure is available. Although there is no evidence that stopping exposure to beryllium decreases the progression of the disease, they still consider it to be an accepted approach to treatment. People with early stages, without lung function abnormalities or clinical symptoms, are periodically monitored, with physical exams, pulmonary function tests, and radiography. All patients require influenza and pneumococcal vaccination and smoking cessation counseling. After the appearance of clinical symptoms or significant abnormalities appears in pulmonary function testing, oxygen and oral corticosteroids are started as well as other supportive therapy as required.
The drugs of choice to treat chronic beryllium disease are corticosteroids. It usually requires a high starting dose and the treatment duration is often for several months before they see symptom resolution. Once symptoms subside, tapering of the steroids is necessary to prevent the adverse effects. Patients who fail to respond to steroids are started on immunosuppressive agents such as methotrexate and azathioprine. Oral methotrexate at a 7.5mg weekly dose is given with folic acid 1 mg. Complete blood counts and liver function tests should be repeated 8 to 12 weeks at a time.
Once a diagnosis of CBD is made, the patient needs life-long follow up with serial arterial blood gases, chest x-ray, and pulmonary function tests.
Differential diagnosis includes sarcoidosis, idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, asthma, and other granulomatous lung diseases such as histoplasmosis, tuberculosis, silicosis. It is estimated that 6 percent of all patients diagnosed with sarcoidosis may have CBD.
Patients with beryllium sensitization in the absence of CBD do not require treatment but should undergo periodic evaluation. Among these patients, the risk of progression to CBD is increased compared with non-sensitized workers. Overall mortality rates are 5% to 38%. CBD has a variable clinical course. A higher percentage of lymphocytes in the bronchoalveolar lavage correlates with greater severity of illness. Disability is common in people with preexisting lung disease and smokers. The granulomas lead to nodule formation, which can impair lung function.
Prevention is the key in the management of berylliosis. OSHA has recommendations for the workplace including requiring work practice controls such as ventilation or enclosure to limit exposure, provide protective equipment such as respirators, train workers on beryllium hazards, and requiring medical exams to monitor exposed workers. In 2000, a study found that new workers who went through a comprehensive preventive program had reduced beryllium sensitization compared with workers working in the past.
A study of workers in a beryllium facility found that people developed CBD when exposed to above 0.2 mcg/m3. The current United States Occupational Safety and Health Administration (OSHA) reduces the permissible exposure limit for beryllium to 0.2 mcg/m3 averaged over 8 hours or less than 2 mcg/m3 over a 15 minute period.
The American Conference of Governmental Industrial Hygienists (ACGIH) in 2005 issued a recommendation to reduce the threshold limit value (TLV) by 100 fold from 2 to 0.02 mcg/m3 over a 15 minute period. Although ACGIH carries no legal force as OSHA does, it is important to note the recommendation. Beryllium exposure is difficult to control in an industrial work environment, so methods that reduce the possibility of airborne and surface contamination are needed. These include minimal use of beryllium and beryllium-containing alloys and employee education about the possible hazards when the dust or fumes of beryllium are encountered in the workplace.
Several guidelines have been developed to help prevent berylliosis in the workplace. However, an interprofessional approach is required to ensure that the diagnosis is not missed. Patients often present to the primary health care provider who may not be aware of the disorder, hence referral to a pulmonologist is recommended. The pharmacist should advise the patient to discontinue smoking, and the nurse should educate the patient and the family on the disease. A pulmonologist may help make the diagnosis and help monitor the disease. In industries that handle beryllium, the public health nurse should create awareness of the disorder and how to prevent it. Workers should be told to wear a mask and appropriate long-sleeved garments. Some industries also refer the workers for annual chest exams. Patients should be told to quit smoking and change occupation if the exposure is high. The pharmacist should discuss the potential side effects of steroids, and monitor the patient for complications, reporting to the healthcare team. [Level V]
In the USA, berylliosis is declining, but outside North America, it is still a problem because of unregulated textile industries. A detailed work exposure, history, physical examination, radiography, pulmonary function test, selected lab studies, and bronchoalveolar lavage fluid can be used to identify early stages of disease.  [Level V]
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