Pulmonary Medicine


What every physician needs to know:

Chronic beryllium disease is a hypersensitivity response to the metal beryllium. This condition occur only in individuals who have a potential exposure to beryllium. Beryllium is a lightweight metal that, because of its light weight, is used in the aerospace and aircraft industries as an alloy with copper and other metals to make them harder, in nuclear reactors because it is a neutron reflector, and in dental bridges and crowns and in costume jewelry.

It is also made into a ceramic (BeO) because of its ability to absorb heat and its light weight. Because of beryllium's potential to become airborne as either dust or fumes, anyone who works with a product that contains beryllium has the potential to develop chronic beryllium disease. Because of the rarity and expense of the metal, most individuals who work with it are aware that they have worked with it.


Chronic beryllium disease presents mainly as a chronic granulomatous pneumonitis. Skin granuloma are the second most common form of presentation. Among individuals who have had high exposures to beryllium, involvement of the liver, spleen, lymph nodes, kidney, and muscle have been reported. Hyperuricemia has also been reported.

Are you sure your patient has berylliosis? What should you expect to find?

Most patients with chronic beryllium disease present with shortness of breath; cough and wheezing may be present. Occasionally, patients may have a non-specific chest pain, fever and night sweats. On physical examination, the chest examination is usually normal, though one can occasionally hear basilar rales or wheezing. With advanced disease, the signs of cor pulmonale may be present (i.e., distended neck veins, enlarged liver, edema, and a split second heart sound with an S3).

Beware: there are other diseases that can mimic berylliosis:

The major diseases that mimic chronic beryllium disease are sarcoidosis, hypersensitivity pneumonitis, and pulmonary fibrosis.

How and/or why did the patient develop berylliosis?

Exposure to beryllium is essential for the disease to occur. Exposure can occur in an industrial situation in which beryllium as a pure metal, an oxide, or an allow can become airborne. Beryllium can become airborne as a result of any heat treatment of the metal, machining, grinding, or lapping or when alloys or metal have been exposed to the environment and a rust of beryllium oxide forms on the surface.

In addition, family members of beryllium workers can be exposed to beryllium that is taken into the home on the work clothes. Finally, residents of neighborhoods surrounding a beryllium plant can be exposed to beryllium that contaminants the ambient air. While the lowest concentration in the air is that can still cause beryllium disease is not certain, the OSHA standard of an average of 2 ugm/m3over an eight-hour day is not thought to be protective.

Which individuals are at greatest risk of developing berylliosis?

Currently, any worker who has the potential to be exposed to greater than 0.1 ugm/m3 of beryllium is thought to be at risk for developing beryllium disease. The risk for these workers is probably between 1 percent and 10 percent.

In addition to the environmental risk, genetic risk factors play a role is the susceptibility to beryllium disease. The HLA polymorphism of having a glutamate on position 69 of the HLA DP protein, which carries the greatest risk, is present in about 90 percent of patients with beryllium disease as well as about 40 percent of the general population. This genetic marker appears to be a risk factor for the ability to develop a hypersensitivity reaction to beryllium but not of whether someone who has developed a hypersensitivity reaction will develop the disease.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

The diagnosis of chronic beryllium disease requires the demonstration of an immune response to beryllium and evidence of a granulomatous pneumonitis. The immune response to beryllium can be demonstrated by performing a blood BeLPT (beryllium lymphocyte proliferation assay). If the blood BeLPT is negative, then a similar test can be performed on cells obtained by bronchoalveolar lavage. Only four laboratories in the United States perform BeLPT testing.

Evidence for a granulomatous pneumonitis is best demonstrated by having the patient undergo a bronchoscopy with trans-bronchial lung biopsies. If the patient is too sick to undergo a bronchoscopy, the Department of Labor criteria for chronic beryllium disease is 1) evidence of obstructive or restrictive disease on pulmonary function tests or an abnormal diffusion capacity not otherwise explained or 2) chest x-ray or CT evidence of granulomatous disease consistent with beryllium disease (fibronodular upper lobe infiltrates).

What imaging studies will be helpful in making or excluding the diagnosis of berylliosis?

High-resolution chest CT is the best imaging study to screen for the presence of beryllium disease.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of berylliosis?

The non-invasive diagnostic studies that are helpful in making the diagnosis of beryllium disease are blood BeLPT and pulmonary function studies and cardiopulmonary exercise tests. A fall in the oxygen saturation with exercise may be the most sensitive screening test in patients with known hypersensitivity to beryllium. Pulmonary function abnormalities in CBD may be restrictive (decreased total lung capacity), obstructive (decreased FEV1/FVC ratio), or abnormal diffusion (decreased Dlco). However, with immunologic screening, many patients are diagnosed before there are any physiologic abnormalities.

What diagnostic procedures will be helpful in making or excluding the diagnosis of berylliosis

Bronchoscopy with BAL cell differential, BeLPT and transbronchial biopsies is the most useful diagnostic study. Subjects with beryllium disease usually have increased BAL lymphocytes (usually greater than 20%), a positive BAL BeLPT, and evidence of non-caseating granulomatous inflammation on biopsy. Trans-bronchial biopsies should be stained for acid fast bacilli and fungi to exclude infectious causes of granulomatous disease, and the BAL fluid should also be cultured for fungus and mycobacteria to exclude infectious causes.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of berylliosis?

While a strong association has been found between the disease and the HLA polymorphism of a glutamate at position 69 on the HLA DP beta change (present in ~90% of cases), this polymorphism is also found in 40 percent of the control population so genetic testing has not been useful.

Bronchoscopy with BAL cell differential, BeLPT, and transbronchial biopsies is the most useful diagnostic study. Subjects with beryllium disease usually have increased BAL lymphocytes (usually greater than 20%), a positive BAL BeLPT, and evidence of non-caseating granulomatous inflammation on biopsy. Transbronchial biopsies should be stained for acid fast bacilli and fungi to exclude infectious causes of granulomatous disease. The BAL fluid should also be cultured for fungus and mycobacteria to exclude infectious causes.

If you decide the patient has berylliosis, how should the patient be managed?

Since beryllium disease is a hypersensitivity pneumonitis, it is treated with immunomodulatory drugs when there is impairment of function (abnormal PFTs) or significant symptoms (shortness of breath). Since the disease can undergo spontaneous remission, only patients with impairment of function or significant symptoms should be treated. Patients who have no symptoms or impairment are usually monitored for disease progression with yearly PFTs, cardiopulmonary exercise studies, and chest x-rays or CTs, in addition to a physical examination and history.

For patients with significant symptoms and abnormal PFTs, corticosteroids (usually prednisone) are the drugs of first choice. High doses are usually not required; patients can be started on 0.5 mg/kg in daily or every other day doses. The dose is then tapered at three month intervals until the lowest dose that prevents symptoms (cough or shortness of breath) or deterioration of PFTs is achieved. Patients usually need to be on a low dose (5-10 mg) of prednisone for many years.

If the only symptom of berylium disease is cough, inhaled steroids should be tried first. If the patient is intolerant of corticosteroids, steroid-sparing drugs (methotrexte, imuran, or mycophenolate mofetil) may be used. The anti-TNF monoclonal antibodies may be useful if a patient is intolerant of all the other medication. Patients on treatment should be followed at least every three months while the dose of immunosuppressive medication is being adjusted, and they should have PFTs (spirometry, lung volumes, and Dlco) at each visit. Blood studies should be performed at each visit to monitor for toxicity. More frequent blood studies are needed if the patient is on a steroid-sparing regimen.

Progressive beryllium disease should be preventable and should not lead to right heart failure and respiratory insufficiency if the disease is detected early and treated. The major risks of treatment are the side effects of the medication. For corticosteroids, side effects include weight gain, diabetes, hypertension, GERD, bone demineralization, and depression. For the steroid-sparing drugs, side effects usually include opportunistic infections, bone marrow suppression, and liver and pulmonary disease.

What is the prognosis for patients managed in the recommended ways?

The natural history of beryllium disease is varied. Some individuals have evidence of disease and no impairment and do not progress to impairment, while others may develop progressive impairment that leads to right heart failure, respiratory insufficiency, and death. The latter cases may be more common in individuals who have had exposures to higher concentrations of beryllium. While there have been no placebo-controlled studies in beryllium disease, it is believed that treatment should be started before there is irreversible fibrosis. Treatment usually prevents fibrosis and progressive impairment.

What other considerations exist for patients with berylliosis?

Since beryllium disease is occupationally related, patients should be advised that they are eligible for compensation. Government workers and workers at Department of Energy sites are eligible for a screening and medical management program offered by the DOE and DOL. Workers in private industry may have to contact a lawyer to obtain compensation. If the worker wore work clothes home, then family members might have been exposed to beryllium.

What’s the evidence?

Andrews, JL, Kazemi, H, Hardy, H. "Patterns of lung dysfunction in chronic beryllium disease". American Review of Respiratory Disease. vol. 100. 1969. pp. 791-800.

Best documentation of PFT abnormalities in CBD in the era before immunologic screening and diagnosis.

Frieman, DG, Hardy, HL. "Beryllium disease: the relation of pulmonary pathology to clinical course and prognosis based on a study of 130 cases from the US beryllium case registry". Human Pathology. vol. 1. 1970. pp. 25-44.

Best description of course and prognosis of CBD prior to early diagnosis and widespread use of immunosuppressive agents.

Rossman, MD, Kern, JA, Elias, JA, Cullen, MR, Epstein, PE, Preuss, OOP. "Proliferative response of bronchalveolar lymphocytes to beryllium: a test for chronic beryllium disease". Annals of Int Med. vol. 108. 1988. pp. 687-693.

Original report documenting that beryllium disease is due to a hypersensitivity response to beryllium.

Mroz, MM, Maier, LA, Strand, M, Silviera, L, Newman, LS. "Beryllium lymphocyte proliferation tests surveillance identifies clinically significant beryllium disease". Am J Int Med. vol. 52. 2009. pp. 762-773.

Best long-term follow up study of individuals identified with either CBD or BeS by the BeLPT with long-term follow-up data and pulmonary function.
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