What every clinician should know

Chronic beryllium disease (CBD) may develop in individuals who are exposed to beryllium due to a hypersensitivity immune response to the metal beryllium.

Beryllium is a lightweight metal used in many industries, including but not limited to aerospace and aircraft, alloy manufacturing, nuclear reactors, dental implants, ceramics and costume jewelry.

Beryllium has a potential to become airborne as either dust or fume and most workers that have potential exposure may develop beryllium sensitization and eventually, chronic beryllium disease. However, it must be noted that exposure by other methods, such as transdermal sensitization have not been excluded and development of the disease may not be purely related to airborne particle exposure. Given the rarity and expense of the metal, and the availability of compensation and screening on the basis of such exposure, most individuals at risk should be aware of their occupational risk.

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There is also an acute form of the disease which presents as an acute chemical pneumonitis from a non-specific inflammatory reaction; this is now uncommon due to improved industrial preventative measures.

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

CBD presents mainly as a chronic granulomatous pneumonitis with non-caseating granulomas.

Skin granulomas are the second most common presentation and involvement of the liver, spleen, lymph nodes, kidney, and muscle have been reported, though these are less common.

Hyperuricemia has also been reported as a feature of this disease.

Most patients with CBD present with shortness of breath; cough and wheezing may be present. Occasionally, patients may have nonspecific chest pain, fever and night sweats. On physical examination, the chest exam is usually normal, though one can occasionally hear wheezing or basilar inspiratory crackles. As with any advanced lung disease, signs of cor pulmonale may eventually develop.

Beware: there are other diseases that can mimic berylliosis:

One must keep in mind that a wide variety of common diagnoses must be entertained before implicating CBD i.e. sarcoidosis, hypersensitivity pneumonitis, and idiopathic pulmonary fibrosis. It is extremely important to confirm CBD and exclude other diseases as the treatment for CBD includes chronic corticosteroids, which may not be indicated in other disease processes.

The non-caseating granulomas are similar to sarcoidosis. However, extrapulmonary manifestations are rare in CBD and do not present without pulmonary involvement.

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, oxide or alloy can become airborne. Beryllium can become airborne as a result of any heat treatment of the metal, machining, grinding, 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 home on work clothes. Finally residents of neighborhoods surrounding a beryllium plant can be exposed to beryllium that contaminates the ambient air.

The current US limit for airborne beryllium is 0.2 mcg/m3exposure for an eight hour day with a short term exposure limit of 2 mcg/m3over a 15 minute sampling period according to the Occupational Safety and Health Administration (OSHA).

A threshold limit value of 0.05 mg/m3 inhalable beryllium averaged over an 8-hour period has been adopted by the American Council of Governmental Industrial Hygienists in 2009.

Which individuals are at greatest risk of developing berylliosis?

Workers who have the potential to be exposed to greater than 0.1 ugm/m3 of beryllium can be thought of as 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 in 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.

The route and degree of exposure are uncertain and the effects on individuals are variable and are likely related to degree and duration of exposure and individual susceptibility. Aside from the aforementioned genetic polymorphism, no other clearly defined predisposing factors have yet been identified. This is further highlighted by the possibility of disease in populations living in the vicinity of beryllium utilizing industries.

Once an individual is sensitized to beryllium (BeS or Beryllium Sensitization), progression to CBD can occur even after removal of the individual from a beryllium containing environment. CBD can develop several years after sensitization occurs.

CD4+ T cells are activated due to the presentation of beryllium to its surface receptors by MHC II molecules of antigen presenting cells. Furthermore, CD4 + T cells derived from broncholoalveolar lavage (BAL) demonstrate oligoclonal expression specific for beryllium. These T cells have also been shown to secrete various cytokines such as IL2, Interferon Gamma and Tumor Necrosis Factor Alpha, which are contributors to granulomatous inflammation.

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

Beryllium sensitization and CBD can be detected by screening with the Beryllium Lymphocyte Proliferation Assay (BeLPT) which can be performed with peripheral blood or BAL fluid.

Bronchoscopy only needs to be performed if there are no contraindications and if there is evidence of diminished lung function or radiographic evidence of disease.

BeLPT assays are performed by inoculation of mononuclear cells with beryllium salts at three different concentrations over two different time intervals.

If two or more assays are over the normal range of proliferation, it is considered an abnormal or positive test. If only one assay is abnormal, the test is said to be borderline. All borderline and negative tests are repeated in order to improve the sensitivity. If repeat testing is negative, it does not exclude BeS or CBD as there is a 7-10% false negative rate.

By and large, two abnormal BeLPTs or one abnormal and one borderline BeLPT are sufficient to make the diagnosis of BeS.

There are only 4 reference laboratories at academic centers in the US which process such specimens. Care must be taken to contact the receiving laboratory to ensure that specimen handling, processing and transfer are appropriately performed. The centers include the Oak Ridge Institute for Science and Education, Cleveland Clinic Foundation, Hospital of the University of Pennsylvania, and National Jewish Center for Immunology and Respiratory Medicine.

CBD can be said to exist when there is demonstrable lung disease in addition to evidence of BeS by BeLPT testing. Ideally, biopsies are needed for a confirmatory diagnosis of CBD. As such, probable CBD can be diagnosed in the presence of a history of beryllium exposure, clinical manifestations, and radiographic evidence of granulomatous inflammation in the setting of positive BeS by BeLPT testing.

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. Mediastinal or hilar adenopathy may be present, but are not essential as in sarcoidosis. Nodules are the most common finding. Ground glass opacities, bronchial wall thickening, sub pleural cysts, honeycombing, calcification and conglomerate masses can all be seen on CT imaging. None of these findings are particularly specific for CBD.

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

The non-invasive studies that are helpful in making the diagnosis of beryllium disease are blood BeLPT as described above, pulmonary function studies, exercise testing for oxygen desaturation, and occasionally cardiopulmonary exercise testing. A fall in the oxygen saturation with exercise may be the most sensitive screening test in patients with known hypersensitivity to beryllium. Pulmonary function test (PFT) abnormalities in CBD may be restrictive (decreased total lung capacity), obstructive (decreased FEV1/FVC ratio), or show 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 useful as it can confirm the diagnosis and exclude other possible diagnoses. Subjects with beryllium disease usually have increased BAL lymphocytes (usually greater than 20%), a positive BAL BeLPT, and non-caseating granulomatous inflammation on biopsy. Transbronchial biopsies should be stained for acid fast bacilli and fungi to exclude infectious causes of granulomatous disease, and 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.

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

Since CBD is an inflammatory process related to hypersensitivity, it is treated with immunomodulatory drugs when there is impairment of PFTs or significant symptoms.

Since the disease can undergo spontaneous remission, only patients with PFT impairment 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 history and physical examination.

For patients with significant symptoms and abnormal PFTs, corticosteroids (usually prednisone) are first line. High doses are not usually 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 low dose (5-10 mg) prednisone for many years as complete cessation can lead to recrudescence of disease. Patients on chronic corticosteroid therapy must be evaluated with DEXA scanning and treated with calcium and vitamin D. In addition, bisphosphonates may need to be added in the event of prolonged courses of >5mg of prednisone, based on the guidelines suggested by the American College of Rheumatology.

If the only symptom is cough, inhaled steroids may be tried first. If the patient is intolerant of corticosteroids or if the patient is symptomatic despite steroids, immunosuppressive agents such as methotrexate, azathioprine or mycophenolate mofetil may be used.

There is limited data with regard to other medications, such as anti-TNF alpha monoclonal antibodies.

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 at each visit. Blood studies should be performed at each visit to monitor for toxicity. The patient should have complete blood counts, liver function testing and hepatitis screening and folic acid supplementation if methotrexate is being used.

All patients regardless of the degree of disease should be prescribed pulmonary rehabilitation and supplemental oxygen as applicable as well as pneumococcal and seasonal influenza vaccinations as appropriate.

With the patient’s permission, the employer and the regional OSHA office can be notified in order to begin preventive measures at the workplace, if applicable.

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

The natural history of beryllium disease is variable. Not all individuals who develop BeS go on to progress to CBD, though they are at increased risk. The degree of BeLPT positivity is not indicative of prognosis.

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 exposure 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 CBD?

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. Family members of workers may also have been at risk if work clothing was carried home.