monary granulomas or other signs of disease. In a follow-up study 31% of those individuals progressed to symptomatic CBD within four years [18]. At present the test still remains the standard diagnostic test, since it is the only way to add an etiologic criterion. Whether patients with a positive Be-LPT in a surveillance program and the demonstration of granuloma suffer from early disease when they are asymptomatic and do not develop pulmonary function defects is a matter of debate.

The use of Be-LPT is cumbersome and alternatives using different readouts of cell activation are under investigation. Flow cytometry [57, 58], ELI-spot techniques [32, 59], and other cytokine based assays may be close to clinical practice. The use of metabolomic signatures to identify CBD and to differentiate CBD from beryllium sensitization is still in its infancy [60].

Measuring beryllium in urine and tissue samples may unequivocally identify exposure; however, concentrations of biological relevance are far below the sensitivity of routine tests, which limits the clinical value of negative results [37, 61–63].

Thus, for the unequivocal diagnosis of CBD the following criteria should be ful lled [3]:

•\ A granulomatous disorder otherwise diagnosed as sarcoidosis needs to be established.

•\ Evidence of exposure.

•\ Proof of beryllium sensitization by positive Be-LPT ndings or a positive equivalent.

In this context it has to be noted that granulomatous disease is not regarded mandatory for making diagnosis of CBD. Mononuclear alveolitis in the presence of beryllium exposure and hypersensitivity in combination with symptomatic disease may be suf cient to support the diagnosis. This is why some authors suggest for reasons of practicability to omit histopathologic criteria [43]. Many different criteria are used to de ne chronic beryllium disease. The differences in these criteria refect the change in our understanding of the disease pathophysiology and the availability of diagnostic tests. Other differences may be related to the purpose of making the diagnosis such as clinical care, surveillance, research, or compensation.

nated [64, 65]. Although there are no studies demonstrating unequivocally a bene t of this step, it is recommended for CBD patients. Whether its social implications are justi ed in sensitized individuals has to be decided on an individual basis in combination with a genetic counseling [66]. Patients with early disease (i.e., sensitization in combination with granuloma but without symptoms or lung function defects) should be monitored using routine lung function tests, exercise physiology, and chest radiographs to detect progressive disease which is considered an indication for corticosteroid therapy. Serological markers of disease activity used in sarcoidosis, such as angiotensin converting enzyme, soluble interleukin-2 receptor or neopterin, can be used to gauge the infammatory activity of CBD [67–69]. However, treatment decisions need to be made on the basis of symptoms and progressing organ dysfunction.

Systemic corticosteroids are the mainstay of CBD treatment and drug regimens established for sarcoidosis are used. Starting doses of 0.5–0.8 mg prednisolone per kg body weight per day are recommended, and stabilization or improvement will take place in most patients. However, under tapering the dose or after cessation of therapy some patients relapse, which may result in long-lasting maintenance therapy. The response to corticosteroids in CBD is quite variable. Long lasting remissions and recalcitrant disease have been observed [70]. Frequently recalcitrant disease can be suppressed with low dose corticosteroid maintenance therapy [70]. There have been no systematic studies of the use of other immunosuppressive, immunomodulatory or anti-infammatory drugs in CBD. For patients who either do not respond to high doses of prednisolone, or require unacceptable high maintenance doses, second line therapy should be guided by experience in sarcoidosis, and corticosteroid-­ sparing regimens can be recommended as a second step [71, 72]. Relatively few patients progress to end-stage lung disease and lung transplantation should be offered to those who qualify for this type of therapy.

Supportive and rehabilitative therapy should be used as necessary. These include supplemental oxygen if rest or exercise-induced hypoxemia is present, bronchodilators if bronchial hyperresponsiveness or obstructive lung disease is present, pulmonary rehabilitation to maintain muscle strength and tone.

Treatment and Monitoring

The rst therapeutic measure is elimination of exposure as occupational studies reported reversibility of physiologic and radiographic defects when exposure is reduced or termi-

Prevention of Beryllium Sensitization

and Chronic Beryllium Disease

At workplaces with contact with beryllium-containing substances, appropriate occupational safety measures should be