Suspected chronic beryllium disease (CBD) is a clinical indication for bronchoscopy. The bronchoalveolar lavage (BAL) fluid from a patient with CBD typically reveals evidence of lung inflammation, indicated by an elevated white blood cell count with an increased number of lymphocytes. Cells from bronchoalveolar lavage should be tested with the beryllium lymphocyte proliferation test (BeLPT) as previously described in the Clinical Assessment section. Lung histopathology reveals interstitial infiltration with mononuclear cells, well-defined noncaseating granulomas (sometimes with multinucleated giant cells and calcific inclusions), and varying degrees of pulmonary fibrosis (Meyer 1994). The granulomas are primarily found in the interstitium and bronchial submucosa.

Besides the BeLPT, several other tests for beryllium sensitization (BeS) or CBD severity have been used, or have been proposed for use. Their ultimate utility is yet to be determined and requires additional research.

• Patch testing: Patch testing for BeS has been used in the past. However, beryllium patch testing fell out of favor, in part because of a potential risk of inducing sensitization and a theoretical risk of aggravating underlying disease.
• Flow cytometric assays (immuno-BeLPT): T-lymphocyte flow cytometry may provide a sensitive alternative to the traditional BeLPT. It offers a test for sensitization without the use of radioactivity and may prove to be easier to standardize for clinical use (Farris et al. 2000; Milovanova et al. 2004).
• Beryllium stimulated serum neopterin: Neopterin may be a useful diagnostic adjunct in the noninvasive assessment of CBD. Elevated levels differentiate CBD from BeS (Maier et al. 2003).
• ELISPOT analysis: The frequency of beryllium-specific T cells in the blood of beryllium-exposed subjects is measured using ELISPOT analysis and may be a useful biomarker that helps discriminate between BeS and progression to CBD (Pott et al. 2005).

Further laboratory evaluation for a patient with a positive initial workup for CBD is performed to determine disease progression. Additional tests include (Glazer and Newman 2003; Newman et al. 1996).

• Repeat chest radiographs. The chest radiograph is usually normal in early disease. Later, it may reveal diffuse, bilateral, small opacities predominantly in the middle and upper lung fields, which are similar to the findings in sarcoidosis. The chest radiograph is insensitive for the detection of CBD, so high resolution CT scan (HRCT) may be required. Approximately one third of patients have enlarged hilar or mediastinal lymph nodes. In more advanced cases, honeycombing may be seen. Importantly, the HRCT may not show evidence of CBD in many cases identified by BeLPT screening (Meyer 1994).

• Repeat pulmonary function and gas exchange tests. The most sensitive physiologic test for the detection of CBD is the cardiopulmonary exercise capacity test (Pappas and Newman 1993). The exercise capacity test reveals gas exchange or ventilatory abnormalities, including an elevation in the dead space-to-tidal volume ratio, in most patients with CBD. Exercise test specificity is improved when an indwelling arterial catheter is used (Lundgren et al. 2001). For many patients with CBD, results of resting pulmonary function tests, including spirometry values, lung volumes, and carbon monoxide-diffusing capacity (DLCO), are normal but resting and exercise arterial blood gas levels indicate hypoxemia. Most symptomatic patients have resting pulmonary function abnormalities; however, there is no classic pattern, and normal function may be seen. Of those with pulmonary function abnormalities, one third of patients present with an obstructive pattern, one fourth with a restrictive pattern of decreased lung volumes, one third with an isolated decreased DLCO, and the remainder have a mixed pattern of obstruction and restriction with varying amounts of gas exchange abnormality (Newman and Maier 2001). In many patients, disease progresses from an obstructive pattern to a mixed pattern and finally to a purely restrictive pattern as it worsens (Newman 1998).

Experts in the evaluation and management of suspected CBD have recommended a two-pronged approach:

1. bronchoscopy to establish a definitive diagnosis and,
2. other testing to evaluate the clinical severity.

The clinician must maintain a high degree of suspicion when evaluating any patient who has had direct or indirect beryllium exposure, especially if the patient has respiratory symptoms or diffuse lung disease. It is important not to prejudge the significance of someone's beryllium exposure level, since seemingly trivial exposures may result in disease (Glazer and Newman 2003).

Current diagnostic criteria for CBD require evidence of both BeS and disease (inflammation and granuloma formation) (Newman and Maier 2001). Therefore, once you suspect CBD, the next step is to perform a blood BeLPT. Most clinicians require two positive blood BeLPT results to define sensitization. Patients with positive blood BeLPT results ideally should undergo bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsy to look for evidence of pathology, which confirms the diagnosis. In situations where an individual is unable to undergo bronchoscopy for medical reasons, chest radiograph or chest computed tomography (CT) abnormalities consistent with CBD may be used as substitute supporting evidence of granulomatous inflammation. If the clinical suspicion remains high despite negative results on blood BeLPTs, consider referral to a pulmonologist with experience in the diagnosis and treatment of CBD for further evaluation (Newman 1996).

Many patients identified as sensitized to beryllium have CBD at the time of initial evaluation even if they are asymptomatic and have normal chest radiographs and resting pulmonary function (Henneberger et al. 2001). In CBD patients, further testing is warranted, including pulmonary function tests, measurement of DLCO, and exercise capacity testing (preferably with an arterial blood gas analysis) to assess severity of disease. Results from these tests serve as a baseline for future monitoring and as a guide for treatment decisions (Glazer and Newman 2003).

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