Introduction

The remainder of this case study focuses on a diagnostic approach in chronic beryllium disease (CBD). Although the primary care physician can do the initial visit, history, physical, and basic lab evaluation, positive or suspicious findings warrant referral to a pulmonologist for more definitive evaluation and treatment.

History and Physical Examination

If beryllium exposure is suspected, the respiratory tract and skin should be examined carefully.

Initial evaluation of a patient with a history of beryllium exposure should include a thorough occupational and environmental history, medical history, and physical examination. During the medical history and physical examination, particular attention should be focused on the skin and respiratory tract (Rossman 2001; Newman et al. 1996).

Signs and Symptoms

Patients with CBD may exhibit a wide spectrum of physical signs and symptoms. Patients with beryllium sensitization (BeS) exhibit no signs or symptoms related to this cell-mediated immune response, except for an abnormal blood beryllium lymphocyte proliferation test (BeLPT). Some patients with CBD identified through workforce medical surveillance with the BeLPT are asymptomatic with only granulomatous inflammation in the lung or an abnormal BeLPT in bronchoalveolar lavage fluid. Patients with CBD may present with a variety of respiratory and systemic symptoms, such as:

• nonproductive cough,
• fatigue,
• exertional dyspnea,
• weight loss,
• fever, and
• myalgias.

The earliest clinical signs are scattered bibasilar crackles and wheezing. As the disease progresses, lymphadenopathy may develop, along with cyanosis, digital clubbing, and other signs of chronic lung disease (Glazer and Newman 2003).

Beryllium can cause contact dermatitis. If beryllium penetrates the patient's skin or enters open cuts, ulceration or subcutaneous tender nodules can be seen, especially on exposed areas of skin. Cutaneous granulomas can eventually appear. Although rare, cutaneous granulomas can also be a manifestation of the systemic process of CBD, not necessarily related to direct dermal contamination (Berlin et al. 2003).

Differential Diagnosis

The differential diagnosis for interstitial and granulomatous lung disease is involved and exhaustive. Conditions that may resemble CBD include

• asbestosis,
• fungal disease,
• hypersensitivity pneumonitis,
• lymphangitic spread of carcinoma,
• pulmonary hemosiderosis,
• sarcoidosis,
• silicosis, and
• tuberculosis (Muller-Quernheim 2005).

Of these, the clinical features of sarcoidosis are most similar to the characteristics of CBD (Table 3). Although each disease possesses characteristic clinical features, no feature has proved adequately sensitive and specific to be pathognomonic. CBD does not usually have extrapulmonary manifestations. Furthermore, CBD is progressive and often requires lifelong corticosteroid therapy to slow its course (Glazer and Newman 2003; Fireman et al. 2003; Verma et al. 2003). Early stage CBD may present similar to asthma with cough, wheezing, shortness of breath, and with obstructive changes on pulmonary function testing.

Initial Laboratory Evaluation

Initial laboratory evaluation for a patient with a history of beryllium exposure may include: (Glazer and Newman 2003; Newman et al. 1996).

• Chest radiograph—often normal, but can reveal diffuse infiltrates and hilar adenopathy if CBD is present. Infiltrates may be nodular or diffusely linear. Hilar adenopathy, noted eventually in 30% to 40% of patients, is usually mild, bilateral, and associated with parenchymal infiltrates.
• Pulmonary function tests—usually normal on initial evaluation but may demonstrate a lower forced vital capacity, and lower diffusion capacity for carbon monoxide. Restriction, obstruction, or a mixed pattern may be evident on pulmonary function tests.
• Arterial blood gas (ABG) can provide an early sign to distinguish beryllium sensitized individuals from those with CBD. Pulse oximetry is not an adequate substitute for ABGs (Lundgren et al. 2001). Measures of gas exchange on ABG testing may reveal lower partial pressure of oxygen (PaO₂) at rest, and a higher arterial-alveolar gradient at rest if CBD is present (Maier et al. 2003). These abnormalities may be more prominent with exercise.
• Complete blood count and erythrocyte sedimentation rate (ESR) elevated ESR and hematocrit (due to hypoxemia).
• BeLPT.

BeLPT

The BeLPT is an in vitro immunologic test that can detect individuals who are sensitized to beryllium and are at risk of progressing to CBD (Stange et al. 2004). The BeLPT has revolutionized the approach to the diagnosis, screening, and surveillance of beryllium health effects. The test is based on the development of a beryllium-specific, cell-mediated immune response. The BeLPT has allowed us to define early health effects of beryllium, including BeS, and CBD at an early stage (Maier 2001).

This test is performed in only a small number of specialized laboratories. The “Where Can I Find More Information?” section lists some laboratories that perform this test in the United States. Use of trade names and commercial sources is for identification only and does not imply endorsement by the Agency for Toxic Substances and Disease Registry or the U.S. Department of Health and Human Services.

How Does the BeLPT Work?

The clinical significance of the BeLPT was described, and a standard protocol developed, in the late 1980s (Frome et al. 2003; Kreiss et al. 1989). In the BeLPT, a patient's mononuclear cells are collected from blood or bronchoalveolar lavage fluid and then cultured in vitro with and without beryllium salts. Cell proliferation is measured by the incorporation of tritiated thymidine in dividing cells. The beryllium-specific cellular immune response is then quantified and reported as a "stimulation index," which is the ratio of the counts per minute of radioactivity in the cells stimulated by beryllium salts divided by the counts per minute for that person's cells that have not been stimulated with any beryllium (Barna et al. 2003).

Results

Results may be reported as abnormal, uninterpretable, or negative. Two or more abnormal results constitute possible sensitization of the patient and warrant further work-up by a pulmonologist.

Reliability and Sensitivity

As in other immunologic tests, occasionally results are uninterpretable or may not be perfectly reproducible (Newman 1996). Inter - and intra-laboratory disagreement in results may exist between and within laboratories that conduct this test (Bobka et al. 1997; Deubner et al. 2001). Nonetheless, the BeLPT is the best available assay and is efficacious in medical surveillance of beryllium-exposed individuals.

The sensitivity of the BeLPT is estimated at 68%, with a specificity of nearly 97% (Stange et al. 2004). (Confirmation of an abnormal result is recommended to assure appropriate referral for CBD medical evaluation.) The positive predictive value of the BeLPT is comparable to other widely accepted medical tests and is better than other screening tools, including pulmonary function testing, the chest radiograph, and the symptom questionnaire (Glazer and Newman 2003; Stange et al. 2004).

Progress Check