To our knowledge this is the first reported clinical follow-up of a population-based groups of subjects identified as being blood BeLPT positive on routine workplace surveillance. Overall, the findings are mixed. On the one hand, this study shows that the fraction of subjects who have developed objective clinical manifestations typical of CBD, at 11.1%, is low. Moreover, from a clinical perspective the severity in each of the 8 cases observed is mild to moderate; only one of the patients has been treated with systemic corticosteroids by their physician, although each is under the care of a pulmonologist. For the subset of subjects who proved negative on initial full lung evaluation, the results appear even more favorable; only 1 of 50 meets our criteria for clinical CBD. Half of these subjects, unlike most who had CBD at the outset, have lost their BeLPT positivity.

On the other hand, while few subjects met criteria for CBD, there appears to be a drop in % predicted D_LCO in many more subjects, including those without established lung involvement at baseline. Although not associated with group changes in lung volumes or flow rates, three lines of evidence suggest these decrements are not merely an artifact of the fact that pre and post testing was conducted in different labs, nor that only two data points were used to calculate change. First, the average drop of 17.4% was almost identical for subjects at each testing site, which speaks against lab variation as the major explanation. Second, the significant trend with time since initial BeLPT positivity (Figure 2)--but not age or duration of exposure--would seem most consistent with progressive, albeit slow loss. As noted, those with CBD at baseline appear to be losing faster than those without, on average. Third, among the subset of still active workers between 1994 and 2001 continuously tested at the plant, losses averaged well over 1% decline from predicted per year.

Unfortunately, we were unable to delineate any factor or factors other than baseline pathology that predicted rate of loss or development of clinical signs. However, two of the most important potential factors, smoking cessation and cessation of all beryllium exposure, would only have been noticeable with an overwhelming effect since the population size is too small. Two other factors considered relevant, extent of prior exposure to beryllium and HLA-DP polymorphism [10,11], could not yet be evaluated because we have not linked our results with sources for these data.

Beyond these, there are some other important limitations of our study. Most obviously, although we recruited 54% of the eligible cohort members at the largest site, recruitment overall was less than hoped (72/182 identified) so we cannot be certain that no selection bias was introduced. In theory, subjects with better or worse outcomes could have selectively chosen to either participate or not, although except for the lesser participation of younger workers and non-whites, baseline characteristics were very similar between those who did and did not come. Notwithstanding our efforts to communicate the independence of the investigators from the employer-sponsor, all subjects were aware of our funding source. This may have influenced some subjects' decisions introducing bias in either direction in theory,

Another important limitation of this study was the reliance on clinical observations to establish key end-points of the study, namely the paired chest X-rays and paired lung function tests--done in different labs. Most problematic were the lung function studies. While all attempts were made to follow ATS procedures [21,22] at follow-up exams, we were unable to verify the procedures where baseline respiratory examinations were conducted, though most were in the laboratories of university medical centers. Furthermore, the high prevalence of COPD in the study population by our definition (N = 12, 16.7%), whose changes over the follow-up period could potentially confound group interpretation of the physiologic data, dictated that we use a clinical end-point for the study rather than rely strictly on group physiologic observations. In point of fact, however, each of the cases were, on review, easily classifiable despite the fact that diminished D_LCO was the most prevalent reason for classification as CBD (present in 6 subjects and the only basis for classification in 2, see Table 3). Still, some physiologic contribution by CBD in the 12 patients with COPD cannot be ruled out. This possibility underscores a final limitation, namely that we did not, like Newman [18](Newman et al, 2005), repeat the biologic assessment for pathologic or BAL changes of CBD; some of those initially classified as BeS may have evolved over time, and subsequently be, theoretically, at greater risk for clinical disease.

Where does this new data leave us in the effort to control CBD? First, we have affirmed our earlier impression that the BeLPT, despite its limitations [26,27] (Table 5), detects subjects at some risk for clinical disease once confirmed by a second positive test. In fact, some of those detected at screening already had evidence of clinically manifest disease at first recognition (cf patients 2 and 5, Table 3), suggesting that the often used term "sub-clinical CBD" may be less precise for describing such patients than an alternative designation such as "surveillance-detected CBD." Whether BeLPT positivity (confirmed) carries similar implications among individuals whose exposures may have been more limited is uncertain, as our subjects were all workers in primary beryllium-related occupations. Also uncertain is the benefit of identifying at-risk individuals in the absence of any action known to alter their clinical outcome.

When testing is performed, the optimal approach to follow-up of confirmed BeLPT positives also remains unresolved. Full pulmonary evaluation, with bronchoscopy, biopsy, and BAL, may be justified given the suggestion of a different prognosis for those with vs. those without lung involvement, but this benefit remains unproved. Although we continue to support removal from continued occupational beryllium exposure based on a precautionary point of view, we would be hard pressed to take a more rigid position based on our results in a case where an individual chose to remain in exposed work, as many of our subjects in this study did, despite advice and a generous economic package, without obviously greater risk than those who chose to leave. Hopefully, given the continued interest in CBD, better scientific foundations for these clinical and public health decisions will not be far off.