To the Editor:
Sarcoidosis is a multiorgan disease of unknown cause characterized by nonnecrotizing granulomatous inflammation, most commonly involving the lung.1 Confirming the diagnosis entails ruling out alternative conditions mimicking sarcoidosis.2 Important among these is sensitization to beryllium causing chronic beryllium disease (CBD). This rare disease is indistinguishable from sarcoidosis without targeted testing.3 Although CBD develops mainly via inhalation, skin sensitization is a potential risk,4 and saliently, sensitization through being embedded in tissue has been observed.5 Not ordering a specific serum assay, the beryllium lymphocyte proliferation test (BeLPT), to confirm sensitization can lead to the misdiagnosis of CBD as sarcoidosis.6
Because of the unique properties of beryllium, it is commonly used in aerospace and defense armament applications, opening up the potential for exposure through aircraft maintenance. A recent study found that sarcoidosis incidence among US veterans varied by the branch of military service. Specifically, veterans who served in the Army or Air Force showed an increased risk, while those who served in the Coast Guard or National Guard had a decreased risk.7 Service branch can be considered a proxy for service-related occupational and environmental exposures.8,9 Thus, differences in sarcoidosis by service branch may be explicable by beryllium exposure, including the risk of embedded fragment-induced sensitization as a result of combat-related injury. This prompts the question of whether screening for CBD is adequate among veterans presumed to have sarcoidosis. In a national cohort of US veterans receiving care through the Veterans Health Administration (VHA), we aimed to examine patient characteristics associated with ordering a BeLPT assay among veterans and to investigate the factors associated with test ordering.
Methods
We analyzed data from national VHA electronic health records available through the central VHA Corporate Data Warehouse, which was transformed into the Common Data Model of the Observational Medical Outcomes Partnership. We queried these data to identify patient characteristics associated with laboratory test orders for BeLPT among veterans with a diagnosis of sarcoidosis received between 2002 and 2020. We defined sarcoidosis based on medical record coding that relied on the International Classification of Diseases (ICD), Ninth or 10th Revision (code 135 for the former and D86 for the latter). Like prior electronic health records-based studies of sarcoidosis epidemiology,7 we considered patients to have sarcoidosis if one inpatient or two outpatient visits at least 1 month apart with ICD codes for sarcoidosis were documented in the electronic health record. Following the American Thoracic Society’s practice guidelines,2 our case definition also required the absence of diagnostic codes for alternative diagnoses except for pneumoconiosis, including CBD. The exclusion window spanned 3 years from the first sarcoidosis-specific ICD code date (index date): 2 years before and 1 year after. We extracted demographic and geographic data, branch of service, and ICD codes for CBD or pneumoconiosis. A BeLPT order was defined dichotomously using specific concept codes available in the VHA Observational Medical Outcomes Partnership. Data on the history of embedded fragments (shrapnel) was extracted using ICD codes and Systematized Nomenclature of Medicine Clinical Terms.
Categorical variables were characterized by number of observations and percentage frequency. Missing data for race were categorized as unknown. We performed the χ2 test or Fisher exact test to assess the likelihood that the frequencies of patient characteristics differed statistically by BeLPT order status. We first conducted unadjusted logistic regression to estimate the OR for BeLPT associated with the presence of embedded fragments. Then, we performed multivariable logistic regression to adjust for other factors that also might be associated with ordering a BeLPT assay. To evaluate the goodness of fit of our multivariable logistic regression model, we applied the Hosmer-Lemeshow test statistic. This analysis also accounted for the months elapsed between the first and last visits in the Veterans Administration health care system. We selected these risk factors a priori for model inclusion. Statistical significance was defined as P < .05.
Results
Among 27,659 veterans identified with a diagnosis of sarcoidosis received between 2002 and 2020, 129 veterans (0.5%) had at least one BeLPT order, including 9 of 886 patients (1%) with embedded fragments and 120 of 26,773 patients (0.5%) without (Table 1). No veteran with sarcoidosis had a specific ICD code for CBD, although 78 patients (0.3%) had a nonspecific ICD code for pneumoconiosis. Compared with veterans with sarcoidosis who did not have a BeLPT order, those with a BeLPT order were more likely to be White (62.8% vs 43.4%; P < .001), to live in the West region (20.9% vs 13.7%; P = .051), to have nonspecific ICD codes for pneumonoconiosis (3.1% vs 0.3%; P < .001), and to have embedded fragments (7.0% vs 3.2%; P = .03).
Table 1.
Characteristics of the Study Population, Stratified by BeLPT Order Status
| Characteristic | BeLPT Order |
P Valuea | |
|---|---|---|---|
| No (n = 27,530) | Yes (n = 129) | ||
| Age (categorical), y | .57b | ||
| ≤ 30 | 61 (0.2) | 0 (0) | |
| 31-50 | 3,606 (13) | 14 (10.9) | |
| 51-70 | 15,251 (55.5) | 68 (52.7) | |
| > 70 | 8,612 (31.3) | 47 (36.4) | |
| Sex | .40 | ||
| Male | 23,963 (87) | 116 (89.9) | |
| Female | 3,567 (13) | 13 (10.1) | |
| Race | < .001 | ||
| White | 11,954 (43.4) | 81 (62.8) | |
| Black | 13,422 (48.8) | 41 (31.8) | |
| Other or unknown | 2,134 (7.8) | 7 (5.4) | |
| Ethnicityc | .10 | ||
| Hispanic | 659 (2.5) | 6 (4.7) | |
| Non-Hispanic | 25,785 (97.5) | 121 (95.3) | |
| Residence by region | .051 | ||
| South | 13,660 (49.6) | 53 (41.1) | |
| Northeast | 4,421 (16.1) | 18 (14) | |
| Midwest | 5,664 (20.6) | 31 (24) | |
| West | 3,785 (13.7) | 27 (20.9) | |
| Branch of service | .74 | ||
| Air Force | 4,304 (15.5) | 23 (17.8) | |
| Army | 15,381 (55.9) | 66 (51.2) | |
| Marines | 2,804 (10.2) | 15 (11.6) | |
| Navy | 5,041 (18.3) | 25 (19.4) | |
| Nonspecific ICD codes for pneumoconiosis | < .001b | ||
| No | 27,456 (99.7) | 125 (96.6) | |
| Yes | 74 (0.3) | 4 (3.1) | |
| Exposure to embedded fragments | .03 | ||
| No or unknown | 26,653 (96.8) | 120 (93) | |
| Yes | 877 (3.2) | 9 (7) | |
Data are presented as No. (%), unless otherwise indicated. BeLPT = beryllium lymphocyte proliferation test; ICD = International Classification of Diseases.
All P values refer to comparisons of patients with sarcoidosis with and without the BeLPT order. P values were calculated by a χ2 test for categorical variables.
Fisher exact test.
Missing: 1,086 patients with no BeLPT order, compared with only two patients with a BeLPT order.
In unadjusted logistic regression analysis that included the sole predictor of embedded fragments, the odds of BeLPT testing were more than doubled (OR, 2.28; 95% CI, 1.15-4.50). In multivariable logistic regression analysis that included other covariates (Table 2), embedded fragments remained associated with twofold greater odds of having a BeLPT order (OR, 2.13; 95% CI, 1.01-3.98). The only other statistically significant association was for race: Black (vs White) veterans were less likely to have a BeLPT order (OR, 0.46; 95% CI, 0.31-0.68). Veterans from the Western region (referent region, Northeast) demonstrated a nonsignificant increase in odds of having a BeLPT order (OR, 1.76; 95% CI, 0.97-3.26; P = 0.06). The goodness of fit of the multivariable logistic regression model was confirmed (Hosmer-Lemeshow test, 8.45; P = 0.39).
Table 2.
Patient Characteristics Associated With BeLPT Orders Among US Veterans With Sarcoidosis (n = 27,659)
| Variable | Multivariable Logistic Regression OR (95% CI) | P Value |
|---|---|---|
| Embedded fragments | 2.13 (1.01-3.98) | .03 |
| Age (per 10-y increase) | 1.02 (0.88-1.19) | .78 |
| Sex | ||
| Female | Reference | … |
| Male | 1.16 (0.67-2.18) | .62 |
| Race | ||
| White | Reference | … |
| Black | 0.46 (0.31-0.68) | < .001 |
| Other or unknown | 0.51 (0.21-1.03) | .09 |
| Residence by region | ||
| Northeast | Reference | … |
| South | 1.15 (0.68-2.04) | .61 |
| Midwest | 1.38 (0.78-2.53) | .28 |
| West | 1.76 (0.97-3.26) | .06 |
| Branch of service | ||
| Army | Reference | … |
| Air Force | 1.14 (0.69-1.81) | .60 |
| Marines | 1.15 (0.63-1.96) | .64 |
| Navy | 1.01 (0.62-1.58) | .98 |
| No. of months in VA health care system (per 1-mo increase) | 1.004 (1.001-1.01) | .002 |
BeLPT = beryllium lymphocyte proliferation test; VA = Veterans Administration.
Discussion
We found that < 1% of veterans with a diagnosis of sarcoidosis had a BeLPT assay ordered between 2002 and 2020. Although the odds of ordering a BeLPT assay were higher among veterans with a history of embedded fragments, only one in 100 had been screened for CBD. This finding suggests that neither veterans exposed to embedded fragments nor their clinicians may be aware that this carries a risk for embedded fragment-induced sensitization resulting from trace beryllium in armament-related aluminum.4,5,10 The perception of risk also may account for lower odds of testing among Black veterans, who more frequently have sarcoidosis,7 if health care providers or their patients assume that this is simply an idiopathic disease that need not be investigated for an alternate cause.
It is crucial for clinicians to conduct a thorough occupational history and to recognize when to screen for CBD among high-risk populations, including for both veterans and nonveterans, because it may help to determine patients' associated disease trajectories and disability benefits. Because it can be difficult to avoid misdiagnosing CBD as sarcoidosis without a BeLPT assay, it is essential to consider ordering this test routinely for veterans with a sarcoidosis diagnosis who are at increased risk for CBD, particularly those with a history of embedded fragments. By increasing awareness and understanding of the similarities between these conditions, we aim to improve diagnostic accuracy and patient outcomes. Moreover, future research that includes job titles or even industrial hygiene sampling could improve our understanding of the impact of occupational exposure on sarcoidosis and CBD diagnostics.
Funding/Support
This work was supported by funds from (1) the National Center for Advancing Translational Science, National Institute of Health, through the University of California San Francisco (UCSF) - Clinical Research Informatics Postdoctoral (CRISP) Fellowship Award [UCSF-CTSI grant no. TL1-5TL1TR001871-05] to M. I. S. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH; (2) a UCSF Academic Senate Committee on Research – Resource Allocation Program (RAP) grant to M. I. S.; (3) the California Tobacco-related Disease Research Program (T29IR0715) to M. A.; and (4) the Department of Veterans Affairs (CXV-00125) to M. A.
Financial/Nonfinancial Disclosures
The authors have reported to CHEST the following: M. A. reports grants from the Departments of Defense (W81XWH-20-1-0158) and Veterans Affairs (CXV-00125), the Flight Attendant Medical Research Institute (012500WG and CIA190001), and the California Tobacco-related Disease Research Program (T29IR0715), as well as investigator-initiated research, financial support from Guardant Health and Genentech during the conduct of the study. M. A. W. reports financial support from the US Veterans Health Administration—Office of Research Quality Enhancement Research Initiative, National Institute of Health—NCATS, and McGraw Hill Education. None declared (M. I. S., M. T. A., L. L. K., P. D. B.).
Acknowledgments
Role of sponsors: The sponsors had no role in the study design, data collection, analysis, decision to publish, or manuscript preparation. The statements and conclusions in this publication are those of the authors and not necessarily those of the funding agencies. The mention of commercial products, their source, or their use in connection with the material reported herein is not to be construed as an actual or implied endorsement of such products.
Footnotes
M. Seedahmed is currently at the the Division of Pulmonary, Critical Care, Allergy and Immunology, and Sleep, University of Pittsburgh, and the Pittsburgh Veterans Affairs Healthcare System (Pittsburgh, PA).
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