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Correspondence |

Occupational Causation of Sarcoidosis FREE TO VIEW

Jerome M. Reich, MD, FCCP
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: None declared.

Thoracic Oncology Section, Earl A. Chiles Research Institute, Portland, OR

CORRESPONDENCE TO: Jerome M. Reich, MD, FCCP, 7400 SW Barnes Rd, A 242, Portland, OR 97225-7007


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;150(6):1422-1423. doi:10.1016/j.chest.2016.09.039
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Published online

Liu et al, authors of an article in a recent issue of CHEST (August 2016), used an innovative design and sophisticated statistical analysis to systematically identify occupational sarcoidosis associations with the intent of inferring causation. However, the Bradford Hill criteria (biological plausibility, association strength, consistency, temporality, and dose response) are unsatisfied due to design limitations and observations.

1. Assumption of Causal Occupational Exposure

Temporality: The design does not exclude cases in which sarcoidosis preceded the usual occupation.

Cause-effect: Cardiopulmonary limitations due to severe sarcoidosis might preclude physically demanding tasks, leading to an occupation unrelated to cause (eg, banking).

Historical consistency: Some putative occupational associations have been challenged (eg, firefighting and exposure to the World Trade Center disaster).

2. Evidence of Causation

Biological plausibility: The authors supply no putative immunogen and no shared, biologically plausible mechanism by which occupations with an elevated mortality OR (MOR) might cause a systemic granulomatous response.

Consistency: Occupations with an MOR > 2 did not reproduce the previous associations with occupational/environmental exposure incidences reported in sarcoidosis clusters, specific occupational exposures, or in the A Case Control Etiologic Study of Sarcoidosis (ACCESS) study.

Association strength: MOR was barely above 2 and was compared in 20 occupational categories, some with large CIs. The decision to not correct for multiple comparisons could be challenged. An OR < 0.50 or > 2.0 is viewed as a clinically important effect size. Compelling evidence of causation requires a very high OR. For example, Doll and Hill reported an OR for cigarette smoking and lung cancer of 9.

3. Violation of Occam’s Razor

Invocation of additional, explanatory hypotheses is required to account for differential MOR according to sex and occupation.

4. Data Accuracy

It is difficult to credit the assumption that signers of death certificates accurately distinguished between deaths that were sarcoidosis related (eg, sublethal cardiopulmonary involvement) but not directly attributable to sarcoidosis. Accuracy of the certified cause of death relies on a correct premortem diagnosis; lacking this information, it might be classified as pulmonary fibrosis or congestive heart failure.

5. Confounding by Observer Effect

Sarcoidosis frequently presents as asymptomatic bilateral hilar adenopathy, discoverable only by a chance or systematic chest radiograph. Ascertainment depends on access to care and the sophistication and experience of the provider and radiologist, conditions more likely to be fulfilled in employed individuals. This contingency might account for the 1.52 MOR of any vs no occupational exposure. Occupations requiring screening chest radiographs will increase ascertainment; periodic imaging will augment this effect by including individuals with a brief course of sarcoidosis.

The investigation by Liu et al was premised on the belief that identifying occupations associated with sarcoidosis might lead, indirectly, to identifying its elusive cause(s). While the concept that sarcoidosis is caused by a specific, albeit elusive exposure(s) remains viable, an alternative premise, advanced separately by Scadding and Mitchell, Munro et al, and Thomas and Hunninghake, that the systemic granuloma reflect an abnormal response to a variety of immunogens, seems a more productive arena for investigation. This premise has, moreover, immunological support.

References

Liu H. .Patel D. .Welch A.M. .et al Association between occupational exposures and sarcoidosis: an analysis from death certificates in the United States, 1988-1999. Chest. 2016;150:289-298 [PubMed]journal. [CrossRef] [PubMed]
 
Reich J.M. . Shortfalls in imputing sarcoidosis to occupational exposures. Am J Ind Med. 2013;56:496-500 [PubMed]journal. [CrossRef] [PubMed]
 
Newman L.S. .Rose C.S. .Bresnitz E.A. .et al A case control etiologic study of sarcoidosis: environmental and occupational risk factors. Am J Respir Crit Care Med. 2004;170:1324-1330 [PubMed]journal. [CrossRef] [PubMed]
 
Streiner D.L. .Norman G.R. . Mine is bigger than yours: measures of effect size in research. Chest. 2012;141:595-598 [PubMed]journal. [CrossRef] [PubMed]
 
Doll R. .Hill A.B. . A study of the aetiology of carcinoma of the lung. Br Med J. 1952;2:1271-1286 [PubMed]journal. [CrossRef] [PubMed]
 
Scadding JG, Mitchell DN. Definition. In:Sarcoidosis, 2nd ed. Cambridge, UK: University Press; 1985:13-35.
 
Munro C.S. .Mitchell D.N. .Poulter L.W. .Cole P.J. . Early cellular responses to intradermal injection of Kveim suspension in normal subjects and those with sarcoidosis. J Clin Pathol. 1986;39:176-182 [PubMed]journal. [CrossRef] [PubMed]
 
Thomas P.D. .Hunninghake G.W. . Current concepts of the pathogenesis of sarcoidosis. Amer Rev Respir Dis. 1987;135:747-760 [PubMed]journal
 

Figures

Tables

References

Liu H. .Patel D. .Welch A.M. .et al Association between occupational exposures and sarcoidosis: an analysis from death certificates in the United States, 1988-1999. Chest. 2016;150:289-298 [PubMed]journal. [CrossRef] [PubMed]
 
Reich J.M. . Shortfalls in imputing sarcoidosis to occupational exposures. Am J Ind Med. 2013;56:496-500 [PubMed]journal. [CrossRef] [PubMed]
 
Newman L.S. .Rose C.S. .Bresnitz E.A. .et al A case control etiologic study of sarcoidosis: environmental and occupational risk factors. Am J Respir Crit Care Med. 2004;170:1324-1330 [PubMed]journal. [CrossRef] [PubMed]
 
Streiner D.L. .Norman G.R. . Mine is bigger than yours: measures of effect size in research. Chest. 2012;141:595-598 [PubMed]journal. [CrossRef] [PubMed]
 
Doll R. .Hill A.B. . A study of the aetiology of carcinoma of the lung. Br Med J. 1952;2:1271-1286 [PubMed]journal. [CrossRef] [PubMed]
 
Scadding JG, Mitchell DN. Definition. In:Sarcoidosis, 2nd ed. Cambridge, UK: University Press; 1985:13-35.
 
Munro C.S. .Mitchell D.N. .Poulter L.W. .Cole P.J. . Early cellular responses to intradermal injection of Kveim suspension in normal subjects and those with sarcoidosis. J Clin Pathol. 1986;39:176-182 [PubMed]journal. [CrossRef] [PubMed]
 
Thomas P.D. .Hunninghake G.W. . Current concepts of the pathogenesis of sarcoidosis. Amer Rev Respir Dis. 1987;135:747-760 [PubMed]journal
 
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