Are infectious diseases risk factors for sarcoidosis or a result of reverse causation? Findings from a population-based nested case–control study

Abstract

Findings from molecular studies suggesting that several infectious agents cause sarcoidosis are intriguing yet conflicting and likely biased due to their cross-sectional design. As done in other inflammatory diseases to overcome this issue, prospectivelycollected register data could be used, but reverse causation is a threat when the onset of disease is difficult to establish. We investigated the association between infectious diseases and sarcoidosis to understand if they are etiologically related. We conducted a nested case-control study (2009-2013) using incident sarcoidosis cases from the Swedish National Patient Register (n = 4075) and matched general population controls (n = 40,688). Infectious disease was defined using inpatient/ outpatient visits and/or antimicrobial dispensations starting 3 years before diagnosis/matching. Adjusted odds ratios (aOR) of sarcoidosis were estimated using conditional logistic regression and tested for robustness assuming the presence of reverse causation bias. The aOR of sarcoidosis associated with history of infectious disease was 1.19 (95% confidence interval [CI] 1.09, 1.29; 21% vs. 16% exposed cases and controls, respectively). Upper respiratory and ocular infections conferred the highest OR. Findings were similar when we altered the infection definition or varied the infection-sarcoidosis latency period (1-7 years). In bias analyses assuming one in 10 infections occurred because of preclinical sarcoidosis, the observed association was completely attenuated (aOR 1.02; 95% CI 0.90, 1.15). Our findings, likely induced by reverse causation due to preclinical sarcoidosis, do not support the hypothesis that common symptomatic infectious diseases are etiologically linked to sarcoidosis. Caution for reverse causation bias is required when the real disease onset is unknown.

Risk of first and recurrent serious infection in sarcoidosis: a Swedish register-based cohort study

“…During this time, patients are under frequent follow-up and ∼40% receive immunosuppressants [ 10 ]. As indicated in sensitivity analyses and previous research [ 12 ], the peak in serious infection risk could be partly explained by the increased healthcare interaction, or possibly a lower threshold of hospitalisation for infection. However, our analyses suggested that initiation of immunosuppressants, particularly that of systemic corticosteroids, remains a major risk factor for serious infection in sarcoidosis.…”

“…During this time, patients are under frequent follow-up and ∼40% receive immunosuppressants [10]. As indicated in sensitivity analyses and previous research [12], the peak in serious infection risk could be partly explained FIGURE 1 Risk of first serious infection in individuals with sarcoidosis (overall and stratified by treatment status around diagnosis) and their general population comparators. Treatment data were available for individuals with sarcoidosis entering the cohort starting 2006, hence follow-up for those was shorter than overall sarcoidosis and the general population comparators.…”

Sarcoidosis: Epidemiology and clinical insights

“…Among bacterial antigens, Cutibacterium acnes was identified in cultures of sarcoid lesions, and remnants of Mycobacterium tuberculosis were found in granulomas [23,24]. Epidemiological studies on the role of these and other infections show conflicting results [25,26]. It is important to acknowledge that bias due to reverse causation is likely because latent sarcoid inflammation increases the risk of infections before diagnosis [26].…”

Diagnosis and Treatment of Pulmonary Sarcoidosis

“…[22][23][24] However, whether infection contributes to the development of sarcoidosis is unknown. [22][23][24][25] Autoimmunity may contribute to the development of sarcoidosis. Vimentin, a structural protein coded by the VIM gene may be implicated in the development of sarcoidosis.…”

“…Microbes, such as Propionibacterium species and Mycobacterium , have been associated with the presence of sarcoidosis . However, whether infection contributes to the development of sarcoidosis is unknown . Autoimmunity may contribute to the development of sarcoidosis.…”