(BSPOT40) Incident benzodiazepine and Z-drug use and subsequent risk of serious infections

Background: There has been evidence from animal models and in vitro studies showing an immunosuppressive effect of benzodiazepines and Z-drugs (BZDR). Studies on humans, however, vary in findings regarding the role of BZDRs in developing infections.

Objectives: To examine the association of incident BZDR use with the risk of developing severe infections using Swedish nationwide registers.

Methods:

Design: The study population included 7,362,979 individuals who had at least one dispensation record of any prescribed medication in 2007-2019, were BZDR naïve by January 1, 2007 and did not initiate BZDR treatment after 2019. We subsequently derived three cohorts from the study population: a demographically matched cohort consisting of 713,896 BZDR-recipients and the 1:1 matched non-recipients; a co-twin control cohort of 9197 BZDR-recipients and their 9298 unexposed co-twins/co-multiples; and an active comparator cohort of 434,900 BZDR-recipients and 428,074 selective serotonin reuptake inhibitors (SSRI)-recipients.
Exposure: Incident dispensed BZDR prescription in 2007-2019. The cumulative dosage of BZDRs was calculated for each recipient using the defined daily doses (DDD) of all BZDR dispensations under the follow-up, and was then analyzed as a time-varying variable.
Outcome: The first recorded inpatient or specialist outpatient visit with any diagnosis of serious infections, or death from any infections recorded as the underlying death cause.
Statistical analysis: Cox proportional hazards regression models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs). The models were controlled for multiple demographic, socioeconomic, clinical, and pharmacological confounders, including familial confounding (in the co-twin cohort) and confounding by indication (in the active comparator cohort).

Results: In the demographically matched cohort, the incidence of any serious infections in incident BZDR recipients and non-recipients were 4.18 and 1.86 per 100 person-years, respectively. BZDR use was associated with 83% relative increase in risk of any infections (HR 1.83; 95%CI 1.79-1.89) after we adjusted for a wide range of potential confounders. In the dose-response analysis, the highest outcome risk was observed in BZDR recipients with the cumulative dosage of >65 DDD (HR 3.94; 95%CI 3.72-4.17) and the lowest risk among those with < 20 DDD (HR 1.56; 95%CI 1.51-1.61). The associations of interest remained consistent in the co-twin control cohort (HR 1.55; 95%CI 1.23-1.97) and the active comparator cohort (HR 1.33; 95%CI 1.30-1.35).

Conclusions: Incident use of BZDR was associated with increased risks of serious infections. Further studies exploring neurobiological mechanisms of the association are needed.