Using a nationwide cohort database from South Korea, in this study, we showed that the chronic use of BZD contributed to an increase in the risk of the need for hospitalization among COVID-19 patients. However, BZD use did not significantly influence the risk of SARS-CoV-2 positivity, severe outcomes, or mortality.
In animal studies, BZD increased mortality due to a variety of bacterial infections19–22 and bacterial superinfections related to influenza.19 In human subjects, controversy persists regarding a causal connection between BZD use and infections.23 The association between BZD use and the increased need for hospitalization in this study may be in line with previous studies which showed increased susceptibility to superinfections in influenza-infected animals24 and humans.5 The underlying mechanism may be related to the effects of BZD on the immune system; BZD amplifies the effect of the gamma-aminobutyric acid receptor in immune cells, which may lead to an immune-suppressant profile.24 Regarding the long term use of BZD, chronic consumption of BZD was related to the appearance of modified lymphocyte subsets.25,26 However, relatively few cases of severe COVID-19 and inaccessible variables in our data, such as the dosage of BZD, may require replication of pharmacoepidemiologic research on the relationship between BZD and COVID-19.
Recent studies on the association between mental illness and COVID-19 outcomes have shown a higher risk for severe COVID-19 outcomes in patients with a mental illness, though the analyses did not include adjustment for BZD use.27,28 Since BZD is frequently prescribed for anxiety symptoms and sleep disturbances, our findings suggest that BZD use should be considered in further studies on the relationship between mental illness and COVID-19 outcomes. Likewise, adjusting for mental illness in future studies in the association between BZD and COVID-19 outcomes would uncover the risk of BZD use regardless of psychiatric diagnoses. However, it is interesting to note that 87·7% of BZD prescriptions were related to non-psychiatric diagnoses in a nationwide cohort study from South Korea.16
Due to limited medical resources, especially with reference to negative pressure beds, policies on the priority for hospitalization among COVID-19 patients have been amended. For example, South Korea has introduced a residential treatment center to isolate asymptomatic patients or patients who do not need hospital care. Therefore, patients with moderate-to-severe symptoms may be hospitalized first.29 In this regard, the results of this nationwide cohort study may be applied to efficiently set strategies for managing COVID-19 patients, based the finding that patients with chronic BZD use need to be monitored frequently due to a high risk of need for hospitalization; however, the strategies should also consider our finding that BZD use does not imply increased severity of clinical outcomes related to COVID-19.
Some limitations of this study should be acknowledged. Although a validation study showed the overall agreement of diagnosis at 82·0%,30 outcomes were identified by diagnostic and procedural codes, and possible misclassifications cannot be ruled out. Moreover, data about the indication and BZD dose, as well as the hospitalization period were unavailable, which precluded a full assessment. The use of nationwide longitudinal data strengthens the causal relationship established in our study, and the generalizability of our findings. However, we could not include all the COVID-19 patients up to the present, and thus may have missed analyzing new clinical outcomes that may have resulted due to various mutations in SARS-CoV-2.
In summary, BZD use was not associated with the risk of SARS-CoV-2 positivity, severe outcomes, or mortality. However, BZD use, especially for more than 180 days, conferred a higher risk of need for hospitalization among COVID-19 patients. Health professionals and public health authorities need to be alert about patients with long-term use of BZD, and these patients need to be closely monitored even if they currently do not need hospital care.