Association of Benzodiazepines With SARS-CoV-2 Infection and Clinical Outcomes: a Nationwide Cohort Study

Abstract

The evidence for the impact of benzodiazepine (BZD) use on infection or clinical outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is limited. We evaluated the association of BZD use with SARS-CoV-2 infection and the clinical outcomes of coronavirus disease 2019 (COVID-19) using a nationwide COVID-19 database from South Korea. This nationwide cohort study was performed using the COVID-19 database from the Health Insurance Review and Assessment Service of Korea, and SARS-CoV-2 positivity was investigated according to BZD use. SARS-CoV-2-positive adult patients were assessed in three groups, those who needed hospitalization, those with severe symptoms requiring intensive care, and those who died. A multivariate logistic regression model was used for all the analyses. After adjusting for potential confounding factors, there was no association between BZD use and SARS-CoV-2 positivity. SARS-CoV-2-positive patients with BZD use showed an increased risk of need for hospitalization from COVID-19 compared to those without BZD use (odds ratio [OR]: 1·33, 95% confidence interval [CI]: 1·07–1·65). In addition, there was a higher risk for long-term users (OR: 2·64, 95% CI: 1·08–6·47). Chronic BZD use contributed to a higher risk of the need for hospitalization among COVID-19 patients, whereas BZD use did not increase the risk of SARS-CoV-2 test positivity, severe outcomes, or mortality.

Introduction

The coronavirus disease (COVID-19) pandemic is causing a global crisis. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with consequences ranging from asymptomatic disease to death.¹ However, 14% of SARS-CoV-2-positive patients show severe disease, and 5% show critical health conditions;² the risk of mortality (0.1%) associated with COVID-19 is much higher than that associated with seasonal influenza.³ Various risk factors such as age ≥ 65 years, chronic obstructive pulmonary disease (COPD), asthma, hypertension, cardiovascular disease, chronic kidney disease, diabetes, obesity, malignancy, immunosuppressant use and transplantation, and chronic human immunodeficiency virus (HIV) infection have been identified.³

Benzodiazepines (BZD) and BZD receptor agonists have been known to increase the risk of pneumonia and death due to pneumonia.^4,5 There is also concern about the risk of respiratory depression by BZD use in people with pre-existing respiratory problems, although reports have been conflicting; an increased risk of respiratory exacerbations was reported for patients with COPD,⁶ while associations of BZD use with hospital admission or impaired blood gases were not significant in COPD patients.⁷ A few recent studies on the characteristics of severe COVID-19 cases^8–10 have focused on the use of BZD. However, the results have been inconsistent.

Given the high prevalence (2·6–23·7%) of BZD use,^11–16 investigating the impact of BZD use on infection or clinical outcomes of SARS-CoV-2 is beneficial for public health. Here, we assessed the association of BZD use with SARS-CoV-2 positivity and clinical outcomes in three groups of patients, those in need of hospital admission, those with severe symptoms requiring intensive care, and those who died, using a nationwide cohort data from South Korea.

Methods

Results

The characteristics of the study participants are shown in Table 1. A total of 328,373 individuals were divided into two groups as follows: those who did not use BZD (n = 276,222) and those who used BZD (n = 52,151). The two groups were matched by propensity scoring, and 52,151 propensity-matched pairs were defined (eTable 1). Of the total subjects, 145,758 (44·4%) were men and 182,615 (55·6%) were women. A majority of the participants (84·1%) was aged 20–39 years; 31·1% were in the 40–59 age group. Comorbidities were recorded in 193,945 (59·1%) individuals, while no comorbidities were observed in 134,428 (40·9%) individuals.

Table 2 shows the association between BZD use and the risk of SARS-CoV-2 positivity; we identified these associations before and after adjusting for potential confounders. After PSM, there was no association between BZD use and the risk of SARS-CoV-2 positivity (model 1: odds ratio [OR]: 1·01, 95% confidence interval [CI]: 0·93 − 1·10, model 2: OR: 1·01, 95% CI: 0·93 − 1·10, model 3: OR: 1·09, 95% CI: 1·00–1·20). Moreover, model 4 and 5 showed that there were no associations between chronic BZD use and the risk of SARS-CoV-2 positivity (model 4: OR: 0·94, CI: 0·81 − 1·10, model 5: OR: 0·99, CI: 0·83 − 1·18).

Table 3 shows the distribution of the study population who tested positive for SARS-CoV-2. Of 7,596 individuals, 1,074 (14·1%) used BZD and 6,522 (85·9%) did not use BZD. Of the BZD use group, 59 (5·5%) individuals died, 111 (10·3%) needed intensive care or invasive ventilation, and 939 (87·4%) were in need of hospitalization.

Figure 2 shows the association between BZD use and the clinical outcomes of COVID-19 among patients who tested positive for SARS-CoV-2. After adjusting for potential cofounding variables, the risk of need for hospitalization due to COVID-19 was higher in those with BZD use that in those without BZD use (OR: 1·33, 95% CI: 1·07 − 1·65). In addition, the risk of need for hospitalization was higher in COVID-19 patients who used BZD for more than 180 days than in those who did not use BZD (OR: 2·64, 95% CI: 1·08 − 6·47).

Discussion

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 infections^19–22 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.

Declarations

Ethics approval and consent to participate

The data were anonymized before they were obtained; thus, informed consent was not required. The Yonsei University Institutional Review Board approved this study (Approval number: 4-2020-1240).

Consent for publication

Not applicable

Availability of data and materials

The data that support the findings of this study are available from the National Health Insurance Service in South Korea but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of the National Health Insurance Service in South Korea.

Competing interests

There are no conflicts of interest to declare.

Funding

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning, Republic of Korea (grant number 2017R1A2B3008214). The funder of the study had no role in the study design; data collection, analysis, and interpretation; writing the report; and the decision to submit the paper for publication.

Authors’ contributions

H.Y.P. and J.K. designed the study and drafted the manuscript. H.Y.P. is responsible for study concept and design. J.K. took responsibility for acquisition, analysis, or interpretation of data. H.Y.P., J.K., S.K.A., and E.C.P. contributed to the discussion and reviewed and edited the manuscript. S.K.A. and E.C.P. are the guarantors of this work and as such, had full access to all study data. S.K.A. and E.C.P. assume responsibility for the integrity of the data and the accuracy of the data analysis.

Acknowledgments

Not applicable

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Tables

Table 1. General characteristics of the study population

Table 2. The results of the analysis of the association between benzodiazepine use and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positivity after 1:1 propensity score matching

Table 3. General characteristics of the patients who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)