Impact Of Non-steroidal Anti-inflammatory Drugs And Proton Pump Inhibitors On COVID-19-related Clinical Outcomes

Objective:Since the outbreak of severe acute respiratory syndrome coronavirus 2,the effect of the use of non-steroidal anti-inflammatory drugs(NSAIDs)and proton pump inhibitors(PPIs)on the susceptibility to SARS-Co V-2 has aroused widespread concern.Also,whether the use of NSAID and PPI may adversely affect the clinical outcome of COVID-19 has been highly controversial.To resolve this controversial issue,we conducted a meta-analysis using SARS-Co V-2-specific data for the first time to systematically study the following issues:(1)Does NSAIDs increase the susceptibility to SARS-Co V-2?(2)Will NSAIDs worsen the prognosis of COVID-19patients?(3)Does PPIs increase the risk of SARS-Co V-2 infection?(4)Will PPIs lead to a more serious clinical outcome of COVID-19?Methods:We obtained comparative data of observational study or randomized controlled trials by searching the COVID-19 database of U.S.Centers for Disease Control and Prevention,Pub Med,the COVID-19 database of World Health Organization,Scopus,med Rxiv(preprint),bio Rxiv(preprint)and two Chinese databases,which includes(1)the evaluation of the effects of exposure to NSAIDs and PPIs on susceptibility to SARS-Co V-2 in people with SARS-Co V-2 infection;(2)the evaluation of the relationship between the use of NSAIDs and PPIs and the clinical outcome of COVID-19 in patients with COVID-19.The odds ratio(OR),risk ratio(RR)or hazard ratio(HR)of binary variables and weighted mean difference(WMD)of continuous variables were summarized by random effect model.I~2statistics were used to quantify the heterogeneity among different studies.Funnel plots and Egger’s linear regression test were used to evaluate publication bias.Sensitivity analysis was performed to evaluate the robustness of the overall aggregate value of clinical results according to pre-established criteria.The first part of this study is registered in PROSPERO,and numbered as CRD42020217995.Results:Meta-analysis showed that the use of NSAID had nothing to do with the high incidence of COVID-19(OR=0.92,95%CI:0.86-0.98,p=0.01;adjusted RR=0.86,95%CI:0.66-1.14,p=0.3),and there were no poor clinical outcomes,including mortality(OR=0.89,95%CI:0.66-1.19,p=0.43;adjusted HR=0.71,95%CI:0.43-1.15,p=0.16),hospital admission(OR=1.04,95%CI:0.87-1.25,p=0.64),length of hospital stay(WMD=-0.13,95%CI:-2.08-1.81,p=0.89),intensive care unit(ICU)admission(OR=0.97,95%CI:0.71-1.33,p=0.85),oxygen supplementation(RR=1.09,95%CI:0.84-1.43,p=0.51),mechanical ventilation(OR=0.75,95%CI:0.52-1.09,p=0.13),severe COVID-19(OR=1.15,95%CI;0.89-1.47,p=0.29;RR=0.89,95%CI:0.78-1.02,p=0.08),hospital discharge rate(OR=0.71,95%CI:0.48-1.05,p=0.09),clinical improvement time(adjusted HR=0.94,95%CI:0.71-1.26,p=0.69),and there were no high heterogeneity and significant publication bias between studies.In addition,sensitivity analysis(study with covariates adjustment only)showed that there was no correlation between the use of NSAID and the incidence of acute kidney injury in COVID-19patients(adjusted OR=1.35,95%CI:0.82-2.20,p=0.23).The analysis also showed that people who currently use PPI have a higher but not significant risk of SARS-Co V-2 infection compared to people who do not use PPI(OR=1.33,95%CI:0.86-2.07,p=0.20).In addition,in a subgroup analysis of non-Korean populations,we found a significant correlation between current use of PPI and an increased risk of SARS-Co V-2 infection(OR=1.94,95%CI:1.59-2.36,p<0.0001).Current PPI users are more likely to have severe COVID-19 than non-PPI users(OR=1.67,95%CI:1.19-2.33,p=0.003;HR=1.87,95%CI:1.29-2.70,p<0.001).Although there was no statistically significant difference,patients who currently use PPI tend to stay longer than those who do not use PPI(MD=1.13,95%CI:-0.18-2.43,p=0.09).Finally,past use of PPIs was not associated with an increased risk of SARS-Co V-2 infection(OR=0.85,95%CI:0.57-1.27,p=0.43),nor was it associated with the severe outcome of COVID-19(OR=1.03,95%CI:0.85-1.23,p=0.79).Conclusion:By conducting specialized research on individuals who record SARS-Co V-2infection status or patients with COVID-19,our meta-analysis reinforces current evidence,and discontinuation or avoidance of NSAIDs in COVID-19 patients or people at risk of COVID-19 infection is discouraged.In addition,it is emphasized that care should be taken in the treatment of COVID-19 patients who are currently using PPIs during the epidemic of COVID-19.