RESUMO
In the global COVID-19 pandemic, there is a substantial need for effective, low-cost therapeutics. We investigated the potential effects of disulfiram on the incidence and outcomes of COVID-19 in an observational study in a large database of US Veterans Administration clinical records, the VA Corporate Data Warehouse (CDW). The study is motivated by the unique properties of disulfiram, which has been used as an anti-alcoholism drug since 1948, is non-toxic, easy to manufacture and inexpensive. Disulfiram reduces hyperinflammation in mammalian cells by inhibition of the gasdermin D pore. In a mouse model of sepsis, disulfiram reduced inflammatory cytokines and mortality. Disulfiram also is a low micromolar inhibitor of the Mpro and PLpro viral proteases of SARS-CoV-2. To investigate the potential effects of disulfiram on the incidence and severity of COVID-19, we carried out an epidemiological study in the CDW. The VA dataset used has 944,127 patients tested for SARS-Cov-2, 167,327 with a positive test, and 2,233 on disulfiram, of which 188 had a positive SARS-Cov-2 test. A multivariable Cox regression adjusted for age, gender, race/ethnicity, region, a diagnosis of alcohol use disorders, and Charlson comorbidity score revealed a reduced incidence of COVID-19 with disulfiram use with a hazard ratio of 0.66 and 95% confidence interval of 0.57 to 0.76 (P < 0.001). There were no deaths among the 188 SARS-Cov-2 positive patients treated with disulfiram. The expected number of deaths would have been 5-6 according to the 3% death rate among the untreated (P-value 0.03). Our finding of a lower hazard ratio and less severe outcomes for COVID-19 in patients treated with disulfiram compared to those not treated is a statistical association and does not prove any causative effect of disulfiram. However, the results of this study suggest that there is a pharmacological contribution to the reduced incidence and severity of COVID-19 with the use of disulfiram. Given the known anti-inflammatory and viral anti-protease effects of disulfiram, it is reasonable and urgent to initiate accelerated clinical trials to assess whether disulfiram reduces SARS-CoV-2 infection, disease severity and death. STRUCTURED OUTLINEO_ST_ABSImportanceC_ST_ABSIdentifying already approved medications with well characterized antiviral or anti-inflammatory properties supported by real world evidence as candidates for clinical trials for repurposing is an important strategy to manage the pandemic given the ongoing challenges with producing and administering vaccines, the emergence of more infectious viral mutants and the paucity of approved therapies. ObjectiveTo investigate the potential effects of disulfiram on the incidence and severity of COVID-19. DesignRetrospective cohort study from February 20, 2020 to February 1, 2021. SettingVeterans Health Administration. Veterans who had visited a VA primary care provider in the 18 months before their first SARS-CoV-2 test. Participants2,233 Veterans with at least one SARS-CoV-2 laboratory (positive or negative) test result on or after February 20, 2020 and at least one pharmacy record for disulfiram on or after February 20, 2019 and 941,894 Veterans without a pharmacy record for disulfiram. ExposureTreatment with disulfiram Main OutcomePositive test result for SARS-CoV-2 ResultsA multivariable Cox regression analysis adjusted for age, gender, race/ethnicity, region, diagnosis of an alcohol use disorder, and Charlson comorbidity score resulted in a reduced hazard of COVID-19 infection with disulfiram use, with a hazard ratio of 0.66 and 95% confidence interval of 0.57 to 0.76 (P < 0.001). Conclusions and RelevanceThe results of this study suggest that disulfiram use contributes to a reduced incidence of COVID-19. Given the known anti-inflammatory and anti-protease effects of disulfiram, its low cost, low side effects, and general availability, it is reasonable and urgent to initiate accelerated clinical trials to assess the effect of disulfiram on infection and the development of advanced disease.
RESUMO
SARS-CoV-2 causes acute respiratory distress that can progress to multiorgan failure and death in some patients. Although severe COVID-19 disease is linked to exuberant inflammation, how SARS-CoV-2 triggers inflammation is not understood. Monocytes are sentinel blood cells that sense invasive infection to form inflammasomes that activate caspase-1 and gasdermin D (GSDMD) pores, leading to inflammatory death (pyroptosis) and processing and release of IL-1 family cytokines, potent inflammatory mediators. Here we show that ~10% of blood monocytes in COVID-19 patients are dying and infected with SARS-CoV-2. Monocyte infection, which depends on antiviral antibodies, activates NLRP3 and AIM2 inflammasomes, caspase-1 and GSDMD cleavage and relocalization. Signs of pyroptosis (IL-1 family cytokines, LDH) in the plasma correlate with development of severe disease. Moreover, expression quantitative trait loci (eQTLs) linked to higher GSDMD expression increase the risk of severe COVID-19 disease (odds ratio, 1.3, p<0.005). These findings taken together suggest that antibody-mediated SARS-CoV-2 infection of monocytes triggers inflammation that contributes to severe COVID-19 disease pathogenesis. One sentence summaryAntibody-mediated SARS-CoV-2 infection of monocytes activates inflammation and cytokine release.
