key: cord-0803577-vwniafat authors: Salvarani, Carlo; Mancuso, Pamela; Gradellini, Federica; Viani, Nilla; Pandolfi, Paolo; Reta, Massimo; Carrozzi, Giuliano; Sandri, Gilda; Bajocchi, Gianluigi; Elena, Galli; Muratore, Francesco; Boiardi, Luigi; Pipitone, Nicolò; Cassone, Giulia; Croci, Stefania; Marata, Anna Maria; Costantini, Massimo; Giorgi Rossi, Paolo title: Susceptibility to COVID‐19 in patients treated with antimalarials: a population based study in Emilia‐Romagna, Northern Italy date: 2020-08-06 journal: Arthritis Rheumatol DOI: 10.1002/art.41475 sha: a023bf3f290700d8bd2b27879191f678c5c2bf24 doc_id: 803577 cord_uid: vwniafat OBJECTIVES: To evaluate the susceptibility of coronavirus disease 2019 (COVID‐19) in patients with autoimmune conditions treated with antimalarials in a population‐based study. METHODS: All residents treated with chloroquine/hydroxychloroquine (CQ/HCQ) from July through December 2019 and living in 3 provinces of Regione Emilia‐Romagna were identified by drug prescription registries and matched with the registry containing all residents, living in the same areas, who have had swabs and positive swabs for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). RESULTS: 4,408 patients were identified. The prevalence of antimalarial users was 0.85/1000 in males and 3.3/1000 in females. The cumulative incidence of being tested during the study period was 2.7% in the general population and 3.8% in CQ/HCQ users, while the cumulative incidence of testing positive was 0.55% in the general population and 0.70% in users. Multivariate models showed that CQ/HCQ users had a slightly higher probability of being tested compared to general population (OR 1.09, 95%CI 0.94‐1.28), the same probability of being diagnosed with COVID‐19 (OR 0.94, 95%CI 0.66‐1.34), and a slightly lower probability of being positive once tested (OR 0.83, 95%CI 0.56‐1.23). All three differences were not statistically significant. CONCLUSIONS: Our study did not support the prophylactic use of antimalarials for COVID‐19. Given the increasingly widespread use of antimalarial drugs chloroquine (CQ) and hydroxychloroquine (HCQ), not only as therapy but also as prophylaxis for coronavirus disease 2019 (COVID-19) (1) (2) (3) (4) , there is an immediate unmet need to obtain insights into their efficacy, particularly because of their potential toxicity (5) . Antimalarial drugs are well known disease modifying antirheumatic drugs (DMARDs) used in the treatment of several autoimmune conditions such as rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIR), systemic lupus erythematosus (SLE), discoid lupus erythematosus (DLE), and other off label uses including antiphospholipid syndrome and primary Sjögren syndrome. In addition to their immunomodulatory capacity, they protect patients with inflammatory rheumatic diseases against infection. For example in SLE the duration of antimalarial treatment is a protective factor for infections (6) . Antimalarials have also been reported to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro (7, 8) . Therefore, because of their immunomodulatory and antiviral effects these drugs have been proposed to be repurposed not only for the treatment of COVID-19, but also for the primary prophylaxis in healthy subjects living in highest risk areas. Patients with autoimmune conditions, chronically treated with antimalarials before the onset of SARS-CoV-2 infection, potentially represent the best candidates to test the efficacy of these drugs in preventing symptomatic Covid-19 (9, 10) . In these patients CQ/HCQ accumulate at cell and tissue level including the lungs, where they may exert an antiviral effect, although it is unclear whether such antiviral action may be achieved using the standard therapeutic doses of antimalarials (7, 8, 11) . We decided to evaluate in a population-based Accepted Article study the risk of COVID-19 in the patients treated with antimalarials before the start of the infection in a large geographic area (3 provinces of Emilia-Romagna) at high diffusion of COVID-19. The three provinces included in the catchment areas, Bologna, Modena and Reggio Emilia, have 2,251,903 residents. We identified all resident population who have been prescribed with CQ or HCQ during the period from July 1 through December 31 2019, via the local drug prescription registries. The database is updated every 3 months. Drug users were linked to the archive of the oral nasopharingeal swabs for SARS-CoV-2 RT-PCR test and with the COVID-19 registry. All residents in the study areas who have had oral nasopharingeal swabs from February 21, 2020, date of the first diagnosed COVID-19 case in Italy, are registered in a local registry. Those who tested positive were included in the COVID-19 registry, collected at local level and gathered at national level (12, 13). With a few exceptions, swabs were performed only in symptomatic subjects. Therefore, patients included in the COVID-19 registry are considered all COVID-19 patients. Initially, only patients with a contact with other SARS-Cov-2 patients were tested, but after the second week of the outbreak all patients with symptoms compatible with COVID-19 were tested with RT-PCR on oral nasopharingeal samples. The fiscal code was used to identify and match patients treated with antimalarials agents and those with COVID19 infection. We used data updated at May 13th. In Emilia-Romagna, the epidemic curve peaked in the last third of This article is protected by copyright. All rights reserved March and then decreased. At the end of the study period, cumulative incidence of COVID-19 in the general population was 0.48%, 0.54%, and 0.9%, in Bologna, Modena and Reggio Emilia, respectively. The study was approved by local Ethic Committee on 07/04/2020 n° 2020/0045199. We present age-and gender-specific cumulative rates of being tested and of testing positive in the general population and in patients who received CQ or HCQ during the second half of 2019. Multivariate logistic regression models were used to evaluate if treatment, age classes and gender increased the odds of being tested or to have a positive test. We also present the probability of being positive once tested. From drug prescription databases, 4,408 patients had at least one prescription of CQ or HCQ during the second half of 2019. The mean age was 62.4 + 18.2 years, 80.2% were females. The median number of packs (30 200 mgtablets) per patient was 6 (interquartile range 4 -9), only 3.6% of patients had only one pack in the period. CQ or HCQ were mainly prescribed for their approved indications that is RA, JIA, SLE, and DLE. The prevalence of drug users was 0.85/1000 in males and 3.3/1000 in females, with no differences between provinces. It increased with age until the This article is protected by copyright. All rights reserved group aged from 80 to 89 years, when it reached 2.7/1000 and 6.1/1000 in males and females, respectively, while after the age of 90 years, prevalence dropped, at least in females, to 3.8/1000. The cumulative incidence of being tested during the study period was 2.7% in the general population and 3.8% in CQ/HCQ users. Age-and sex-specific rates did not show differences between users and non-users ( Table 1 ). The cumulative incidence of testing positive was 0.55% in the general population and 0.70% in users. Multivariate models confirmed that females were more frequently tested, while people below 40 years were less frequently tested; from 40 to 79 years the probability of being tested was quite homogenous, then it increased ( Table 2) . CQ/HCQ users had a slightly non-significant higher probability of being tested compared to the general population (OR 1.09, 95%CI 0.94-1.28). The cumulative incidence of COVID-19 increased exponentially with age, with females showing a slightly higher incidence. CQ/HCQ users had almost the same probability of being diagnosed with COVID-19 than the general population (OR 0.94, 95%CI 0.66-1.34). The probability of being positive once tested was slightly, albeit non-significantly, lower in CQ/HCQ users compared to general population (OR 0.83, 95%CI 0.56-1.23). In a recent observational study involving a large sample of consecutive patients who had been hospitalized in New York City with Covid-19, HCQ use was not associated with a significantly higher or lower risk of intubation or death (14). Although these results may be affected by prescription bias, with more severe patients receiving the drug, they do not support the use of HCQ at present, outside randomized clinical trials testing its efficacy. Furthermore, a randomized trial did not demonstrate a significant benefit of hydroxychloroquine as postexposure prophylaxis for Covid-19 (15). Accordingly, the Italian Drug Agency (AIFA), as other regulatory national agencies, has recently stopped the use of HCQ both for treatment and prophylaxis in COVID-19 patients, outside clinical trials. Our study is the first population-based study in a geografic area at high diffusion of COVID-19 evaluating in a large (4,408) number of patients chronically treated with CQ/HCQ for autoimmune conditions if antimalarials might be effective in preventing symptomatic COVID-19. These drugs have been reported to have antiviral activity in vitro against SARS-CoV-2, in particular they seem able to block or decrease viral replication in a time-and concentration-dependent manner, as well as to inhibit the fusion of the virus to the cell membrane (7, 8) . Taken together, these effects have prompted suggestions for the use of antimalarials as prophylactic treatment for COVID-19. However, in our study antimalarial users had the same probability of being diagnosed with COVID-19 compared to the general population, therefore our study does not support a role for CQ or HCQ in preventing symptomatic COVID-19 at the dosage used for the treatment of autoimmune conditions. The maximum prescribed dose for HCQ , the most used antimalarial, is 400 mg daily. Safety is a major concern at higher doses. The probability of being tested in CQ/HCQ users was slightly increased, while the probability of being positive at swabs once tested was slightly lower. These differences are compatible with an increased propensity to test patients with autoimmune conditions considered at higher risk of infection, including also Accepted Article patients with less typical symptoms or at lower risk of COVID-19. However, the differences were minimal and not significant and cannot have impeded the observation of an important prophylactic effect of antimalarials. In particular, the 95% confidence interval suggests that a reduction larger than one third is extremely unlikely. In the patients followed for at least 4 weeks, we observed in Emilia Romagna COVID-19 population a high case fatality rate (18%), outlining the severity of the disease in our patients (16). We cannot rule out that a group of patients with asymptomatic or mildly symptomatic COVID-19 may have been tested, however such a high case fatality rate suggests that patients with asymptomatic disease did not represent a consistent part of our COVID-19 registry. Only 3.6% of patients were treated with a single pack of antimalarials, possibly prescribed as anti-malarial prophylaxis in travelers, suggesting that most patients were chronically treated for autoimmune conditions and therefore, with regard to the accumulation of the drugs in the cells and tissues related to longterm treatment, our patients represented an ideal population for evaluating the prophylactic effectiveness of antimalarials. This study has many limitations, but also some strengths. First of all the number of patients with COVID-19 was too small to provide definitive conclusions, however our study is the first population-based study on this topic, the case ascertainment was accurate using two reliable sources, and we examined a large population of patients (more than 4,000 patients) chronically treated with antimalarials. However, we compared the incidence of COVID-19 in patients with autoimmune conditions with that of the general population and we could adjust This article is protected by copyright. All rights reserved only for sex and age. The two populations are not comparable for their health conditions and possibly also for their probability of being infected by SARS-CoV2 and develop COVID-19. In fact, the underlying autoimmune condition and immunosuppressive treatment could have influenced the susceptibility or the course of the infection. It is worth to note that, at least for susceptibility, we did not observe any impact of biological disease-modifying antirheumatic drugs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs) chronic use (17 This article is protected by copyright. All rights reserved This article is protected by copyright. All rights reserved Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: A retrospective analysis of 1061 cases in Marseille Hydroxychloroquine or Chloroquine for Treatment or Prophylaxis of COVID-19: A Living Systematic Review To consider or not antimalarials as a prophylactic intervention in the SARS-CoV-2 (Covid-19) pandemic Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology Infections in newly diagnosed Spanish patients with systemic lupus erythematosus: data from the Accepted Article This article is protected by copyright. All rights reserved RELES cohort. RELES In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro Clinical course of coronavirus disease 2019 (COVID-19) in a series of 17 patients with systemic lupus erythematosus under long-term treatment with hydroxychloroquine COVID-19 infection in a northern-Italian cohort of systemic lupus erythematosus assessed by telemedicine This article is protected by copyright. All rights reserved