COVIDOSE: Low-dose tocilizumab in the treatment of Covid-19

BackgroundInterleukin-6 (IL-6)-mediated hyperinflammation may contribute to the high mortality of coronavirus disease 2019 (Covid-19). Tocilizumab, an IL-6 receptor blocking monoclonal antibody, has been repurposed for Covid-19, but prospective trials and dose-finding studies in Covid-19 are lacking. MethodsWe conducted a phase 2 trial of low-dose tocilizumab in hospitalized adult patients with Covid-19, radiographic pulmonary infiltrate, fever, and C-reactive protein (CRP) [≥] 40 mg/L who did not require mechanical ventilation. Dose cohorts were determined by a trial Operations Committee, stratified by CRP and epidemiologic risk factors. A range of doses from 40 to 200 mg (low-dose tocilizumab) was evaluated, with allowance for one repeat dose at 24-48 hours. The primary objective was to assess the relationship of dose to fever resolution and CRP response. Outcomes were compared with retrospective controls with Covid-19. Correlative studies evaluating host antibody response were performed in parallel. FindingsA total of 32 patients received low-dose tocilizumab. This cohort had improved fever resolution (75{middle dot}0% vs. 34{middle dot}2%, p = 0{middle dot}001) and CRP decline (86{middle dot}2% vs. 14{middle dot}3%, p < 0{middle dot}001) in the 24-48 hours following drug administration, as compared to the retrospective controls (N=41). The probabilities of fever resolution or CRP decline did not appear to be dose-related (p=0{middle dot}80 and p=0{middle dot}10, respectively). Within the 28-day follow-up, 5 (15{middle dot}6%) patients died. For patients who recovered, median time to clinical recovery was 3 days (IQR, 2-5). Clinically presumed and/or cultured bacterial superinfections were reported in 5 (15{middle dot}6%) patients. Correlative biological studies demonstrated that tocilizumab-treated patients produced anti-SARS-CoV-2 antibodies comparable to controls. InterpretationLow-dose tocilizumab was associated with rapid improvement in clinical and laboratory measures of hyperinflammation in hospitalized patients with Covid-19. Results of this trial and its correlative biological studies provide rationale for a randomized, controlled trial of low-dose tocilizumab in Covid-19. FundingClinicalTrials.gov number NCT04331795. Study infrastructure was supported by NIH CTSA UL1 TR000430. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSMany patients with novel coronavirus disease 2019 (Covid-19) develop acute lung injury and hypoxic respiratory failure possibly due to a hyperinflammatory state similar to the cytokine release syndrome that occurs as a complication of chimeric antigen receptor T-cell therapy. Interleukin-6 (IL-6) has been implicated in both processes, leading to the hypothesis that patients with Covid-19 may benefit from IL-6 axis-directed therapies such as the IL-6 receptor-blocking monoclonal antibody tocilizumab. No dose-finding studies have been performed for tocilizumab in the setting of Covid-19. Added value of this studyThis prospective phase 2 clinical trial is, to our knowledge, the first to evaluate low-dose tocilizumab in patients with Covid-19 and the first to evaluate the effect of tocilizumab on anti-SARS-CoV-2 antibody response. Implications of all the available evidenceThe COVIDOSE study, together with retrospective and real-world evidence studies demonstrating the efficacy of tocilizumab, suggests that low-dose tocilizumab is a potential treatment for hyperinflammation among patients with Covid-19 and merits randomized, controlled testing in this patient population.

Outcomes and Cardiovascular Comorbidities in a Predominantly African-American Population with COVID-19

ImportanceRacial disparities in COVID-19 outcomes have been amplified during this pandemic and reports on outcomes in African-American (AA) populations, known to have higher rates of cardiovascular (CV) comorbidities, remain limited. ObjectiveTo examine prevalence of comorbidities, rates of hospitalization and survival, and incidence of CV manifestations of COVID-19 in a predominantly AA population in south metropolitan Chicago. Design, Setting, ParticipantsThis was an observational cohort study of COVID-19 patients encountered from March 16 to April 16, 2020 at the University of Chicago. Deidentified data were obtained from an institutional data warehouse. Group comparisons and logistic regression modeling based on baseline demographics, clinical characteristics, laboratory and diagnostic testing was performed. ExposuresCOVID-19 was diagnosed by nasopharyngeal swab testing and clinical management was at the discretion of treating physicians. Main Outcomes and MeasuresPrimary outcomes were hospitalization and in-hospital mortality, and secondary outcomes included incident CV manifestations of COVID-19 in the context of overall cardiology service utilization. ResultsDuring the 30 day study period, 1008 patients tested positive for COVID-19 and 689 had available encounter data. Of these, 596 (87%) were AA and 356 (52%) were hospitalized, of which 319 (90%) were AA. Age > 60 years, tobacco use, BMI >40 kg/m2, diabetes mellitus (DM), insulin use, hypertension, chronic kidney disease, coronary artery disease (CAD), and atrial fibrillation (AF) were more common in hospitalized patients. Age > 60 years, tobacco use, CAD, and AF were associated with greater risk of in-hospital mortality along with several elevated initial laboratory markers including troponin, NT-proBNP, blood urea nitrogen, and ferritin. Despite this, cardiac manifestations of COVID-19 were uncommon, coincident with a 69% decrease in cardiology service utilization. For hospitalized patients, median length of stay was 6.2 days (3.4-11.9 days) and mortality was 13%. AA patients were more commonly hospitalized, but without increased mortality. Conclusions and RelevanceIn this AA-predominant experience from south metropolitan Chicago, CV comorbidities and chronic diseases were highly prevalent and associated with increased hospitalization and mortality. Insulin-requiring DM and CKD emerged as novel predictors for hospitalization. Despite the highest rate of comorbidities reported to date, CV manifestations of COVID-19 and mortality were relatively low. The unexpectedly low rate of mortality merits further study. KEY POINTSO_ST_ABSQuestionsC_ST_ABSWhat comorbidities are present in African Americans (AA) with COVID-19 and what are the associations with subsequent hospitalization and mortality? What is the incidence of COVID-19-associated cardiac manifestations requiring cardiology service utilization? FindingsIn this observational cohort study that included 689 patients with COVID-19 from south metropolitan Chicago (87% AA), cardiovascular (CV) comorbidities were highly prevalent and more common in those that required hospitalization. In addition to AA, age > 60 years, tobacco use, BMI >40 kg/m2, diabetes mellitus, hypertension, chronic kidney disease, coronary artery disease (CAD), and atrial fibrillation (AF) were more common in those hospitalized. Age > 60 years, tobacco use, CAD, and AF were associated with in-hospital mortality. Despite this, cardiac manifestations of COVID-19 were uncommon, and cardiology service utilization was low. In-hospital mortality was 13%. AA patients were more commonly hospitalized, but without increased mortality. MeaningIn a predominantly AA population with COVID-19 at a major academic hospital located in south metropolitan Chicago, CV comorbidities were common and were risk factors for hospitalization and death. Although the highest rates of comorbidities to date were present in this cohort, mortality was relatively low and merits further study.