Comparing hospitalised, community and staff COVID-19 infection rates during the early phase of the evolving COVID-19 epidemic Dear Editor, a descriptive and modelling study. Lancet Infect Dis 2020 Apr 2 pii: S1473-3099(20)30230-9[Epub ahead of print].

Background Tocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients. Methods A multicenter, single-arm, hypothesis-driven trial was planned, according to a phase 2 design, to study the effect of tocilizumab on lethality rates at 14 and 30 days (co-primary endpoints, a priori expected rates being 20 and 35%, respectively). A further prospective cohort of patients, consecutively enrolled after the first cohort was accomplished, was used as a secondary validation dataset. The two cohorts were evaluated jointly in an exploratory multivariable logistic regression model to assess prognostic variables on survival. Results In the primary intention-to-treat (ITT) phase 2 population, 180/301 (59.8%) subjects received tocilizumab, and 67 deaths were observed overall. Lethality rates were equal to 18.4% (97.5% CI: 13.6–24.0, P = 0.52) and 22.4% (97.5% CI: 17.2–28.3, P < 0.001) at 14 and 30 days, respectively. Lethality rates were lower in the validation dataset, that included 920 patients. No signal of specific drug toxicity was reported. In the exploratory multivariable logistic regression analysis, older age and lower PaO2/FiO2 ratio negatively affected survival, while the concurrent use of steroids was associated with greater survival. A statistically significant interaction was found between tocilizumab and respiratory support, suggesting that tocilizumab might be more effective in patients not requiring mechanical respiratory support at baseline. Conclusions Tocilizumab reduced lethality rate at 30 days compared with null hypothesis, without significant toxicity. Possibly, this effect could be limited to patients not requiring mechanical respiratory support at baseline. Registration EudraCT (2020-001110-38); clinicaltrials.gov (NCT04317092).

Background It is uncertain whether higher doses of anticoagulants than recommended for thromboprophylaxis are necessary in COVID‐19 patients hospitalized in general wards Methods This is a multicentre, open‐label, randomized trial performed in 9 Italian centres, comparing 40 mg b.i.d. versus 40 mg o.d. enoxaparin in COVID‐19 patients, between April 30 2020 and April 25 2021. Primary efficacy outcome was in‐hospital incidence of venous thromboembolism (VTE): asymptomatic or symptomatic proximal deep vein thrombosis (DVT) diagnosed by serial compression ultrasonography (CUS), and/or symptomatic pulmonary embolism (PE) diagnosed by computed tomography angiography (CTA). Secondary endpoints included each individual component of the primary efficacy outcome and a composite of death, VTE, mechanical ventilation, stroke, myocardial infarction, admission to ICU. Safety outcomes included major bleeding. Results The study was interrupted prematurely due to slow recruitment. We included 183 (96%) of the 189 enrolled patients in the primary analysis (91 in b.i.d., 92 in o.d.). Primary efficacy outcome occurred in 6 patients (6.5%, 0 DVT, 6 PE) in the o.d. group and 0 in the b.id. group (ARR 6.5, 95% CI: 1.5–11.6). The absence of concomitant DVT and imaging characteristics suggests that most pulmonary artery occlusions were actually caused by local thrombi rather than PE. Statistically nonsignificant differences in secondary and safety endpoints were observed, with two major bleeding events in each arm. Conclusions No DVT developed in COVID‐19 patients hospitalized in general wards, independently of enoxaparin dosing used for thromboprophylaxis. Pulmonary artery occlusions developed only in the o.d. group. Our trial is underpowered and with few events.

Early reports from Asia suggested that increased serum levels of the muscular enzyme creatine-(phospho)-kinase (CK/CPK) could be associated with a more severe prognosis in COVID-19. The aim of this single-center retrospective cohort study of 331 consecutive COVID-19 patients who were hospitalized during Italy’s “first wave” was to verify this relationship, and to evaluate the role of possible confounding factors (age, body mass index, gender, and comorbidities). We subdivided our cohort in two groups, based on “severe” (n = 99) or “mild” (n = 232) outcomes. “Severe” disease is defined here as death and/or mechanical invasive ventilation, in contrast to “mild” patients, who were discharged alive with no need for invasive ventilation; this latter group could also include those patients who were treated with non-invasive ventilation. The CK levels at admission were higher in those subjects who later experienced more severe outcomes (median, 126; range, 10–1672 U/L, versus median, 82; range, 12–1499 U/L, p = 0.01), and hyperCKemia >200 U/L was associated with a worse prognosis. Regression analysis confirmed that increased CK acted as an independent predictor for a “severe” outcome. HyperCKemia was generally transient, returning to normal during hospitalization in the majority of both “severe” and “mild” patients. Although the direct infection of voluntary muscle is unproven, transient muscular dysfunction is common during the course of COVID-19. The influence of this novel coronavirus on voluntary muscle really needs to be clarified.

Prevalence of TDR to nucleoside reverse transcriptase inhibitors seems to have declined in Italy over time. Increased prevalence of non-B subtypes partially justifies this phenomenon.