Background No therapy is approved for COVID-19 pneumonia. The aim of this study was to assess the role of tocilizumab in reducing the risk of invasive mechanical ventilation and death in patients with severe COVID-19 pneumonia who received standard of care treatment.Methods This retrospective, observational cohort study included adults (≥18 years) with severe COVID-19 pneumonia who were admitted to tertiary care centres in Bologna and Reggio Emilia, Italy, between Feb 21 and March 24, 2020, and a tertiary care centre in Modena, Italy, between Feb 21 and April 30, 2020. All patients were treated with the standard of care (ie, supplemental oxygen, hydroxychloroquine, azithromycin, antiretrovirals, and low molecular weight heparin), and a non-randomly selected subset of patients also received tocilizumab. Tocilizumab was given either intravenously at 8 mg/kg bodyweight (up to a maximum of 800 mg) in two infusions, 12 h apart, or subcutaneously at 162 mg administered in two simultaneous doses, one in each thigh (ie, 324 mg in total), when the intravenous formulation was unavailable. The primary endpoint was a composite of invasive mechanical ventilation or death. Treatment groups were compared using Kaplan-Meier curves and Cox regression analysis after adjusting for sex, age, recruiting centre, duration of symptoms, and baseline Sequential Organ Failure Assessment (SOFA) score. FindingsOf 1351 patients admitted, 544 (40%) had severe COVID-19 pneumonia and were included in the study. 57 (16%) of 365 patients in the standard care group needed mechanical ventilation, compared with 33 (18%) of 179 patients treated with tocilizumab (p=0•41; 16 [18%] of 88 patients treated intravenously and 17 [19%] of 91 patients treated subcutaneously). 73 (20%) patients in the standard care group died, compared with 13 (7%; p<0•0001) patients treated with tocilizumab (six [7%] treated intravenously and seven [8%] treated subcutaneously). After adjustment for sex, age, recruiting centre, duration of symptoms, and SOFA score, tocilizumab treatment was associated with a reduced risk of invasive mechanical ventilation or death (adjusted hazard ratio 0•61, 95% CI 0•40-0•92; p=0•020). 24 (13%) of 179 patients treated with tocilizumab were diagnosed with new infections, versus 14 (4%) of 365 patients treated with standard of care alone (p<0•0001).Interpretation Treatment with tocilizumab, whether administered intravenously or subcutaneously, might reduce the risk of invasive mechanical ventilation or death in patients with severe COVID-19 pneumonia.

The immune system of patients infected by SARS-CoV-2 is severely impaired. Detailed investigation of T cells and cytokine production in patients affected by COVID-19 pneumonia are urgently required. Here we show that, compared with healthy controls, COVID-19 patients' T cell compartment displays several alterations involving naïve, central memory, effector memory and terminally differentiated cells, as well as regulatory T cells and PD1 + CD57 + exhausted T cells. Significant alterations exist also in several lineage-specifying transcription factors and chemokine receptors. Terminally differentiated T cells from patients proliferate less than those from healthy controls, whereas their mitochondria functionality is similar in CD4 + T cells from both groups. Patients display significant increases of proinflammatory or anti-inflammatory cytokines, including T helper type-1 and type-2 cytokines, chemokines and galectins; their lymphocytes produce more tumor necrosis factor (TNF), interferon-γ, interleukin (IL)-2 and IL-17, with the last observation implying that blocking IL-17 could provide a novel therapeutic strategy for COVID-19.

Background Few small studies have described hospital-acquired infections (HAIs) during COVID-19. Research Question What patient characteristics in critically ill patients with COVID-19 are associated with HAIs and how do HAIs associate with outcomes in these patients? Study Design and Methods Multicenter retrospective analysis of prospectively collected data including adult patients with severe COVID-19, admitted to 8 Italian hub hospitals from February 20, 2020, to May 20, 2020. Descriptive statistics, univariable and multivariable Weibull regression models were used to assess incidence, microbial etiology, resistance patterns, risk factors (i.e., demographics, comorbidities, exposure to medication), and impact on outcomes (i.e., ICU survival, length of ICU and hospital stay and duration of mechanical ventilation) of microbiologically-confirmed HAIs. Results Of the 774 included patients, 359 (46%) patients developed 759 HAIs (44.7 infections/1000 ICU patient-days, 35% multi-drug resistant (MDR) bacteria). Ventilator-associated pneumonia (VAP) (389, 50%), bloodstream infections (183, 34%), and catheter related blood stream infections (74, 10%) were the most frequent HAIs, with 26.0 (23.6-28.8) VAPs/1000 patient intubation-days, 11.7(10.1-13.5) BSIs/1000 ICU patient-days, and 4.7 (3.8-5.9) CRBSIs/1000 patient-days. Gram-negative bacteria (especially Enterobacterales ) and Staphylococcus aureus caused 64% and 28% of VAPs. Variables independently associated with infection were age, PEEP and treatment with broad-spectrum antibiotic at admission. 234 patients (30%) died in ICU (15.3 deaths/1000 ICU patient-days). Patients with HAIs complicated by septic shock had almost doubled mortality (52% vs. 29%), while non-complicated infections did not affect mortality. HAIs prolonged mechanical ventilation (24(14-39) vs. 9(5-13) days; p<0.001), ICU and hospital stay (24(16-41) vs. 9(6-14) days, p=0.003; and (42(25-59) vs. 23(13-34) days, p<0.001). Interpretation Critically-ill COVID-19 patients are at high risk for HAIs, especially VAPs and BSIs due to MDR organisms. HAIs prolong mechanical ventilation and hospitalization, and HAIs complicated by septic-shock almost doubled mortality.