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).

Bleeding in COVID-19 severe pneumonia: The other side of abnormal coagulation pattern?To the Editor A novel coronavirus (SARS CoV-2) spread in China in December 2019, becoming soon a relevant problem of international public health concern [1]. In Italy the SARS-CoV-2 officially spread around the 20th of February 2020 and the country became the first in Europe to register a high number of infections and deaths. The beta-coronavirus mainly creates a severe acute respiratory syndrome (COVID-19), with fever, cough, fatigue, pneumonia and acute respiratory distress syndrome, eventually. The patient management mainly focuses on supportive care: oxygenation, fluid management, and treatments with multiple drugs as antiviral therapies, chloroquine or hydroxyichloroquine, antibiotics, steroids, nonsteroidal anti-inflammatory drugs, bronchodilators and immunosuppressive drugs. Many patients require invasive ventilation, whereas others are treated with non-invasive ventilation (NIV) support or C-PAP (Continuous Positive Airway Pressure). In the available studies, COVID-19 patients showed alterations of coagulation test, with significant increase of D-Dimer levels associated with severity of illness and adverse outcomes [2]. Besides, a high risk for venous thromboembolism has been recently highlighted with high prevalence of symptomatic acute pulmonary embolism and deep vein thrombosis in patients [3]. Therefore, currently low molecular weight heparin (LMWH) has become part of the clinical management of the hospitalized COVID-19 patients, even if evidences about the right prophylactic dose are still lacking. In this scenario, we describe two cases of spontaneous abdominal internal bleeding in hospitalized patients with bilateral interstitial pneumonia and SARS-CoV-2 throat swab positive, supported with C-PAP ventilation, as the invasive ventilation was not recommended for both.The first patient, a 76-year-old man, was supported with C-PAP helmet, with PEEP 12.5 and FiO2 50%. The comorbidity were arterial hypertension and chronic ischemic heart disease. He was treated with antiviral drugs, azythromicine, steroids and LMWH 6000 UI daily. Suddenly, after 7 days from the admission to the hospital, he started complaining of severe abdominal pain, the blood pressure decreased to 80/60 mmHg and the blood test showed Hb 8.6 g/dl (from 12 g/dl), fibrinogen of 324 mg/dl; normal protrombine time (PT) and platelet count (PTL). The abdominal CT scan demonstrated a large pelvic blood collection anterior to the left ileo-psoas muscle (size. 9×13 cm) (Fig. 1A). The lesion showed enhanced contrast tardive spot of 10 mm, above the ischiopubic branch, as sign of active arterial bleeding. The second case refers to a 72-year-old woman with severe respiratory insufficiency, treated with C-PAP helmet, PEEP 12 cm H2O, FiO2 60%. The comorbidities were arterial hypertension and anxious syndrome. During a sonography performed to place a CVC, a venous femoral thrombosis was detected; LMWH at therapeutic dose 100UI/kg/BID was promptly started. Suddenly, ...

Take home message: utility and safety of bronchoscopy during SARS-CoV-2 outbreak Funding: the work is funded by Università degli Studi di Milano in the context of the Registry for COVID19 Emergency (RECOVER) electronic database

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