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).
Several patients experience pulmonary sequelae after Sars-Cov-2 infection, ranging from self-limited abnormalities to major lung diseases. Morphological analysis of lung tissue may help in understanding pathogenic mechanisms and provide consistent personalised management. Aim of the study was to ascertain morphologic and immuno-molecular features of lung tissue. Transbronchial lung cryobiopsy was carried out in patients with persistent symptoms and computed tomography suggestive of residual lung disease after recovery from Sars-CoV-2 infection. 164 patients were referred for suspected pulmonary sequelae after COVID-19; 10 patients with parenchymal lung disease extent >5% underwent lung biopsy. Histological pattern was not homogeneous, as three different case clusters could be evidenced, which were mirrored in clinical and radiological features: cluster one (“chronic fibrosing”) characterised by post-infection progression of pre-existing interstitial pneumonias; cluster two (“acute/subacute injury”) characterised by different types and grades of lung injury, ranging from organising pneumonia and fibrosing NSIP to diffuse alveolar damage; cluster three (“vascular changes”) characterised by diffuse vascular increase, dilatation and distortion (capillaries and venules) within otherwise normal parenchyma. Clusters two and three were characterised by immunophenotypical changes similar to those observed in early/mild covid-19 pneumonias (abnormal expression of STAT3 in hyperplastic pneumocytes and PD-L1, IDO and STAT3 in endothelial cells). This is the first study correlating histological/immunohistochemical patterns with clinical and radiological pictures of patients with post-COVID lung disease. Different phenotypes with potential different underlying pathogenic mechanisms have been identified.
Three cases are reported of spondylodiscitis caused by coagulase-negative staphylococci in patients without osteosynthetic material. All three patients had bacteraemia associated with an infected intravascular device left in place. On the basis of this observation, it is concluded that such devices should be removed promptly in cases of prolonged or relapsing bacteraemia. Furthermore, spondylodiscitis should be suspected in patients with back pain after bacteraemia caused by coagulase-negative staphylococci.
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