Efficacy and Safety of IL-6 Inhibitors in Patients with COVID-19 Pneumonia: A Systematic Review and Meta-Analysis of Multicentre, Randomised Trials (preprint)

Introduction: The novel coronavirus disease 2019 (COVID-19) is frequently characterized by dysregulated host immune response with hyperinflammation and self-induced host inflammatory damage that results in severe respiratory failure and frequently death. Interleukin-6 (IL-6) appeared among the key cytokines involved in COVID-19 associated cytokine storm. Therefore, several trials investigated whether IL-6 inhibition with tocilizumab or sarilumab could improve symptoms and outcome of COVID-19 patients. We performed a meta-analysis of randomized trials to test this hypothesis.Methods: PubMed, Scopus, Cochrane central register and medRxiv were searched by two independent investigators up to February 23rd, 2021. Inclusion criteria were: administration of tocilizumab or sarilumab, COVID-19 pneumonia, randomized controlled trials. Studies in setting other than adult human COVID-19 were excluded. The primary outcome was mortality at the longest follow-up available. Secondary outcomes included need for intubation and incidence of adverse events. Two independent investigators examined and extracted data from eligible trials.Results: A total of 371 studies were assessed, with a total of 10 studies (6,465 patients) finally included in the meta-analysis. All the trials were multicentre and the majority were open-label vs standard treatment. IL-6 inhibitors use was associated with reduced all-cause mortality at the longest follow-up available (823/3,310 [24·9%] in the IL-6 inhibitors group versus 902/3,038 [29·7%] in the control group, RR = 0·89; 95% CI 0·82 to 0·96; p for effect = 0·003, I2 = 6%, with eight studies included). Use of IL-6 inhibitors was associated with a significant reduction in need for intubation, while we found no difference in rate of adverse events and secondary infections.Conclusion: Administration of IL-6 inhibitors may reduce all-cause longest follow-up mortality and need for intubation in COVID-19 patients, without increasing risk of adverse events. However, these findings need to be confirmed in high-quality randomized controlled trials.Funding Statement: None.Declaration of Interests: None.

The Effect of Angiotensin II Infusion on Markers of Organ Function in Invasively Ventilated COVID-19 Patients (preprint)

Background: The use of angiotensin II (ANGII) in invasively ventilated COVID-19 patients is controversial. Its effect on markers of organ function is unknown.Methods: We used ANGII either as rescue vasopressor agent or as low dose vasopressor support. Patients treated before ANGII availability or in an adjacent COVID-19 ICU served as controls. For data analysis, we applied Bayesian modelling as appropriate. We assessed the effects of ANG on markers of organ function.Results: We compared 46 ANGII patients with 53 controls. Compared with controls, ANGII increased MAP (median difference, 9.05 mmHg [95% confidence interval, 1.87 to 16.22]; p = 0.013) and PaO2/FiO2 ratio (median difference, 23.17 [95% confidence interval, 3.46 to 42.88]; p = 0.021). ANGII had no effect on lactate, urinary output, serum creatinine, C-Reactive protein, platelet count, or thromboembolic complications. However, it significantly decreased the odd ratio of liver dysfunction (odds ratio: 0.32; 0.09 to 0.94) and, on Bayesian modelling, in patients with abnormal baseline serum creatinine, ANGII carried a 95.7% probability of decreasing renal replacement therapy use. Conclusions: In ventilated COVID-19 patients, ANGII therapy was associated with increased blood pressure and PaO2/FiO2 ratios, decreased odds ratio of liver dysfunction, and a high probability of decreasing renal replacement therapy use in patients with abnormal baseline serum creatinine. 

Viral Clearance After Early Corticosteroid Treatment In Patients With Moderate Or Severe Covid-19 (preprint)

The aim of this study was to evaluate the impact of early treatment with corticosteroids on SARS-CoV-2 clearance in hospitalized COVID-19 patients.Retrospective analysis on patients admitted to the San Raffaele Hospital (Milan, Italy) with moderate/severe COVID-19 and availability of at least two nasopharyngeal swabs.The primary outcome was the time to nasopharyngeal swab negativization.A multivariable Cox model was fitted to determine factors associated with nasopharyngeal swab negativization.Of 280 patients included, 59 (21.1%) patients were treated with steroids.Differences observed between steroid users and non-users included the proportion of patients with a baseline PaO2/FiO2 ≤200 mmHg (45.8% vs 34.4% in steroids and non-steroids users, respectively; p=0.023) or ≤100 mmHg (16.9% vs 12.7%; p=0.027), and length of hospitalization (20 vs 14 days; p<0.001).Time to negativization of nasopharyngeal swabs was similar in steroid and non-steroid users (p=0.985).According to multivariate analysis, SARS-CoV-2 clearance was associated with age ≤70 years, a shorter duration of symptoms at admission, a baseline PaO2/FiO2 >200 mmHg, and a lymphocyte count at admission >1.0*109/L. SARS-CoV-2 clearance was not associated with corticosteroid use.Our study shows that delayed SARS-CoV-2 clearance in moderate/severe COVID-19 is associated with older age and a more severe disease, but not with early use of corticosteroids