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).
The objective of this study was to examine the relation between respiratory function tests, disease activity and disease severity in ambulatory patients with systemic lupus erythematosus (SLE) who did not present with overt respiratory problems. Lung volumes, maximal expiratory flows at 50% and 25% of vital capacity (MEF50 and MEF25), bronchial threshold to methacholine (PD15FEV1), transfer factor CO (KCO) were measured in 24 consecutive SLE outpatients (22 women, age 41 +/- 14.8 years) and in 24 healthy controls matched for age and sex. In SLE patients alveolar-arterial oxygen gradient (AaO2) was also measured. Disease activity was assessed by European Consensus Lupus Activity Measurement (ECLAM) scoring system and disease severity by Lupus Severity of Disease Index. In comparison to controls SLE patients showed a significant decrease of total lung capacity (TLC) (91.7 +/- 16.5 vs 102.7 +/- 12.9% predicted, P < 0.01), MEF25 (58.4 +/- 25.2 vs 73.5 +/- 19.5% predicted, P < 0.005) PD15FEV1 (2164 +/- 1122 vs 4230 +/- 1014 micrograms methacholine, P < 0.0001) and KCO (77.1 +/- 20.5 vs 96.3 +/- 12.4% predicted, P < 0.001). AaO2 (mean value 13.2 +/- 8.4) was abnormally high (> 20 mmHg) in 12 patients. The ECLAM score of activity was inversely related with KCO (r = 0.48, P < 0.02). The severity index was significantly related with FEV1/VC ratio (r = 0.43, P < 0.05), MEF50 (r = 0.51, P < 0.01), MEF25 (r = 0.40, P < 0.05) and PD15FEV1 (r = 0.51, P < 0.01). In eight patients, evaluated also after treatment intensification, there was a significant increase in KCO (from 71.8 +/- 24.7 to 84.9 +/- 22.3% predicted, P < 0.01) along with a decrease in ECLAM score (from 3.0 +/- 1.34 to 0.69 +/- 0.75, P < 0.01). The relation between disease activity and KCO suggests a relation between systemic and alveolar inflammation whereas the relation between severity index, airway patency and reactivity indices suggests a cumulative damage to the airways in SLE patients, even in the absence of overt respiratory manifestations.
Objectives To evaluate the accuracy of a new COVID‐19 prognostic score based on lung ultrasound (LUS) and previously validated variables in predicting critical illness. Methods We conducted a single‐center retrospective cohort development and internal validation study of the COVID‐19 Worsening Score (COWS), based on a combination of the previously validated COVID‐GRAM score (GRAM) variables and LUS. Adult COVID‐19 patients admitted to the emergency department (ED) were enrolled. Ten variables previously identified by GRAM, days from symptom onset, LUS findings, and peripheral oxygen saturation/fraction of inspired oxygen (P/F) ratio were analyzed. LUS score as a single predictor was assessed. We evaluated GRAM model's performance, the impact of adding LUS, and then developed a new model based on the most predictive variables. Results Among 274 COVID‐19 patients enrolled, 174 developed critical illness. The GRAM score identified 51 patients at high risk of developing critical illness and 132 at low risk. LUS score over 15 (range 0 to 36) was associated with a higher risk ratio of critical illness (RR, 2.05; 95% confidence interval [CI], 1.52‐2.77; area under the curve [AUC], 0.63; 95% CI 0.676‐0.634). The newly developed COVID‐19 Worsening Score relies on five variables to classify high‐ and low‐risk patients with an overall accuracy of 80% and negative predictive value of 93% (95% CI, 87%‐98%). Patients scoring more than 0.183 on COWS showed a RR of developing critical illness of 8.07 (95% CI, 4.97‐11.1). Conclusions COWS accurately identify patients who are unlikely to need intensive care unit (ICU) admission, preserving resources for the remaining high‐risk patients.
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