Red blood cell distribution width as a marker of hyperinflammation and mortality in COVID-19.

BACKGROUND: Red blood cell distribution width (RDW) could reflect interleukin-6 (IL-6) systemic activity since anisocytosis represents the inhibition of erythropoiesis, leaded by the hyperinflammatory background. Our objective was to analyze RDW performance to predict outcome in coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS). METHODS: Retrospective observational study including 173 patients with COVID-19-associated ARDS. Data was analyzed at hospital admission, inclusion in the TOCICOV Study (day 0), days 1, 3, 7 and 15 post-inclusion. RESULTS: Overall, 57% patients received tocilizumab. Overall mortality was 20.8%. RDW was higher in non-survivors compared to survivors at admission (13.53% vs. 14.35, P=0.0016), day 0 (13.60% vs. 14.42, P=0.026), day 3 (13.43% vs. 14.36, P<0.001) and day 7 (13.41% vs. 14.31, P=0.046), presenting better discrimination ability for mortality than other prognostic markers [area under the curve-receiver operating characteristic (AUC-ROC) =0.668 for admission RDW, 0.680 for day 0 RDW, 0.695 for day 3 RDW and 0.666 for day 7 RDW]. RDW values did not vary significantly according to tocilizumab treatment. When adjusted by hemoglobin and tocilizumab treatment, only RDW at admission, day 0, day 3 and C reactive protein (CRP) at day 0 and day 1 were associated with mortality (P<0.05). Only in non-tocilizumab treated patients, IL-6 levels at day 0 were correlated with day 3 RDW (r=0.733, P=0.004) and with day 3 CRP (r=0.727, P=0.022). Both parameters showed significant statistical correlation (r=0.255 for day 1 RDW and CRP in the overall cohort and r=0.358 for day 3 RDW and CRP in patients not treated with tocilizumab, P<0.015). CONCLUSIONS: RDW predicts COVID-19-associated ARDS mortality and reflects the hyperinflammatory background and the effects of cytokines such as IL-6, irrespective of tocilizumab treatment.

A multicenter randomized open-label clinical trial for convalescent plasma in patients hospitalized with COVID-19 pneumonia.

BACKGROUNDPassive immunotherapy with convalescent plasma (CP) is a potential treatment for COVID-19. Evidence from controlled clinical trials is inconclusive.METHODSWe conducted a randomized, open-label, controlled clinical trial at 27 hospitals in Spain. Patients had to be admitted for COVID-19 pneumonia within 7 days from symptom onset and not on mechanical ventilation or high-flow oxygen devices. Patients were randomized 1:1 to treatment with CP in addition to standard of care (SOC) or to the control arm receiving only SOC. The primary endpoint was the proportion of patients in categories 5 (noninvasive ventilation or high-flow oxygen), 6 (invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), or 7 (death) at 14 days. Primary analysis was performed in the intention-to-treat population.RESULTSBetween April 4, 2020, and February 5, 2021, 350 patients were randomly assigned to either CP (n = 179) or SOC (n = 171). At 14 days, proportion of patients in categories 5, 6, or 7 was 11.7% in the CP group versus 16.4% in the control group (P = 0.205). The difference was greater at 28 days, with 8.4% of patients in categories 5-7 in the CP group versus 17.0% in the control group (P = 0.021). The difference in overall survival did not reach statistical significance (HR 0.46, 95% CI 0.19-1.14, log-rank P = 0.087).CONCLUSIONCP showed a significant benefit in preventing progression to noninvasive ventilation or high-flow oxygen, invasive mechanical ventilation or ECMO, or death at 28 days. The effect on the predefined primary endpoint at 14 days and the effect on overall survival were not statistically significant.TRIAL REGISTRATIONClinicaltrials.gov, NCT04345523.FUNDINGGovernment of Spain, Instituto de Salud Carlos III.

Efficacy and Safety of Sarilumab in patients with COVID19 Pneumonia: A Randomized, Phase III Clinical Trial (SARTRE Study).

INTRODUCTION: SARS-CoV-2 pneumonia is often associated with hyper-inflammation. The cytokine-storm-like is one of the targets of current therapies for coronavirus disease 2019 (COVID-19). High Interleukin-6 (IL6) blood levels have been identified in severe COVID-19 disease, but there are still uncertainties regarding the actual role of anti-IL6 antagonists in COVID-19 management. Our hypothesis was that the use of sarilumab plus corticosteroids at an early stage of the hyper-inflammatory syndrome would be beneficial and prevent progression to acute respiratory distress syndrome (ARDS). METHODS: We randomly assigned (in a 1:1 ratio) COVID-19 pneumonia hospitalized patients under standard oxygen therapy and laboratory evidence of hyper-inflammation to receive sarilumab plus usual care (experimental group) or usual care alone (control group). Corticosteroids were given to all patients at a 1 mg/kg/day of methylprednisolone for at least 3 days. The primary outcome was the proportion of patients progressing to severe respiratory failure (defined as a score in the Brescia-COVID19 scale ≥ 3) up to day 15. RESULTS: A total of 201 patients underwent randomization: 99 patients in the sarilumab group and 102 patients in the control group. The rate of patients progressing to severe respiratory failure (Brescia-COVID scale score ≥ 3) up to day 15 was 16.16% in the Sarilumab group versus 15.69% in the control group (RR 1.03; 95% CI 0.48-2.20). No relevant safety issues were identified. CONCLUSIONS: In hospitalized patients with Covid-19 pneumonia, who were under standard oxygen therapy and who presented analytical inflammatory parameters, an early therapeutic intervention with sarilumab plus standard of care (including corticosteroids) was not shown to be more effective than current standard of care alone. The study was registered at EudraCT with number: 2020-002037-15.

Evaluation of convalescent plasma versus standard of care for the treatment of COVID-19 in hospitalized patients: study protocol for a phase 2 randomized, open-label, controlled, multicenter trial.

BACKGROUND: COVID-19 is a respiratory disease caused by a novel coronavirus (SARS-CoV-2) and causes substantial morbidity and mortality. At the time this clinical trial was planned, there were no available vaccine or therapeutic agents with proven efficacy, but the severity of the condition prompted the use of several pharmacological and non-pharmacological interventions. It has long been hypothesized that the use of convalescent plasma (CP) from infected patients who have developed an effective immune response is likely to be an option for the treatment of patients with a variety of severe acute respiratory infections (SARI) of viral etiology. The aim of this study is to assess the efficacy and safety of convalescent plasma in adult patients with severe COVID-19 pneumonia. METHODS/DESIGN: The ConPlas-19 study is a multicenter, randomized, open-label controlled trial. The study has been planned to include 278 adult patients hospitalized with severe COVID-19 infection not requiring mechanical ventilation (invasive or non-invasive). Subjects are randomly assigned in a 1:1 ratio (139 per treatment arm), stratified by center, to receive intravenously administered CP (single infusion) plus SOC or SOC alone, and are to be followed for 30 days. The primary endpoint of the study is the proportion of patients that progress to category 5, 6, or 7 (on the 7-point ordinal scale proposed by the WHO) at day 15. Interim analyses for efficacy and/or futility will be conducted once 20%, 40%, and 60% of the planned sample size are enrolled and complete D15 assessment. DISCUSSION: This clinical trial is designed to evaluate the efficacy and safety of passive immunotherapy with convalescent plasma for the treatment of adult patients hospitalized with COVID-19. The results of this study are expected to contribute to establishing the potential place of CP in the therapeutics for a new viral disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT04345523 . Registered on 30 March, 2020. First posted date: April 14, 2020.

Combination of Tocilizumab and Steroids to Improve Mortality in Patients with Severe COVID-19 Infection: A Spanish, Multicenter, Cohort Study.

BACKGROUND: We aimed to determine the impact of tocilizumab use on severe COVID-19 (coronavirus disease 19) pneumonia mortality. METHODS: We performed a multicentre retrospective cohort study in 18 tertiary hospitals in Spain from March to April 2020. Consecutive patients admitted with severe COVID-19 treated with tocilizumab were compared to patients not treated with tocilizumab, adjusting by inverse probability of the treatment weights (IPTW). Tocilizumab's effect in patients receiving steroids during the 48 h following inclusion was analysed. RESULTS: During the study period, 506 patients with severe COVID-19 fulfilled the inclusion criteria. Among them, 268 were treated with tocilizumab and 238 patients were not. Median time to tocilizumab treatment from onset of symptoms was 11 days [interquartile range (IQR) 8-14]. Global mortality was 23.7%. Mortality was lower in patients treated with tocilizumab than in controls: 16.8% versus 31.5%, hazard ratio (HR) 0.514 [95% confidence interval (95% CI) 0.355-0.744], p < 0.001; weighted HR 0.741 (95% CI 0.619-0.887), p = 0.001. Tocilizumab treatment reduced mortality by 14.7% relative to no tocilizumab treatment [relative risk reduction (RRR) 46.7%]. We calculated a number necessary to treat of 7. Among patients treated with steroids, mortality was lower in those treated with tocilizumab than in those treated with steroids alone [10.9% versus 40.2%, HR 0.511 (95% CI 0.352-0.741), p = 0.036; weighted HR 0.6 (95% CI 0.449-0.804), p < 0.001] (interaction p = 0.094). CONCLUSIONS: These results show that survival of patients with severe COVID-19 is higher in those treated with tocilizumab than in those not treated and that tocilizumab's effect adds to that of steroids administered to non-intubated patients with COVID-19 during the first 48 h of presenting with respiratory failure despite oxygen therapy. Randomised controlled studies are needed to confirm these results. TRIAL REGISTRATION: European Union electronic Register of Post-Authorization Studies (EU PAS Register) identifier, EUPAS34415.

Sarilumab versus standard of care for the early treatment of COVID-19 pneumonia in hospitalized patients: SARTRE: a structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: In some patients, acute, life-threatening respiratory injury produced by viruses such as SARS-CoV and other viral pneumonia are associated with an over-exuberant cytokine release. Elevated levels of blood IL-6 had been identified as a one of the risk factors associated with severe COVID-19 disease. Anti-IL6 inhibitors are among the therapeutic armamentarium for preventing the fatal consequences of acute respiratory and multi organ failure in around 20% of the COVID-19 infected patients. At present, their use is prioritized to patients with severe interstitial pneumonia (Brescia-COVID Scale-COVID 2-3) with hyperinflammation as determined by the presence of elevated IL6 and/or d-dimer, or progressive d-dimer increase, in patients who otherwise are subsidiary to ICU admission. However, many uncertainties remain on the actual role of anti-IL6 inhibitors in this setting, and whether current use and timing is the right one. There is the hypothesis that the use of anti-IL6 inhibitors at an earlier state during the hyperinflammatory syndrome would be beneficial and may avoid progressing to ARDS. On the other hand, the standard of care has changed and nowadays the use of corticosteroids has become part of the SOC in the treatment of COVID-19 pneumonia. Our limited experience suggests that better treatment outcomes can be achieved when combining IL6-inhibitors (e.g. sarilumab) with corticosteroids. The aim of the present study is to evaluate if an earlier therapeutic intervention with sarilumab plus SOC (including corticosteroids) may be more effective than current standard of care alone, in preventing progression to respiratory failure in COVID-19 infected patients with interstitial pneumonia. This study will also provide supportive evidence to that provided by currently ongoing studies on the efficacy and safety of sarilumab in this clinical context. TRIAL DESIGN: A phase two multi-center randomised controlled trial (RCT) with two parallel arms (1:1 ratio). PARTICIPANTS: They will be hospitalized patients, of at least 18 years of age, with severe COVID-19 who have positive RT-PCR test and have radiographic evidence of pulmonary infiltrates by imaging or rales/crackles on exam and SpO2 ≤ 94% on room air that requires supplemental oxygen. Patients must present elevation of inflammatory parameters (IL-6 > 40 pg/mL or d-dimer >1.0 mcg/ml) or, alternatively, progressive worsening in at least two of these inflammatory parameters in the prior 24-48h: CRP, LDH, serum ferritin, lymphopenia, or d-dimer. EXCLUSION CRITERIA: high oxygen requirements (including face mask with reservoir, non-invasive mechanical ventilation or high flow nasal cannula, or mechanical ventilation), admission to ICU, pregnancy or lactation, allergy or hypersensitivity to sarilumab or corticoesteroids, immunosuppressive antibody therapy within the past 5 months, AST/ALT values > 10 x ULN, neutropenia (< 0.5 x 109/L), severe thrombocytopenia (< 50 x 109/L), sepsis caused by an alternative pathogen, diverticulitis with risk of perforation or ongoing infectious dermatitis. The study will be conducted in several hospitals in Spain. INTERVENTION AND COMPARATOR: Patients randomised to the experimental arm will receive sarilumab + methylprednisolone plus SOC for COVID-19. Patients included in the control arm will receive methylprednisolone plus SOC for COVID-19. Corticosteroids will be given to all patients at a 1mg/kg/d of methylprednisolone for at least 3 days. Clinical follow-up visits will be performed at 3, 5, and 15 days after treatment randomization. Patients in the control group (SOC group without sarilumab) progressing to Brescia- COVID 2-3 plus inflammatory markers, will be given the option to be rescued with sarilumab at the same doses and, in that case, be included in an open-label phase and be followed up for additional weeks (with visits at 3, 7 and 15 days after sarilumab rescue administration). Patients randomly assigned to sarilumab therapy at baseline progressing to Brescia-COVID 2-3 will be rescued according to local clinical practice protocols. A final follow-up visit will be conducted for all patients at day 29 from randomization, regardless of initial treatment assignment. MAIN OUTCOMES: Primary end point is the proportion of patients progressing to either severe respiratory failure (Brescia-COVID ≥2), ICU admission, or death. RANDOMIZATION: Randomization codes were produced by means of the PROC PLAN of the SAS system, with a 1:1 assignment ratio, stratifying by centre and using blocks multiple of 2 elements. The randomization schedule will be managed through the eCRF in a concealed manner. BLINDING (MASKING): All study drugs will be administered as open label. No blinding methods will be used in this trial. NUMBERS TO BE RANDOMISED (SIMPLE SIZE): The target sample size will be 200 COVID-19 patients, who will be allocated randomly to control arm (100) and treatment arm (100). TRIAL STATUS: Protocol Code: SARTRE Protocol Date: May 05th 2020. Version: 2.0 The study has been approved by the Spanish Competent Authority (AEMPS) as a low intervention clinical trial. Start of recruitment: August, 2020 End of recruitment: May, 2021 TRIAL REGISTRATION: Identifier: EudraCT Number: 2020-002037-15 ; Registration date: 26 May 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

A Retrospective Controlled Cohort Study of the Impact of Glucocorticoid Treatment in SARS-CoV-2 Infection Mortality.

Evidence to support the use of steroids in coronavirus disease 2019 (COVID-19) pneumonia is lacking. We aim to determine the impact of steroid use for COVID-19 pneumonia on hospital mortality. We performed a single-center retrospective cohort study in a university hospital in Madrid, Spain, during March of 2020. To determine the role of steroids in in-hospital mortality, patients admitted with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia and treated with steroids were compared to patients not treated with steroids, and we adjusted with a propensity score for patients on steroid treatment. Survival times were compared using the log rank test. Different steroid regimens were compared and adjusted with a second propensity score. During the study period, 463 out of 848 hospitalized patients with COVID-19 pneumonia fulfilled inclusion criteria. Among them, 396 (46.7%) patients were treated with steroids and 67 patients were not. Global mortality was 15.1%. The median time to steroid treatment from symptom onset was 10 days (interquartile range [IQR], 8 to 13 days). In-hospital mortality was lower in patients treated with steroids than in controls (13.9% [55/396] versus 23.9% [16/67]; hazard ratio [HR], 0.51 [95% confidence interval, 0.27 to 0.96]; P = 0.044). Steroid treatment reduced mortality by 41.8% relative to the mortality with no steroid treatment (relative risk reduction, 0.42 [95% confidence interval, 0.048 to 0.65]). Initial treatment with 1 mg/kg of body weight/day of methylprednisolone versus steroid pulses was not associated with in-hospital mortality (13.5% [42/310] versus 15.1% [13/86]; odds ratio [OR], 0.880 [95% confidence interval, 0.449 to 1.726]; P = 0.710). Our results show that the survival of patients with SARS-CoV-2 pneumonia is higher in patients treated with glucocorticoids than in those not treated. Rates of in-hospital mortality were not different between initial regimens of 1 mg/kg/day of methylprednisolone and glucocorticoid pulses.