Clinical characteristics and outcomes of critically ill mechanically ventilated COVID-19 patients receiving interleukin-6 receptor antagonists and corticosteroid therapy: a preliminary report from a multinational registry.

BACKGROUND: Interleukin-6 receptor antagonists (IL-6RAs) and steroids are emerging immunomodulatory therapies for severe and critical coronavirus disease (COVID-19). In this preliminary report, we aim to describe the epidemiology, clinical characteristics, and outcomes of adult critically ill COVID-19 patients, requiring invasive mechanical ventilation (iMV), and receiving IL-6RA and steroids therapy over the last 11 months. MATERIALS AND METHODS: International, multicenter, cohort study derived from Viral Infection and Respiratory Illness University Study registry and conducted through Discovery Network, Society of Critical Care Medicine. Data were collected between March 01, 2020, and January 10, 2021. RESULTS: Of 860 patients who met eligibility criteria, 589 received steroids, 170 IL-6RAs, and 101 combinations. Patients who received IL-6RAs were younger (median age of 57.5 years vs. 61.1 and 61.8 years in the steroids and combination groups, respectively). The median C-reactive protein level was > 75 mg/L, indicating a hyperinflammatory phenotype. The median daily steroid dose was 7.5 mg dexamethasone or equivalent (interquartile range: 6-14 mg); 80.8% and 19.2% received low-dose and high-dose steroids, respectively. Of the patients who received IL-6RAs, the majority received one dose of tocilizumab and sarilumab (dose range of 600-800 mg for tocilizumab and 200-400 mg for sarilumab). Regarding the timing of administration, we observed that steroid and IL-6RA administration on day 0 of ICU admission was only 55.6% and 39.5%, respectively. By day 28, when compared with steroid use alone, IL-6RA use was associated with an adjusted incidence rate ratio (aIRR) of 1.12 (95% confidence interval [CI] 0.88, 1.4) for ventilator-free days, while combination therapy was associated with an aIRR of 0.83 (95% CI 0.6, 1.14). IL-6RA use was associated with an adjusted odds ratio (aOR) of 0.68 (95% CI 0.44, 1.07) for the 28-day mortality rate, while combination therapy was associated with an aOR of 1.07 (95% CI 0.67, 1.70). Liver dysfunction was higher in IL-6RA group (p = 0.04), while the bacteremia rate did not differ among groups. CONCLUSIONS: Discordance was observed between the registry utilization patterns (i.e., timing of steroids and IL-6RA administration) and new evidence from the recent randomized controlled trials and guideline recommendations. These data will help us to identify areas of improvement in prescribing patterns and enhance our understanding of IL-6RA safety with different steroid regimens. Further studies are needed to evaluate the drivers of hospital-level variation and their impact on clinical outcomes. Trial registration ClinicalTrials.gov: NCT04486521. Registered on July 2020.

Efficacy and safety of azithromycin in Covid-19 patients: A systematic review and meta-analysis of randomized clinical trials.

Azithromycin (AZM) is commonly used in Covid-19 patients based on low-quality evidence, increasing the risk of developing adverse events and antimicrobial resistance. The current systematic review and meta-analysis investigated the safety and efficacy of AZM in treating Covid-19 patients using published randomized controlled trials. Google Scholar, PubMed, Scopus, Cochrane Library, Clinical Trials.gov, MEDLINE, bioRxiv and medRxiv were searched for relevant studies. The random-effects model was used to pool estimates using the Paule-Mandel estimate for heterogeneity. The odds ratio and raw difference in medians were used for dichotomous and continuous outcomes, respectively. The analysis included seven studies with 8822 patients (median age, 55.8 years; 61% males). The risk of bias was assessed as 'low' for five of the seven mortality results and as 'some concerns' and 'high' in one trial each. There were 657/3100 (21.2%) and 1244/5654 (22%) deaths among patients randomized to AZM and standard of care, respectively. The use of AZM was not associated with mortality in Covid-19 patients (OR = 0.96, 95% CI 0.88-1.05, p = 0.317 based on the random-effect meta-analysis). The use of AZM was not associated with need for invasive mechanical ventilation (OR = 0.96, 95% CI 0.49-1.87, p = 0.85) and length of stay (Δ = 1.11, 95% CI -2.08 to 4.31, p = 0.49). The results show that using AZM as routine therapy in Covid-19 patients is not justified due to lack of efficacy and potential risk of bacterial resistance that is not met by an increased clinical benefit.

Characteristics and outcomes of coronavirus disease 2019 (COVID-19) in critically ill pediatric patients admitted to the intensive care unit: A multicenter retrospective cohort study.

BACKGROUND: Characteristics of critical Severe Acute Respiratory Syndrome-related Coronavirus 2 (SARS-CoV-2) infection in children is not well understood. This study described the clinical characteristics of children admitted to intensive care units (ICU) and explored factors associated with the need for invasive ventilation or mortality. METHODS: A multicenter, retrospective, cohort study was conducted over eight medical centers, including all patients younger than 18 years of age and admitted to the ICU due to a direct consequence of coronavirus disease 2019 (COVID-19). Patients who were admitted to the ICU for any alternate reason and tested positive for SARS-CoV-2 by screening test, and patients who were admitted due to multi-inflammatory syndrome in children, were excluded. Demographic, laboratory, imaging, and clinical data were collected. Descriptive statistics were used to compare survivors and non-survivors. Fine and Gray's hazard model was used to estimate the association between clinical variables and ICU death. RESULTS: During the study period, 25 pediatric COVID-19 patients received care in the ICUs. The median age was 2.78 years (IQR 0.21-8.51), and 60% were male. Only three patients were reported to be previously healthy at admission. Nine (36%) patients required invasive mechanical ventilation, including two were on extracorporeal membrane oxygenation. Four (16%) patients died during ICU care. In univariate analysis, the presence of comorbidity (HR 0.0001; 95%CI 0.00001-0.00016), platelets count (HR 0.99; 95% CI 0.98-0.99), elevated procalcitonin (HR 1.05; 95%CI 1.016-1.09), and circulatory compromise (HR 16.34; 95%CI 1.99-134.35), all at the time of ICU admission, were associated with in-ICU mortality. CONCLUSION: Our findings suggest that children admitted to the ICU with SARS-CoV-2 infection, generally, have a favorable outcome. Low platelets count, elevated procalcitonin, presence of comorbidity, and shock at the time of ICU admission were associated with death. This study may shed more light on the disease dynamics of critical pediatric COVID-19.

Anticoagulation outcomes in hospitalized Covid-19 patients: A systematic review and meta-analysis of case-control and cohort studies.

BACKGROUND: Coagulopathy and thromboembolic events are common in Covid-19 patients and are poor prognostic factors. Controversy exists regarding the potential of anticoagulation (AC) to reduce mortality and incidence of thromboembolic events in Covid-19 patients. The current systematic review and meta-analysis investigated the association between anticoagulants and mortality in adult hospitalized COVID-19 patients using the available published non-randomized studies. METHODS: Google Scholar, PubMed, Scopus, the Cochrane Library and Clinical Trials.gov were searched for relevant studies. A meta-analysis of adjusted and unadjusted estimates was performed. The relative risk was used as a measure of effect. The random-effects model was used to pool estimates using the generic inverse variance method. RESULTS: Sixteen studies were included in the quantitative data synthesis. Results showed a statistically significant association between AC and mortality (RR = 0.56, 95% CI 0.36; 0.92, p = 0.02). Both therapeutic (Relative risk [RR] = 0.4, 95% CI 0.27; 0.57) and prophylactic AC (RR = 0.54, 95% CI 0.41; 0.71) were associated with lower risk of mortality. Pre-admission AC was not associated with mortality (RR = 0.84, 95% CI 0.49; 1.43, p > 0.05) while prophylactic AC was associated with higher risk of mortality compared to therapeutic AC (RR = 1.58, 95% CI 1.34; 1.87, p < 0.001). CONCLUSION: Findings support the association of AC with mortality in Covid-19 patients. The results, synthesized from mostly low-quality studies, show that prophylactic and therapeutic AC might reduce mortality in Covid-19 patients. Findings suggest that therapeutic doses might be associated with better survival compared to prophylactic doses.