Immunomodulators for immunocompromised patients hospitalized for COVID-19: a meta-analysis of randomized controlled trials.

BACKGROUND: Although immunomodulators have established benefit against the new coronavirus disease (COVID-19) in general, it is uncertain whether such agents improve outcomes without increasing the risk of secondary infections in the specific subgroup of previously immunocompromised patients. We assessed the effect of immunomodulators on outcomes of immunocompromised patients hospitalized for COVID-19. METHODS: The protocol was prospectively registered with PROSPERO (CRD42022335397). MEDLINE, Cochrane Central Register of Controlled Trials and references of relevant articles were searched up to 01-06-2022. Authors of potentially eligible randomized controlled trials were contacted to provide data on immunocompromised patients randomized to immunomodulators vs control (i.e., placebo or standard-of-care). FINDINGS: Eleven randomized controlled trials involving 397 immunocompromised patients hospitalized for COVID-19 were included. Ten trials had low risk of bias. There was no difference between immunocompromised patients randomized to immunomodulators vs control regarding mortality [30/182 (16.5%) vs 41/215 (19.1%); RR 0.93, 95% CI 0.61-1.41; p = 0.74], secondary infections (RR 1.00, 95% CI 0.64-1.58; p = 0.99) and change in World Health Organization ordinal scale from baseline to day 15 (weighed mean difference 0.27, 95% CI -0.09-0.63; p = 0.15). In subgroup analyses including only patients with hematologic malignancy, only trials with low risk of bias, only trials administering IL-6 inhibitors, or only trials administering immunosuppressants, there was no difference between comparators regarding mortality. INTERPRETATION: Immunomodulators, compared to control, were not associated with harmful or beneficial outcomes, including mortality, secondary infections, and change in ordinal scale, when administered to immunocompromised patients hospitalized for COVID-19. FUNDING: Hellenic Foundation for Research and Innovation

Palliative care consultation and end-of-life outcomes in hospitalized COVID-19 patients

Rationale:The impact of palliative care consultation on end-of-life care has not previously been evaluated in a multi-center study. Objectives:To evaluate the impact of palliative care consultation on the incidence of cardiopulmonary resuscitation (CPR) performed and comfort care received at the end-of-life in hospitalized patients with COVID-19. Methods:We used the Society of Critical Care Medicine\u27s COVID-19 registry to extract clinical data on patients hospitalized with COVID-19 between March 31st, 2020 to March 17th, 2021 and died during their hospitalization. The proportion of patients who received palliative care consultation was assessed in patients who did and did not receive CPR (primary outcome) and comfort care (secondary outcome). Propensity matching was used to account for potential confounding variables. Measurements and main results:3,227 patients were included in the analysis. There was no significant difference in the incidence of palliative care consultation between the CPR and no-CPR groups (19.9% vs. 19.4%, p = 0.8334). Patients who received comfort care at the end-of-life were significantly more likely to have received palliative care consultation (43.3% vs. 7.7%, p \u3c 0.0001). After propensity matching for comfort care on demographic characteristics and comorbidities, this relationship was still significant (43.2% vs. 8.5%; p \u3c 0.0001). Conclusion:Palliative care consultation was not associated with CPR performed at the end-of-life but was associated with increased incidence of comfort care being utilized. These results suggest that utilizing palliative care consultation at the end-of-life may better align the needs and values of patients with the care they receive

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 \u3e 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

Resuscitation in the First 3 Hours of Sepsis-Induced Hypotension Varies by Patient and Hospital Factors

Patient and hospital factors affects how we resuscitate patients in the first 3 hours of sepsis-induced hypotension.ObjectivesTo evaluate variability in compliance to the 3-hour surviving sepsis campaign (SSC) bundle and explore the association of early compliance with subsequent shock and in-hospital mortality.DesignRetrospective cohort study between September 2017 and February 2018.SettingThirty-four academic medical centers.ParticipantsA subgroup sepsis-induced hypotensive patients from a larger shock cohort study.Main outcomes and measuresCompliance to SSC bundle that was defined as receiving appropriate antibiotics, 30 mL/kg of crystalloid or initiation of vasopressors, and lactate, obtained in the first 3 hours following sepsis-induced hypotension.ResultsWe included 977 patients with septic-induced hypotension. Bundle compliance was 43.8%, with the lowest compliance to fluid or vasopressor components (56%). Patients with high Sequential Organ Failure Assessment scores and physiologic assessments were more likely to receive compliant care, as were patients with sepsis-induced hypotension onset in the emergency department (ED) or admitted to mixed medical-surgical ICUs. SSC compliance was not associated with in-hospital mortality (adjusted odds ratio, 0.72; 95% CI, 0.47-1.10). The site-to-site variability contributed to SSC compliance (intraclass correlation coefficient [ICC], 0.15; 95% CI, 0.07-0.3) but not in-hospital mortality (ICC, 0.02; 95% CI, 0.001-0.24). Most patients remained in shock after 3 hours of resuscitation (SSC compliant 81.1% and noncompliant 53.7%). Mortality was higher among patients who were persistently hypotensive after 3 hours of resuscitation for both the SSC compliant (persistent hypotension 37% vs not hypotensive 27.2%; p = 0.094) and noncompliant (30.1% vs 18.2%; p = 0.001, respectively).Conclusions and relevancePatients with a higher severity of illness and sepsis-induced hypotension identified in the ED were more likely to receive SSC-compliant care. SSC compliance was not associated with in-hospital mortality after adjusting for patient- and hospital-level differences. Higher mortality is seen among those who remain in shock after initial resuscitation, regardless of SSC compliance

Resuscitation in the First 3 Hours of Sepsis-Induced Hypotension Varies by Patient and Hospital Factors

IMPORTANCE:. Patient and hospital factors affects how we resuscitate patients in the first 3 hours of sepsis-induced hypotension. OBJECTIVES:. To evaluate variability in compliance to the 3-hour surviving sepsis campaign (SSC) bundle and explore the association of early compliance with subsequent shock and in-hospital mortality. DESIGN:. Retrospective cohort study between September 2017 and February 2018. SETTING:. Thirty-four academic medical centers. PARTICIPANTS:. A subgroup sepsis-induced hypotensive patients from a larger shock cohort study. MAIN OUTCOMES AND MEASURES:. Compliance to SSC bundle that was defined as receiving appropriate antibiotics, 30 mL/kg of crystalloid or initiation of vasopressors, and lactate, obtained in the first 3 hours following sepsis-induced hypotension. RESULTS:. We included 977 patients with septic-induced hypotension. Bundle compliance was 43.8%, with the lowest compliance to fluid or vasopressor components (56%). Patients with high Sequential Organ Failure Assessment scores and physiologic assessments were more likely to receive compliant care, as were patients with sepsis-induced hypotension onset in the emergency department (ED) or admitted to mixed medical-surgical ICUs. SSC compliance was not associated with in-hospital mortality (adjusted odds ratio, 0.72; 95% CI, 0.47–1.10). The site-to-site variability contributed to SSC compliance (intraclass correlation coefficient [ICC], 0.15; 95% CI, 0.07–0.3) but not in-hospital mortality (ICC, 0.02; 95% CI, 0.001–0.24). Most patients remained in shock after 3 hours of resuscitation (SSC compliant 81.1% and noncompliant 53.7%). Mortality was higher among patients who were persistently hypotensive after 3 hours of resuscitation for both the SSC compliant (persistent hypotension 37% vs not hypotensive 27.2%; p = 0.094) and noncompliant (30.1% vs 18.2%; p = 0.001, respectively). CONCLUSIONS AND RELEVANCE:. Patients with a higher severity of illness and sepsis-induced hypotension identified in the ED were more likely to receive SSC-compliant care. SSC compliance was not associated with in-hospital mortality after adjusting for patient- and hospital-level differences. Higher mortality is seen among those who remain in shock after initial resuscitation, regardless of SSC compliance

Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial.

BACKGROUND: The antiviral efficacy of remdesivir against SARS-CoV-2 is still controversial. We aimed to evaluate the clinical efficacy of remdesivir plus standard of care compared with standard of care alone in patients admitted to hospital with COVID-19, with indication of oxygen or ventilator support. METHODS: DisCoVeRy was a phase 3, open-label, adaptive, multicentre, randomised, controlled trial conducted in 48 sites in Europe (France, Belgium, Austria, Portugal, Luxembourg). Adult patients (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and illness of any duration were eligible if they had clinical evidence of hypoxaemic pneumonia, or required oxygen supplementation. Exclusion criteria included elevated liver enzymes, severe chronic kidney disease, any contraindication to one of the studied treatments or their use in the 29 days before random assignment, or use of ribavirin, as well as pregnancy or breastfeeding. Participants were randomly assigned (1:1:1:1:1) to receive standard of care alone or in combination with remdesivir, lopinavir-ritonavir, lopinavir-ritonavir and interferon beta-1a, or hydroxychloroquine. Randomisation used computer-generated blocks of various sizes; it was stratified on severity of disease at inclusion and on European administrative region. Remdesivir was administered as 200 mg intravenous infusion on day 1, followed by once daily, 1-h infusions of 100 mg up to 9 days, for a total duration of 10 days. It could be stopped after 5 days if the participant was discharged. The primary outcome was the clinical status at day 15 measured by the WHO seven-point ordinal scale, assessed in the intention-to-treat population. Safety was assessed in the modified intention-to-treat population and was one of the secondary outcomes. This trial is registered with the European Clinical Trials Database, EudraCT2020-000936-23, and ClinicalTrials.gov, NCT04315948. FINDINGS: Between March 22, 2020, and Jan 21, 2021, 857 participants were enrolled and randomly assigned to remdesivir plus standard of care (n=429) or standard of care only (n=428). 15 participants were excluded from analysis in the remdesivir group, and ten in the control group. At day 15, the distribution of the WHO ordinal scale was: (1) not hospitalised, no limitations on activities (61 [15%] of 414 in the remdesivir group vs 73 [17%] of 418 in the control group); (2) not hospitalised, limitation on activities (129 [31%] vs 132 [32%]); (3) hospitalised, not requiring supplemental oxygen (50 [12%] vs 29 [7%]); (4) hospitalised, requiring supplemental oxygen (76 [18%] vs 67 [16%]); (5) hospitalised, on non-invasive ventilation or high flow oxygen devices (15 [4%] vs 14 [3%]); (6) hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation (62 [15%] vs 79 [19%]); (7) death (21 [5%] vs 24 [6%]). The difference between treatment groups was not significant (odds ratio 0·98 [95% CI 0·77-1·25]; p=0·85). There was no significant difference in the occurrence of serious adverse events between treatment groups (remdesivir, 135 [33%] of 406 vs control, 130 [31%] of 418; p=0·48). Three deaths (acute respiratory distress syndrome, bacterial infection, and hepatorenal syndrome) were considered related to remdesivir by the investigators, but only one by the sponsor's safety team (hepatorenal syndrome). INTERPRETATION: No clinical benefit was observed from the use of remdesivir in patients who were admitted to hospital for COVID-19, were symptomatic for more than 7 days, and required oxygen support. FUNDING: European Union Commission, French Ministry of Health, Domaine d'intérêt majeur One Health Île-de-France, REACTing, Fonds Erasme-COVID-Université Libre de Bruxelles, Belgian Health Care Knowledge Centre, Austrian Group Medical Tumor, European Regional Development Fund, Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation. TRANSLATION: For the French translation of the abstract see Supplementary Materials section