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Differential Cytokine Responses in Hospitalized COVID-19 Patients Limit Efficacy of Remdesivir.

ABSTRACT: A significant proportion of COVID-19 patients will progress to critical illness requiring invasive mechanical ventilation. This accentuates the need for a therapy that can reduce the severity of COVID-19. Clinical trials have shown the effectiveness of remdesivir in shortening recovery time and decreasing progression to respiratory failure and mechanical ventilation. However, some studies have highlighted its lack of efficacy in patients on high-flow oxygen and mechanical ventilation. This study uncovers some underlying immune response differences between responders and non-responders to remdesivir treatment. Immunological analyses revealed an upregulation of tissue repair factors BDNF, PDGF-BB and PIGF-1, as well as an increase in ratio of Th2-associated cytokine IL-4 to Th1-associated cytokine IFN-γ. Serological profiling of IgG subclasses corroborated this observation, with significantly higher magnitude of increase in Th2-associated IgG2 and IgG4 responses. These findings help to identify the mechanisms of immune regulation accompanying successful remdesivir treatment in severe COVID-19 patients.

SUBMITTER: Chan YH

PROVIDER: S-EPMC8275132 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundSevere coronavirus disease 2019 (Covid-19) is associated with dysregulated inflammation. The effects of combination treatment with baricitinib, a Janus kinase inhibitor, plus remdesivir are not known.MethodsWe conducted a double-blind, randomized, placebo-controlled trial evaluating baricitinib plus remdesivir in hospitalized adults with Covid-19. All the patients received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control). The primary outcome was the time to recovery. The key secondary outcome was clinical status at day 15.ResultsA total of 1033 patients underwent randomization (with 515 assigned to combination treatment and 518 to control). Patients receiving baricitinib had a median time to recovery of 7 days (95% confidence interval [CI], 6 to 8), as compared with 8 days (95% CI, 7 to 9) with control (rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.32; P = 0.03), and a 30% higher odds of improvement in clinical status at day 15 (odds ratio, 1.3; 95% CI, 1.0 to 1.6). Patients receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). Serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; difference, -5.0 percentage points; 95% CI, -9.8 to -0.3; P = 0.03), as were new infections (5.9% vs. 11.2%; difference, -5.3 percentage points; 95% CI, -8.7 to -1.9; P = 0.003).ConclusionsBaricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04401579.).

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Differential Cytokine Responses in Hospitalized COVID-19 Patients Limit Efficacy of Remdesivir.

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