RESUMO
Background: Severe and critical COVID-19 disease is characterized by hyperinflammation involving pro-inflammatory cytokines, particularly IL-6. Tocilizumab is a monoclonal antibody that blocks IL-6 receptors. Objectives: This study evaluated the efficacy of tocilizumab in Filipino patients with severe to critical COVID-19 disease. Methods: This phase 3 randomized double-blind trial, included patients hospitalized for severe or critical COVID-19 in a 1:1 ratio to receive either tocilizumab plus local standard of care or placebo plus standard of care. Patients were eligible for a repeat IV infusion within 24-48 hours if they deteriorated or did not improve. Treatment success or clinical improvement was defined as at least two categories of improvement from baseline in the WHO 7-point Ordinal Scale of patient status, in an intention-to-treat manner. Results: Forty-nine (49) patients were randomized in the tocilizumab arm and 49 in the placebo arm. There was no significant difference in age, comorbidities, COVID-19 severity, need for mechanical ventilation, presence of acute respiratory distress syndrome, or biomarker levels between groups. Use of adjunctive therapy was similar between groups, with corticosteroid used in 91.8% in tocilizumab group and 81.6% in the placebo group, while remdesivir was used in 98% of participants in both groups.There was no significant difference between groups in terms of treatment success in both the intention-to-treat analysis (relative risk=1.05, 95% CI: 0.85-1.30) and per-protocol analysis (relative risk=0.98, 95% CI: 0.80 to 1.21). There was no significant difference in time to improvement of at least two categories relative to baseline on the 7-point Ordinal Scale of clinical status. Conclusion: The use of tocilizumab on top of standard of care in the management of patients with severe to critical COVID-19 did not result in significant improvement as defined by the WHO 7-point Ordinal Scale of patient status, nor in significant improvement in incidence of mechanical ventilation, incidence of ICU admission, length of ICU stay, and mortality rate.
RESUMO
Purpose: This study was performed to determine the clinical biomarkers and cytokines that may be associated with disease progression and in-hospital mortality in a cohort of hospitalized patients with RT-PCR confirmed moderate to severe COVID-19 infection from October 2020 to September 2021, during the first wave of COVID-19 pandemic before the advent of vaccination. Patients and methods: Clinical profile was obtained from the medical records. Laboratory parameters (complete blood count [CBC], albumin, LDH, CRP, ferritin, D-dimer, and procalcitonin) and serum concentrations of cytokines (IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-18, IFN-γ, IP-10, TNF-α) were measured on Days 0-3, 4-10, 11-14 and beyond Day 14 from the onset of illness. Regression analysis was done to determine the association of the clinical laboratory biomarkers and cytokines with the primary outcomes of disease progression and mortality. ROC curves were generated to determine the predictive performance of the cytokines. Results: We included 400 hospitalized patients with COVID-19 infection, 69% had severe to critical COVID-19 on admission. Disease progression occurred in 139 (35%) patients, while 18% of the total cohort died (73 out of 400). High D-dimer >1 µg/mL (RR 3.5 95%CI 1.83-6.69), elevated LDH >359.5 U/L (RR 1.85 95%CI 1.05-3.25), lymphopenia (RR 1.91 95%CI 1.14-3.19), and hypoalbuminemia (RR 2.67, 95%CI 1.05-6.78) were significantly associated with disease progression. High D-dimer (RR 3.95, 95%CI 1.62-9.61) and high LDH (RR 5.43, 95%CI 2.39-12.37) were also significantly associated with increased risk of in-hospital mortality. Nonsurvivors had significantly higher IP-10 levels at 0 to 3, 4 to 10, and 11 to 14 days from illness onset (p<0.01), IL-6 levels at 0 to 3 days of illness (p=0.03) and IL-18 levels at days 11-14 of illness (p<0.001) compared to survivors. IP-10 had the best predictive performance for disease progression at days 0-3 (AUC 0.81, 95%CI: 0.68-0.95), followed by IL-6 at 11-14 days of illness (AUC 0.67, 95%CI: 0.61-0.73). IP-10 predicted mortality at 11-14 days of illness (AUC 0.77, 95%CI: 0.70-0.84), and IL-6 beyond 14 days of illness (AUC 0.75, 95%CI: 0.68-0.82). Conclusion: Elevated D-dimer, elevated LDH, lymphopenia and hypoalbuminemia are prognostic markers of disease progression. High IP-10 and IL-6 within the 14 days of illness herald disease progression. Additionally, elevated D-dimer and LDH, high IP-10, IL-6 and IL-18 were also associated with mortality. Timely utilization of these biomarkers can guide clinical monitoring and management decisions for COVID-19 patients in the Philippines.