Potential Benefits of Tryptophan Metabolism to the Efficacy of Tocilizumab in COVID-19.
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ABSTRACT:
SUBMITTER: Belladonna ML
PROVIDER: S-EPMC7319082 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
Publications
Potential Benefits of Tryptophan Metabolism to the Efficacy of Tocilizumab in COVID-19.
Belladonna Maria Laura ML Orabona Ciriana C
Frontiers in pharmacology 20200619
Tocilizumab has been proposed as a means of opposing hyperinflammatory responses in intensive care patients with COVID-19. Here, we briefly discuss the potentially multiple, synergistic mechanisms whereby tocilizumab might exert therapeutic activity, mostly focusing on the production of tryptophan-derived catabolites that would result from blockade of IL-6 signaling, as contextualized to the cytokine storm occurring in COVID-19 patients. ...[more]
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Project description:BackgroundThe efficacy of interleukin-6 receptor blockade in hospitalized patients with coronavirus disease 2019 (Covid-19) who are not receiving mechanical ventilation is unclear.MethodsWe performed a randomized, double-blind, placebo-controlled trial involving patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hyperinflammatory states, and at least two of the following signs: fever (body temperature >38°C), pulmonary infiltrates, or the need for supplemental oxygen in order to maintain an oxygen saturation greater than 92%. Patients were randomly assigned in a 2:1 ratio to receive standard care plus a single dose of either tocilizumab (8 mg per kilogram of body weight) or placebo. The primary outcome was intubation or death, assessed in a time-to-event analysis. The secondary efficacy outcomes were clinical worsening and discontinuation of supplemental oxygen among patients who had been receiving it at baseline, both assessed in time-to-event analyses.ResultsWe enrolled 243 patients; 141 (58%) were men, and 102 (42%) were women. The median age was 59.8 years (range, 21.7 to 85.4), and 45% of the patients were Hispanic or Latino. The hazard ratio for intubation or death in the tocilizumab group as compared with the placebo group was 0.83 (95% confidence interval [CI], 0.38 to 1.81; P?=?0.64), and the hazard ratio for disease worsening was 1.11 (95% CI, 0.59 to 2.10; P?=?0.73). At 14 days, 18.0% of the patients in the tocilizumab group and 14.9% of the patients in the placebo group had had worsening of disease. The median time to discontinuation of supplemental oxygen was 5.0 days (95% CI, 3.8 to 7.6) in the tocilizumab group and 4.9 days (95% CI, 3.8 to 7.8) in the placebo group (P?=?0.69). At 14 days, 24.6% of the patients in the tocilizumab group and 21.2% of the patients in the placebo group were still receiving supplemental oxygen. Patients who received tocilizumab had fewer serious infections than patients who received placebo.ConclusionsTocilizumab was not effective for preventing intubation or death in moderately ill hospitalized patients with Covid-19. Some benefit or harm cannot be ruled out, however, because the confidence intervals for efficacy comparisons were wide. (Funded by Genentech; ClinicalTrials.gov number, NCT04356937.).
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Project description:BackgroundTocilizumab (TCZ), an interleukin-6 receptor antibody, has previously been used for treating patients with the coronavirus disease 2019 (COVID-19), but there is a lack of data regarding the administration timing of TCZ.ObjectivesThis study aimed to evaluate the timing and efficacy of TCZ in the treatment of patients with COVID-19.MethodsLaboratory-confirmed patients with COVID-19 with an elevated interleukin-6 (IL-6) level (>10 pg/ml) were offered TCZ intravenously for compassionate use. Clinical characteristics, laboratory tests, and chest imaging before and after the administration of TCZ were retrospectively analyzed.ResultsA total of 58 consecutive patients who met the inclusion criteria and with no compliance to the exclusion criteria were included. Of these 58 patients, 39 patients received TCZ treatment, and 19 patients who declined TCZ treatment were used as the control cohort. In the TCZ-treatment group, 6 patients (15.4%) were in mild condition, 16 (41.0%) were in severe condition, and 17 (43.6%) were in critical condition. After TCZ treatment, the condition of 27 patients (69.2%) improved and 12 (30.8%) died. Compared with the improvement group, patients in the death group had higher baseline levels of IL-6 (P = 0.0191) and procalcitonin (PCT) (P = 0.0003) and lower lymphocyte percentage (LYM) (P = 0.0059). Patients receiving TCZ treatment had better prognoses than those without TCZ treatment (P = 0.0273). Furthermore, patients with a baseline IL-6 level of ≥100 pg/ml in the TCZ-treatment group had poorer clinical outcomes than those with an IL-6 level of <100 pg/ml (P = 0.0051).ConclusionThe administration of TCZ in an early stage of cytokine storm (IL-6 level < 100 pg/ml) may effectively improve the clinical prognosis of patients with COVID-19 by blocking the IL-6 signal pathway.
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