Tocilizumab, netakimab, and baricitinib in patients with mild-to-moderate COVID-19: An observational study.

OBJECTIVE: The aim of the study was to assess inflammatory markers and clinical outcomes in adult patients admitted to hospital with mild-to-moderate COVID-19 and treated with a combination of standard-of-care (SOC) and targeted immunosuppressive therapy including anti-IL-17A (netakimab), anti-IL-6R (tocilizumab), or JAK1/JAK2 inhibitor (baricitinib) or with a standard-of-care therapy alone. METHODS: The observational cohort study included 154 adults hospitalized between February and August, 2020 with RT-PCR-confirmed SARS-CoV-2 with National Early Warning Score2 (NEWS2) < 7 and C-reactive protein (CRP) levels ≤ 140 mg/L on the day of the start of the therapy or observation. Patients were divided into the following groups: I) 4 mg baricitinib, 1 or 2 times a day for an average of 5 days (n = 38); II) 120 mg netakimab, one dose (n = 48); III) 400 mg tocilizumab, one dose (n = 34), IV) SOC only: hydroxychloroquine, antiviral, antibacterial, anticoagulant, and dexamethasone (n = 34). RESULTS: CRP levels significantly decreased after 72 h in the tocilizumab (p = 1 x 10-5) and netakimab (p = 8 x 10-4) groups and remained low after 120 h. The effect was stronger with tocilizumab compared to other groups (p = 0.028). A significant decrease in lactate dehydrogenase (LDH) levels was observed 72 h after netakimab therapy (p = 0.029). NEWS2 scores significantly improved 72 h after tocilizumab (p = 6.8 x 10-5) and netakimab (p = 0.01) therapy, and 120 h after the start of tocilizumab (p = 8.6 x 10-5), netakimab (p = 0.001), or baricitinib (p = 4.6 x 10-4) therapy, but not in the SOC group. Blood neutrophil counts (p = 6.4 x 10-4) and neutrophil-to-lymphocyte ratios (p = 0.006) significantly increased 72 h after netakimab therapy and remained high after 120 h. The percentage of patients discharged 5-7 days after the start of therapy was higher in the tocilizumab (44.1%) and netakimab (41.7%) groups than in the baricitinib (31.6%) and SOC (23.5%) groups. Compared to SOC (3 of the 34; 8.8%), mortality was lower in netakimab (0 of the 48; 0%, RR = 0.1 (95% CI: 0.0054 to 1.91)), tocilizumab (0 of the 34; 0%, RR = 0.14 (95% CI: 0.0077 to 2.67)), and baricitinib (1 of the 38; 2.6%, RR = 0.3 (95% CI: 0.033 to 2.73)) groups. CONCLUSION: In hospitalized patients with mild-to-moderate COVID-19, the combination of SOC with anti-IL-17A or anti-IL-6R therapy were superior or comparable to the combination with JAK1/JAK2 inhibitor, and all three were superior to SOC alone. Whereas previous studies did not demonstrate significant benefit of anti-IL-17A therapy for severe COVID-19, our data suggest that such therapy could be a rational choice for mild-to-moderate disease, considering the generally high safety profile of IL-17A blockers. The significant increase in blood neutrophil count in the netakimab group may reflect efflux of neutrophils from inflamed tissues. We therefore hypothesize that neutrophil count and neutrophil-to-lymphocyte ratio could serve as markers of therapeutic efficiency for IL-17A-blocking antibodies in the context of active inflammation.

SARS-CoV-2 evolution in a patient with secondary B-cell immunodeficiency: A clinical case.

The article highlights the course of long-term SARS-CoV-2 infection in a patient with a secondary immunodeficiency developed with B-cell-depleting therapy of the underlying disease. Analysis of the intrapatient virus evolution revealed an inpatient S:G75A mutation that alters the 72GTNGTKR78 motif of the S-protein, with a possible role in binding to alternative cellular receptors. Therapy with a ready-made COVID-19-globulin preparation (native human immunoglobulin G (IgG) derived from the plasma of convalescent COVID-19-patients) resulted in rapid improvement of the patient's condition, fast, and stable elimination of the virus, and passive immunization of the patient for at least 30 days. The results suggest the use of products containing neutralizing antibodies opens new prospects for treatment algorithms for patients with persistent coronavirus infection, as well as for passive immunization schemes for patients with a presumably reduced specific response to vaccination.

Temporal Clinical and Laboratory Response to Interleukin-6 Receptor Blockade With Tocilizumab in 89 Hospitalized Patients With COVID-19 Pneumonia.

BACKGROUND: Pandemic COVID-19 pneumonia due to SARS-2 is an important cause of morbidity and mortality. Emerging evidence links poor outcomes to an inflammatory cytokine storm. METHODS: We treated 89 hospitalized patients with COVID-19 pneumonia and heightened systemic inflammation (elevated serum C reactive protein and interleukin-6 levels) with an infusion of tocilizumab (TCZ), a human monoclonal IgG1 antibody to the interleukin-6 receptor. RESULTS: Clinical and laboratory evidence of improvement was evident when baseline and 1-2-day post-infusion indices were compared. Among the 72 patients receiving supplemental oxygen without mechanical ventilation, severity of condition on the NEWS2 scale scores fell from 5 to 2 (P<0.001), C reactive protein levels fell from 95 to 14 mg/L (P<0.001), and lymphocyte counts rose from 900 to 1000/uL (P=0.036). Sixty-three of 72 patients were discharged from the hospital, one patient died, and eight patients remained in the hospital at the time of this writing. Among the 17 patients receiving mechanical ventilation, despite a rapid decrease in CRP levels from 89 to 35 mg/L (P=0.014) and early improvements in NEWS2 scores in 10 of 17 patients, 10 patients ultimately died and the other seven remain in the hospital at the time of this writing. Overall, mortality was only seen in patients who had markedly elevated CRP levels (>30 mg/L) and low lymphocyte counts (<1000/uL) before TCZ administration. CONCLUSIONS: Inflammation and lymphocytopenia are linked to mortality in COVID-19. Inhibition of IL-6 activity by administration of tocilizumab, an anti-IL-6 receptor antibody, is associated with rapid improvement in both CRP and lymphocyte counts and in clinical indices. Controlled clinical trials are needed to confirm the utility of IL-6 blockade in this setting. Additional interventions will be needed for patients requiring mechanical ventilation.