Severity-Adjusted Dexamethasone Dosing and Tocilizumab Combination for Severe COVID-19

Abstract

Purpose: Real-world experience with tocilizumab in combination with dexamethasone in patients with severe coronavirus disease (COVID-19) needs to be investigated.

Materials and methods: A retrospective cohort study was conducted to evaluate the effect of severity-adjusted dosing of dexamethasone in combination with tocilizumab for severe COVID-19 from August 2020 to August 2021. The primary endpoint was 30-day clinical recovery, which was defined as no oxygen requirement or referral after recovery.

Results: A total of 66 patients were evaluated, including 33 patients in the dexamethasone (Dexa) group and 33 patients in the dexamethasone plus tocilizumab (DexaToci) group. The DexaToci group showed a statistically significant benefit in 30-day clinical recovery, compared to the Dexa group (p=0.024). In multivariable analyses, peak FiO₂ within 3 days and tocilizumab combination were consistently significant for 30-day recovery (all p<0.05). The DexaToci group showed a significantly steeper decrease in FiO₂ (-4.2±2.6) than the Dexa group (-2.7±2.6; p=0.021) by hospital day 15. The duration of oxygen requirement was significantly shorter in the DexaToci group than the Dexa group (median, 10.0 days vs. 17.0 days; p=0.006). Infectious complications and cellular and humoral immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the convalescence stage were not different between the two groups.

Conclusion: A combination of severity-adjusted dexamethasone and tocilizumab for the treatment of severe COVID-19 improved clinical recovery without increasing infectious complications or hindering the immune response against SARS-CoV-2.

Keywords: COVID-19; Dexamethasone; immune response; tocilizumab.

Fig. 1. Study population of the cohort and institutional treatment protocol. The study population of the retrospective cohort study (A) and institutional treatment protocol applied to the cohort (B) are presented. ^*Tocilizumab combination was applied after April 2021. COVID-19, coronavirus disease; FiO₂, fraction of inspired oxygen; LMWH, low-molecular-weight heparin; DVT, deep vein thrombosis; PPI, proton-pump inhibitor; TMP/SMX, trimethoprim/sulfamethoxazole; PJP, Pneumocystis jirovecii pneumonia; IPA, invasive pulmonary aspergillosis; PO, per os.

Fig. 2. Clinical outcomes of the Dexa and DexaToci groups. (A) Thirty-day recovery probabilities of the Dexa and DexaToci groups were compared using the Kaplan-Meier method. (B) The oxygenation improvement between the two groups were compared by calculating the slope of FiO₂ until HD 15. Dexa, dexamethasone; DexaToci, dexamethasone plus tocilizumab; FiO₂, fraction of inspired oxygen; HD, hospital day.

Fig. 3. Cellular and humoral immune responses against SARS-CoV-2 among the cohort patients. Cellular and humoral immune responses against SARS-CoV-2 were measured in the convalescent stage. Cellular responses were measured in nine patients of the Dexa group and 17 patients of the DexaToci group using SARS-CoV-2-specific IGRA test (A). Humoral responses were measured in 28 patients of the Dexa group and 19 patients of the DexaToci group using a quantitative anti-SARS-CoV-2 S antibody test kit (B). SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; Dexa, dexamethasone; DexaToci, dexamethasone plus tocilizumab; IGRA, interferon-gamma release assay; Ag, antigen.