Use of Immune Modulating Agents to Regulate Hyperinflammation in Severe COVID 19: Assessment of Tocilizumab Use in Combination with Steroids

Abstract

Objective: In severe cases, COVID-19 can lead to a hyperinflammatory state, resulting in devastating outcomes. Immune modulation using steroids or other immune modulators can regulate the intensity of the inflammatory response; however, this theory has not been adequately assessed in practice. The current study aims to investigate the use of corticosteroids alone or in combination with tocilizumab to treat patients with severe COVID-19.

Methods: This cross-sectional study was conducted on 166 Iranian patients with severe COVID-19 infection at Al-Zahra Hospital, who were treated with the standard treatment for severe COVID-19 infection, as per the 11^th version of the Iranian guideline for COVID-19 treatment. Patients were categorized into three treatment groups based on the dose of corticosteroid treatment and tocilizumab therapy: (a) high-dose methylprednisolone (>1 mg/kg) alone, (b) low-dose methylprednisolone (<1 mg/kg) followed by one dose of tocilizumab (8 mg/kg); and (c) high-dose methylprednisolone (>1 mg/kg) followed by one dose of tocilizumab (8 mg/kg). Mortality of patients as our primary outcome, laboratory parameters, length of hospitalization, intensive care unit (ICU) admission requirement, and drug-related adverse events were compared between groups.

Findings: The second group showed significantly better outcomes, including shorter ICU stays, lower C-reactive protein and lactate dehydrogenase levels, and higher oxygen saturation and platelet counts than the other groups. Logistic regression revealed increased risks of mortality, nosocomial infection, and adverse effects, including hepatic and renal dysfunction and gastrointestinal bleeding, in Groups B and C compared with Group A.

Conclusion: In all evaluated parameters, a low-dose steroid followed by tocilizumab was superior to a high-dose steroid alone or combined with tocilizumab. Although this combination treatment has been assessed worldwide, few studies have focused on its application in Iranian patients with severe COVID-19.

Keywords: COVID-19; Tocilizumab; steroids.

Figure 1

(a) Adjusted odd mortality ratio in the logistic regression model of Groups B (0.07 with 95% confidence interval of 0.02–0.24) and C (2.46 with 95% confidence interval of 1.07, 5.62) compared to Group A. (b) Mortality rate (%) between Groups A, B, and C. Group A: High-dose methylprednisolone alone (>1 mg/kg). Group B: Low-dose methylprednisolone (<1 mg/kg) followed by one dose of tocilizumab (8 mg/kg). Group C: High-dose methylprednisolone (>1 mg/kg) followed by one dose of tocilizumab (8 mg/kg)

Figure 2

Incidence of drug-related adverse effects, including hepatic and renal dysfunction, nosocomial infection, and gastrointestinal bleeding in Groups A, B, and C. Renal dysfunction and nosocomial infection significantly decreased in Group B. Group A: High-dose methylprednisolone (>1 mg/kg) alone, Group B: Low-dose methylprednisolone (<1 mg/kg) followed by one dose of tocilizumab (8 mg/kg), and Group C: Reference group with high-dose methylprednisolone (>1 mg/kg) only followed by one dose of tocilizumab (8 mg/kg). ★: significantly lower (P < 0.005). GIB = Gastrointestinal bleeding

Figure 3

Laboratory parameters on day 5^th in groups A, B, and C. (a) C-reactive protein (CRP, mg/dl); (b) lactate dehydrogenase (LDH, Unit/l); (c) Ferritin (ng/ml); (d) Serum platelet count (×1000/µL). CRP, LDH, and ferritin levels significantly decreased (P < 0.001) after treatment with low-dose methylprednisolone, followed by one dose of tocilizumab. In addition, plate count significantly increased in the same treatment group. Group A: The reference group with high-dose methylprednisolone (>1 mg/kg) alone. Group B: Low-dose methylprednisolone (<1 mg/kg) followed by one dose of tocilizumab (8 mg/kg). Group C: High-dose methylprednisolone (>1 mg/kg) followed by one dose of tocilizumab (8 mg/kg). ★: Significantly different (P < 0.005). LDH = Lactate dehydrogenase, CRP = C-reactive protein