A total of 459 patients were admitted to the Hokkaido University Hospital with the diagnosis of COVID-19 during the study period. Of these, 100 patients received biological agents for treating the symptoms of COVID-19. Sixty-four patients were treated with TCZ (TCZ group) and 34 with BRT (BRT group). Two patients, who were excluded from the study, were initially treated with BRT but switched to TCZ (Figure 1).
The median age of total patients (N = 98) was 60.5 years, and 74.5 % were males (Table 1). Compared with the TCZ group (n = 64), BRT group (n = 34) had lower age (58.5 vs. 65.5 years, P = 0.03) and lower prevalence of chronic heart disease (5.9 % vs. 23.4 %, P = 0.03). There were no significant differences in sex, smoking history, immunosuppressive drug use, obesity, chronic kidney disease, diabetes mellitus, collagen disease, hypertension, or comorbid respiratory disease. Only one patient—in BRT group—was fully vaccinated with two doses of the vaccine against SARS-CoV-2. Days from the onset of illness to the administration of biological agents were not significantly different between the two groups (10 vs. 9 days, P = 0.50). Analysis of blood samples revealed that, compared to the BRT group, the TCZ group had a significantly lower eosinophil count and hemoglobin (0 vs. 0, P = 0.047, 13.8 vs. 14.5, P = 0.04, respectively), higher levels of lactate dehydrogenase (LDH), krebs von den Lungen-6 (KL-6), and D-dimer (540 vs. 470, P = 0.02, 444 vs. 319, P = 0.03, 1.5 vs. 1.0, P < 0.01, respectively).
Most patients in both groups received steroid treatment for COVID-19 (98.4 % in TCZ and 97.1 % in BRT group). The TCZ group were administered heparin more frequently and antivirals less frequently than the BRT group (86.0 % vs. 67.7 %, P = 0.03, 70.3 % vs. 88.2 %, P = 0.046, respectively). Only one patient was treated with a combination of monoclonal antibodies (casirivimab and imdevimab) in the BRT group. The severity of COVID-19 was similar in both groups at the time of initiating treatment with the biological agents, with severity level 3 or higher in 93.2 % of the patients in TCZ group and 85.3 % in BRT group.
(InsertTable 1 here)
Risk factors for death within 28 days after initiating treatment with biological agents
Among the group of patients administered biological agents (N = 98), univariate analysis showed that the use of TCZ was significantly associated with increased all-cause mortality. Additionally, increased age, presence of chronic kidney disease, administration of biological agents at less than seven days from onset, and no antiviral drug use were significantly associated with all-cause mortality (Table 2). In multivariate analysis, older age [OR = 1.10, 95 % confidence interval (CI) 1.00 –1.21, P = 0.02], presence of chronic kidney disease (OR = 43.10, 95 % CI 2.71–686.04, P = 0.008), and early administration of biological agents from onset (OR = 18.09, 95 % CI 1.70–192.47, P = 0.02) were shown to be independent risk factors for all-cause mortality within 28 days. In contrast, the use of TCZ was not an independent prognostic factor for death (OR = 13.28, 95 % CI 0.45–392.92, P = 0.13) (Table 2).
(Insert Table2 here)
Factors contributing to improvement in respiratory status
In the univariate logistic regression analysis, factors contributing significantly to the improvement of respiratory status were BRT use, young age, absence of chronic heart disease, chronic kidney disease or hypertension, more than seven days from onset to drug administration, and use of any anti-viral drug (Table 3). However, in multivariate analysis, BRT use was not a contributing factor (OR = 1.75, 95 % CI 0.35–8.67, P = 0.50), while the use of the anti-viral drug was an independent contributing factor (OR = 6.5, 95 % CI 1.13–37.56, P = 0.04). Early administration of biological agents was the risk factor that reduced the likelihood of improving the respiratory status (OR = 0.82, 95 % CI 0.02–0.40, P = 0.002).
(Insert Table 3 here)
Development of secondary infections
The rates of acquiring any secondary infection in patients within 28 days after initiation of treatment with TCZ and BRT were 15.6 and 14.7%, respectively. Univariate analysis did not identify any factors associated with the development of secondary infections after initiation of treatment with biological agents (Supplementary table). There was also no significant difference in infection-free survival (P = 0.95) (Figure 2).