Tocilizumab demonstrates superiority in decreasing C-reactive protein levels in hospitalized COVID-19 patients, compared to standard care treatment alone

Abstract

Severe acute respiratory syndrome coronavirus 2 has caused a global pandemic, leading to health, economic, and political crisis. The virus triggers the activation of inflammatory reactants including interleukin-6 (IL-6), ferritin, and C-reactive protein (CRP), causing multiorgan damage, particularly affecting the lungs. Tocilizumab, an IL-6 receptor blocker, has the potential to diminish the progression of the disease and reduce organ damage and long-term complications. The aim of this observational retrospective cohort study was to evaluate the efficacy of tocilizumab in decreasing CRP levels in hospitalized coronavirus disease 2019 (COVID-19) patients compared to standard care without the drug. The study included 141 patients during their Hospital Stay (HS), with 100 in the Tocilizumab group and 41 in the non-Tocilizumab group. Clinical information was collected from the electronic clinical record, analyzed using statistical software, and homogenized the CRP levels from the severe group to the levels of the less complicated group at 48 h of hospitalization. The results showed a statistically significant greater decrease in CRP levels in the Tocilizumab group at 48 h after the use of the treatment, with no differences in mortality or length of stay between the groups. In conclusion, tocilizumab accelerates the diminishing of CRP levels compared to standard treatment alone, and its use may have potential benefits in the management of severe COVID-19 patients when used alongside with follow-up quantification of CRP levels reduction.IMPORTANCESevere acute respiratory syndrome coronavirus 2 has caused a global pandemic, leading to health, economic, and political crises. International guidelines for managing coronavirus disease 2019 (COVID-19) give recommendations according to the severity of the disease and the level of oxygen therapy needed. Tocilizumab is an option for the therapeutic management of hospitalized patients with any level of oxygen therapy; IL-6 serum level is the parameter for the follow-up on the efficacy, but it is not available at many hospitals. In this study, we demonstrate that C-reactive protein determination can predict the response to tocilizumab in severe COVID-19, the target patients for treatment with this drug. The use of this affordable and extensively available biomarker supports clinical decisions for the early escalation of the therapy and for the rational use of this drug on those prone to improve with the use of it.

Keywords: C reactive protein; COVID-19; interleukin 6; tocilizumab.

Fig 1

Tocilizumab group was significantly more severe at admission compared to non-Tocilizumab group in terms of Ferritin, CRP, and CT score.(A) Box-plot of serum ferritin (ng/mL) divided by group, where the Tocilizumab group arrived with greater levels than non-Tocilizumab patients (P < 0.001). (B) Box-plot of blood CRP (mg/L) levels by group with higher levels presented in the Tocilizumab group (P = 0.007). (C) Box-plot of lung CT severity score vs group, with a significantly greater score observed among the Tocilizumab group based on the disease extension along pulmonary lobes (P = 0.022). (D) Boxplot of transdermic SpO2 (%) by group, where there is not a statistical difference between groups (P = 0.072). The gray horizontal lines represent the cutoff point that defines the severe stage of disease according to the literature in both laboratory (6) and imaging evaluation (11). Nonsevere patients received standard treatment, labeled here as non-Tocilizumab group, whereas severe patients, received tocilizumab alongside standard treatment, labeled here as Tocilizumab group. Comparisons between groups were analyzed with Student’s t test. The indicators used to assess clinical severity due to COVID-19 infection were blood ferritin, blood CRP, lung computerized tomography (CT) score according to INER’s classification and transdermic oxygen saturation (SpO2). Gray area represents the therapeutic window in which patients are likely to benefit the most from tocilizumab (Materials and Methods) for ferritin and CRP (A,B panels), cut off values for Ferritin and CRP and CT score are described on Materials and Methods.

Fig 2

The Tocilizumab group includes patients with more severe CT scores and with a higher prevalence of advanced-stage lung injury associated with CT patterns, compared to the non-Tocilizumab group. (A) Data are presented as the number of patients divided by Tocilizumab and non-Tocilizumab group and subdivided by severity of the disease based on the lung CT score at admission. There was a significantly higher prevalence of moderate and severe patients among the Tocilizumab group according to Pearson’s chi-squared (P = 0.001). (B) Data are presented as a proportion of the pattern according to the severity of their CT score, subdivided on Tocilizumab and non-Tocilizumab groups. A higher lung CT score was associated with crazy-paving and consolidation in both groups (P < 0.001), being these patterns the most common in the Tocilizumab patients, whereas the ground-glass opacity was the main pattern in the non-Tocilizumab group and was related with lower CT score.

Fig 3

Elevated CRP at admission is correlated with a higher CT score and SpO2, indicating advanced lung damage and poor oxygenation are associated with increased inflammatory response. (A) Scatter plot of CRP (mg/L) divided by group and according to their CT score at admission. In both groups, the levels of CRP are related to greater CT score, with a moderate correlation effect in the non-Tocilizumab patients and a mild effect among Tocilizumab patients. Due to higher CRP levels, there is a greater proportion of lung damage and higher CT scores in the Tocilizumab patients with a significant difference compared to the non-Tocilizumab group (P = 0.001). (B) Scatter plot of CRP (mg/L) divided by groups and according to their SpO2 (%). There is a significant association between CRP at admission and lower SpO2 (%) in both groups (P = 0.017 and P = 0.021 in Tocilizumab and non-Tocilizumab groups, respectively) although there is no significant difference in SpO2 between the groups (P = 0.072).

Fig 4

Despite the Tocilizumab group presenting a more severe condition at admission, the treatment homogenized the CRP levels from the severe Tocilizumab group to the levels of the less complicated non-Tocilizumab group at 48 h of hospitalization. (A) Blood CRP (mg/L) means at admission, 24 h, and 48 h of hospital stay in the Non-Tocilizumab group (n = 14) and in the Tocilizumab group (n = 23). A two-way, three levels mixed design ANOVA was performed without statistically significant difference between groups (P = 0.311) nor within groups by time interaction (P = 0.166), but with a significant association in the decrease of the marker by time (P < 0.001). (B) The slope of the CRP levels from 24 h to 48 h of hospital stay between groups presented a significantly steeper decline (P = 0.011) within the Tocilizumab group in comparison to non-Tocilizumab patients after a two-way, two levels mixed design ANOVA was performed. The density of patients who received the first dose of tocilizumab in a specific time of hospital stay is presented in the scale bar that involves the first 48 h of HS. None of the patients included in this analisis received the first dose of tocilizumab after 21 h of HS nor more than one dose of the drug within the first 48 h after admission.