Prompt Reduction in CRP, IL-6, IFN-γ, IP-10, and MCP-1 and a Relatively Low Basal Ratio of Ferritin/CRP Is Possibly Associated With the Efficacy of Tocilizumab Monotherapy in Severely to Critically Ill Patients With COVID-19

Abstract

Background and Aim: Tocilizumab, a humanized anti-IL-6 receptor antibody, has been used to treat severely to critically ill patients with COVID-19. A living systematic review with meta-analysis of recent RCTs indicates that the combination therapy of corticosteroids and tocilizumab produce better outcomes, while previous observational studies suggest that tocilizumab monotherapy is beneficial for substantial numbers of patients. However, what patients could respond to tocilizumab monotherapy remained unknown. Methods: In this retrospective study we evaluated the effects of tocilizumab monotherapy on the clinical characteristics, serum biomediator levels, viral elimination, and specific IgG antibody induction in 13 severely to critically ill patients and compared with those of dexamethasone monotherapy and dexamethasone plus tocilizumab. Results: A single tocilizumab administration led to a rapid improvement in clinical characteristics, inflammatory findings, and oxygen supply in 7 of 11 patients with severe COVID-19, and could recover from mechanical ventilation management (MVM) in 2 patients with critically ill COVID-19. Four patients exhibited rapidly worsening even after tocilizumab administration and required MVM and additional methylprednisolone treatment. Tocilizumab did not delay viral elimination or inhibit IgG production specific for the virus, whereas dexamethasone inhibited IgG induction. A multiplex cytokine array system revealed a significant increase in the serum expression of 54 out of 80 biomediators in patients with COVID-19 compared with that in healthy controls. Compared with those who promptly recovered in response to tocilizumab, patients requiring MVM showed a significantly higher ratio of basal level of ferritin/CRP and a persistent increase in the levels of CRP and specific cytokines and chemokines including IL-6, IFN-γ, IP-10, and MCP-1. The basal high ratio of ferritin/CRP was also associated with clinical deterioration even in patients treated with dexamethasone and tocilizumab. Conclusion: Tocilizumab as monotherapy has substantial beneficial effects in some patients with severe COVID-19, who showed a relatively low level of the ratio of ferritin/CRP and prompt reduction in CRP, IL-6, IFN-γ, IP-10, and MCP-1. The high ratio of ferritin/CRP is associated with rapid worsening of pneumonia. Further evaluation is warranted to clarify whether tocilizumab monotherapy or its combination with corticosteroid is preferred for severely to critically ill patients with COVID-19.

Keywords: COVID-19; IL-6; cytokine storm; dexamethasone; tocilizumab.

Figure 1

Changes in CRP, ferritin, and peripheral blood lymphocyte number before and after tocilizumab administration. The red line represents the data of patients requiring mechanical ventilation.

Figure 2

Widespread increase in biomediator levels in severely to critically ill patients with COVID-19. Expression of 80 biomediators in the sera of 12 patients with severely to critically ill patients with COVID-19 (COV-19) and 38 healthy controls (HC) was measured using a multiplex cytokine array system. The boxplots show medians (middle line) with first and third quartiles (boxes), while the whiskers show 1.5x the interquartile range (IQR) above and below the box. (A) Increased biomediators in COVID-19, (B) decreased biomediators in COVID-19, (C) no difference in serum levels of biomediators between COVID-19 and healthy controls.

Figure 3

Changes in the serum levels of IL-6, soluble IL-6 receptor, and soluble gp130 before and after tocilizumab administration. The serum levels of IL-6, soluble IL-6 receptor (sIL-6R), and soluble gp130 (sgp130) in 10 patients with COVID-19 before and after tocilizumab administration were measured using a multiplex cytokine array system. The red line represents the data of patients requiring mechanical ventilation.

Figure 4

Increased cytokines and chemokines in patients requiring mechanical ventilation before and after tocilizumab administration. The serum levels of IP-10, MCP-1, IFN-α2 and γ in 10 patients with COVID-19 before and after tocilizumab injection were measured using a multiplex cytokine array system. The red line represents the data of patients requiring mechanical ventilation.

Figure 5

Clinical outcomes of severe-to-critically ill COVID-19. Both 7 of 11 patients (63.6%), who received tocilizumab (TCZ) monotherapy and 10 of 12 patients (83.3%), who received additional tocilizumab after rapid deterioration with dexamethasone (DEX) monotherapy were able to avoid mechanical ventilation management (MVM). Two patients, who received tocilizumab monotherapy under MVM were able to recover from MVM. However, 5 of 6 patients, who deteriorated even after single or additional tocilizumab administration and required MVM, improved with additional methylprednisolone (mPSL) treatment, and a total of 39 of 40 were cured (survival rate 97.5%).

Figure 6

Changes in SARS-CoV-2 load before and after tocilizumab administration. Viral RNA in the sera of 10 patients with COVID-19 patients before and after tocilizumab administration were quantified by RT-PCR. The red line represents the data of patients requiring mechanical ventilation.

Figure 7

Induction of IgG antibody for SARS-CoV-2. The sera were obtained from 10 patients with mild COVID-19 receiving symptomatic therapy, 20 patients with moderate COVID-19 receiving antiviral drug(s), 13 patients with severe to critical COVID-19 receiving antiviral drug(s) plus tocilizumab, 15 patients with severe COVID-19 receiving antiviral drug(s) plus dexamethasone, and 12 patients with severe COVID-19 receiving antiviral drug(s) plus dexamethasone followed by tocilizumab. The SARS-CoV-2 specific IgG antibody titer was measured by using the Corona Virus COVID-19 Antibody Rapid Detection Kit on blood samples collected several times in each patient after 10 days of the onset of illness. In patients who showed clearly detectable in detection kit (4+), the earliest sample was plotted on the graph, while in patients who did not show clearly detectable (4+), the last sample was plotted. The horizontal axis shows the day after onset, and the vertical axis shows the antibody scale for patients in the five treatment groups. The maximum value of antibody titer of each patient and the number of days from the onset of blood sampling date were graphed, and a logarithmic approximation curve was drawn. The highest antibody titers of each patient during the course were compared among the five treatment groups. *Statistically significant.