Sunday, June 4, 2023

Evaluation of infliximab/tocilizumab versus tocilizumab among COVID-19 patients with cytokine storm syndrome – Scientific Reports

Covid-19 pneumonia therapeutic approaches are needed for the different races and ethnicities who were excessively affected by the pandemic12,13.

Covid-19 might be associated with a hyper-inflammatory state, which may play a role in the development of acute respiratory distress syndrome14,15. High levels of the inflammatory cytokine interleukin-6 (IL-6) were associated with severe manifestations of the Covid-19 virus, while low IL-6 levels were associated with mild disease16,17. Additionally, the elevation of interleukin-6 levels has been shown as a predictor of the need for ventilator support18.

This is the first study we are aware of to directly compare the effects of treatment with tocilizumab/infliximab versus treatment with tocilizumab in moderate-severe COVID patients.

This study showed that the need for oxygen, mechanical ventilator, ICU admission, death and occurrence of sepsis were lower significantly in the tocilizumab/infliximab group and tocilizumab group compared to the standard of care group. However, there was no significant difference between the three groups in the occurrence of myocarditis, myocardial infarction (MI), heart failure, pulmonary embolism (PE), hypertension and tachycardia. To add, the tocilizumab/infliximab group had significantly lower CRP, LDH, ALC, and NLR levels before and after therapy compared to the tocilizumab group.TNF is a pro-inflammatory cytokine that contributes to the hyperinflammatory response. TNF is increased in COVID-19 patients, and high baseline levels may be a predictor of mortality. Inhibiting tumour necrosis factor (TNF) is an example of an immunomodulatory strategy that shows significant potential as a treatment for COVID-1919,20. Additionally, TNF inhibitors are capable of reducing inflammation, especially pro-inflammatory cytokines associated with poor COVID patient outcomes21. Neuharth’s study questioned whether or not TNF inhibitors provide protection against severe COVID-199.

Additionally, the TNF inhibitor, tocilizumab has been approved as one of the treatment options available for multiple inflammatory diseases22,23,24 and in several previous studies, had shown to improve COVID-19 patients with respiratory symptoms in different populations globally25. Nevertheless, tocilizumab clinical studies showed conflicting results among patients with COVID-19 who have varying levels of disease severity and variable standards of care approaches26,27.

Similar to this study findings was the Evaluating Minority Patients with Actemra study (EMPACTA), which investigated the use of tocilizumab in Covid-19 pneumonia patients who were not on mechanical ventilation. In this study, Tocilizumab lowered the incidence of the composite outcome of mechanical ventilation or mortality in hospitalized patients with Covid-19 pneumonia who were not receiving mechanical ventilators, but it did not enhance survival28.

Supportive of the presented study results, Stallmach et al.29 retrospectively explored the effect of infliximab on patients in severe conditions who have tested positive for COVID-19 compared to patients with COVID-19 who were receiving supportive therapy only. Among patients treated with infliximab, the inflammatory markers; IL-6, CRP, and LDH have shown a rapid reduction in their levels in addition to a marked increase in the lymphocytic count from baseline to post-treatment as well as an obvious clinical improvement29.

Contrariwise, the Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) study which compared anti-TNF administration to placebo, showed no significant association between TNF inhibitor use and the following clinical outcomes; ICU admission, ventilator use, and/or death30. However, infliximab use was strongly associated with a reduction in hospitalization and mortality rate consistent with the other studies31,32. Additionally, a case series study showed that patients who received infliximab treatment did not require a mechanical ventilator and showed no mortality compared to patients on other COVID-19 medications33.

In alignment with the current study, concomitant serious infection especially sepsis was significantly lower in patients on long-term treatment with infliximab (Li, 2020). However, in studies evaluating infliximab use as a treatment for the septic shock of bacterial origin, patients showed no significant difference in mortality rate though infective and inflammatory markers did not deteriorate34,35.

Similar to the current study, Hachem et al. showed a rapid resolution of lymphopenia for patients with baseline lymphopenia. These patients, upon discharge had a significant increase in lymphocytic and monocyte counts from baseline and a significant reduction of the inflammatory mediators involved in the pathogenesis of severe COVID-19 infection36. Additionally, patients on infliximab therapy showed improvement in respiratory parameters in terms of SpO2/FiO2 and reduced need for ventilator support36.

Indicators of the severity of illness, such as the necessity for intensive care, multi-organ failure, and mortality, have been linked to elevated serum concentrations of tumour necrosis factor alpha (TNF) and its established regulatory targets, such as interleukin-6 (IL-6) and ferritin6,37.

In the current study, there was a decrease in ferritin and CRP in the tocilizumab/infliximab group. In the context of these results, Liu et al. concluded that patients with elevated IL-6 levels at baseline (> 10 pg/ml) were positively correlated with increased baseline levels of CRP, LDH, ferritin, and D‐dimer38. Additionally, this study showed that patients who received Infliximab/Tocilizumab had significantly better survival compared to the standard of care, and the parameter neutrophil lymphocytic ratio (NLR) was suitable to distinguish between those patients who could eventually be discharged and those who died with AUC of 76.5%38.

Similar to this study findings was Salama et al.’s28 study, in which there was reduced mortality among severe COVID-19 hospitalized patients who received tocilizumab added to standard treatment versus those treated with placebo. In contrast to our study results, two previous studies suggested that IL-6 receptor inhibition has an extensive therapeutic effect on patients with Covid-19. On the contrary, the results of a limited number of unpublished randomized controlled trials are not suggestive of its use39,40. The mean time to hospital discharge was 2.11 days shorter in the Infliximab/Tocilizumab group than in the Tocilizumab and standard of care group. Similar to our study findings was Salama et al.28 study, which showed that tocilizumab plus standard care showed a significantly shorter hospital stay by 1.5 days than placebo plus standard care.

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