The United States continues to site at the top of the list of countries most affected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic with over 8.6 million severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cases to date and over 225,000 deaths from COVID-19 disease. At the peak of the pandemic to date, more than 1,000 Americans died from COVID-19 each day.
Multiple studies have shown that SARS-CoV-2 infection can cause a wide range of symptoms starting from asymptomatic to mild or severe disease in humans that can even require mechanical ventilation in the worst cases.
In some patients, SARS-CoV-2 infection leads to hypoxemic respiratory failure caused by a severe inflammatory response called a ‘cytokine storm.’ Patients in this phase are shown to have significantly abnormal inflammatory markers, including elevated levels of serum interleukin-6 (IL-6), ferritin, and C-reactive protein. Since high serum IL-6 levels are associated with high SARS-CoV-2 viral load and severe disease leading to death, it was hypothesized that this inflammatory cascade might be interrupted by IL-6 receptor blockade. However, the efficacy of (IL-6) receptor blockade in hospitalized COVID-19 patients not receiving mechanical ventilation is not clear.
Cytokines 3d illustration. Image Credit: Sciencepics
A randomized trial to determine the effects of IL-6 receptor blockade on COVID-19 progression
Researchers from the various Massachusetts hospitals performed the Boston Area COVID-19 Consortium (BACC) Bay Tocilizumab Trial using tocilizumab administered early in the disease course to determine if early IL-6 receptor blockade limits progression of COVID-19 to hypoxemic respiratory failure or death. Their work is published in the prestigious New England Journal of Medicine.
The authors performed a randomized, double-blind, placebo-controlled trial in patients with SARS-CoV-2 infection, who showed hyperinflammatory signs and had at least 2 of the following symptoms: fever (>38°C), cannot maintain oxygen saturation >92% without supplemental oxygen, or pulmonary infiltrates.
Patients received standard care and a single dose of either 8 mg / kg body weight of tocilizumab or placebo. The primary outcome was either intubation or death and was assessed in a time-to-event analysis. The secondary outcomes were clinical worsening and supplemental oxygen discontinuation, both determined by time-to-event analyses.
Tocilizumab group had fewer serious infections compared to placebo group
The study had 243 patients, out of which 102 (42%) were women, and 141 (58%) were men. The participants’ median age was 59.8 years (range – 21.7 to 85.4), and 45% of the study cohort were Hispanic or Latino. The hazard ratio for intubation or death in patients who received tocilizumab compared with those who received a placebo was 0.83 (95% confidence interval [CI], 0.38 to 1.81; P = 0.64). The hazard ratio for the worsening of disease was 1.11 (95% CI, 0.59 to 2.10; P = 0.73).
Eighteen percent of patients in the tocilizumab group and 14.9% of the participants in the placebo group experienced disease worsening at 14 days. The median time to supplemental oxygen discontinuation was 5 days (95% CI, 3.8 to 7.6) in patients who received tocilizumab and 4.9 days (95% CI, 3.8 to 7.8) in patients who received placebo (P=0.69). 24.6% of patients in the tocilizumab group and 21.2% in the placebo group were still receiving supplemental oxygen at 14 days. Patients on tocilizumab had fewer serious infections compared to patients who received a placebo.
“Although tocilizumab did not show efficacy in this trial, the drug was not associated with excessive high-grade toxic effects in this population, which was characterized by multiple coexisting conditions.”
Tocilizumab not effective in affecting COVID-19 clinical outcomes
The study results proved that tocilizumab was not effective in preventing intubation or death in patients who were moderately ill and hospitalized with COVID-19. However, as the confidence intervals for efficacy comparisons were wide, the possibility of tocilizumab treatment causing some benefit or harm in some patients cannot be entirely ruled out.
These results do not agree with the findings of multiple open-label trials, which suggested that IL-6 receptor blockade can play a significant role in preventing severe disease in COVID-19 patients. The authors say that although there is no clear explanation for the failure of tocilizumab to affect disease outcomes in their study, it is possible that patients with different demographic characteristics from the ones targeted by this trial may still benefit from IL-6 receptor blockade.
“Our results stand in contrast to those of multiple open-label trials and nonrandomized case series, some of which have suggested that interleukin-6 receptor blockade has a substantial positive effect on patients with COVID-19.”