Two new studies have revealed that rheumatoid arthritis medication tocilizumab is associated with lower death rates in COVID-19 patients receiving mechanical ventilation. Tocilizumab blocks interleukin-6 (IL-6), an inflammatory protein involved in a potential “cytokine storm” that can lead to respiratory failure in patients with coronavirus.
In the first single-center observational study, published late last week in Clinical infectious diseases, Researchers from the University of Michigan at Ann Arbor discovered that tocilizumab was linked to a 45% reduction in the risk of death (risk ratio [HR], 0.55 (95% confidence interval [CI], 0.33 to 0.90) and better state after adjusting the inverse probability weighting propensity score (IPTW).
In the second study, researchers in Milan found that tocilizumab halved the death rate of coronavirus patients compared to standard care, but lengthened hospital stays, according to a study last week. Infection journal.
Improves despite more superinfections
The Michigan study involved 78 COVID-19 patients hospitalized in Michigan Medicine on mechanical ventilation who received tocilizumab and 76 who did not receive from March 9 to April 20.
Tocilizumab was linked to twice the frequency of superinfections (54% vs. 26%; P <0.001), more attributed to a large increase in ventilator-associated pneumonia (45% vs. 20%; P <0.001); Superinfections are secondary infections with a different pathogen resistant to the treatment administered to treat the first infections. Approximately half of bacterial pneumonia cases were identified as due to Staphylococcus aureus.
But there was no difference in the 28-day mortality rate between patients who received tocilizumab with or without superinfection (8 of 37 [22%] vs 6/41 [15%]; P = 0.42). In addition to the overall 45% lower mortality rate, the 28-day case fatality rate in patients treated with tocilizumab was halved (18% vs. 36%).
Patients treated with tocilizumab had greater improvement on a six-point ordinal scale that assessed mechanical ventilation, the development of superinfections, and discharge from hospital (odds ratio). [OR], ~ 0.6; P ≤ 0.03) in IPTW-weighted models.
The improvement in status in the tocilizumab-treated group is related to the statistically significant increase in patients discharged from the hospital during the study period (56% vs. 40%; P = 0.04). Seventeen patients in each group were still hospitalized at the end of follow-up, but only 3 of 17 (18%) of the tocilizumab-treated patients continued to receive mechanical ventilation, compared to 8 of 17 (47%) of the controls.
Although the two groups were similar, the patients who received tocilizumab were younger (mean age, 55 vs. 60), were less likely to have chronic lung disease (10% vs. 28%) or chronic kidney disease (35% vs. 49 %), and had lower levels of D-dimer (indicating blood clots) on intubation than control patients. The median follow-up was 47 days (range, 28 to 67).
Most of the patients in both groups were intubated within 48 hours after transfer to the center or within 24 hours after admission.
“These data are encouraging and may help inform clinical practice while awaiting results from randomized controlled trials of IL-6 inhibitors,” the authors wrote.
Critically ill patients and clinical benefit.
The single-center Italian retrospective study compared the results of 74 COVID-19 patients treated with tocilizumab from March 13 to April 3 with those of 148 paired controls. Although patients with less severe COVID-19 did not appear to benefit from tocilizumab, those with critical illness did benefit.
Patients treated with tocilizumab had improved survival (HR, 0.49, 95% CI 0.26 to 0.95; P = 0.035) compared to controls, but also had longer hospital stays (HR, 1.66; 95% CI, 1.08 to 2.52; P = 0.019), mainly due to biochemical, respiratory and infectious adverse events.
At the end of follow-up, 35% of the 74 tocilizumab-treated patients had clinical deterioration in terms of mechanical ventilation requirements or death, while 65% remained stable or improved.
Patients treated with tocilizumab had increased IL-6 levels 12 hours after drug administration, but later, IL-6 levels in those who continued to show deterioration continued to increase, while others had smaller increases.
During the 7 days after tocilizumab treatment, levels of C-reactive protein (indicating inflammation) decreased substantially, and levels of leukocyte and lymphocyte white blood cells and platelets (involved in coagulation) increased.
D-dimer levels increased dramatically on day 5 and then decreased without returning to baseline. Additionally, a substantial increase in alanine transaminase levels (indicating inflammation or liver damage) was observed on day 7.
Patients who received noninvasive mechanical ventilation after hospitalization benefited from tocilizumab, but those who received the medication outside the intensive care unit (ICU) required emergent noninvasive mechanical ventilation after receiving tocilizumab.
Twenty-seven infectious adverse events occurred in 24 patients (32%), 21 of them in ICU patients. Eleven serious events (15%) occurred, six of them due to sepsis caused by gram-negative bacteria, two due to sepsis caused by gram-positive bacteria, one due to candidemia, one due to a lung abscess and one caused by an abscess Epidural Of all the patients with adverse events, one died of septic shock after being released from the ICU.
The number of tocilizumab doses did not appear to affect survival (HR, 0.75, 95% CI, 0.20 to 2.79; P = 0.38). Neither did the basal levels of IL-6 (HR, 0.45; 95% CI, 0.10 to 2.39; P = 0.376).
The median age of the patients was 59 years; 82% were male, 82% were white, and 70% were in critical condition.
“This study confirms the potential effectiveness of [tocilizumab] on COVID-19, especially in critically ill patients, with a reliable comparison group that allows us to weigh the potential clinical impact of this treatment, “the authors wrote.” However, we suggest using it with caution due to drug-related adverse events, notably transient respiratory worsening and bacterial infections. ”
According to the authors, several trials of tocilizumab in coronavirus patients with different study designs, drug combinations, and target populations are listed on ClinicalTrials.gov and should provide more detail on the use of tocilizumab in these patients.
