An observational study finds that patients on ventilators who received a drug that dampens excessive immune responses had a 45% lower risk of dying compared with controls.
Despite being twice as likely to develop secondary infections, patients who received a single dose of the immune suppressing drug appeared to have a better chance of survival, researchers at the University of Michigan discovered.
Doctors usually prescribe the drug, called tocilizumab, for rheumatoid arthritis, a painful condition in which a person’s immune system attacks their joints.
The immune system of people with COVID-19, the illness that the coronavirus SARS-CoV-2 causes, can also go into overdrive, producing excessive quantities of immune signaling molecules called cytokines.
This cytokine release syndrome, or “cytokine storm,” results in hyperinflammation, which exacerbates the person’s breathing difficulties and can lead to potentially fatal acute respiratory distress syndrome (ARDS).
Tocilizumab is a monoclonal antibody that suppresses the immune response by blocking receptors for a key cytokine known as interleukin-6 (IL-6).
Doctors have used the drug to combat cytokine release syndrome in people receiving immunotherapy for cancer, and case studies have suggested that it might also be effective in people severely ill with COVID-19.
However, the drug is known to increase the likelihood of secondary infections, which are a risk factor for death in those with COVID-19.
Early in the pandemic, doctors at Michigan Medicine — the university’s academic medical center — were split on whether the limited evidence of benefits and known risk of secondary infections justified using the drug to treat their patients.
This lack of consensus had the fortuitous effect of creating a natural experiment, with some doctors at the center prescribing it while others did not.
The researchers included in their analysis 154 patients who needed mechanical ventilation, of whom 78 received a single injection of tocilizumab, and 76 did not.
The two groups were broadly similar, but those who received tocilizumab were slightly younger and less likely to have chronic pulmonary disease or chronic kidney disease.
The patients were admitted during the first 6 weeks after the start of the outbreak in Michigan, from early March to late April.
At 28 days’ follow-up, 14 (18%) of the patients in the tocilizumab group had died, compared with 27 (36%) of those who did not receive the drug.
After adjusting for variables, such as age, sex, race, ethnicity, transfer status, and preexisting conditions, the researchers calculated that patients who received the drug were 45% less likely to die.
The study features in the journal Clinical Infectious Diseases.
The people who received the drug were also more than twice as likely to develop a secondary infection (or “superinfection”) — mostly bacterial pneumonia — than those who did not (54% vs. 26%).
However, among those who received the drug, there was no difference in survival at 28 days between those who developed an infection and those who did not.
“We kept trying to prove ourselves wrong as signals of benefit emerged in the data,” says Emily Somers, Ph.D., an associate professor of internal medicine at the University of Michigan Medical School and a co-first author of the study. “But the difference in mortality despite the increase in secondary infection is quite pronounced, even after accounting for many other factors.”
Nonetheless, the researchers recognize the need for randomized, controlled clinical trials to test the efficacy and safety of the drug.
“In conclusion, tocilizumab was associated with improved survival, despite higher occurrence of superinfections, in a cohort of COVID-19 patients requiring mechanical ventilation. These data are encouraging and can help to inform clinical practice while results from randomized, controlled trials of IL-6 inhibitors are awaited.”
– The study authors
The authors emphasize that the timing of tocilizumab treatment is critical in COVID-19.
They point out that IL-6 may have beneficial effects, such as suppressing the reactivation of the virus, protecting against secondary infections, and facilitating the healing of damage to the lungs resulting from the infection.
Therefore, they chose to give a single high dose of the drug within 24 hours of intubation to saturate IL-6 receptors in the short term but limit longer term immune suppression.
Until clinical trials have taken place, however, they remain cautious.
Senior author Jason Pogue, a clinical professor at the University of Michigan College of Pharmacy and an infectious disease pharmacist at Michigan Medicine, says that he recommends the steroid dexamethasone as the first line of treatment for critically ill COVID-19 patients.
This recommendation follows the recent publication of evidence from a clinical trial in the United Kingdom, which found that the steroid is effective and safe.
At Michigan Medicine, tocilizumab remains reserved for patients who respond poorly to dexamethasone or for whom the risks of adverse events from steroid therapy outweigh the benefits, says Pogue.
“Further studies of tocilizumab, which is more targeted than dexamethasone in addressing the hyperinflammatory process, could include combining these agents or comparing them head to head,” he adds.
Another consideration is that, in common with other monoclonal antibodies, tocilizumab is expensive.
Pogue notes that a single dose of tocilizumab costs roughly 100 times more than an entire course of dexamethasone.
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