Researchers from 68 sites across the country, led by David E. Leaf, MD, MMSc and Shruti Gupta, MD, MPH from the Division of Renal Medicine at Brigham and Women's Hospital, have investigated the effects of the anti-inflammatory drug tocilizumab on critically ill patients with laboratory-confirmed COVID-19. Unlike steroids, which suppress the immune system more broadly, tocilizumab specifically inhibits the receptor for the pro-inflammatory cytokine, IL-6. The investigators found that when tocilizumab was administered within the first two days of intensive care unit (ICU) admission, there was a 30 percent relative decrease (and a 10 percent absolute decrease) in mortality compared to patients whose treatment did not include early use of tocilizumab. Results are published in JAMA Internal Medicine.
"Tocilizumab has been used for several years to treat a condition known as cytokine release syndrome, which can be observed in cancer patients receiving certain types of immunotherapy," said Leaf, the senior author of the study. "In the setting of COVID-19, it has been observed that much of the morbidity and mortality that occurs may be due to our own body's inflammatory response to the virus as opposed to the virus itself."
The monoclonal antibody tocilizumab is currently approved to treat rheumatoid arthritis and giant cell arteritis, an inflammatory condition affecting large blood vessels. It is also administered to cancer patients who have received chimeric-antigen receptor therapy (CAR-T), a treatment that can stoke the body's immune system to attack cancer cells but can also cause toxic side effects due to cytokine release syndrome (CRS), an overwhelming inflammatory response that can cause multiorgan failure. Tocilizumab is used to treat CRS in cancer patients and is currently under investigation for use in COVID-19 patients. Since the start of the pandemic, several tocilizumab studies have been conducted in Europe and China, but none this large or thorough.
The multicenter study utilized data accumulated from over 4,000 critically ill patients with COVID-19 admitted to ICUs at 68 sites across the US as part of the Study of the Treatment and Outcomes in Critically Ill Patients with COVID-19 (STOP-COVID). STOP-COVID was initiated by Leaf and Gupta in March 2020 as an unfunded, grassroots network, and now includes over 400 collaborators across the U.S. These collaborators ascertained detailed data from critically ill adults with COVID-19 by manually reviewing electronic medical records and entering over 800 unique data elements per patient into a centralized electronic database. For the current study, Leaf and his team used a 'target trial emulation' approach to examine whether tocilizumab reduces mortality in COVID-19. Target trial emulation, a novel method of analyzing observational data, is the idea of simulating a randomized control trial to reduce bias.
"Discussions about the biases of observational studies tend to focus on lack of randomization, but many common biases of observational analyses have nothing to do with lack of randomization," said co-author Miguel Hernán, pioneer of this technique and professor of biostatistics and epidemiology at the Harvard T.H. Chan School of Public Health. "Emulating a target trial using observational data allows us to eliminate those common biases and appropriately focus the discussion on potential confounding due to lack of randomization."
Of the 3,924 patients included in the analysis, 433 received tocilizumab in the first two days of ICU admission. The risk of death at 30-days was 27.5 and 37.1 percent among tocilizumab-treated and non-tocilizumab-treated patients, respectively (absolute risk difference, 9.6 percent). The beneficial effect of tocilizumab on survival was consistent across categories of age, sex, and illness severity, and was also observed in patients who either did or did not receive corticosteroids. Notably, patients with a more rapid disease trajectory, defined as three days or fewer from symptom onset to ICU admission, benefited from tocilizumab to a greater extent than patients with a slower disease trajectory.
"I think the single most important thing we can do with the large and granular database that we assembled in STOP-COVID is to evaluate which interventions are helpful in reducing death," said Leaf. "Obviously, randomized clinical trials ...
(All Rights Reserved)