Tocilizumab May Reduce Mortality in Certain COVID-19 Patients

Early in the COVID-19 pandemic, researchers believed severely ill patients had cytokine storm, leading them to propose the use of existing antiinflammatory drugs that damp the immune system, such as tocilizumab. Although we have since learned that levels of inflammation are lower in COVID-19 patients than in other severely ill patients (such as those with sepsis or acute respiratory distress syndrome), research into these immune-damping drugs had already begun. While early results were mixed, two recent trials are more promising, suggesting that these drugs may reduce mortality in patients with severe COVID-19. But, as with all therapies used to treat COVID-19, there are qualifiers, including the patient population most likely to benefit, rapid dissemination of results in preprint form, and a paucity of long-term follow-up.

“Ultimately, the early data suggest that tocilizumab may be a new option to treat COVID-19 patients who are rapidly deteriorating or have more severe forms of inflammation, such as very elevated C-reactive protein,” said Greg S. Martin, MD, MSc, FCCM, professor of pulmonary and critical care medicine at Emory University and president of SCCM. “While it is impossible to make a definitive recommendation at present, it appears most beneficial when given to patients within 24 to 48 hours of hospitalization.”

REMAP-CAP and RECOVERY

Tocilizumab is a recombinant anti-IL-6 receptor monoclonal antibody that is approved for intravenous treatment of patients with rheumatoid arthritis and those with chimeric antigen receptor T cell (CAR-T) induced cytokine release syndrome. Based on these properties, researchers began studying tocilizumab use in patients with severe COVID-19 with hypoxia and significant inflammation.
 
In January 2021, the international Randomised, Embedded, Multi-factorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP), released early results of patients with severe COVID-19, with 402 randomized to standard care, 353 to tocilizumab, and 48 to sarilumab. The goal was to reduce inflammation due to SARS-CoV-2. More than 90% of patients also received a corticosteroid such as dexamethasone.
 
The investigators reported that the drugs led to an 8.5% drop in absolute risk of death for patients receiving tocilizumab versus those receiving standard care. The benefit was observed when the antiinflammatory drug was administered to patients within 24 hours of ICU admission.
 
In February 2021, a larger trial, the Randomised Evaluation of COVID-19 Therapy (RECOVERY), from the United Kingdom, reported their results of administering tocilizumab to hospitalized patients with severe COVID-19. RECOVERY included patients with a wider range of characteristics than REMAP-CAP. In RECOVERY, 2022 patients were randomized to receive tocilizumab by intravenous infusion and 2094 received usual care. As with REMAP-CAP, most patients (82%) were also receiving a systemic corticosteroid such as dexamethasone.
 
Researchers reported a 4% reduction in the absolute risk of death in patients receiving the treatment versus those receiving usual care. They said the data suggest that in COVID-19 patients with hypoxia and significant inflammation, treatment with a corticosteroid and tocilizumab reduces mortality by about one-third for those requiring supplemental oxygen and nearly one-half for those requiring mechanical ventilation. When combining the results of RECOVERY with seven other tocilizumab trials, 28-day mortality was reduced by 13%.

Qualifiers and Questions

 During the pandemic, there has been an understandable desire to treat patients based on the best available evidence. While this is a pragmatic approach, in most cases this means that the research is unable to provide the rigor typically demanded when choosing therapies. As is often the case, the results of the two studies were published as preprints, and neither has undergone peer review.
 
The results suggest that tocilizumab may work best when administered to rapidly deteriorating patients with signs of inflammation early in the course of their illness—within nine days of the first symptoms and 24 to 48 hours of hospitalization.
 
“A patient who has required supplemental oxygen through high-flow nasal canula and requires transfer to the ICU for mechanical ventilation after 11 days in the hospital is likely already receiving corticosteroids and remdesivir and is unlikely to benefit from tocilizumab,” said Amy L. Dzierba, PharmD, FCCP, BCCCP, FCCM, clinical pharmacy manager at New York-Presbyterian Hospital. “The patient who requires an ICU-level of care with high levels of supplemental oxygen, including mechanical ventilation, may benefit if tocilizumab is provided along with corticosteroids within 24 to 48 hours of hospitalization.”
 
Tocilizumab is a robust immunosuppressive and may increase patients’ risk of serious secondary short- or long-term infectious complications, such as bloodstream infections and secondary pneumonia. Patients at high risk for serious infection may not be good candidates.
 
“While the RECOVERY trial reported three infectious adverse events attributed to tocilizumab, additional details are needed about how adverse drug reactions were assessed, and there is a need for longer-term mortality data,” said Sandra L. Kane-Gill, PharmD, MS, FCCP, FCCM president-elect of SCCM. “It’s important to determine whether there is a sustained mortality benefit at six months, which seems to be a preplanned analysis.”
 
Dr. Kane-Gill noted that RECOVERY included patients with a C-reactive protein level greater than or equal to 75 mg/L, leaving unanswered the question of whether patients with systemic inflammation whose levels fell below that would benefit. She also wonders whether a huge demand for tocilizumab might affect the supply for those who need it for approved indications, such as CAR-T-induced cytokine release syndrome and rheumatoid arthritis, a situation that occurred early in the pandemic for hydroxychloroquine.
 
There are many other unanswered questions. Should tocilizumab always be provided with corticosteroids or is it beneficial alone? Does the combination provide a synergistic effect? How is usual or standard care defined? Clearly it varies by hospital. Can it be used in children, especially those with multisystem inflammatory syndrome in children (MIS-C)? What about pregnant patients? As with other COVID-19 treatments, more research and longer follow-up is vital.