How suppressing the immune system can save lives in severe COVID-19 cases
An Oxford University-led trial testing a commonly available immunosuppressive drug on COVID-19 patients has found the cheap steroid significantly reduces deaths when administered to severely sick patients in intensive care. The treatment, described as “the first major breakthrough in the therapeutics of COVID-19 infection”, suggests immune suppressing drugs, if delivered at the right time to late-stage patients, can improve survival outcomes.
Dexamethasone was originally developed in the 1950s as part of the first wave of anti-inflammatory drugs that revolutionized medicine at the time. Classified as a cortocosteriod, dexamethasone is an immunosuppressive drug often used to treat acute allergic responses, skin diseases and asthma.
While it may seem somewhat counter-intuitive to suggest inhibiting the body’s natural defenses could help one survive a life-threatening viral infection, it is not unprecedented for this method to be used to save lives in the face of virus-induced pneumonia.
Although this medical use of cortocosteriods remains controversial, some data from H1N1 swine flu outbreaks suggests it can be helpful in patients suffering severe viral pneumonia. However, a large meta-review published last year on the effect of cortocosteriods in adults with influenza-induced pneumonia did conclude the treatment was associated with higher rates of death.
In the earliest stages of the current pandemic doctors quickly began noting patients most often dying from COVID-19 were suffering from a condition known as acute respiratory distress syndrome (ARDS). This occurs when the body’s natural immune defenses overreact causing respiratory failure due to excessive inflammation in the lungs. As the University of Westminster’s David Gaze explains, in the case of COVID-19 this condition can be caused by an immune response known as a cytokine storm.
“In severe cases, the body’s immune system over-reacts to the virus and mounts an attack on the cells that contain it,” writes Gaze. “This is known as a cytokine storm, where chemicals called cytokines are released by cells of the immune system, causing excessive inflammation.”
In early March Oxford University quickly began a large series of randomized control trials called RECOVERY (Randomised Evaluation of COVid-19 thERapY). RECOVERY was designed to explore whether pre-existing drugs or treatments could be effectively repurposed for COVID-19. Six different treatments were initially explored by the RECOVERY program, including azithromycin – a common antibiotic, dexamethasone and hydroxychloroquine.
The hydroxychloroquine arm of the trial was recently halted due to a lack of efficacy after a steering committee evaluated the ongoing results from over 1,500 treated patients. The dexamethasone arm of the trial was also recently halted, but for exactly the opposite reason. The drug had demonstrated clear clinical success.
The full dataset from the trial is yet to be published in a peer-reviewed journal, however, the researchers have revealed the data in a pre-print article. The results show 2,104 severe COVID-19 patients received a small daily dose of dexamethasone for 10 days, compared to a control of 4321 receiving standard care.
The findings suggest the corticosteroid reduced deaths by around 20 percent in intensive care patients receiving oxygen compared to the control. The results were even more pronounced for patients on ventilators, with the treatment reducing deaths by 30 percent.
Importantly, the study also showed the treatment conferred no benefit in patients not requiring respiratory support. This affirms the immunosuppressive treatment as only useful for patients in severe life-threatening stages of the disease.
Martin Landray, one of the chief investigators on the trial, suggests this data is incredibly clear and may be immediately applied by intensive care physicians around the world.
“These preliminary results from the RECOVERY trial are very clear – dexamethasone reduces the risk of death among patients with severe respiratory complications. COVID-19 is a global disease – it is fantastic that the first treatment demonstrated to reduce mortality is one that is instantly available and affordable worldwide,” Landray says.
Simon Maxwell, an independent clinical pharmacologist from the University of Edinburgh, says the RECOVERY trials affirm the importance of carefully controlled randomized clinical research in helping doctors around the world decide on the best treatments for COVID-19 patients.
“This is the first major breakthrough in the therapeutics of COVID-19 infection,” says Maxwell. “It demonstrates the efficacy of a simple, cheap, familiar and widely successful treatment in those who are most severely affected. Although many units have already been using corticosteroid therapy, these results provide confidence that this treatment delivers a better outcome for many patients."
Tocilizumab is another immunosuppressive treatment being repurposed for severely ill COVID-19 patients that's showing beneficial early data. Tocilizumab is a very different drug to dexamethasone. Unlike the broad immunosuppressive actions of cortocosteriods such as dexamethasone, tocilizumab is a monoclonal antibody designed to block the activity of one type of cytokine immune cell called Interleukin 6 (IL-6).
A Yale University study investigating tocilizumab for severely ill COVID-19 patients is suggesting similar benefits in overall mortality to dexamethasone, although unlike the RECOVERY trial, that research does not have a randomized control component. The RECOVERY is also investigating the efficacy of tocilizumab, but no data has been revealed as of yet.
These results offer incredibly encouraging indications that immunosuppressive drugs, if administered at the right point, can reduce mortality risks from COVID-19. However, this novel repurposing of a pre-existing therapy only helps those patients suffering from the worst of COVID-19. As Devi Sridhar, from the University of Edinburgh, points out to ScienceMag, we still need treatments to prevent the virus from taking hold in the first place and to stop mild cases from progressing to life-threatening situations.
“The real game-changer will be a drug that prevents people going from mild symptoms to a severe state, and a vaccine,” says Sridhar.
The RECOVERY dexamethasone pre-print study has been published on MedRxiv.