At a time when COVID-19 has claimed over 4,40,000 lives worldwide (as of June 18) and a vaccine or cure is still a long way off, a breakthrough finding in the United Kingdom randomised trial presents a slender ray of hope. Named RECOVERY (Randomised Evaluation of COvid-19 thERapY), the trial, which began in March, seeks to test a range of potential treatments for the disease.
From among the trials of six drugs for treating COVID-19, one trial that used low-dose dexamethasone, a commonly available steroid used to reduce inflammation in other ailments, has found that it reduces by 35 per cent the mortality of COVID-19 patients with severe respiratory complications who require ventilator support, and by 20 per cent the mortality of those requiring only oxygen support, as compared to the corresponding cohort groups who were not administered dexamethasone. The trial also showed that the drug had no significant effect on the mortality rate of COVID-19 positive cases who were not under any severe respiratory stress.
For the entire trial of all the six repurposed drugs, RECOVERY had enrolled over 11,500 patients from over 175 National Health Service (NHS) hospitals in the United Kingdom. Of these, a total of 2,104 patients had enrolled for the dexamethasone trial; the last enrolment for this was on June 8. The dosage for the dexamethasone trial was 6 mg once a day, either orally or intravenously, for 10 days. This effect on this group was compared with 4,321 randomised COVID-19 patients under normal care. According to the June 16 press release from RECOVERY on the results of the trial, among the patients who received usual care, the 28-day mortality rate was highest in those requiring ventilation (41 per cent), intermediate in those on oxygen support only (25 per cent) and lowest in those who did not require any respiratory intervention (13 per cent).
Dexamethasone brought down the mortality in ventilated patients by nearly one-third (rate ratio between those being given the steroid and those who did not receive was 0.65) and one-fifth in those receiving oxygen only (rate ratio 0.80). There was “no benefit” to those who did not need any respiratory support (rate ratio 1.22). In other words, these results mean that dexamethasone prevents about 1 death in 8 ventilated patients and 25 patients receiving oxygen alone. “Overall,” the release said, “dexamethasone reduced the 28-day mortality rate by 17 per cent with a highly significant trend showing greatest benefit among those patients requiring ventilation.”
A news report in Nature , soon after the announcement of RECOVERY results, quoted Anthony Fauci, Director of the United States’ National Institute for Allergy and Infectious Diseases (NIAID), as saying: “The pattern of response matches the notion that a hyperactive immune response is more likely to be harmful in long-term, serious infections. When you’re so far advanced that you’re on a ventilator, it’s usually that you have an aberrant or hyperactive inflammatory response that contributes as much to the morbidity and mortality as any direct viral effect.”
Note of caution
( Correspondent’s note : A note of caution is necessary in interpreting the results for those not receiving any oxygen support, both in the control group and in the group receiving the drug. In the former, the 13 per cent mortality rate appears to be high. It is presumed that this set may have included patients who were very elderly or with severe co-morbidities. In the group that received the drug, the phrase “no benefit” appears to be slightly misplaced when the mortality rate has in fact gone up by as much as 22 per cent on administration of the drug, which is by no means small. Unfortunately, the release does not give any information about the age distribution of the sampled patients or reason for rate ratio being significantly greater than 1. The mortality rate can go up if there were many patients from a younger age group in that set, because the immunosuppressant action of the drug had a dominating effect.)
The results of the dexamethasone trial are yet to be published in any peer-reviewed journal, although the release said, “Given the public health importance of these results, we are now working to publish the full details as soon as possible.” The writer and well-known medical specialist from Harvard, Atul Gawande, tweeted: “After all the retractions [referring to retractions of studies on hydroxychloroquine (HCQ) by Lancet ] and walk backs, it is unacceptable to tout study results by press release without releasing the paper.”
One of the greatest puzzles that remains unsolved is the cause of death in COVID-19—whether it is the virus itself or the host’s immune response that goes into an overdrive and overwhelms the patient. According to clinicians, the immune system does seem to play a role; this has led doctors to turn to anti-inflammatory drugs, which are usually given for other conditions, including auto-immune disorders, when the immune system begins to act against the host itself, resulting in chronic inflammation.
‘Cytokine storm’
Early on in the pandemic, doctors in China had observed in cases of death that the immune system had overreacted to the external pathogen, the SARS-CoV-2. It was found that some critically ill COVID-19 patients had high levels of proteins called cytokines in their blood. Cytokines include proteins called interleukins and interleukin-6 (IL-6), which are signals for ramping up some parts of the immune system, particularly cells called macrophages. Macrophages cause a heightened inflammatory response, which can sometimes damage normal lung cells as well. The release of such cytokines, often referred to as a “cytokine storm”, are known to occur in other viral infections such as HIV-AIDS.
Anti-inflammatory drugs called IL-6 inhibitors are used for the treatment of chronic inflammatory conditions or auto-immune disorders such as rheumatoid arthritis. One such drug, a non-steroidal injectable called tocilizumab, has been approved in China for treating COVID-19 patients as well. In fact, tocilizumab is one of the other five drugs under the RECOVERY trial in the U.K. It would, therefore, be interesting to see the results of this trial when they come out.
Steroidal anti-inflammatory drugs such as dexamethasone also suppress the immune system unlike IL-6 inhibitors, which suppress those immune responses governed by IL-6, but allow other immune responses that can help fight the virus function as usual. But steroids, which tend to dampen the immune system, can hamper the host’s ability to fight the virus by affecting other immune responses. In an early report in Nature , Daniel Chen, an immunologist at the IGM Biosciences in California, has been quoted as saying, “You have to assume that there’s an ongoing antiviral immune response [as well] that is important to these patients.” According to him, although IL-6 levels are high in some critically ill COVID-19 patients, viral loads are high as well, which is indicative of an active immune response to fight the infection. In that case, he added, reducing immune response in the form of (CD4 and CD8) T-cells could undermine that response.
Responding to apprehensions expressed by some clinicians against trials using steroidal anti-inflammatory drugs such as dexamethasone, Peter Horby of Oxford University, who heads the RECOVERY trial, had said in April that the trial would use relatively low doses of the steroid. “Higher doses are not routinely recommended but the jury is out on lower doses. And many authorities, including the WHO, recommend a trial,” he said.
According to Horby, data from steroid trials during SARS and MERS outbreaks, also caused by coronaviruses, were inconclusive. Given some promising results from steroid studies in previous outbreaks and dexamethasone’s widespread availability, Horby had said that RECOVERY investigators felt it prudent to include it among the drugs on trial. Now, following the RECOVERY results, Horby has called it a major breakthrough.
Interestingly, the document “Clinical Management Protocol: COVID-19”, published by the Union Ministry of Health and Family Welfare, includes steroidal anti-inflammatory drugs in its guidelines for clinical management. It has not recommended the use of dexamethasone, but advises the use of methylprednisolone. For moderate cases requiring oxygen support, the document says: “Consider intravenous methylprednisolone 0.5 to 1 mg/kg for 3 days (preferably within 48 hours of admission or if oxygen requirement is increasing and if inflammatory markers are increased).”
For severe cases, among the many recommended therapeutic interventions, it has included: “For patients with progressive deterioration of oxygenation indicators, rapid worsening on imaging and excessive activation of the body’s inflammatory response, glucocorticoids can be used for a short period of time (3 to 5 days). It is recommended that dose should not exceed the equivalent of methylprednisolone 1–2mg/kg/day. Note that a larger dose of glucocorticoid will delay the removal of coronavirus due to immunosuppressive effects.” In the light of the latest results from RECOVERY, it is not yet clear if the guidelines will include dexamethasone as well.
Till date, the antiviral drug remdesivir, which interferes with the virus’s replication, is the only drug that has shown to work on COVID-19 patients, following a large randomised controlled clinical trial involving over 1,000 patients in the U.S. On April 29, Fauci announced that the trial had found that those who took remdesivir recovered in 11 days whereas those on a placebo took 15 days. However, he added that while remdesivir shortened the hospitalisation time for a patient, it did not have any statistically significant effect on deaths. But remdesivir is apparently in short supply worldwide; also, the drug has to administered through injection over several days. From the RECOVERY results, it would seem that dexamethasone will become the drug of choice for those on ventilator support.
U.K. government’s decision
The release quoted Horby as saying: “Dexamethasone is the first drug to be shown to improve survival in COVID-19…The survival benefit is clear and large in those patients who are sick enough to require oxygen treatment, so dexamethasone should now become standard of care in these patients. Dexamethasone is inexpensive, on the shelf, and can be used immediately to save lives worldwide.” Indeed, shortly after the results were announced, the U.K. government immediately authorised the use of dexamethasone for patients hospitalised with COVID-19 and requiring oxygen support, including ventilators.
“Had we been able to use dexamethasone from the start of the epidemic in the U.K., scientists estimate up to 5,000 lives could have been saved,” wrote Devi Sridhar, Chair of Global Public Health at the University of Edinburgh, in The Guardian . But she also added the caveat, “But we also should not think of dexamethasone as a magic bullet….The real game-changer will be a drug that prevents people transitioning from mild symptoms to a severe state. With such a drug, alongside widespread testing and early detection, patients could be treated in community and outpatient clinics. It also does not address the long-term health issues associated with the virus for those with mild and severe symptoms, given that it affects so many parts of the body including the brain, heart, kidney and blood vessels.”
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