Mutual pick: DEXAMETHASONE for COVID-19 – Ready for Prime Time
For over a week the medical world has reeled after being assailed by a press release from the UK telling us a study from Oxford (part of the massive national RECOVERY trial, a five-arm investigation designed to identify treatments that may be beneficial for people hospitalized with suspected or confirmed COVID-19) telling us that 10 days of dexamethasone reduced COVID-19-related mortality by ⅓ in patients requiring ventilation and ¼ in those requiring supplemental oxygen. A game-changer? Let’s discuss it a bit.
First, we suppose we shouldn’t bristle at the press release format but still, this is not the traditional way biomedical research is conducted, or at least not the way it used to be. In the UK, based on the power of the credibility of the national trial itself and the Oxford research team, the results rapidly changed the standard of care. Len knows this as he has participated in recent global discussions considering how ongoing clinical trials may be affected by a changing therapeutic landscape. As of Monday however, the paper was released in medRxiv format that is not peer-reviewed, but a format we are now becoming quite familiar with https://www.medrxiv.org/content/10.1101/2020.06.22.20137273v1 .
Overall we believe the results are clean but with numerous caveats. The randomization is a little awkward, as the only entry criteria for enrolment was to be an adult and be hospitalized for COVID-19 (cases were confirmed). From a practical perspective, patients could be enrolled early in the course or late in the course of the infection. As a result, the entered patients ranged from looking good on no supplemental oxygen (no biomarkers as of yet) to being on a ventilator or somewhere in between. Thus in a disease where timing is everything, we are left to extrapolate.
What is clear, however, is the sicker the patient, the more impressive the outcomes were. Furthermore, the results revealed a critical delay factor, suggesting the optimal timing of treatment initiation appears not to be at diagnosis but somewhere after 7 days from clinical onset. We believe this is important. In fact, the benefits were most stark for ventilated patients where the number needed to treat was 8, while the number need to treat for those only on oxygen was 25. Most importantly in those not requiring oxygen, there was no benefit and possibly harm where the curves go the other way (Figure 1b).
In terms of the therapy itself, the intervention was 6mg of dexamethasone given PO or IV for 10 days where possible. As we all are aware this equals about 32mg of prednisone daily and is not what we would consider blistering immunosuppression. Considering how little we know about glucocorticoids and infections we could construct a narrative telling us that in those who are suffering more from host mediated tissue damage, dexamethasone appears beneficial, whereas early in the course of the infection when patients are just mounting their innate to adaptive immune response, this may be dangerous. As we discussed in a previous COVID Corner, the Rheumatology Global COVID Alliance has demonstrated that baseline glucocorticoids in rheumatic disease patients, at doses of 10mg and higher of prednisone equivalent, may be deleterious in terms of COVID-19 outcomes. Furthermore, previous studies examining the effects of glucocorticoids on other respiratory viral infections such as influenza and SARS have been equivocal at best. Finally, not all infections are equal and we are just starting to understand pathogenesis in the lens of individual immune responsiveness.
We will close with three thoughts:
- We are impressed with the results and would favor dexamethasone over no treatment for patients with progressive COVID-19, probably at the moment of clinically significant hypoxia but not before.
- We also believe that if used in this fashion other experimental therapies can still be examined in combination with dexamethasone.
- Finally, we are now getting to the dog days of COVID-19 disease where the going is going to get tougher from all aspects. Hang in!!
Listen to Adam Brown’s brilliant Podcast series “Rheuminations – a ripping yarn of the immune system gone awry!” The topic this month is spot on!
Please give us a shout out with any questions!
Leonard H. Calabrese, DO, is the head of the RJ Fasenmyer Center for Clinical Immunology and Vice-Chair of the Department of Rheumatic and Immunologic Diseases at Cleveland Clinic Dr. Calabrese has lectured nationally and internationally on the subjects of immunology, rheumatology, and viral diseases. He is the author of more than 400 published peer-reviewed articles, book chapters, and reviews. @LCalabreseDO
Cassandra Calabrese, DO, is a staff physician in the Department of Rheumatic and Immunologic Diseases and the Department of Infectious Diseases at Cleveland Clinic and directs the combined Rheumatology-Infectious Disease training program. She also directs the Clinic for immune-related adverse events form cancer immunotherapy within the department of Rheumatic and Immunologic Diseases. @CCalabreseDO