News came yesterday from the Recovery trial effort in the UK that they had seen positive results from dexamethasone treatment in severely ill COVID-19 patients (news article from Science here). This set off a number of headlines that everyone has since been trying to deal with, unfortunately, so I thought I should try to do my part, too.
Let me start off by echoing journalist Kai Kupferschmidt here, and pointing out that – as has been too damn often the case in the last few months – we don’t have the real data on this yet. What we have is basically a press release, with the most impressive top-line numbers in it, and that makes interpretation and context a lot harder. We saw this with the initial remdesivir numbers, with Moderna’s human data on their vaccine, and all over the place during the hydroxychloroquine story. Under normal conditions this wouldn’t be acceptable – and this “new normal” shouldn’t be different. Make your headlines when you release your data, folks.
So here’s what we have: 2104 patients, either on ventilation or receiving supplemental oxygen, were given 6mg dexamethasone (oral or i.v.) daily for ten days. Comparing them with 4321 patients on standard-of-care, the death rates definitely decreased with dexamethasone: the 28-day mortality for patients on ventilation with standard of care was 41%, and dex treatment decreased that to 27%. For patients receiving supplemental oxygen, the 28-day mortality was 25%, which decreased to 20%. And the 28-day mortality for patients who needed no respiratory intervention, the 28-day mortality was 13%, and dexamethasone had no effect on that whatsoever. p-values for these numbers and confidence intervals were very good indeed, as one would hope from the large number of patients – these look like very solid results, from what we can see so far.
Now, the headlines have all been about “first drug to show reduction in deaths”, but while that’s true for intentional RCT data, it ignores the recent observational study on tocilizumab, which showed similar effects. There are a lot of key similarities in these results – you’ll note that such treatment really only seems to have an effect on the sickest patients, and that is almost surely because those patients are in trouble because of the “cytokine storm” immune response. That, in fact, is where I think we can expect the real improvements in clinical outcome, because we have far more options to modulate something like that than we do to treat the viral infection itself. The good news here is that dexamethasone is far, far cheaper and more widely available than the anti IL-6-receptor antibody.
Are they doing the same thing? There’s probably a great deal of overlap. Dexamethasone itself is of course a steroid derivative, a corticosteroid that is used to damp down inflammation and immune response.Such compounds have a huge number of downstream effects in cells and in organ systems (among them a decrease in IL-6 signaling). It’s administered in a wide variety of situations, everything from severe poison ivy through arthritis, Crohn’s disease, asthma, lymphoma, Addison’s disease, multiple sclerosis, and many more. It’s an extremely useful drug, but has to be used with care and generally for a short period, because it’s so powerful – the number of potential side effects with high or prolonged dosing is impressive indeed. The dosage in this study was not particularly high, which is a good thing to see.
A point that I think should be made with all of these therapies is that they’re not actually “drug repurposing” per se. What they are is a new use for a drug’s intended mechanism. Dexamethasone is given to lower inflammation and immune response, and that’s exactly what it’s doing here (and exactly why it was put into the Recovery trial in the first place – it’s clearly something that you would want to investigate). I’m very glad that it’s worked out, because there are never any guarantees – this sort of thing was tried, for example, during SARS and in the H1N1 epidemic, with unclear results.
Another key point, which others have emphasized as well during the pandemic, is that it’s become increasingly obvious that therapy for coronavirus patients needs to be biphasic. In the early part of the infection, you would want to have something with antiviral activity – slow or shut down viral entry and replication. Now, we don’t have much in that line – remdesivir is about it at the moment, possibly faviparivir (another broadly acting RNA polymerase inhibitor) – their effects are real, but not as big as one would like. If a patient later goes on to severe respiratory problems, that usually seems to be caused or exacerbated by the overactive immune response, which has to be treated as a separate issue. And the drugs used to treat that would be a bad idea earlier in the infection, since you need all the immune function you can get at that stage. Note that dexamethasone did nothing in this study for patients who weren’t in respiratory distress – that’s exactly what you’d expect. This also means, of course, that such compounds are completely useless as prophylactics, and would likely be outright harmful. It’s a good thing that dexamethasone is a prescription drug, because that last thing you want is a bunch of people running out and taking it in hopes that it will protect them from the coronavirus. It’ll probably do the opposite, and cause all sorts of side effects besides if people aren’t careful.
The other thing to emphasize, as Kai Kupferschmidt did yesterday, is that none of these drugs directly alter the pandemic itself. They will save more lives when people get infected, but we really need to try to keep more people from getting infected in the first place, especially now that it’s become more apparent that social distancing and as trivial a thing as public use of face masks can help. We could be mitigating this pandemic with such measures in this country, but in too many regions we don’t seem to be doing that. Eventually, though, what makes this disease go away will be a vaccine.
The people (a minority, but a loud one) ranting about how such masks are an infringement on their liberties can go to hell, in my considered view of the situation, and I only wish that they could do that without taking other innocent people with them. Of course, some of those same never-wearing-a-mask people are also publicly swearing never to take a vaccine. Idiots. Loud, dangerous idiots who are endangering all our lives and our livelihoods.