A Covid-19 blog post for the non-expert
It stared with a 16th June 2020 press release from the University of Oxford “Low-cost dexamethasone reduce death by up to one third in hospitalised patients with severe respiratory complications of COVID-19” – which triggered the equivalent of a media cytokine storm (pun explained shortly).
I do not want, for one moment, to dowse good news when it comes to Covid-19, but medical science is progressing during the crisis by press release and so I think it worth taking a step back to understand at the time of writing, the clinical trial is unpublished and not peer reviewed. Trawl through the media, newspapers and websites, and you’ll find pretty much a rejigging of what’s in the Oxford press release. A few newspapers, such as the Guardian, took the trouble to add some interviews but overall there was no explanation of what dexamethasone is, or what it does. So I thought I’d try to address that question in this blog post.
I once attended a lecture by Sir Martin Rees, the Astronomer Royal here in the UK, who said Astronomy was a simple subject. Many in the audience expressed surprise by this but he explained he thought real complexity was in biochemistry where there were so many interactions between molecules, membranes, cells and different tissues of the body. We might one day be able to understand the Universe’s beginnings and perhaps even how it will end, but he doubted if we would ever fully understand the multifariousness nature of biochemistry. Looking at the action of dexamethasone, I think, Martin Rees is right.
The immune system is complicated – beyond Martin Rees’s astronomy complicated. There’s probably more that scientists don’t understand about the immune system than they do. It’s evolved because there’s a whole world out there intent on killing you, one way or another, and the immune system is the ultimate defending army. A key part of the immune defence is inflammation, which is difficult to precisely define in immunological terms but in a nutshell, it’s a response against an irritant, anything from a splinter to a deadly virus, or indeed in some people, nutshells. Symptoms are erythema (redness), raised temperature, swelling and pain, which in the case of a splinter are external. Inflammation can also occur internally, such as with nut allergy for example, in which case it might become life-threatening.
Inflammation results in an increase in blood flow and an influx of a wide range immune system cells, commonly called white cells. Many of these cells were identified before their action was understood and so were named after their reaction to different stains under the microscope. And so you get, for example, basophils, neutrophils and eosinophils (eosin is a pink-red dye) as well as cells types, not named after microscopic dyes, such as mast cells, monocytes and macrophages. These cells come piling into the affray, like the proverbial Fifth Cavalry in a western movie to the sound of a bugle. Infected cells, of course, don’t have a bugle, instead they communicate with the immune system through small proteins called cytokines. There are around 80 known cytokines, including interferons, interleukins and TNF. TNF stands for tumour necrosis factor (although disregard the tumour part in the current context) and it’s one of the first cytokines produced to open surrounding capillaries to increase blood flow to allow more white cells in.
This plethora of cells and cytokines, together with other factors of the immune response such as a cascade of proteins called complement and, of course, antibodies, all react with each other making the complexity of the universe look trivial. Usually this biochemical and cellular mêlée is pretty good at seeing off infection and the inflammatory response plays an important role in that process. Don’t get the idea it’s all completely chaotic because the entire operation is controlled – or regulated in biochemistry-speak, chiefly through a structure in the cytoplasm called the “inflammasome”. Sometimes however, it all gets out of control, like a scrap between two schoolboys turning into a full scale riot. The communication proteins, the cytokines, go mad, attracting more immune cells, releasing more cytokine. It’s like the schoolboy fight going viral on social media, inviting anyone who wants a scrap from miles around. This has attained the name, cytokine storm and although it doesn’t have a precise definition, it became notorious in the 2006 clinal trial with TGN1412, which went horribly wrong. The term cytokine storm (or cytokine storm syndrome) actually originated earlier from a 1993 paper concerning adverse effects of organ transplants (1).
Now enter dexamethasone. In some cases, infection with SARS-CoV-2, the causative virus of Covid-19, sends the inflammatory response into overdrive, and that is the ultimate cause of fatality. Dexamethasone is a synthetic steroid of the type produced in the cortex (outer layer) of the adrenal gland, located just above the kidneys, and hence is called a corticosteroid. Corticosteroids find receptors in cells which initiate a chain of events involving RNA and DNA, down-regulating protein synthesis, damping down production of cytokinins and calming the inflammatory response like switching off social media in the middle of our metaphorical riot. Dexamethasone comprises a molecular skeleton common to all steroids, but with a fluorine atom added. It is a very potent anti-inflammatory drug, being around 25-times more potent than cortisol, for example. (Cortisol is more associated with the “fight-or-flight” response but it also has a role in moderating inflammation and is used as a hydrocortisone cream to treat eczema and dermatitis).
Dexamethasone is a well-establish drug used to treat a wide range of inflammatory disease including allergic responses, arthritis, lupus and some breathing disorders. In many ways it’s not surprising it helps in cases of severe SARS-CoV-2-induced inflammation and so unlike hydroxychloroquine, promoted so heavily at one point, it does seem to hold a lot of promise.
It is not however, an anti-viral, it does not inhibit infection, it is not a prophylactic, but it may save lives and for that some celebration is justified.
(1) Ferrara, J. L., Abhyankar, S. and Gilliland, D. G. (1993) Cytokine storm of graft-versus-host disease: a critical effector role for interleukin-1. Transplant. Proc. 25 1216–1217