Drug treatment for the systemic inflammatory response in covid-19

Interview and article by Christine Clark

Dr Mark Tomlin, consultant critical care pharmacist, describes how recent trial findings have identified effective treatments for the systemic inflammatory response syndrome in covid-19.

Coronavirus infection provokes an inflammatory response which activates the immune system and triggers the production of antibodies to fight and kill the virus. For some people this is a mild disease with minor symptoms because their bodies recognise foreign protein, attack it and clear it out of the system. However, “there are other people who seem to have a very large inflammatory response to the virus – indeed the virus may be killed off but the inflammatory response carries on and these are the patients who end up in intensive care with multi-organ failure”, explains Dr Tomlin.

The RECOVERY trial showed that administration of dexamethasone could quench the inflammatory response. This was the first trial that showed that steroids work in this condition. “It is not just killing the virus – it is quenching this inflammatory response that is fundamental”, says Dr Tomlin.

Another agent that has been used in the RECOVERY trial is tocilizumab which is a monoclonal antibody directed against interleukin 6 (IL-6).²  The REMAP-CAP study showed that patients who reach the intensive care unit (ICU) benefit from tocilizumab treatment but hospitalised patients who only require oxygen do not.³ “In the middle there is a group of people who slide into trouble – they don’t have this profound cytokine storm so tocilizumab is of marginal, if any, benefit”, says Dr Tomlin.

Dexamethasone is one of the most active glucocorticoids and has minimal mineralocorticoid effects. “If we were going to replace dexamethasone with something else, we would use something with a similar profile and that’s where methylprednisolone comes in”, says Dr Tomlin. Hydrocortisone, which has both mineralocorticoid and glucocorticoid activity, would not be the first choice. Prednisolone also has a very profound glucocorticoid activity. “Indeed, if supplies of dexamethasone or methylprednisolone were threatened we might then go for hydrocortisone injection or prednisolone orally because they have glucocorticoid effects, which I think is key to this. It’s not just something that raises blood sugar; it’s something that quenches the inflammatory process which is our aim in this”, he adds.

Commenting on the dose of dexamethasone, Dr Tomlin notes that doses as high as 32mg have been used to treat cerebral oedema associated with brain tumours. “A dose of 6mg was chosen in the [RECOVERY] trial so the evidence base is with 6 mg”, he says. Without dose-ranging studies it is not possible to say whether this is the optimal dose. “Some people have gone as high as 20mg and said this is better and maybe it is [better] in quenching inflammation but we must remember that these are powerful drugs which are upsetting the immune system …… but longer term we may end up selecting out fungal and viral infections as secondary events”, he says. Dr Tomlin also notes that the duration of treatment was 10 days in the trial, although some patients appear to need treatment for longer.   

A further practical problem has arisen because the injection vial contains 6.6mg of dexamethasone sodium phosphate and this has led to delays as nurses try to calculate the volume required to administer 6.0mg. It would be preferable simply to administer the entire contents of the vial says Dr Tomlin. 

REMAP-CAP

The Randomised, Embedded, Multi-factorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) trial design was an innovative way to tackle the situation where many agents had to be tested and results were needed quickly. Whereas most trials look at one drug, maybe two or three, and compare it against placebo, the adaptive design of REMAP–CAP allowed many treatments to be tested quickly.  There are about nine different arms to the REMAP-CAP trial including aspirin, antivirals, dexamethasone, hydroxychloroquine, azithromycin and colchicine.  “What we discovered fairly early on was that some of the exciting drugs like remdesivir and antivirals didn’t prove as effective as we had hoped so we stopped recruiting to those arms”, explains Dr Tomlin. It had been assumed that antiviral agents would knock out the virus and lead to shorter stays in ICU. “What we found was if you got to intensive care giving antivirals didn’t seem that helpful,  which plays to this story of, ‘the virus may be dead but the patient has still got a profound inflammatory response which we must quench’. Dexamethasone was again one of the candidates that showed promise so we gave it to more and more patients and as time has gone on so we have introduced new drugs like tocilizumab, sarilumab and anakinra which again proved to be effective in intensive care but not necessarily outside of intensive care”, he says.

Where are we now and what next?

Summarising the current position, Dr Tomlin says that for patients who reach intensive care,  giving antivirals doesn’t necessarily shorten the length of stay but giving drugs like steroids and tocilizumab, which quench the inflammatory response, does offer benefits.  It is assumed that the patients, who have a profound inflammatory response which they are unable to quench, respond to drugs that help to suppress their overactive immune systems. This allows them to recover and avoid the consequences of infection such as oedema, inflammation and fibrosis (which may be what ‘long covid’ is).

In future, other drugs will be incorporated into the REMAP-CAP studies, including, possibly, ivermectin.  “We have noticed that patients have low vitamin D levels and it could be that the BAME cohort of people, particularly in the UK and the Northern hemisphere, don’t get enough sunlight and so their levels of vitamin D synthesis are lower than required or it could be that if we treat the low levels of vitamin D that we are seeing, then maybe that will improve them and I think vitamin D will be an interesting story for the future”, concludes Dr Tomlin.

References

1. Dexamethasone in Hospitalized Patients with Covid-19. The RECOVERY Collaborative Group NEJM 2021;384:693-704
2. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial. The RECOVERY Collaborative Group Preprint https://www.medrxiv.org/content/10.1101/2021.02.11.21249258v1
3. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 – Preliminary report. The REMAP-CAP Investigators. Preprint https://www.medrxiv.org/content/10.1101/2021.01.07.21249390v1.full.pdf

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