What are corticosteroids?
Corticosteroids are a category of molecules grouped together because they are structurally similar to cortisol, a hormone produced by the adrenal glands. Corticosteroid drugs have been synthesised by taking natural cortisol as a model, in order to reproduce its ability to modulate inflammatory reactions and the overall activity of the immune system. Corticosteroids inhibit those processes that lead to the synthesis of pro-inflammatory substances, and activate those processes that lead to the synthesis of anti-inflammatory and immunosuppressive substances. The result is the containment of the events that are responsible for the symptoms of the disease, in localised inflammations or in generalised immune responses, as happens in the most serious evolution of patients with COVID-19.
Corticosteroids are very cheap and have been used in medicine for over 40 years to cure a range of diseases, such asthma and arthritis. Numerous synthetic corticosteroids are currently available which differ from each other in the intensity of the anti-inflammatory action or the duration of the action. Examples of corticosteroids include prednisone, prednisolone, hydrocortisone and dexamethasone.
The Recovery study on dexamethasone
In the absence of reliable evidence from large-scale randomised clinical trials, there was great uncertainty about the effectiveness of corticosteroids in treating COVID-19. Corticosteroids have been widely used in syndromes closely related to COVID-19, including SARS, MERS and community- acquired pneumonia. However, the evidence to support or discourage the use of corticosteroids in these conditions has been weak and fragmented.
In the Recovery clinical trial, patients were randomly assigned to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. A total of 2 104 patients were assigned to receive dexamethasone and 4 321 to receive usual care. Around 15 % of all UK hospitalised patients with COVID-19 were enrolled in the trial.
Dexamethasone provides an effective treatment for patients with COVID-19 and – given its low cost and general availability – it can be used worldwide.
Professor Martin Landray, University of Oxford, UK : “In patients who have been admitted to hospital with COVID, for those who require a ventilator treatment with dexamethasone reduces the risk of dying by one third. Among the patients who do not yet need a ventilator but might be treated with oxygen, it reduces the risk of death by one fifth. In patients who are admitted to hospital but whose lungs are working well, so they do not need oxygen or a ventilator, then dexamethasone has no effect. This drug is for people who have the more severe forms of COVID, those affecting the lungs’ function.” – Read the full interview
The Recovery trial provides evidence that treatment with dexamethasone reduces 28-day mortality in patients with COVID-19 who are receiving respiratory support. On the basis of these results, one death could be prevented by treatment of around 8 patients requiring invasive mechanical ventilation or around 25 patients requiring oxygen without invasive mechanical ventilation. There was no benefit (and the possibility of harm) among patients who did not require oxygen.
It is likely that the beneficial effect of corticosteroids in severe viral respiratory infections depends on using the right dose at the right time. The peak viral shedding in COVID-19 appears to be higher in the first days of the illness and declines thereafter. The greater mortality benefit of dexamethasone in patients with COVID-19 who required respiratory support suggests that at this stage the disease is dominated by an overreaction of the immune system, with active virus replication playing a secondary role.
Prior to Recovery, many COVID-19 treatment guidelines stated that corticosteroids were either ‘contraindicated’ or ‘not recommended’. These positions now came under review.
Professor Massimo Galli, University of Milan, Italy : “The study published in the New England Journal of Medicine by British colleagues shows that dexamethasone, at not particularly high dosages, has the ability to significantly reduce mortality …The need to clarify the most valuable dosage is one of the open questions with which the study ends, a sign that new research is needed.” – Read the full interview
‘The new normal’: to be prepared for the months to come
Eight months on from the first reports of a new virus emerging in China in December 2019, the EU and countries worldwide are experiencing surges in new cases. Just as Asian countries were the first to be affected by COVID-19, they were also the first to experience a new surge of infection. The development of an effective vaccine is both difficult and insufficient: it must also be manufactured, distributed, and administered.
Professor Martin Landray, University of Oxford, UK : We do not have vaccines and we are unlikely to get vaccines in time for this winter. We might get some, but not at millions of doses, so all the social distancing and testing are really important. From a UK perspective, now is the time to do it when things are sufficiently quiet, because when things get busy, it is too late. You can see all around the world that if you do not prepare, by the time the virus really hits it is just too late.
Until that happens, we must be able to reduce the chances of being infected or spreading coronavirus by taking simple precautions, isolating infected subjects, testing their contacts, and providing appropriate treatment to those having the disease.
Professor Massimo Galli, University of Milan, Italy : “To stay out of trouble, greater effort and investment will have to be made at community level towards an effective surveillance activity, associated with other simple precautions. Given that flu and COVID-19 have an overlapping symptomatology, and that the flu has a mortality rate of 7 000 to 8 000 deaths per year in Italy, to reduce diagnostic doubts a widespread vaccination for influenza is crucial, not only for the elderly but also for younger people and children, who are the great reservoir of the flu.”