Many novel therapies have been developed to battle Covid-19, caused by Sars-CoV-2 virus, including vaccines, monoclonal antibodies and antivirals.
Yet, medicines already in our arsenal have also given clinicians a vast array of options for treating some of the symptoms of Covid-19 illness. Some of these ‘repurposed’ medicines have been the reason that, only two years down the line from the first identification of Covid-19, we are able to help many sufferers. Indeed, monoclonal antibodies (Tocilizumab) and antivirals (Barictinib) had already been in use for treating Rheumatoid Arthritis, and so were at the forefront of testing in Covid-19 cases, with beneficial results. Another such medicine to demonstrate a beneficial effect in severe Covid-19 was an inexpensive drug that has been around for a very long time: a Corticosteroid called Dexamethasone.
What are Corticosteroids?
The first corticosteroid drug approved for use in the USA was cortisone in 1949, for the treatment of Rheumatoid Arthritis. Since then, corticosteroid drugs have been extensively researched and used to treat inflammatory conditions such as Asthma, Eczema and graft-versus-host disease following organ transplant. They are often referred to by the shortened term "steroids" with more common ones being Dexamethasone, Hydrocortisone, Prednisolone and Betamethasone, to name a few.
There are no such things as magic bullets in Pharmacology, but in terms of reducing inflammation, corticosteroids come close. They are highly immunosuppressant, mainly because they produce a two-pronged effect. Firstly, they slow the expression of pro-inflammatory proteins. A key component of some inflammatory illnesses is an effect called cytokine release syndrome or the ‘cytokine storm’. It occurs when our own body’s immune system produces large amounts of proteins that keep the inflammation signals going continually. This creates an overactive and inappropriate immune response which, rather than helping us fight infection, starts to damage our own tissue. Corticosteroids such as Dexamethasone turn off these pro-inflammatory cytokines and calm down our immune response. Secondly, almost like a back-up, they increase the expression of anti-inflammatory proteins. This means they help to encourage the production of proteins in our bodies that act as natural brakes in our immune response, again effecting a shut-down of inflammation.
Low-dose, short-term corticosteroid therapy usually comes without problems and is often used in exacerbations of inflammatory diseases (eg. Asthma). However, higher doses and prolonged use of them can result in some serious side effects such as Cushing’s Syndrome – a condition caused by having too much cortisol in your body, – Osteoporosis and Diabetes.
Systemic Corticosteroids in Covid-19
In terms of Covid-19, Dexamethasone, systemically administered (either orally or intravenously) was the first intervention proven to reduce mortality in hospitalised patients. More recent meta-analyses also show that in patients requiring oxygen support, corticosteroids:
reduced the odds of mortality
reduced the need for mechanical ventilation and
did not increase the chances of serious adverse events or superinfection.
All of this is good news when treating a virus like Sars-CoV-2 that tends to set off a cytokine storm.
However, a corticosteroid suppression of the immune response to infection or injury is not always a desired effect. For example, the use of systemic corticosteroids in hospitals can also leave a patient susceptible to impaired wound healing and secondary infections as a result of immunosuppression.
Since corticosteroids are so effective at shutting down the immune response, it is thought that if given too early in the course of Sars-CoV-2 infection, they may suppress immune activation and reduce viral clearance, paradoxically leading to more severe Covid-19. Indeed, when the RECOVERY trial first demonstrated the positive effect of Dexamethasone treatment in Covid-19, there was a caveat: the benefit was only observed after more than 7 days since symptom onset, in patients receiving supplemental oxygen or mechanical ventilation. There was no evidence that it provided any benefit among patients who were not receiving respiratory support at randomization and the results were consistent with possible harm in this subgroup. Furthermore, another study observed that treatment with Dexamethasone was also associated with a longer viral clearance time, supporting the concept that the treatment needs to be patient appropriate – the right time and the right patient.
Taking this into consideration, most governmental bodies along with the World Health Organisation recommend the use of systemic corticosteroids only in people with severe Covid-19 who:
need supplemental oxygen to meet their prescribed oxygen saturation levels or
have a level of hypoxia (whole or part of the body deprived of adequate oxygen supply at the tissue level) needing supplemental oxygen but who are unable to have or tolerate it.
Inhaled Corticosteroids in Covid-19
Inhaled corticosteroids (eg. Budesonide) are frequently used in the treatment of Asthma and Chronic Obstructive Pulmonary Disease (COPD). Inhalation is a preferred route because it maximises the delivery of drug to the target tissue while simultaneously minimising the systemic effects, making them safer for longer term use.
Early on it the pandemic, epidemiological data showed that patients with COPD and Asthma had a lower incidence of Covid-19 infection, which led to speculation that inhaled corticosteroids could have some benefit. The large platform trial, PRINCIPLE, showed that using inhaled corticosteroids early in Covid-19, in patients aged 65 years and older and those aged 50 years and older with more than one health condition, shortened the time to first self-reported recovery by around 3 days. Another study (STOIC) demonstrated that early administration of inhaled Budesonide for a short duration reduced the likelihood of needing urgent medical care and reduced time to recovery after early Covid-19, irrespective of age or existing health conditions. However, this effect was not observed in a trial using a different inhaled corticosteroid, Ciclesonide, demonstrating a need for more thorough evaluation of the role of inhaled corticosteroids in the treatment of Covid-19. Studies are currently ongoing to assess the place these drugs may have in treatment protocol.
So, while corticosteroids can play a beneficial role in treating severe Covid-19, the course of therapy is not so straightforward, with the potential for serious side effects when not used appropriately. It is imperative to leave the decision of when and how to take corticosteroids to treat Covid-19 up to the professionals in possession of the most recent data; the clinicians. It’s not just about the right drug, but the right drug in the right patient at the right time.