What is Dexamethasone? Is it really the wonder cure for Covid-19?

A drug known for decades is being hailed as a wonder cure for Covid-19 after the study group conducting a clinical trial in United Kingdom said Dexamethasone “reduces death by up to one third in hospitalised patients with severe respiratory complications”.

The hype around Dexamethasone reminds us of the time when Hydroxychloroquine was announced as a “cure” for Covid-19.

HCQ had quite a ride over the past two months. It started with in-vitro or laboratory data showing antiviral action and a flawed observational study showing 100% patient recovery. Major well designed trials have subsequently found HCQ had no benefit in the treatment of severely ill Covid-19 patients, or for post-exposure prophylaxis when a drug is taken after exposure to a virus. The results are still awaited on its utility as a pre-exposure drug and for mild illness.

This week, the United States Food and Drugs Administration announced the decision to end the emergency use authorisation for the drug on June 15 and the World Health Organisation decided to drop the hydroxychloroquine arm in the multinational Solidarity trial on June 17.

Ironically, just as the hype around HCQ dies out, Dexamethasone is making headlines devoid of vital context.

Have scientists finally discovered a wonder drug for Covid-19? No.

Is Dexamethasone the cure for Covid-19? No.

Can Dexamethasone be used for all Covid-19 patients? No.

Can I use Dexamethasone to prevent Covid-19? Absolutely, not!

So, it is like Hydroxychloroquine? Not really.

Is it a cheap alternative to Remdesivir? No.

What is Dexamethasone?

It is a synthetic hormone.

Natural corticosteroids (commonly called as steroids) are hormones secreted by the adrenal glands situated right above the kidneys. They are required for sustaining many vital functions of the body. Babies born without adrenal glands don’t survive beyond half an hour without hormone supplementation.

Dexamethasone is a long acting potent synthetic steroid available in oral (tablet), topical (ointment) and intravenous (injection) forms. It has been around for decades. Some of the indications to use it include cancer (tumor compressing spine, Multiple myeloma), tuberculosis (some specific forms), mountain sickness (to decrease brain swelling) and severe asthma. It is also a potent drug for highly vomiting inducing chemotherapy.

Many studies have been done on its role in acute respiratory distress syndrome with mixed results. ARDS is a type of severe lung injury which is treated primarily with mechanical ventilation. It is a complication of many illnesses like toxins, drowning, bacterial and viral pneumonias (including Covid-19).

What is RECOVERY Trial?

RECOVERY (Randomised Evaluation of Covid-19 Therapy) is the largest randomised clinical trial underway right now in the UK to evaluate treatment possibilities for Covid-19. As many as 11,500 patients have enrolled in the trial from 175 National Health Service hospitals.

It has six arms, testing six different treatments in patients. The detailed 35-page trial protocol is publicly available. It is funded by public health organisations and the Bill and Melinda Gates foundation. A massive trial like this requires money, political commitment and large scale co-ordination.

What did the trial find regarding dexamethasone?

Six mg of Dexamethasone per day was administered to 2,104 patients for 10 days, while 4,321 patients were provided standard care without Dexamethasone. The death rate at 28 days was compared between these two groups.

Preliminary results: Dexamethasone reduced deaths by one-third in ventilated patients and by one fifth in other patients receiving oxygen only. One death would be prevented by treating around eight patients on ventilator, while among patients on oxygen support, one death would be prevented by treating 25 patients.

There was no benefit among those patients who did not require respiratory support. The final published data is awaited for the complete picture.

The Dexamethasone arm was stopped early because of overwhelming benefit – based on the rule called the Haybittle-Peto boundary. The Hydroxychloroquine arm was stopped because of no clinical benefit.

How does Dexamethasone work in Covid-19?

Dexamethasone is not an anti-cancer drug but it is used for certain tumors. It is not an anti-tuberculosis drug but it is used in certain forms of TB. Similarly, it is not an antiviral drug. It does not ‘kill’ or prevent the novel coronavirus. The action is similar for all these diseases: it is anti-inflammatory.

Covid-19 like other viral illnesses initially has a high viral load stage when the amount of virus in the body is high and immune response is low. Some are able to clear it with a heightened immune response. Others go into the next phase of disarrayed immune response when the body damages its own normal organs and tissue especially the lung. This is when most of the severe symptoms start and things go downhill. Dexamethasone helps tone down this “immune response gone bad stage”. It is at best an adjunct for a proper antiviral drug against Covid-19.

Why was Dexamethasone not used from day 1 globally?

The mechanism of steroids like Dexamethasone has been known for decades. Why wasn’t it tried from day 1 for Covid-19?

A possible reason is that clinical evidence of the drug’s use to treat viral illnesses closely related to the novel coronavirus (MERS, SARS, Influenza and Respiratory syncytial virus) showed no clinical benefit and some showed even harm.

These were based on observational studies (lower down the evidence pyramid) with inherent biases.

The RECOVERY trial is a large randomised clinical trial (higher up the evidence pyramid) with several strengths. The new positive evidence trumps the older negative ones.

The good, the bad and the ugly

First, the good part of the news on Dexamethasone: It is a cheap, mass produced generic drug, with side effects known to doctors who have decades of experience using it. It is a useful addition to the armamentarium against Covid-19.

The bad: unrestricted sales and hoarding can make the drug non-available for the patients already depending on it.

The ugly: various known side effects of steroids include increased vulnerability to fungal infections, tuberculosis, muscle weakness, psychiatric disturbances, increased blood sugar, brittle bones, fractures – it is a lengthy list. Needless to say, self medication is dangerous. Immune response is critical in fighting the infection in the initial stage. Early dexamethasone use can be harmful and even life threatening.

The use of steroids in Covid-19 before RECOVERY trial announcement was restricted to proven indications like asthma, chronic obstructive pulmonary disease, and shock (critically ill because of low blood pressure). It was in accordance with WHO guidance in March 2020 and some major society guidelines (ATS Covid-19 Guidance and SCCM Covid-19 guidance). Read more here.

Will Covid-19 mortality in India come down after the use of Dexamethasone?

It is doubtful, because we are already using steroids for the moderate to severely ill Covid-19 patients. The Indian health ministry recommended use of Methylprednisolone for Covid-19 treatment from the first revised guidelines published on March 31.

The latest Indian guidelines released on June 13 also recommends Methylprednisolone for three days in moderate illness and five-seven days for severe illness.

Methylprednisolone is superior to Dexamethasone in its anti-inflammatory activity, is faster acting but has a shorter duration of action.

Methylprednisolone is less potent per dose than Dexamethasone. Sixty mg (1mg/kg/day) of methylprednisolone is equivalent to 11 mg of dexamethasone (6mg was used in the trial).

Will a lower dose of dexamethasone for a longer duration (10 days vs three-five days) make a difference? Only a head-on trial can confirm.

Is the lower number of deaths in India compared to the rest of the world because of early guidelines to use steroids?

Will there be more studies on Dexamethasone or other steroids?

A new study comparing patients with and without Dexamethasone or other steroids is unlikely because it is unethical to deny patients a treatment that has mortality benefit. However, there can be studies comparing Dexamethasone versus Dexamethasone in combination with a new drug. The story would change if the RECOVERY trial when published has major flaws.

The results of the other four arms of the RECOVERY trial are eagerly awaited. These include the use of Lopinavir Ritonavir, Azithromycin, Convalescent Plasma and Tocilizumab. These drugs have already been tried in India. Convalescent Plasma and Tocilizumab are part of the latest Indian guidelines.

Dr Amith Viswanath’s Twitter handle is @avstmd.

This article was supported by a grant from the Thakur Family Foundation. Thakur Family Foundation has not exercised any editorial control over the contents of this article.