Low-dose corticosteroids extremely effective against severe COVID-19

Low-dose corticosteroids significantly reduce mortality for the people most severely ill with COVID-19. This is the conclusion of a major international meta-analysis. The research, which supports the results of several smaller clinical trials, found that treating people with COVID-19 in intensive care in Denmark with low-dose corticosteroids reduced mortality from 33% to 25% in Denmark.

“The outcome of the meta-analysis makes us much more certain that treating the most severely ill people with COVID-19 with corticosteroids is effective. We almost never find such great effectiveness, at least not among people who are this ill,” says Anders Perner, Professor, University of Copenhagen and Staff Specialist, Department of Intensive Care, Rigshospitalet, who explains that the results, which also document the source of the data, were recently published in the Journal of the American Medical Association.

The research showing that corticosteroids are an effective and safe treatment with few side effects was based on data from 1703 critically ill people with COVID-19 who participated in one of seven clinical trials in 12 countries that measured the effectiveness of short-term low-dose treatment with corticosteroids, with the primary endpoint being all-cause mortality after 28 days.

“The analysis confirms the quality of the treatment by showing a class effect: the same great effectiveness regardless of the type of corticosteroid. Since the result was achieved in many countries, we can conclude that the treatment works regardless of the type of healthcare system,” says Anders Perner.

Corticosteroids already standard practice

Although the evidence of excellent effectiveness of corticosteroids has just been presented, many intensive care units have already introduced this treatment for the most severely ill people with COVID-19 based on a trial in 176 hospitals in the United Kingdom that investigated the effectiveness of the corticosteroid dexamethasone for people with severe COVID-19 that markedly improved survival.

The effectiveness was so noticeable that other research groups immediately stopped similar trials so that the patients who had been given placebo could start treatment with corticosteroids.

“To confirm the results of the trial in the United Kingdom, WHO decided to collect data from the many ongoing and stopped clinical trials and meta-analyse them, and the results have now been published,” says Anders Perner.

The reason why the many research groups stumbled on the idea that corticosteroids could be useful against COVID-19 is that they have proved to be effective in treating similar groups of patients, such as those with bacterial pneumonia or sepsis. An overactive immune system can cause severe COVID-19, and corticosteroids can suppress this excessive activity.

“Since one longstanding hypothesis is that an excessively aggressive immune system triggers severe COVID-19, it is reasonable to think that corticosteroids can benefit these people," says Anders Perner, who nevertheless indicates that researchers were initially concerned about pursuing this strategy, since there is no effective antiviral agent for treating COVID-19 and the patient therefore depends on the immune system being able to overcome the virus.

“There has been concern about whether doctors risk giving COVID-19 free rein if they suppress the immune system too much. This is why all research groups so far have been cautious and given low-dose corticosteroids,” he says, noting, however, that the analysis still reveals the biology of the disease.

“The results indicate that an overreactive immune system triggers severe COVID-19. So our action is a reversed way of understanding biology – we have a well-known drug that reduces inflammation," says Anders Perner, who describes how it works.

“When the immune cells encounter a virus, they view it as an enemy and analyse its genes to tailor the defence. The corticosteroids suppress the reaction the body mobilizes,” he adds.

Deadly viruses are rare

Anders Perner does not know why the immune system overreacts among many people. One explanation, however, could be that humans have encountered very few deadly viruses throughout history.

“Evolution is apparently driven by the people who have been optimally able to survive infections. Our defence against them is imprinted in our current genes. There are indications that we have primarily encountered bacterial infections and are therefore designed to survive these,” says Anders Perner, who speculates that there may have been too few deadly viruses to enable our immune system to fine-tune its viral defences.

Regardless of the explanation, the new meta-analysis leaves no doubt that low-dose corticosteroids are effective against severe COVID-19, which has given Anders Perner and his colleagues plenty of motivation to investigate whether corticosteroids at higher doses similar to those given to other groups of patients can be even more effective.

“We are using the rest of the grant from the Novo Nordisk Foundation to continue testing whether a higher dose is more effective. We were very cautious with low-dose dexamethasone of only 6 mg per day and are increasing the dose to 12 mg daily, which is closer to what we give to other people with severe lung damage,” says Anders Perner.

Many infectious disease specialists in hospitals throughout Denmark contributed to the meta-analysis. Lars Østergaard, Professor and Chief Physician, Department of Infectious Diseases; Aarhus University Hospital was not involved but praises the meta-analysis.

“The scientific article is excellent, the analysis is good, the results are important – and it is also great to see that the research group has managed to gather results from many trials so that the effectiveness of this medicine can be more quickly assessed,” says Lars Østergaard.

Lars Østergaard noted that the analysis shows unprecedented effectiveness of a drug that has been around for many years.

“I commend Anders Perner for his fantastic efforts in this area. Although the research group in the United Kingdom produced the first evidence of effectiveness, Anders Perner and his colleagues have insisted that corticosteroids be tested properly and their effectiveness investigated in a meta-analysis. It is great that we now have such solid evidence,” says Lars Østergaard.

“Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis” has recently been published in the Journal of the American Medical Association. In 2019, the Novo Nordisk Foundation awarded a Distinguished Investigator grant under its Research Leader Programme to Anders Perner for the project IMPROVE-ICU – Improving Intensive Care through Clinical Trials.