Dexamethasone for severe patients

New Covid-19 Drug Saves Seriously Ill and Harms Others

Alexander Berezin, Naked Science

Dexamethasone, a popular steroid, proved to be the first known effective means of reducing the mortality of severe coronavirus patients. The reason, apparently, was his ability to suppress the work of the immune system. The researchers who discovered the effect are confident that if the drug had been used since the beginning of the epidemic, it would have saved many lives. However, given the ongoing epidemic in many countries, including Russia, the drug can still play a huge role in the treatment of people.

The coronavirus pandemic has killed more than 440 thousand people, and, according to a number of indirect signs, the real figure may be significantly higher. In most cases, a serious patient does not survive even with artificial lung ventilation.

Attempts to reduce the severity of the problem with the help of some drugs with antiviral activity have shown mixed results. Although a number of studies have pointed to the effectiveness of remdesivir or hydroxychloroquine, others have talked about their uselessness or even harm.

However, at least one revealing study with a detailed check turned out to be based on fake data – from a commercial firm that traded statistics on the epidemic, "saving" on the actual collection of such statistics.

A new candidate: a steroid hormone that inhibits the immune system, However, now during the RECOVERY Trial (Randomized Evaluation of COVid-19 thERapY) clinical trials conducted in the UK, a different result has been achieved for the first time: a relatively large sample of patients has been able to reliably show that the survival rate of coronavirus victims in the case of one long-known drug is really growing. We are talking about dexamethosone. It is a synthetic steroid hormone that has a versatile effect on the human body.

The main group of 2104 patients participated in the study of the effect of this drug on humans: they were given six milligrams of dexamethasone per day for ten days. In addition, another 4321 patients received the usual treatment, without this drug.

As a result, mortality among patients with severe form of the disease who took dexamethasone decreased markedly. Those of the patients who took the medicine who received oxygen noninvasino (a tube near the face) died 20% less often than the same people who did not receive steroid hormone. Patients on a ventilator (a more severe form of the disease) died 35% less often than similar patients not taking dexamethasone.

It should be noted that patients who had the disease in a milder form – hospitalized, able to breathe normally without ventilators and oxygen – the drug may even have harmed. Mortality among them was 22% higher than among those who also did not need oxygen and a ventilator, but did not receive this steroid hormone. However, the statistical reliability here is somewhat less than for positive results: the number of deaths among lung patients is lower, and it is more difficult to collect statistics of the required volume among them for this reason.

The press release of the group conducting the RECOVERY Trial (Low-cost dexamethasone reduces death by up to one third in hospitalized patients with severe respiratory complications of COVID-19) adds that "giving such a drug to eight patients on a ventilator can prevent the death of one of them, and the same is true in the case of admission medications by 25 patients who are given oxygen." But this is a conservative, minimal assessment: most likely, the actual effectiveness of the drug is higher.

The researchers limited themselves to such a verbal assessment because dexamethasone showed different effects on mortality for different groups of patients. For example, for patients on a ventilator, the mortality reduction ranged from 52% for some groups to 12% for others. Saving one out of eight is the lowest bar for the effectiveness of the drug. Since the scientific work on the results of clinical trials has not yet been published, it is not clear what was the difference between these subgroups of patients.

The study had both a number of strengths and individual weaknesses. The patients did not know whether they were receiving a new drug, that is, the probability of a placebo effect was extremely small. The sample of both groups – both the main and the control – was quite large, that is, the results are reliable.

Weaknesses of the study include the fact that some patients received dexamethasone in tablets, and another in injections, while, based on the text of the press release, at the same dose (six milligrams per day).

However, the absorbability of active substances from tablets is often far from 100%, that is, those who received exactly the tablets could de facto take a smaller dose of dexamethasone. In this regard, the effect of the drug for different patients may vary significantly.

The second weakness of the work – although not from a scientific point of view – is that it could cause the death of some of the patients who were given dexamethasone. Among those of them who could breathe on their own, without ventilators and oxygen, mortality when taking the drug increased by 22%.

During clinical trials, 41% of all patients who were on a ventilator died, 25% received only oxygen and 13% of those who could breathe themselves. Thus, a 22% increase in mortality in the last of these groups in any case killed fewer people than it saved as a result of a decrease in mortality in the first and second groups.

Why did the drug increase mortality among patients with a milder form of Covid-19?

The question arises: why does the same steroid hormone threaten death to a patient with a milder form of coronavirus infection, but helps severe patients?

The experts who conducted the tests have not yet given an answer to it: the corresponding work is only being prepared for publication. Nevertheless, biologically it is quite understandable. Dexamethasone has (like some other steroid hormones) a depressing effect on the immune system. In particular, it inhibits the formation of T-lymphocytes, as well as the migration of immune B-cells and the interaction of T- and B-lymphocytes. In addition, it significantly inhibits the release of cytokines from lymphocytes, as well as reduces the formation of antibodies.

Cytokines are small molecules that play the role of information transmitters in the body. They are secreted by cells of the immune system, and when cytokines touch the surface of ordinary cells, they activate a number of reactions in them.

If there are too many cells of the immune system in the focus of coronavirus infection (which is typical for severe patients), then cytokines falling on the surface of a neighboring immune cell make it produce its own cytokines more strongly. As a result, the concentration of these molecules increases so much that a cytokine storm occurs.

The concentration of cytokines in this case becomes so high that ordinary cells that are not related to immunity begin to participate massively in the protective (normal) process of inflammation. It becomes systemic and so strong that a person's internal organs may begin to fail and he will die, even though the infection itself does not threaten his life.

In patients at a young age, the immune system copes with the coronavirus quite well, so it rarely comes to a cytokine storm. Therefore, the overwhelming release of cytokines dexamethasone is unlikely to help such patients. At the same time, by depressing the immune system, it reduces its chances of effectively fighting infection.

In severe coronavirus patients, immunity in Covid-19, on the contrary, is already working excessively hard – due to the fact that it "processes", and a cytokine storm is playing out. In such conditions, the weakening of the activity of immunity is more likely to benefit patients: they do not risk getting all the disadvantages of a cytokine storm, often deadly for them.

It follows from this that it is unwise to stock up on a new drug in advance. Most people get over Covid-19 in a relatively mild form, that is, dexamethasone can seriously harm them, significantly increasing the risk of death (oddly enough, it is possible even without serious breathing problems).

Those who get on a ventilator, in any case, will receive a remedy as prescribed by a doctor. Moreover, dexamethasone is a cheap and massive generic, the shortage of which is extremely doubtful.

What could be the global effect of dexamethasone in a pandemic

Despite the fact that the coronavirus is gradually disappearing from the focus of public attention, the scale of the epidemic itself is still huge. In the USA, up to the last few days, 20 thousand new cases were registered per day. In Russia, outside Moscow, the number of new coronavirus patients fluctuates about seven thousand per day – that is, not much below the peak, which has so far been overcome only in the capital.

The coronavirus has shown all the signs of seasonality: it rages the most where the temperature is below the local norm. For example, in Brazil, where it is winter. Therefore, it is obvious that in the fall of 2020 and in the winter of 2020-2021, it can give a very strong second wave – like the "Spaniard" once. To date, 0.44 million people have died from the epidemic, and by autumn this number will noticeably exceed half a million. With the second wave of deaths, there could be many more than a million.

So dexamethasone can save many lives. British researchers believe that if this remedy had been used in England since the beginning of the epidemic, it could have allowed at least five thousand people to survive – about one in nine who died from the virus in this country.

Thus, during the current sluggish epidemic process, as well as during the autumn second wave, dexamethasone can potentially save many tens of thousands of lives.

The UN World Health Organization has called the treatment of Covid-19 with dexamethasone a "scientific breakthrough." It is particularly noted that this is the first known drug that reduces the mortality of coronavirus patients connected to a ventilator by up to 30% or more.

Tedros Ghebreyesus, Director-General of WHO, stated in this regard: "This is great news and I congratulate the UK government, Oxford University and the many hospitals and their patients who have contributed to this life-saving scientific breakthrough."

The new clinical trial was also responded to in Russia. Sergey Avdeev, Head of the Department of Pulmonology at Sechenov University and Chief Pulmonologist of the Ministry of Health, said that dexamethasone is used to treat covid patients in our country, moreover, it is included in the guidelines for the treatment and prevention of COVID-19. But, alas, it cannot be called a panacea, the specialist added.

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