This week, the University of Oxford (United Kingdom) assured in a press release that dexamethasone reduces the risk of death in COVID-19 patients with respiratory complications. Although no study has yet been published, the announcement raised expectations for being part of the RECOVERY trial, whose objective is to evaluate the efficacy of different drugs against the coronavirus.
Dexamethasone belongs to the family of corticosteroids (or corticosteroids), which have anti-inflammatory, immunosuppressive, and antiallergic properties. These drugs are essential in the management of pathologies such as asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress, bronchopulmonary, nasal, skin and eye allergies. They are also used for anaphylactic shock, rheumatoid arthritis, multiple sclerosis, brain edema, and even reduce the side effects of chemotherapy, among other disorders.
The history of corticosteroids dates back to the year 1843, when the English physician Thomas Addison first described some cases of adrenal insufficiency in patients who presented “a general state of languor and weakness, weakness in the action of the heart, irritability in the stomach and a peculiar change in the skin ”. These inevitably passed away.
Later, in 1935, Edward Calvin Kendall and his collaborators at the Mayo Clinic (USA) isolated six unknown substances from ox adrenal glands. One of them was called “compound E”: in order not to confuse it with vitamin E, they changed its name to “cortisone”. This was the first naturally occurring steroid.
The discovery earned them the Nobel Prize in Physiology or Medicine in 1950. During the following years, other synthetic compounds, derived from cortisone, were obtained through changes in their chemical structure. Thus, its pharmacokinetic properties and, above all, its potency were improved.
What properties does dexamethasone provide?
One of these synthetic corticosteroids is dexamethasone. It has great potency, but without many of the adverse effects of natural corticosteroids like cortisone. It is very fat-soluble, which increases its absorption in the digestive tract and its penetration into the tissues, which improves its therapeutic efficacy. For all this, it was a novelty at the time.
Dexamethasone acts as a powerful anti-inflammatory and immunosuppressant: it decreases or eliminates the response of tissues to inflammation. However, although it reduces the symptoms associated with this process, it does not treat the cause that generates it.
In other words, this drug prevents the accumulation of inflammatory cells such as macrophages and leukocytes, phagocytosis, the release of lysosomal enzymes and inflammation mediators. The time of action is prolonged and its effect is 7.5 times greater than that of other corticosteroids such as prednisone and prednisolone, and 30 times greater than that of hydrocortisone.
COVID-19: the perfect storm
Inflammation is a mechanism that is triggered by a threat, infectious or not, and whose purpose is to maintain the homeostasis of our body. However, this response needs to be precisely regulated, both in intensity and duration, to be beneficial.
Otherwise, the “cytokine release syndrome” may arise. This “cytokine storm” is caused by an acute systemic inflammatory response, mediated by natural pro-inflammatory substances that our body manufactures; cytokines. It can be triggered by a wide variety of factors, such as infections and reactions to some medications.
In patients affected by COVID-19, when the response of the immune system is not able to effectively control the coronavirus, as it can happen in older people, the virus spreads more aggressively . This causes lung tissue damage, which activates macrophages and granulocytes and leads to the massive release of pro-inflammatory cytokines.
This entire inflammatory process can become complicated, leading to the “cytokine storm” frequently seen in severely COVID-19 patients. Neutrophils also increase and the number of total lymphocytes is reduced. Other inflammatory markers have also been detected in the blood at elevated levels in COVID-19 patients.
Why the corticosteroids?
Given their anti-inflammatory power, corticosteroids are widely used for the treatment of COVID-19 in its most serious stages. But do not forget that they suppress the functioning of the immune system, so they cannot be used in the initial stages of the disease: they are only useful in the inflammatory stage.
Thus, desamethaxone is used in these patients to stop part of the damage produced when the immune system is over-activated in this cytokine storm, while the body tries to fight against the coronavirus.
The use of corticosteroids in positive COVID-19 patients has already been considered in protocols in different countries, including Spain, especially in seriously ill adult patients admitted to the ICU. However, a dose or a specific therapeutic regimen has not yet been standardized . It is routinely used in low doses and for short periods of time, in order to minimize the risk of adverse effects.
Although the scientific evidence is scarce, the first data provided by the University of Oxford is very encouraging. They seem to confirm that dexamethasone, at a dose of 6 mg once a day for 10 days, reduces mortality in a third of patients who required artificial ventilation and in a fifth of patients who received oxygen.
However, no benefits have been seen among those patients who did not require ventilation. Based on these results, dexamethasone could prevent one death in eight treated patients requiring ventilation, and one death in 25 among those receiving oxygen.
Although this is preliminary data, the researchers are working on obtaining the definitive data from this trial in the shortest possible time.
Spain also investigates corticosteroids
The data provided, although provisional and unpublished, are very promising, as recently reported by officials from the World Health Organization. They seem to confirm a notable reduction in mortality and complications associated with infection.
Also in Spain, the use of corticosteroids is being investigated in clinical trials already authorized and in the recruitment phase of patients in advanced stages.
Dexamethasone may become the standard of care in this specific group of COVID-19 patients as it is also very inexpensive, fully available, and can be used immediately to save lives around the world.
But do not confuse the fact that this drug may show promise for individual patients with its widespread use in all of them, or for treating or preventing this disease. The use of corticosteroids without medical supervision is extremely dangerous, due to the development of serious adverse effects, such as immunosuppression and acute adrenal insufficiency due to the abrupt withdrawal of treatment.
Francisco López-Muñoz, Associate Professor of Pharmacology and Vice-Rector for Research and Science, Camilo José Cela University and Jose Antonio Guerra Guirao, Professor of Pharmacology and Toxicology. Pharmacy faculty. Complutense University of Madrid., Complutense University of Madrid
This article was originally published on The Conversation. Read the original.
