Just over a year and a half after the first cases of Covid-19 were discovered in China, an explosion of research has helped clear many of the mysteries surrounding the disease.
The picture that emerges from these studies is that of a complex disease that can affect a wide variety of organs and has the potential to cause serious effects in patients of all ages and physical conditions, with the elderly being much more likely to die and people with chronic health problems. Despite great advances in vaccine production, it has been more difficult to identify drugs that can effectively fight the infection or its effects.
The different types of coronaviruses that affect humans typically attack only or primarily the respiratory tract. This is where the Sars-CoV-2 virus, which causes Covid-19, differs from its relatives in the frequency and severity of symptoms it can cause outside of the lungs, explains Marisa Dolhnikoff, a professor at the Medical Faculty at USP.
One of the reasons for this systemic (ie widespread) effect is the receptor or chemical “lock” that the virus uses to enter human cells. It is a molecule that is designated by the abbreviation ACE-2 or ECA-2 (in English or Portuguese) and occurs in a wide variety of tissues and organs and is therefore exposed to the direct influence of the viral invader.
The USP researcher, who examined the lesions in the organs of patients who died of Covid-19, points out that the virus also usually infects endothelial cells, i.e. those that line the inside of blood vessels that spread Sars-CoV-2 through them.
The damage caused by the pathogen in such vessels can lead to circulatory disorders in several organs, and the virus is also able to trigger a systemic inflammatory reaction, also affecting the entire body. The lack of control over inflammatory processes, with the exaggerated production of molecules associated with this mechanism, is likely to be responsible for some of the most serious cases of Covid-19 (see infographic). So the patient’s death does not always occur from breathing difficulties caused by the infection, but sometimes from heart, kidney, and blood clotting problems as well.
With all of these effects associated with the virus’ use of ACE-2, it makes sense that people with cardiovascular disease (hypertension, heart disease), kidney disease, and diabetes are among the most at risk of complications from disease belong. These are problems in which the condition of blood vessels and the presence of inflammatory processes play an important role. The frequency of these symptoms also tends to be higher with age and with males, which could explain the higher incidence of severe forms of Covid-19 in older people and men.
Another risk factor identified in a survey published in April by Brazilian researchers appears to be the presence of neurodegenerative diseases such as Alzheimer’s disease. “Another important factor in the progression of Alzheimer’s disease is the malfunction of the blood vessels that supply the brain. Our hypothesis is that this dysfunction could be one of the mechanisms that increase the susceptibility of patients to Sars-CoV-2, ”explains Sergio Verjovski-Almeida, professor at the USP’s Chemical Institute and coordinator of the study.
Given the wide spread of the disease in the population, however, serious cases and deaths in children and adolescents cannot be ruled out. These patients may experience what is known as SIM-P (Pediatric Multisystem Inflammatory Syndrome) with symptoms such as high and persistent fever, red spots on the skin, diarrhea, vomiting, and even neurological problems. The virus can cause patients’ hearts to become inflamed, leading to heart failure.
“In an autopsy study on three children who died of SIM-P, we showed that Sars-CoV-2 infects several organs such as the lungs, heart, intestines and brain, which both through the action of the virus lead to changes in these tissues leads and aggravated by the inflammatory reaction, ”says Dolhnikoff. According to her, some adult patients had symptoms similar to those of pediatric syndrome.
Evidence is mounting that Sars-CoV-2 would be able to convert another antiviral defense of the organism into something that favors its spread. This is known as apoptosis, one of the forms of programmed cell death. For example, apoptosis can be triggered when a cell becomes infected with a virus, which would reduce the likelihood that the viral invader will kill neighboring cells.
However, a study published this week in the journal Science Advances offers indications that this process can also have benefits for coronaviruses. In the work coordinated by Kwok Yung-Yuen and Jasper Fuk-Woo Chan from the University of Hong Kong, the researchers analyzed the mechanisms of apoptosis in three coronaviruses that began to affect humans a few years ago: the Mers-CoV (very fatal, from camels), the Sars-CoV (originator of SARS, which killed thousands of people in the 2000s) and the person responsible for Covid-19.
It was already known that all three viruses are able to cause programmed cell death. But the new study, primarily using Mers-CoV in the lab, has identified the molecules in human cells that are affected by the presence of coronaviruses. They are essential genes in the mechanism of apoptosis, and blocking their activation reduced the damage caused by the three types of coronavirus to infected laboratory mice.
This suggests that the “suicide” of infected cells actually facilitates the spread of the virus. In addition, this may also indicate that minimizing apoptosis would be an interesting therapeutic approach. “We have shown that the activation of apoptosis is linked to replication [multiplicação] from the virus. Now we are investigating how apoptosis modulates this process, ”the study’s lead author, Hin Chu, also from the University of Hong Kong, told Folha.
Although indications like the one from the Chinese study have surfaced in several lines of research, it is a fact that very few have succeeded in producing viable therapies. The only drug that is highly recommended for the treatment of seriously ill Covid-19 patients today is the anti-inflammatory drug dexamethasone. It has been shown to reduce mortality by almost 40% in patients who are intubated or who require supplemental oxygen (use is not recommended in other patients with Covid-19).
Monoclonal antibodies are among the few promising therapeutic approaches. Roughly speaking, they are standardized mass defense molecules, the shape of which allows them to bind to certain regions of the virus and prevent it from working in the body.
This week, for example, the University of Oxford, UK, announced the completion of a clinical trial combining the two monoclonal antibodies casirivimab and imdevimab in nearly 10,000 patients hospitalized with Covid-19 in September 2020 and May 2021 Test data show that the combination was able to reduce the mortality of people whose organism was unable to produce its own antibodies against Sars-CoV-2 by a fifth.
“We saw that about a third of the patients did not have their own antibodies a day or two after admission,” explains Dr. Richard Haynes, one of the study coordinators. “They were people who were a little older and had more comorbidities [outros problemas de saúde] as the others. That is not to say that they could never produce antibodies themselves, but perhaps their immune response was less strong. ”According to Haynes, this proportion is likely to be expected in a population that has not yet been vaccinated against the disease on a large scale.
In this patient subgroup, there were 6 fewer deaths in each group of 100 treated patients than those who received conventional treatment. In people who had already developed their own antibodies, however, the effect of the drug was not significant. The results will be presented to a scientific journal for publication. These and other monoclonal antibodies have already received US approval for emergency use in patients.
Approaches that try to influence the way the virus works in infected cells have been less successful. In a way, this is expected, says Glaucius Oliva, a researcher at the USP’s Physics Institute in São Carlos and coordinator of the Center for Research and Innovation in Biodiversity and Pharmaceuticals. “We’ve only had two big hits with antivirals throughout history, in the case of AIDS and, more recently, hepatitis C and some other more modest hits, but it’s not easy to get there,” he says.
The difficulty lies, among other things, in the fact that the compact genetic makeup of the virus offers only a few points of attack for possible drug weapons. In any case, the successes against HIV bring an important lesson, says Oliva: It is important to try to attack more than one important molecular mechanism for the virus at the same time. This will reduce the chance that he will develop mutations that make him resistant to the antiviral drug.
Of these drugs, only remdesivir has been approved for use in the United States and other developed countries to date. Its effects are modest – in clinical studies, it has helped reduce patient stays by a few days.