The seven big questions about the coronavirus that we have not yet been able to answer (and are essential for the future)

Six months have passed since the city of Wuhan closed its live animal market and raised the alarm that an unknown disease was beginning to spread. Since then, more than 7 million infected and 400,000 deceased place the COVID-19 pandemic as the greatest health crisis of the 21st century. A crisis that is far from being near the end.

So perhaps the time to recap and realize not only what we have learned about the coronavirus, but especially what we have yet to learn. These are the big questions about COVID19 that, six months later, still remain to be answered.

Where and when did the pandemic start?

Kobu Agency

A few days ago, a team of researchers from Harvard University published a work in which, crossing search data for the terms 'cough' and 'diarrhea' in the Chinese search engine Baidu and satellite images of the parking lots of Wuhan hospitals , They concluded that the virus could have had its first staging in August 2018. Needless to say, this is a magnificent example of those studies with which you have to be very careful. A priori, if only for its ability to get out of control, it seems unlikely that the virus started six months earlier than we thought.

Today, the most widely supported theory is that "patient zero", the first person to contract the virus, should have been infected late last fall. If we look at the first 41 confirmed cases, we can verify that the first hospitalized patient began to have symptoms on December 1 and entered the clinic on December 16. This places the start of that first outbreak on the Wuhan market at the latest in mid-November. Everything else is unfortunately speculative.

However, this gives us a good sample of everything we have left to know about the origin of the virus. The best-known part of this search was surely the theory that placed the pangolin as an "intermediate step" by which the virus passed from bats (its original host) to humans. The pangolin was pardoned, but the issue did not end there. Geneticists have been searching for clues in the genetic material of the virus for months to reconstruct the path they followed until they reached the human being (a path that seems to exclude any conspiracy theory).

Be that as it may, we would be wrong if we thought that the interest in answering questions about the exact origin of the pandemic is merely academic or, worse, the result of journalistic "curiosity". A few days ago, researchers from the Global Viroma Project, dedicated to studying the more than half a million viruses with the potential to jump into humans that we estimate are still unidentified, published a study pending publication in Nature Communications in which they identified at least 630 new genetic sequences of coronaviruses in bats from southern China. They have not yet analyzed the complete genome of each virus and, therefore, we do not know if they correspond to 630 new coronavirus species (or some are part of the same virus).

But, with those numbers in mind, the importance of the question is quickly understood. Knowing how the jump to the human species has been and what were its first steps can help us improve our zoonosis control procedures, can make us reflect on the immense task of beginning to map the natural world to have identified all possible viruses and Above all, it can confront us with the true dimension of the threats that await us in an increasingly globalized and interdependent world.

What is the fatality of the virus?

This is a central question that has researchers engaged in controversy from the start. Something that is still curious because, also from the beginning, we know that this number cannot be estimated with certainty until the end of the pandemic. The reason is that, to estimate lethality, we have to know both the number of deaths and the number of infected. Today, and until many months after we consider the pandemic worldwide to be over, we will not have reliable data on either.

However, as I said, that has not prevented numerous experts (some of the world's greatest medical experts) from trying to estimate it. It is something that makes sense because the decisions that the countries have to take depend largely on the danger of the virus in question. Without knowing certain basic epidemiological references (in the basic ones: how much does it spread and how virulent is it), it is very difficult for a country to decide to order things like the confinement of all its citizens.

The clearest example of this controversy occurred on March 17, 2020 when Spain had been in quarantine for a few days and Italy was unraveling in the middle of the pandemic. That day, John Ioannidis, one of the popes of current science, he said in Statnews, that the fatality of COVID was very similar to that of seasonal flu and that paralyzing the world by it was "as if an elephant attacked by a domestic cat accidentally jumps off a cliff and kills itself for trying to avoid it. ”A position that has ended up ending its prestige.

Although the controversy among those who thought it was "just a strong flu" and those who warned that "China would not close a city of 11 million people just because of the flu" became very popular, the truth is that in retrospect it seems inexplicable. . That is, we still do not know what the lethality of the coronavirus is, but today the most reasonable figure is over 0.66% (much higher than the values ​​of seasonal influenza).

What is the exact dynamics of diffusion?

Here we have another mystery. For months, discussions about the routes of transmission of the virus (specifically whether it was spread "via aerosol") starred in the academic debate. Today, the general consensus is that, although the aerosol route is theoretically possible, it is not usual. And the greatest risk comes from transmission by respiratory flow droplets.

However, in recent weeks, the data has led us to talk a lot about "super dispersers". Researchers have found that, unlike other infectious diseases, 10% of those infected cause 80% of transmissions. In other words, with the coronavirus, the vast majority of those infected do not transmit the virus and only a few are contagious (to a large number of people).

The problem is that we have not been able to find characteristics (genetic, immunological or otherwise) that these "super dispersers" share and that are behind the infections. Yes, there are data on the circumstances of these massive infections and everything seems to indicate that they occur "when there are infected people in closed spaces and in continuous contact with other people." This gives us certain guidelines because, according to the most extensive studies, "most of the clusters originated in gyms, pubs, live music venues, karaoke rooms and similar establishments where people gather, eat and drink, chat, they sing, exercise or dance, rubbing their shoulders for relatively long periods of time "; but it is not enough.

In this same sense, we also do not yet know the minimum number of viral particles that are needed to infect a person. If we follow what we have learned about the 2002 SARS, we would be tempted to say that it would take less than a thousand, but there is not yet enough information available to know whether that idea is based or not. And this is important because it is what prevents scientists from evaluating in detail the real danger of touching surfaces or the exact effectiveness of different types of masks.

Why does it affect some more than others?

Marcelo Leal

If there is an answer that clinical practice would need to respond to urgently, it is this: why while some people experience mild and ephemeral symptoms, a minority of patients develop complications that eventually lead to death. There are factors that we already knew from almost the beginning, such as age, and much has been said about the already famous 'cytokine storms', but this question goes one step further and confronts us with the same mechanisms of action of the SARS-CoV -two. Mechanisms that we begin to understand, but that we still do not fully understand.

Ignacio López-Goñi reviewed a few days ago some of the theories that have been put forward to resolve the issue. As mentioned by this professor at the Public University of Navarra, there are indications (not yet confirmed experimentally) that the interaction between the protein S of the virus envelope and the ACE2 receptor on the surface of cells could be behind it.

In summary, "the interaction of SARSCov2 with cells leads to a decrease in the function of ACE2. This can manifest itself as an increase in the concentration of angiotensin II, especially at the endothelial level. This, in turn, generates vasoconstriction, a increased inflammation and increased blood pressure. " In other words, SARSCov2 infection is not just pneumonia, as we sometimes tend to think, but it can manifest itself as "an acute respiratory syndrome, kidney, liver, cardiac, and even brain damage."

That is why "people with diseases such as heart disease, COPD, diabetes, chronic liver or kidney disease, hypertension, or the obese would be more susceptible" to the effects of the virus. As I say, these theories still need enormous confirmation work, but they give us clues as to what the sequels the virus may leave for survivors. Very varied sequelae that make the virus to be considered also as a disease of the circulatory system or even neuropsychological and still to be investigated.

What happen with the kids?

Geronimo Giqueaux

Something very striking during the first months of the pandemic is that, to the surprise of experts, the virus did not seem to affect children. Over time, we have discovered that this is not exactly the case. It is true that COVID19 manifests as an infection is very mild in these patients, but it causes some dermatological alterations. The same interaction of the virus with the ACE2 receptor that was exposed in the previous section could be behind these manifestations, but as it is still early to know.

In any case, that has not been the great unknown around children: the great debate has been whether they could be vectors of contagion and here, I am afraid, we also have bad news. Common sense indicated that if, as it seemed, children were contagious like adults, but had no symptoms, it would be very difficult to control the disease. It does not have to be this way, after all, the same infection does not mean that they infect the same, but it was a reasonable assumption.

For this reason, almost all countries in the world made the decision to close schools. An estimated 1.5 billion children stayed behind from going to school. It is a prudent measure, but also a measure that has prevented us from knowing what the real role of children was in the pandemic. Furthermore, countries that have had the opportunity to study it (because they did not cut classes) have not. Sweden, without going any further, has been widely criticized for this. Thus, many questions that include 'children' and 'coronavirus' remain to be answered.

How long does immunity last?

When the Ministry of Health announced the preliminary results of its seroprevalence study and stated that only 5% of the population had antibodies against SARS-CoV-2, the news fell like a jug of cold water in public opinion. Not surprisingly, the certainty that the epidemic had only reached a very small part of the population was less hopeless. However, even if the results had been better, we would have been sure that it was good news. And we do not know how immunity against the virus works.

As the Pan American Health Organization (PAHO) has been repeating for months, as it is "a new virus, and from which we are still learning more every day, at the moment we cannot say with complete certainty that a person who has been infected with the virus it cannot become infected again "; We do not yet have certainty, although we do have several reasons to believe it.

The first, the other coronaviruses. Our experience with human coranaviruses is that an immunity was generated that could last between three months and 15 years. The second is that preliminary animal studies seem to indicate that the virus does indeed generate immunity. However, it is not surprising that the body generates short-term immunity against different pathogens.

The question is whether that immunity will last over time and allow us to achieve herd immunity at some point. The scarcity of comprehensive and reliable studies on survivors (although we already have some) and, above all, the lack of time to observe them leave us in a very unstable and compromised situation in the face of the dreaded second wave.

Will there be a second wave?

The three waves of H1N1 in Thailand.

This is surely the million dollar question and the answer, again, is that we don't know. However, if we look at other similar situations, the answer cannot be other than "probably". As Andrés Mohorte explained, cases such as SARS, avian influenza or Spanish influenza have a similar structure.When the early outbreaks ended and the measures relaxed or the environmental conditions worsened, new outbreaks were caused (sometimes even more virulently).

In this case, as López-Goñi pointed out, "the appearance of new epidemic waves will depend on the virus itself, on its capacity for variation and adaptation to the new host, to the human being; on our immunity, on whether we are really immunized and protected against it and of our ability to transmit and control it. " Too many factors that, as we have seen, are almost completely unknown.

In short, the models speak of different scenarios. From a much more intense second wave in the winter of 2020 to several epidemic waves over a period of a couple of years going through small outbreaks with no clear pattern. Unfortunately or fortunately, this question will have a clear answer. And we will not take too long to know it.

Image | Fran Boloni

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