CoVid-19, variations in people susceptibility and a promisorius emerging action.

Abstract

This article describes the independent evolution of the different human groups, the immunological diversity that this fact generated in each one of them and the variable susceptibility to unknown agents from other groups when long-distance travel appeared. Based on this background, explains the usefulness of "convalescent" plasma transfusion for the management of high-risk patients infected with COVID-19, reducing the number of cases that require intensive therapy or will succumb to the disease.

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Viruses have been around long before man appeared on earth. They are functional micro-structures rather than micro-organisms. They are not living beings, since the basic structure of life is considered to be the cell and viruses are something much more elemental.

For this reason viruses require getting in a cell in order to replicate. That is their reason to exist, multiplie, perpetuate themself as a basic computer program whose purpose is to create identical and functional copies of itself. Often, the use of the host cell as replication machinery ends with its malfunction and death. Massive cellular destruction will lead to the death of the host, and the extinction of the available hosts will eventually lead to the extinction of the virus.

Until just a few centuries ago, human beings lived at "islands", there was no the mobility that we know today and that led to human groups to develop separately from each other. Thus, the diverse human groups faced not only diverse macroscopic ecosystems but also microscopic ones.

Evolving separately through thousands of years, each one of these human groups faced different kinds of viruses that existed - and evolved or mutated - where they resided. We might think that with the time we developed immunoglobulins (antibodies) capable of defeating these invaders to avoid dying from the disease they could cause us, but according to Darwin's theory, the response may be simpler. We are the descendants of the people who had, by genetic lottery, the immunological tools necessary to survive and leave offspring with the same capacity; the rest died.

Thus, evolving separately through the centuries, facing different viruses, societies developed until mobility began to carry these infectious agents out of their endemic sites, through travelers, often causing severe sickness and death when reaching human groups that had never dealt with them in their evolutionary history. In America, history states that smallpox, brought in by European colonizers, may have wiped out up to 70% of the original populations. Again, as it was until the arrival of mass vaccination, the human beings who remained alive, who left offspring, were those who had their own immune tools to avoid succumbing to the disease.

Eventually with globalization, most viruses ceased to be exclusive from a region or a particular race or ethnic group, they became citizens of the world. For our fortune, already in the last century and a half, this dispersion of infectious agents coincided with the discovery of vaccination and the possibility of reaching it massively to people.

Today, worldwide, we are experiencing an unprecedented situation, which surely has occurred countless times regionallly since the beginning of humanity, where an infectious agent takes the lives of people who do not have the necessary immune tools to deal with it or have a fragile immune system that fails to eliminate the infectious agent at the proper speed.

We should remember earth is permanently exposed to cosmic radiation, human activities generate radiation (ionizing and non-ionizing), mutagenic chemical contamination and, if that were not enough, the replication itself; (viral, cellular, or even the human reproduction) can lead to "errors" known as mutations.

Some mutations can be harmless, they do not compromise the function and existence of the being that develops them (be it a virus, a bacterium or a human being), others can compromise the function or even the existence of the carrier, and some more can represent an evolutionary advantage that not only means that the carrier will exist successfully, but also will transfer the same characteristic to its decendents.

Viruses are no exception and without a doubt constantly, there are mutated viruses trying to make us (and other organisms, even viruses capable of infecting other viruses) their hosts. If the mutation does not represent an advantage to achieve their goal, they will simply disappear or lodge in another host in which they can proliferate. However, occasionally this mutation (accidental or induced in a laboratory as it has been suggested) is successful. This is the case of the COVID-19.

When a virus invades the human body, it can be identified by the immunoglobulins present in the blood, either existing innate in a particular person or have been developed by previous contact with the same agent. That is the first line of defense.

If the virus is not "captured," it will be able to get in the cell, which it aims to turn into a replication factory of its own. When invaded, the cell can issue a “help call”, that is, it express on its surface a protein that allows the cells of the immune system identify that cell infected in order to destroy it, encapsulate it, and often identify and decode the virus in order to generate specific immunoglubulins. Those memory circulating antibodies for that particular agent will allow to eliminate it the next time it enters the body. Unfortunately, there are viruses capable of inhibiting this help call and they can continue infecting other cells in the same way, until the cellular damage is irreversible, causing the death of the host.

I am going to present an unorthodox idea to illustrate the situation we are currently facing, which will also allow us to understand the possible causes of the variation in the morbidity and mortality of those who have contracted this infection according to their nationality.

We all know the famous “LEGO” toys (Image 1) and they could help a better understanding of what is happening at immunological level.

As mentioned before, when virus invades the organism, there may be specialized proteins (immunoglobulins) that bind adequately to "deactivate" it or to signal it so that the specialized cells of the immune system immediately come to destroy it. A particular ethnic group may have a unique type of these proteins that will successfully do the job, but if the virus mutates, that is, "changes shape," they will be unable to do it. (Images 2 and 3)

In this way, the immune system will be unable to act against the invading agent because it cannot "recognize" it. Something similar can occur if this virus, already inside the cell, has the capacity to inhibit the cell's "help call".

However, as I mentioned at the beginning, since different human groups evolved separately, they developed different types of immunoproteins. Some surely have a better chance of dealing with this new virus.

By purely fortuitous reasons, the Italian race (and I hope it is understood that I have used and will use the term race just for scientific reasons) turned out to have the most inadequate response to this virus, something similar to figure 3. That would be the reason because, unfortunately, Italy is the country with the highest mortality rate before COVID-19, about 10%. Other countries have it as low as 1%.

This shows that there are certain human groups that may have more adequate immunoproteins to deal with COVID-19, again, by purely fortuitous reasons. It is very likely that miscegenation represents an even greater advantage, since a person whose ancestry comes from different human groups will have a varied immunological repertoire in which he could have the appropriate “pieces” to face the infectious agent in a better way. (Image 4)

This is the probable explanation why it has been globally seen that COVID-19 does not have a predictable behavior. Certainly we find higher mortality in older adults, but previously healthy young people have also died and nonagenarians have recovered from sickness. It would be necessary to find out if the death of older adults is indeed due to the fragility of the immune system or is there a factor related to “pure” ancestry (that is, without crossbreeding), particularly in the Italian or Spanish case.

It would be convenient, of the deceased people in Italy, to analyze the cases in which the patient's eight great-grandparents were also Italian (probably from the same region of the country) and therefore brought a unique immunological repertoire that, as we saw, has been the least effective to face this infectious agent. Same in the Spain’s case.

I remember my immunology professor used to jok commenting to us: “Remember that 5% of the human genome is mutated, try to find yourself a wife from another country so that the mutations will be in different genes and will have have less probability of a malformation in your children, in addition, the immunological repertoire will be much greater in your sons”.

It is really easy, at least in Mexico, to verify the truth of that assertion. While for people in first world countries a "mongrel dog" is usually the cross between two pure breeds, in Mexico there are true "alebrijes"*, animals which it is almost impossible to infer their ancestry. The experience in Mexico (and developing countries) is that these animals are incredibly resistant to diseases (from parvovirus to distemper) if compared with the "pure breeds" specimens. They have a wide and varied immunological repertoire.

*An “alebrije” is a brightly multi-colored Mexican folk art sculpture of a fantastical (fantasy/mythical) creature.

Curiously, the average Mexican could be also considered as an “alebrije”, without offending anyone. I myself can find among my eight great-grandparents: pure Italians, an Spanish, a French and even a Totonaca indigenous. At the beginning of the pandemic this seemed to me a promising indication that a situation similar to that of Spain or Italy would not be experienced in Mexico.

The current official data today I write (April 4) seem to show that mortality in Mexico is within the world average, however I, like many, question the number of infected people since it does not seem to be in accordance with reality.

Certainly, as already mentioned, the official number of infections can be very low due to the few tests that are performed compared with other countries, but it seems to me that there is a cultural factor that influences even more: the Mexican people generally goes to the hospital when it really feels really, really bad. Otherwise they won’t. Mexico likely has thousands of mildly symptomatic or asymptomatic carriers that are not being reported. Let us remember that the first cases in Mexico had these characteristics and recovered satisfactorily.

It is precisely here to the point that I want to go to propose an emergent action that has already been proposed in recent days. It has even been proposed long before and was put into practice in 1918 during the so-called "Spanish Influenza": "convalescent" plasma transfusions.

But I will go further. The donors of this plasma should be precisely the people who turn out to be asymptomatic carriers or who presented mild symptoms since they seem to have highly effective "antibodies" against COVID-19. Hence the importance of identifying them and asking them to be voluntary donors.

The recipients of these transfusions would ideally be patients who present the first symptoms of the COVID-19 infection and who are in the identified risk groups: older adults, people with associated co-morbidity and would add; with pure Italian and Spanish descent. Plasma could even be sent to Italy where, given the current scenario of the pandemic, it will make many patients willing to receive the transfusion. The bureaucratic requirement is likely to be no more than a letter accepting to receive the transfusion with the aforementioned characteristics.

The advantage of this method is that if it is not successful, it will also not cause additional harm to the patient.

Some have questioned the effectiveness of this treatment because, there really is no way to know for sure its effectiveness, it is not possible to have a control group in the same way as when trying a drug, especially in the current circumstances.

If a patient recoveries after a "convalescent" plasma transfusion, the advocate of the method will claim that it was effective, the skeptics will reply that the patient probably would have recovered anyway. There is certainly no way to know, but given the current scenario, it is an option that is being implemented in a very good time and that, if successful, at least partially, could drastically reduce the number of patients who end up in intensive therapy. It is also much cheaper than purchasing thousands of ventilators.

It should be mentioned that just a few days ago the FDA approved convalescent plasma transfusions for "very serious COVID", but I am convinced that it is essential to perform the transfusion at the first symptoms of the disease, before cell destruction is already irreversible since in that case it would no longer have any effectiveness.

It is necessary to emphasize that the viability of this treatment does not mean that sanitary measures, “healthy distance” between people and the reduction of non-essential activities should be neglected as it will continue to be desirable to keep the number of infections to a minimum. However, a scheme could be considered in which, instead of “isolating” the entire population, affecting the economy (mainly those who live “daily”, those who if “stay at home” do not eat), protect the people with the highest risk and the rest can keep the production plant working, as all projections indicate that the strongest blow could be the economic and social crisis that the health situation is brewing.

I state this hoping some health system to take the initiative and dare to put into practice something that could have the potential to change the current course of the pandemic, not only in Mexico but globally, at least as far as the vaccine arrives ...

References:

1. Owen A. Judith. (2014) Inmunología de Kuby. MÉXICO. Editorial Mc Graw Hill

2. Garcia Sanchez, Celis Salazar y Carboney Mora (s/a). VIRUELA EN LA REPUBLICA MEXICANA* *Manuscrito recibido en octubre de 1954. 03/04/2020 Sitio web: http://saludpublica.mx/index.php/spm/article/view/5623/6106

3. Chenguang Shen PhD; Zhaoqin Wang, PhD; Fang Zhao phD. Treatment of 5 Critically Ill Patiens with COVID-19 With Convalecent Plasma. Published 27/03/2020 at JAMA

4. Carlos Serrano (2020). Qué es el "plasma convaleciente", el tratamiento experimental con trasfusiones de plasma que puede salvarle la vida a pacientes de covid-19. 03/04/2020 Sitio web: https://www.bbc.com/mundo/noticias-52129984

5. s/a. (2020). La FDA aprueba el uso del plasma convaleciente en Covid-19 muy grave.03/04/2020 Sitio web: https://www.diariomedico.com/medicina/farmacologia/la-fda-aprueba-el-uso-del-plasma-convaleciente-en-covid-19-muy-grave.html