From the great pandemics of past centuries to the COVID-19 pandemic. Medicine and society at crossroads

Maria Dorobanțu Membru al Academiei Române de Științe Medicale Membru corespondent al Academiei Franceze de Medicină




Maria Dorobanțu
Member of the Romanian Academy of Medical Sciences
Corresponding member of the French Academy of Medicine


Nicoleta-Monica Popa-Fotea Membru al Societăţii Europene de Cardiologie, ESC Fellow Cambridge Research Institute UK



Nicoleta-Monica Popa-Fotea
Member of the European Society of Cardiology, ESC
Fellow Cambridge Research Institute UK, Department of Centrosomal Studies; ERIBA-European Research Institute for Healthy Aging, Groningen, Deutscher Akademischer Austausch Dienst (DAAD), Deutsches Zentrum für Herz-Kreislauf-Forschung, Universitätsklinikum Hamburg-Eppendorf



The premise or question that generates these reflections is the following: did anyone think that in 2021 humanity would face a global epidemiological situation that would threaten our physical and psychological integrity, but would also divide society to its functional limits? The question above can be answered looking back to similar phenomena in history.

Many centuries ago, smallpox devastated humankind, but few of us today remember it because of the remarkable work of Edward Jenner and his subsequent efforts to eradicate the infection. In the 18th century, 400.000 people died of smallpox each year in Europe, and a third of the survivors lost their sight. The mortality rate ranged from 20 to 60%, and most survivors remained with irreversible scars. The infant mortality rate was even higher, approaching 80% in London and 98% in Berlin in the late 1800s.               The word smallpox was introduced in 570, by Bishop Marius de Avenches (a town near Lausanne, Switzerland), derived from the Latin words varius, meaning "colored", or from varus, meaning "mark on the skin". Jenner's work is widely regarded as the foundation of immunology – despite the fact that he was not the first to suggest that smallpox infection confers specific immunity or to attempt to inoculate smallpox for this purpose. However, Jenner's efforts and tenacity convinced society of the effectiveness of the proposed treatment, because, as Francis Galton suggested, "in science the credit goes to the man who convinces the world, not to the man who has the idea".               Why did we introduce this first historical case of a pandemic? To show that the most important aspect at the time of a pandemic is the research for the eradication treatment necessary for humanity to be continue evolving, and for society to function in an optimal environment. The search for the remedy always comes only through scientific innovation, with the whole tense social framework triggered by the experiment-implementation-result cycle and their correct reception in the field of science, but also in society. For example, the first article sent by Jenner to the British Medical Society was rejected and his initial theory discredited. Despite the major resistance he encountered, he did not stop promoting his method and looking for volunteers. The extraordinary value of vaccination was publicly recognized in England when, in 1802, the British Parliament awarded Edward Jenner £10.000. In spite of all the ridicule directed at him, he continued his activities on behalf of the vaccination program. In 1853, the vaccine became compulsory in Britain, sparking many riots at the time. Through sustained post-World War II vaccination efforts, the World Health Organization declared smallpox eradicated on May 8, 1980, with the last natural case of smallpox being diagnosed in Somalia in 1977. The disease, which killed about 300 million people in the twentieth century, more than any armed conflicts, it is now a thing of the past, its only remaining evidence being the two stocks of smallpox kept in maximum security at the Center for Disease Control and Prevention in Atlanta and at the State Research Center for Virology and Biotechnology in Russia, Novosibirsk.

Although Jenner can be considered the father of modern vaccinology, the one who will really introduce the vaccine as a solution to prevent potentially deadly diseases, which later turned into pandemics, is Louis Pasteur.

Nearly a century after Jenner, Louis Pasteur will produce the first rabies vaccine based on an attenuated strain. The same tension and resistance of society to innovation, mentioned above in the case of Edward Jenner, will Louis Pasteur similarly experiment, being accused in those days of wanting to make unfair profits by producing laboratory strains. Concepts outlined by Pasteur such as viral attenuation, renewed virulence, antitoxins, and others, will be developed 50 years later and will become the foundation of the polio vaccine, but also against other diseases such as chickenpox, measles or mumps.

Another case that fits the same pattern of scientific success against a disease, but which has not been absolved by the conflict between medical novelty, its implementation and social reception, is that of the virologist and researcher Jonas Salk, who will develop the long-awaited vaccine against polio in 1952. To convince parents who were afraid to vaccinate their children, he would vaccinate his own child. Three years later, in 1955, a huge vaccination company began in the United States, but it was not until four decades later, in 1994, that the disease was eradicated from the United States, and much later, in 2002, in Europe.

What we learn from Salk, but also from other predecessors involved in eradicating fatal viral diseases, is that laying the real foundation stones in the field of innovation can be achieved only through perseverance, commitment and the transfer of experimental ideas within their generations, as well as with future ones, resulting in the creation of schools of thought in essential medical fields.

In addition to his extraordinary efforts to eradicate polio, Salk founded a research institute named after him in San Diego, in an attempt to build some sort of Socratic academy in which science and humanism provide the context and atmosphere conducive to evolution through twinning the two vectors, rather complementary than antithetical. And, to give just one example of the personality formed in this context, we call Francis Crick, the one who highlighted the structure of the DNA molecule, Nobel Prize winner, professor at this institute, who proved to be a place of excellence for the creative minds as its founder wanted.

And going from the specific historical cases illustrated by the figures of remarkable medical personalities who had the vision, ability, but also the courage to look beyond their times and the tense context of societies functionally weakened by disease, we come to the justified finding that all great campaigns to eradicate infectious diseases, especially viral ones, have faced numerous resistances from society, generated primarily by a fear of projecting an innovative future, of understanding it and of assuming it through participation.

The COVID-19 pandemic is no exception to the above cases. The current pandemic was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first identified in Wuhan, China, in December 2019; outbreaks in the Wuhan region and other cities in Hubei Province have failed to be controlled and have affected the entire world. The World Health Organization has declared a public health emergency with international involvement on January 30 and a pandemic on March 11, 2020. On September 16, 2021, more than 220 million cases and 4.66 million deaths have confirmed, making it on a hierarchical scale, one of the deadliest pandemics in history.

The COVID-19 pandemic has quickly become a global threat not only because of the large number of deaths it has caused, but also because of the major stress on medical resources. It refers, first of all, to the preferential triage of patients infected with the new type of coronavirus, to the detriment, in most cases, of those with other chronic diseases, such as cardiovascular diseases; this finding can be confirmed by any doctor from specialties other than those of infectious diseases. No one can deny the tension brought by the assault of this virus on humanity, to which are added the confusing reactions of social systems in supporting the medical system, but also in maintaining the boundary of medical authority and responsibility in identifying the best solutions. To describe this social deficiency combined with economic and ethnic factors, Shreya Kangovi, an associate professor at the University from Pennsylvania School of Medicine, spoke of a resemblance of the COVID-19 pandemic to a distorting mirror that amplifies pre-existing imperfections, of which we cannot fail to mention economic inequalities and ethnic differences. This assertion is somewhat confirmed by various studies showing that, for example, socio-economic status is a strong predictor of premature mortality and morbidity in general, and for cardiovascular disease in particular. Individuals living in less-favored areas are twice as likely to die from SARS-CoV-2 infection (128.3/100.000), compared to those in others areas (58.8/100.000). Also, according to studies, in addition to social status, other factors involved in increasing the risk of infection are obesity, high blood pressure and chronic obstructive pulmonary disease.

If we extend the discussion from the risk factors for SARS-CoV-2 infection listed above, we find that, since the onset of the pandemic, subjects with cardiovascular disease have proven to be the most vulnerable to infection. The specificity of SARS-CoV-2 for the angiotensin-2 conversion enzyme protein has fueled further concerns about possible cardiovascular damage and raised concerns about concomitant use of drugs, including conversion enzyme inhibitors of angiotensin and angiotensin receptor blockers. Although more than a year and a half has passed since the first cases reported in 2020, the global community is at a critical juncture in the pandemic, namely the long-term cardiovascular effects of COVID-19. However, as the number of new cases continues to increase worldwide due to new variations in this wave four, the medical community needs to keep abreast of the latest news about acute COVID-19 infection. Bringing some specific medical information, regarding the etiology of myocardial injury in COVID-19, it is clear that the global understanding has evolved continuously; from the first histopathological studies to support the increased prevalence of myocarditis and direct viral toxicity to myocytes, to the conclusion of the study by Lindner et al. which demonstrated that in situ hybridization is located rather in the interstitium and in resident macrophages, with no clear case of myocarditis according to the Dallas criteria. Moreover, in a study comparing intubated and mechanically ventilated subjects with and without COVID-19, it was shown that myocardial injury is more prevalent in those intubated with severe conditions without COVID-19 than in those intubated in the context of SARS-CoV-2 infection.

Turning to a general framework focused on prediction models, we can say that in the COVID-19 pandemic several patterns have been used to predict the evolution of the phenomenon, based on epidemiological data and other predictors. The question that arises is how these types of predictions have an effect in the fight against the pandemic, or do they have remain at the level of philosophical exercise and public discourse. Most appropriately, they should be approached and understood in a logical causal relationship, evidence, hypothetical solutions and the link between the type of prediction and the reality of the phenomenon. We list these notions invoked in any prediction because even if the coronavirus pandemic is unique, by the simple logic of the fact that it has not been previously identified many of the pandemic challenges are part of a general prediction model that has not lacked addressing other similar phenomena from the past.

If we were to start from a simple definition of prediction, we must know that it refers to prediction of the future or, when comparing scenarios, to designate several hypotheses. Because epidemiology informs and outlines public health directives, prediction is the central issue for this area. Epidemiologists compare hypothetical worlds to help the government decide on appropriate social measures, and we have seen that global society has been subjected, for example, to some restrictions and measures of social distancing. To arrive at such a prediction, epidemiology uses models for the evolution of the infectious outbreak in different simulated scenarios. However, what is simulated can distort the real situation and then the prediction becomes false. Alex Broadbent, author of The Philosophy of Epidemiology, argues that a good epidemiological prediction requires an answer to the question "what could go wrong?". He also considers that to predict correctly means to be able to explain first of all why what you predict is happening, rather than what are the most probable hypotheses; extending Broadbent's logic, it is clear that we are talking about identifying the cause-effect relationship. The author considers it essential for the epidemiologist to consider both the situation in which his prediction will be true and what will happen if the prediction turns out to be false. It is clear that the goal is to eliminate false hypotheses, so that epidemiologists can increase their confidence in the reasoning issued. For example, using the antibody titer to estimate previous infections in the population or the degree of post-vaccination immunization, public health authorities could rule out the hypothetical possibility that the coronavirus has been circulating in the population for much longer than thought.

Perhaps it is reasonable to ask ourselves whether we can solve the phenomenon itself by the basis of a prediction. Certainly, the answer is partly positive, as the dynamics of a pandemic is much more complex than a simple prediction model, being dependent on many variables, the most important remaining human behavior during the pandemic, not just immune reactions.

Applying the same epidemiological measures all over the world is not always a solution; certain interventions that operate in a part of the world such as in Europe, but could have very different effects in Africa or South America. For example, if we think strictly in terms of the economic impact generated by social distancing policies, we can say that there are regions around the world where these, on the contrary, instead of decreasing can keep mortality high, if we include low living standards, malnutrition and poverty. If social distancing has prevent deaths, primarily by reducing infections among the elderly, does it work as projected in areas dominated by young people rather than elderly, such as African countries with younger and less prone populations to severe forms of the disease? The question goes beyond the medical framework, also having social considerations. Epidemiological models should not have as their primary function to predict in isolation, but to show how the infection spreads, without losing sight of many elements from the social world in which apllied. Although the pandemic is global, the prediction and measures must remain local.

It is certain that the pandemic generated more questions than answers both in the medical world and beyond, some of these essential questions being addressed in this volume edited by President Constantinescu. What we all need to learn is that history has a role to play in helping us realize where we are, on what we have built what we know scientifically, how to intervene in medical innovation, and how much resources and devotion we need to assign. Regardless of social acceptance, medicine must go further and offer possibilities and solutions to future diseases. Even if the evolution of pandemics can be somewhat anticipated, the general course of the world cannot be predicted, nor can its capacity and openness to medical innovation. In this sense, the question remains valid whether the tension between experiments-implementation-results found since Jenner, Pasteur, Salk, will persist in the post-COVID-19 times. The answer will be given by time as always, and society will judge it for decades to come.

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