From 0.50% of Korea to 3.70% of China: lethality, the great enigma of the coronavirus

The World Health Organization coded this week in a 3.4% Covid-19 overall lethality rate. The figure is exactly the result of the rule of three between the total number of deaths recorded (3,286) and the number of cases, which today marked 95,748 globally.

However, on a more regional scale, there is a lot of disparity: in the province of Hubei, where Wuhan is located, or in areas of Iran the disease has reached over 5% lethality – and depending on the demographic group, those over 80 years have come to triple that figure – while in countries like South Korea, second with the highest number of cases, deaths do not reach 0.5% of those infected, barely a tenth.

There is, in fact, the speculation of whether we are really talking about the same disease. Everywhere, the coronavirus shares several common characteristics such as its high transmission capacity or to affect the elderly, immunosuppressed patients or other diseases. However, in some places it is showing as destructive pneumonia and in others something that hardly distinguishes in severity of the common flu.

In Spain, at the moment, the lethality of Covid-19 is below average with a 1.35% of deaths, much more if we compare ourselves with Italy, a demographically similar country and where the virus entered more or less at the same time. There had died 79 people, a 3.16% of those who contracted the disease.

Of course, we talk about highly variable rates. For example, in Spain, going from one to three cases has meant going from 0.49% to 1.35% in 24 hours. Or the exaggeratedly high rate in the United States does not mean that the coronavirus is more harmful there, only that there is a huge underdiagnosis, as happened in Iran a few days ago. Just as reference, during the first nine months of the influenza A epidemic (2009) 77 estimates of its lethality were published: some said it caused one death per 100,000 cases and others up to 10,000 deaths.

Why in some places does Covid-19 hardly seem like a mild flu and in others hundreds of people are being carried forward?

Within the novelty surrounding the SARS-CoV-2, the huge discrepancy in the deadly capacity of the virus between regions and countries is, without a doubt, the part that confuses epidemiologists the most. Why in some places does it just seem like a mild flu and in others it is taking hundreds of people ahead? These are some of the hypotheses that the scientific community is considering.

Reinforced by other coronaviruses

Jason Tetro, from the University of Guelph (Ontario, Canada) was one of the perplexed scientists because of the difference in severity between the virus in Hubei province compared to other places in the world. His bet is a mechanism called 'antibody-dependent enhancement' (Antibody Dependent Enhancement or ADE) that would have allowed SARS-CoV-2 to learn from other coronaviruses present locally around the city of Wuhan.

Tetro, who has published an article in 'Microbes and infection' reasoning this hypothesis, explains to El Confidencial that what made him suspect were "the clinical characteristics of the infection."

Geographical differences are common in viruses, but with Covid-19 none of the usual factors are involved.

"Geographical differences are common in many infectious diseases, particularly respiratory viruses," says Tetro. "Normally these differences have to do with socioeconomic disparity, with an isolation or a particular strain that circulates, and we have even seen this in relation to changes in the rate of absorption of the vaccine. "But with Covid-19 none of these factors seemed to be involved." This difference seems due to some other factor, "he says.

The virus normally causes pneumonia that causes a certain inflammation, something that has been demonstrated in studies in 'The Lancet' or the 'New England Journal of Medicine'. "For those who have documented risk factors, the degree of inflammation can be serious and possibly lethal, all that makes sense, "says this microbiologist and immunologist." But when healthy people suffer from this uncontrolled inflammation that leads to a cytokine storm, this indicates that a different process may be happening and research on dengue, RSV — respiratory syncytial virus — or on your genetic relative, SARS, suggests that there may be ADE. "

Unfortunately, it's not easy to be 100% sure about this. "To assess whether it is happening, the antibodies of people suffering from a serious infection should be characterized to determine their optimal antigen," says Tetro. "If it turns out to be a sequence present in another coronavirus but not in the SARS-CoV-2, then this process may have happened."

To get out of doubt it would be necessary to explore the virus in the lung cells of those infected to check if polymorphisms occur, small mutations in immune genes that can lead to these more serious infections.

"This work is, in fact, an opinion of a researcher who proposes that, since in China there was infection with SARS-CoV, if there was an ADE effect or increased antibody-dependent infectivity, would explain that the disease is being more severe in China, "Isabel Sola and Sonia Zúñiga, researchers at the coronavirus laboratory of the National Biotechnology Center (CNB-CSIC), explain to El Confidencial." For the moment no solid scientific data that support this hypothesis, apart from the fact that the SARS-CoV affected more countries than China. "

They are different strains

In an article published this week in 'National Science Review', Chinese researchers argue that the epidemic that swept Wuhan between late December and early January would be a particularly aggressive strain of the coronavirus. The virus I would have mutated in those first days in two variants, L and S, being the first more aggressive and with more transmission capacity. Therefore, it was the one that spread most virulence through the Chinese city.

According to these researchers, from Beijing, Shanghai and the Chinese Academy of Sciences, "while type L was more prevalent in the early stages of the outbreak in Wuhan, the frequency of type L dropped from the beginning of January 2020." Why? Because the authorities they focused on chasing and containing those most serious cases, while those affected with type S went more unnoticed, allowing the milder strain of the coronavirus to increase its frequency.

Sola and Zúñiga clarify however this new finding. "The study just published describing what they call variants L and S does not provide data regarding severity or virulence of these isolates, "they explain." What is described there is that there could be two variants of viruses that are grouped based on two mutations – in the almost 30,000 nucleotides of the genome of the virus – one of them silent, meaning no it changes the protein it affects, and another that gives a timely change in one of the accessory genes, "they add.

Since in the 103 strains of the coronavirus analyzed by Chinese researchers there are more L sequences than S, this would mean that the L variant seems prevalent, "which makes them suggest that it may be transmitted more easily," say the Spanish virologists. "Which it doesn't have to mean it's more virulent".

Comorbidity and environmental factors

Other experts point out that there may be much more mundane causes. For example, in Hubei province, coronavirus mortality in men is much higher than in women, and the reason may be that … smoking is too. China, one of the countries where the world is most smoked, may have exacerbated its figures for this reason, as pointed out a few days ago by Bruce Aylward of the World Health Organization. "In the long term, smokers develop cardiovascular or lung diseases, and all of these are factors in terms of a higher probability of mortality. "

This would not be enough to explain, however, the great differences between Hubei, with more than 2,900 dead, and the rest of the Chinese provinces, where only a handful – between one and six – of deaths to date have been recorded. "Environmental factors and diet may also be helping to alter the immune response," adds Tetro. "All these problems have been seen in humans and could be involved."

In Wuhan and surrounding areas there have been cases that defied explanations, such as the 29-year-old doctor Peng Yinhua who ended up dying in dark circumstances where it is never clear what part of the virus is blamed and what part of the strenuous working hours. "These geographical differences could also be due to environmental factors, such as air pollution, or a higher level of stress that leads to a weakened immune response," explains the immunologist. "Some of the risk factors such as hypertension and diabetes they may be occurring more frequently in non-traditional age groups, such as younger people. "

If the number of serious cases or the total number of infected is placed in the denominator, the mortality rate increases or decreases

For the scientists at the National Biotechnology Center, the most likely explanation for the variable severity of the coronavirus is a multitude of factors. "Until there is no more data of the epidemic globally they will not know each other completely", say Sola and Zúñiga." To give two very different examples: depending on how mortality calculations are made; if the number of serious or hospitalized cases is placed in the denominator, the lethality rate increases, if on the contrary it is divided by the total number of infected, the mortality rate decreases. "

Currently, the only thing that Isabel Sola and Sonia Zúñiga are sure is that, with the data in hand, the virus does not seem to be evolving. "Therefore, the evolution of the virus in the epidemic cannot be predicted in that sense," they say. "This will also require identify the animal reservoir from which the virus has jumped to humans, to know its sequence and its properties ".