After the "two positives", the new crown will end in this way

When the first wave of the epidemic peaked at the end of last year, the public experienced firsthand that "COVID-19 is definitely not a large-scale flu"; this year, with the arrival of the "double positive" around May Day, the situation was completely different, and most of the infected people discovered again that "COVID-19 is definitely not a large-scale flu", but the two "definitely not" have very different meanings.

Written by Wang Chenguang (PhD in Biology, former professor at Peking Union Medical College)

Around the May Day holiday, a new round of COVID-19 outbreaks broke out in China. The news of "double positive" was heard everywhere, and the "survivors" around me who had not been infected at the end of last year finally got infected one after another; a small-scale survey showed that within two weeks after the holiday, the proportion of reinfection was as high as more than 30%. The symptoms of this round of infection are generally milder than the first round of infection, and there will also be more asymptomatic infections, so the actual infection rate will be higher. On May 16, the weekly epidemic report released by the Beijing Center for Disease Control and Prevention showed that the new crown surpassed influenza for two consecutive weeks and returned to the top position in the list of statutory infectious diseases.

It has only been half a year since China experienced the first round of the epidemic at the end of last year. It is estimated that the number of infections in that round was as high as 1.2 billion.

Compared with the end of last year, this round of epidemic has not attracted much attention. Even if they are infected, most people can face it calmly. Many people were infected with influenza A during the previous Qingming Festival. The experience of two consecutive infections allows people to intuitively compare influenza and COVID-19. Some people have concluded that COVID-19 infection is not as serious as influenza.

Despite this, people who have experienced three years of COVID-19 prevention still have doubts in their hearts: Is the new round of epidemics caused by virus mutation, or because the protective mechanism established in our bodies after the initial infection has disappeared? The interval between the two infection peaks is only 6 months, when will the next peak come? Will there be a more virulent and pathogenic strain in the future?

When it comes to epidemic prediction, “learning from history” is sometimes true. Tracking the history of other coronaviruses coexisting with humans can help answer the above questions.

Colds are not as mild as you think

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Since the outbreak of the COVID-19 pandemic, experts in the biomedical and public health fields have been discussing various possibilities for the development of the virus, and some experts have made disturbing predictions that new mutations of the virus will be more deadly one day in the future. The negative effects of these predictions have been continuously magnified among the public, evolving into concerns and panic among the public during the three-year epidemic prevention campaign.

But these predictions do not conform to the laws of biological evolution. Comparing the variants that dominated the epidemic at different stages of the COVID-19 pandemic, there is no evidence that the new coronavirus has been replaced by more harmful variants ; from an evolutionary perspective, it is not in the "will" of the new coronavirus to kill human hosts or make hosts seriously ill and lose their social ability, so those variants that no longer cause serious consequences are more likely to spread.

How to judge the pathogenicity of the new coronavirus in the future? Some evidence shows that the Omicron strain causes less severe infection than the previous epidemic strains. For example, in animal experiments, it was observed that Omicron is more likely to infect the upper respiratory tract. However, there are also comparative studies based on unvaccinated first-time infected people infected with different strains, which show that the conversion rate to severe disease after infection with Omicron is not significantly lower than that of Delta and previous strains. Many experts pessimistically concluded that no matter how weak the new coronavirus is, it is still a large-scale flu, which means it is more serious than the flu.

Contrary to this pessimistic prediction, I believe that the new coronavirus will eventually become the fifth endemic coronavirus and join the common cold virus.

Many people know that influenza kills hundreds of thousands of people around the world every year. In the past 100 years, influenza has killed millions or even tens of millions of people more than once, including the most famous 1918 influenza pandemic, which killed at least 50 million people.

Can the common cold cause such severe illness and death?

It is necessary for us to first understand the difference between the common cold (hereinafter referred to as "cold", as distinguished from influenza) and influenza. Influenza is caused by a very similar viral infection; while the cold is a combination of multiple symptoms, including coughing, sneezing, runny nose, fatigue, etc., and may also be accompanied by fever, usually a low-grade fever. The cold is not an infectious disease caused by a single pathogen. There are hundreds of respiratory viruses that cause colds. The most important of these are rhinoviruses, adenoviruses, respiratory syncytial viruses and parainfluenza viruses, in addition to four coronaviruses.

Colds give people the impression that they are relatively mild, do not require treatment, and can heal themselves within a few days. It is rare to see the media, medical institutions, and governments issue warnings about colds. But this does not mean that colds will not cause severe illness and death, but they are not included in the close monitoring and statistics of health institutions like influenza. Infection with rhinovirus or other viruses that cause cold symptoms can have serious consequences for certain groups. In people with underlying diseases and the elderly, colds can also aggravate underlying diseases, induce complications, and cause death, just as the new coronavirus we are familiar with now.

Some cold viruses, such as respiratory syncytial virus infection, are even more lethal to young children than the new coronavirus infection; adenoviruses among cold viruses can also cause systemic symptoms, including the gastrointestinal tract, urinary tract, and liver. In addition, secondary bacterial lung infections and pneumonia caused by colds are the main ways that colds cause death (the same is true after influenza virus infection).

There are special vaccines and drugs targeting the virus for influenza, which can largely prevent viral infection and alleviate symptoms. Given the diversity of cold viruses, there is no simple medical plan for all cold viruses except for drugs that relieve symptoms. If deaths from colds were recorded in the same way as deaths from influenza or COVID-19, the annual number of deaths from colds would also be staggering. Taking respiratory syncytial virus (RSV) infection as an example, about 2% of all-cause deaths among children under the age of 5 worldwide are due to infection with the virus; about 100,000 to 200,000 infants under one year old die from the virus each year.

The number of deaths from RSV infection in the elderly with underlying respiratory diseases such as asthma and chronic obstructive pulmonary disease is far higher than that in infants and young children. According to some studies, the rate of severe illness and hospitalization after RSV infection in the elderly aged 65 and above is about 3% to 10%. The mortality rate of severe illness in this group is also high, usually between 2% and 10%.

This shows that the death toll caused by a disease worldwide is often very different from the public's perceptual understanding. For most people with a healthy immune system, the cold virus is indeed very mild, because our bodies are already familiar with it and the immune system can deal with it more calmly.

Four pieces of evidence show that the novel coronavirus is evolving into the common cold

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First, the epidemic survey data. In September last year, the US Centers for Disease Control and Prevention (CDC) reported that from April to June of that year, the inpatient mortality rate of patients hospitalized for COVID-19 dropped from 15.1% during the Delta variant-dominated epidemic to 4.9%, while the mortality rate of hospitalized influenza patients in ordinary years was between 5% and 12%.

There are many similar studies around the world that have reached a consistent conclusion, that is, the risk of hospitalization and death from COVID-19 infection has gradually decreased as the epidemic develops. For the elderly and people with multiple underlying diseases, the current hospitalization rate and risk of death are still high, but this risk is not unique to COVID-19 infection. The same is true for complications caused by various respiratory viral infections such as common influenza and the common cold.

The second is the evolution of symptoms of reinfection. When the Omicron strain began to spread around the world in late 2021, people noticed that the symptoms after infection were significantly different from those of previous infections. Overall, the symptoms of Omicron infection are milder and more like a common cold. Typical symptoms are sore throat, sneezing, runny nose, and some mild diarrhea, while previous hallmark symptoms such as fever, cough, and loss of smell have been greatly reduced.

The reasons behind these symptom changes are complex, including the virus itself, as well as previous infection or effective vaccination. From the perspective of the virus itself, the emergence of Omicron is the result of random mutations of the new coronavirus, and becoming an epidemic strain is the result of selection. Mutations that infect the upper respiratory tract and cause mild symptoms will dominate. As the number of people infected with natural diseases and vaccinated expands, the immune base of the population gradually improves, and mutations that infect the upper respiratory tract can exist for a long time.

Based on multiple studies in Europe and the United States, the changes in the above symptoms are more obvious in people who have completed mRNA vaccination. In China's first large-scale epidemic at the end of last year, although the dominant strain was also Omicron, the symptoms after infection were different, closer to the previous epidemics in Europe and the United States (unvaccinated and first infection), and most people showed symptoms such as high fever and cough. In the second wave of the epidemic during the May Day holiday this year, almost all reinfected people showed mild symptoms, such as short-term low fever, muscle aches, sneezing and runny nose. These symptoms are almost the same as the common cold.

Another key piece of evidence comes from an analysis of other coronaviruses that cause the common cold.

In 1890, an influenza outbreak occurred in Russia, and two consecutive outbreaks occurred in the following two years, causing global spread and killing more than one million people. Although it was considered influenza at the time, sporadic written records at the time showed that some patients had neurological symptoms, and some patients had atypical influenza symptoms such as diarrhea and loss of smell.

These symptoms overlap significantly with those of the novel coronavirus infection in the past three years or so, and some researchers have speculated that this may be the first recorded outbreak of a coronavirus in human history (rather than influenza). The confirmed information is that this coronavirus, named OC42, was already a type of common cold virus when it was isolated and identified in 1967.

The SARS outbreak in 2003 and the recent COVID-19 outbreak (especially the latter) have made the public aware of coronaviruses. Before this, four coronaviruses in the group of viruses that cause the common cold were little known, including 229E, OC43, NL63 and HKU1. Like other cold viruses, coronaviruses are transmitted through the respiratory tract through coughing and sneezing, and they can cause mild upper respiratory tract diseases in adults.

Are these coronaviruses that cause no symptoms or mild symptoms after infection "born this way"? No, in infants, the elderly and immunocompromised individuals, they can sometimes cause life-threatening bronchiolitis and pneumonia. In addition to respiratory diseases, they can also cause intestinal and nervous system diseases. These coronaviruses become epidemic every 2-3 years, and people can be infected many times in their lifetime, indicating that such viral infections are difficult to induce lifelong or long-term protective immunity (this is due to both viral mutations and the fact that the immune protection formed by human infection decays over time).

Researchers from the Chinese Center for Disease Control and Prevention analyzed the infection of these four cold-causing coronaviruses in the population after the SARS epidemic in 2003. Of the 794 blood samples tested, 765 were IgG positive, and more than 70% of the people tested had been infected with the four coronaviruses.

These four cold coronaviruses were isolated and identified in recent decades. When did they start to infect humans in history? Have they caused major epidemics? Have they also experienced a process of virulence from strong to weak? These questions are difficult to answer clearly due to the lack of direct evidence. Tracking analysis of influenza viruses can partially verify our point of view: through the analysis of virus sequences carried by the skeletons of infected people in the 1918 influenza pandemic, it was found that this influenza virus has never disappeared, and its shadow can be found in the influenza epidemics of 1957, 1968 and 2009.

The last piece of evidence is the migration of age groups infected with COVID-19.

The study by the Chinese Center for Disease Control and Prevention also found an interesting phenomenon, that is, the four coronaviruses that cause colds, people are almost always first infected during childhood. Before the age of 6, the infection rate gradually increases with age and reaches a plateau, and no first infection is detected in adults (indicator is IgM). This phenomenon reflects the history of viral evolution, and the new coronavirus will also follow this pattern: new infections will only occur in infants and young children, and adults will be infected every once in a while. Like other cold coronavirus infections, infections in healthy adults are usually mild.

Regarding the future epidemic pattern of the new coronavirus, other studies have conducted model predictions and concluded that as the epidemic expands and more children are infected, the severity of the new coronavirus will become more consistent with the common cold.

Vulnerable groups still need special protection

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At the beginning of the epidemic, many experts compared the infection mortality rate of the new coronavirus with that of influenza, and concluded that "the new coronavirus will be a large-scale influenza in the future." This is actually unreasonable. As a new virus that has appeared for the first time, almost no one has resistance to it. The high number of deaths is due to the high severity rate of the first infection due to the large infection base and low immunity level.

In addition, the case fatality rate of influenza is calculated based on the estimated number of infections, while the case fatality rate of the early COVID-19 is based on the actual number of positive tests. After the Wuhan epidemic, serological data proved that the actual number of infections was at least 10 times the number of reported cases, and this was under large-scale testing. In addition, influenza data is still based on large-scale vaccination, but hundreds of thousands of people still die from influenza every year worldwide. Other indicators are more comparable, namely the infection hospitalization rate and the mortality rate of hospitalized patients. Data have shown that both of these indicators of the current COVID-19 are lower than those of influenza, and will be lower in the future.

Mild and asymptomatic cases will be the main direction of future COVID-19 infections after the epidemic ends, but like other respiratory infectious diseases, protecting high-risk groups is still the focus of COVID-19 prevention. The introduction and popularization of highly effective vaccines can protect high-risk groups from infection and severe disease transformation; including antiviral special drugs with an efficiency of nearly 90% in preventing severe disease transformation and death in medical insurance will save more lives.

As the old saying goes, "a major epidemic will never last more than three years." The COVID-19 pandemic has lasted for three and a half years and is entering its fifth year. Restrictions on epidemic prevention and control around the world have gradually been lifted, but when the epidemic will end is still a question on many people's minds. I wrote a prediction article in 2021, and the conclusion in it still holds true today: just as the end of the 1918 influenza pandemic, herd immunity will also be a prerequisite for the end of the COVID-19 pandemic, whether immunity comes from natural infection or vaccination. But the end of the epidemic does not mean that the virus has been completely eliminated and disappeared. As the toxicity of the mutant strains gradually weakens and the level of herd immunity increases, the new coronavirus will eventually become a new member of the coronavirus among cold viruses.

"San Yang" will appear in the next winter half a year later. Since other respiratory diseases are easily combined in low temperature weather, the lethality of "San Yang" may appear greater than "Er Yang", even though it has actually become a cold by then.

References

[1] Stacey Adjei S, et al. Mortality Risk Among Patients Hospitalized Primarily for COVID-19 During the Omicron and Delta Variant Pandemic Periods - United States, April 2020-June 2022. MMWR Morb Mortal Wkly Rep . 2022 Sep 16;71(37):1182-1189.

[2] Zhou W et al. First infection by all four non-severe acute respiratory syndrome human coronaviruses takes place during childhood. BMC Infect Dis . 2013 Sep 16;13:433

[3] Lavine JS et al. Immunological characteristics govern the transition of COVID-19 to endemicity. Science . 2021 Feb 12;371(6530):741-745.

[4] Patrick DM, et al. An Outbreak of Human Coronavirus OC43 Infection and Serological Cross-reactivity with SARS Coronavirus. Can J Infect Dis Med Microbiol . 2006 Nov;17(6):330-336.

This article is supported by the Science Popularization China Starry Sky Project

Produced by: China Association for Science and Technology Department of Science Popularization

Producer: China Science and Technology Press Co., Ltd., Beijing Zhongke Xinghe Culture Media Co., Ltd.

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