After testing positive for COVID-19, will you test positive again? Will repeated infection make it more serious?

Many people are concerned about reinfection with the new coronavirus.

In fact, for most people, it is too early to consider this issue. At present, most people in my country have not been infected with the new coronavirus, and there is no question of "reinfection". However, some friends still see the issue of "reinfection" from media or self-media reports, and worry whether the symptoms will be more severe if reinfection occurs.

Today, let’s talk about this topic.

This question consists of two aspects: one is what determines the virulence of the virus, and the other is how our immune system works .

01

Principles of human immunity

Let’s talk about the second question first, ourselves.

A person's life is actually a life of fighting and coexisting with various pathogens.

Our immune system is divided into two parts - innate immunity and adaptive immunity .

The former is also called non-specific immunity (or innate immunity) . It is a natural defense that humans have gradually established during the evolution process. It is innate to us and is not targeted at specific pathogens. For example, it provides protection for the skin, respiratory mucosa, and some white blood cells (such as macrophages and neutrophils).

The latter is also called specific immunity (or acquired immunity) , which is the immunity we produce against a specific pathogen. Specifically, it is the immunity brought about by natural infection with the pathogen or vaccination.

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When it comes to vaccines, we can focus on adaptive immunity. We all know that antibodies are produced after vaccination, but antibodies are far from the only product of vaccination .

In fact, adaptive immunity also consists of two parts, namely B cell-mediated humoral immunity and T cell-mediated cellular immunity . The humoral immune response mainly produces antibodies. Except for BCG, all vaccines we routinely use mainly provide protection through antibodies.

The cellular immune response is mainly T cell response, which is divided into:

Cytotoxic T cells (CD8+ T cells): also called killer T cells, can destroy human cells that have been infected by the virus

Helper T cells (CD4+ T cells): mainly induce and activate other cells of the immune system, such as effector B cells (also called plasma cells) and memory B cells responsible for secreting antibodies in humoral immunity

Schematic diagram of T cell activation mechanism. Image 2 is adapted from Tuchong.com and is not authorized for reproduction.

Memory B cells can survive for a long time, and even if the antibody level in the serum is very low, they can be reactivated and produce antibodies when pathogens invade again.

Antibodies (neutralizing antibodies to be precise) can recognize and prevent viruses in body fluids from invading cells. If some viruses escape the antibodies' invasion of cells, the infected cells will be attacked and eliminated by cytotoxic T cells.

Antibodies are essentially proteins, and their levels in serum will gradually decrease over time. In the future, when antibody levels drop to a relatively low level and the virus invades again, T cells and memory B cells will play a long-term protective role.

02

External factors affecting virus virulence

Let’s go back to the first question that has not been resolved at the beginning: what determines the virulence of the virus?

The pathogenicity (virulence) exhibited by the new coronavirus after invading the human body depends on endogenous toxicity and external factors.

Among them, the external factors mainly include the following four aspects:

One is the ratio of vaccination to natural infection , because both will produce antibodies (and T-cell responses). As the vaccination rate/previous infection rate of the population in many countries increases, the severity/mortality rate caused will decrease even if the same variant is used in the previous and subsequent periods;

Second, during different waves of the epidemic, the median age of the infected population will also affect the severity of the disease , because the risk of severe illness in the elderly is significantly higher than that in the young;

Third, drugs . Using some antiviral drugs in the early stages of infection can significantly reduce the risk of severe illness, so drug development and reserves are very important.

Fourth, medical conditions . If there is a run on the hospital, the COVID-19 patients who should be hospitalized/admitted to the ICU will not be admitted in time, and the mortality rate will also increase.

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In addition, some invisible conditions will also affect the data itself. For example, a large number of infected people are asymptomatic and do not know that they are infected, or they do not report it after testing positive through rapid antigen tests. When the numerator is fixed, a denominator that is smaller than the actual number will also lead to an increase in the statistical severity rate/mortality rate.

03

Will reinfection be more serious?

Seeing this, you may have realized that whether the condition becomes milder or more serious after "reinfection" is actually determined by complex factors .

For most viral acute respiratory infectious diseases, more serious infections tend to occur at two stages of our lives .

One is childhood , which is the first time we are infected in our lives. Because we have no previous immunity, we are completely "naked" facing the virus, unless we are protected by active vaccines. This is why various vaccines are very important for children. Vaccines can protect children from infection or prevent severe illness after infection.

The figure below shows the changes in the incidence of some infectious diseases in China from 1949 to 2016. Through continuous health education and active vaccination efforts over the past 70 years, our country has eliminated smallpox and polio, and the incidence of many other infectious diseases has also dropped significantly.

Another more serious period is usually old age , when the probability of severe illness caused by infection with some viruses (such as influenza) is higher due to the deterioration of the human immune system.

Let’s take a closer look at an example of a “reinfection” viral respiratory infectious disease:

RSV, respiratory syncytial virus , most (68%) infants will be infected in the first year after birth, and almost all (97%) infants have been infected before the age of two. RSV is also the main virus causing acute lower respiratory tract infection (ALRTI) in Chinese children. More than 35 million children are infected with RSV each year worldwide, and repeated infections may occur, causing more than 3 million hospitalizations and nearly 60,000 deaths each year.

But by the time we are middle-aged or young, our risk of severe illness from RSV infection is much lower, and the symptoms are more like the common cold . If a person is infected with RSV multiple times, the symptoms tend to be milder after the first infection.

This is how the body's immune system responds to a respiratory virus.

04

What happens when you are infected with the new coronavirus again?

In March of this year, scholars from Weill Cornell Medical College (Qatar Campus) published a study in NEJM [1] to evaluate the protection provided by previous infection.

The study found that 270 days after infection, the protection against reinfection with different variants was:

Alpha strain: 90.2%

Beta strain: 85.7%

Delta strain: 92%

Omicron strain: 56%

Among the 1,304 patients who were reinfected, 5 developed severe illness (reduced oxygen saturation and required oxygen); no one developed critical illness or died.

However, some studies have reached different conclusions. For example, a study published in the journal Nature Medicine [2] showed that compared with patients who had been infected only once, patients who were reinfected had a higher risk of complications, including pulmonary, cardiovascular, diabetic, gastrointestinal and neurological complications, regardless of vaccination status.

This study has been widely circulated on the self-media, but in fact, the authors of this article themselves wrote: " Our analysis should not be interpreted as an assessment of the severity of the second infection compared with the first infection, nor should it be interpreted as comparing the risk of adverse health outcomes after the second infection with the risk of adverse health outcomes after the first infection ."

Screenshot of the paper. Image source: Nature magazine official website

In addition, the patients in this study were mainly veterans. Those who were reinfected were older (average age 60 years old), mostly male (86%), and had multiple high-risk factors, including obesity (average BMI 31) and diabetes (36%). Each person took an average of 16 medications every day, and most people (87%) had never been vaccinated.

According to a meta-analysis[3] published in Science Reports by Shanghai Jiao Tong University and Yale University in December this year (the analysis included 11 studies and 11 case reports from around the world), we can see a relatively more comprehensive picture: people who have been infected with the new coronavirus before are still at risk of infection, but their risk of reinfection is lower than those who have not been infected .

05

Summarize

Based on basic knowledge of immunology, both natural infection and vaccination with the new coronavirus will produce immune responses , including humoral immune responses (antibodies) and cellular immune responses (T cells), which help prevent subsequent infections . Although the level of antibodies decreases faster, there is still protection from T cells and various memory cells, which can significantly reduce the risk of severe illness.

The meta-analysis mentioned above also showed that the level of neutralizing antibodies produced by previous infection was lower than that produced by vaccination [3]. This suggests that people with previous infections still need to be vaccinated to obtain higher protection .

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Overall, the risk of reinfection and the symptoms after infection depend on a variety of complex factors, including changes in variants, vaccination status, and previous physical conditions. It is true that a small number of infected people are at higher risk of reinfection, but for most people, there is no need to worry that reinfection will become more serious .

Most importantly, regardless of whether you have been infected or not, you should actively get vaccinated . Active infection cannot replace vaccination. While getting vaccinated, we should still do a good job of personal protection, including wearing masks, washing hands frequently, and maintaining social distance.

The best way to avoid severe illness after infection is to avoid infection.

References:

[1] Altarawneh HN, Chemaitelly H, Hasan MR, et al. Protection against the omicron variant from previous SARS-CoV-2 infection[J]. New England Journal of Medicine, 2022, 386(13): 1288-1290.

[2] Bowe B, Xie Y, Al-Aly Z. Acute and postacute sequelae associated with SARS-CoV-2 reinfection[J]. Nature Medicine, 2022, 28(11): 2398-2405.

[3] Deng L, Li P, Zhang X, et al. Risk of SARS-CoV-2 reinfection: a systematic review and meta-analysis[J]. Scientific reports, 2022, 12(1): 1-9.

Author: Zhuang Shili and medical science blogger

Reviewer: Li Dongzeng, Chief Physician, Department of Infectious Diseases, Beijing You'an Hospital, Capital Medical University

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