The “knowns” and “unknowns” about asymptomatic infections

"Asymptomatic infections" have become a focus of attention recently. The National Health Commission has published daily data on asymptomatic infections of the novel coronavirus for the first time since April 1. What scientific attitude should be taken towards asymptomatic infections?

Written by reporter Li Peng, Photo and text editor Chen Yongjie

New Media Editor/Chen Xuanzhi

Interview experts:

Yang Gonghuan (Chinese public health and epidemiology expert, former deputy director of the Chinese Center for Disease Control and Prevention)

Liu Fuqiang (Director of the Emergency Office and Chief Physician, Hunan Provincial Center for Disease Control and Prevention)

In recent times, sporadic cases in the country have once again caused the issue of asymptomatic infections to attract widespread attention.

On March 30, Premier Li Keqiang chaired a meeting of the Central Leading Group for Response to the COVID-19 Epidemic, requiring efforts to consolidate the effectiveness of prevention and control, with a focus on prevention and control of asymptomatic infections. From April 1, my country will publish reports, outcomes, and management of asymptomatic COVID-19 infections in daily epidemic reports to respond to public concerns in a timely manner.

▲From April 1, my country will announce the number of asymptomatic infections every day (picture from the Internet)

Asymptomatic infection is a characteristic of infectious diseases

The so-called asymptomatic infection refers to the part of the population where viruses, bacteria and other pathogens invade the human body and reproduce or replicate, but the human body is not damaged and there are no symptoms. In fact, many of the infectious diseases we are familiar with have asymptomatic infection periods, such as hepatitis B and AIDS. One of the characteristics of these infectious diseases is that asymptomatic infection patients coexist with symptomatic patients, and the same is true for the new coronavirus.

In the history of infectious diseases, the most famous asymptomatic carrier is "Typhoid Mary". This American maid, born in 1869, carried Salmonella typhi but had no symptoms. Whenever she worked as a cook in a household, she would cause many people to contract typhoid fever. Epidemiological investigations eventually identified this asymptomatic carrier, and doctors used various drugs, but Salmonella typhi persisted in her body.

▲The most famous asymptomatic carrier in medical history is Typhoid Mary, the first asymptomatic typhoid carrier discovered in the United States in the early 20th century (picture from the Internet)

Cai Yong, deputy dean of the School of Public Health at Shanghai Jiao Tong University School of Medicine and a member of the Shanghai Overseas Import Epidemic Prevention and Control Expert Group, said in an interview with Xinhua News Agency that there are several common outcomes after pathogens invade the human body: First, the pathogens are quickly killed by the immune system, and there may be no time for clinical symptoms to appear. The second is latent infection, that is, the human body has almost no symptoms or only slight tissue damage, and the infection can be known through antibody testing. Most people can therefore gain specific immunity, which not only clears the pathogens but also prevents reinfection. Third, the pathogens remain in the infected tissues, and the human body may not have any symptoms, but will excrete the pathogens through the blood, respiratory tract or digestive tract, etc., which is somewhat contagious.

"Asymptomatic infections usually refer to the third situation, and also include the second latent infection group where the virus has not been completely cleared." Cai Yong said that they have no obvious symptoms, probably because their immune system is relatively strong and can better inhibit the reproduction or replication of pathogens in the body. But they are likely to be the source of infection, causing infection to others.

Asymptomatic infections are also called "silent carriers" of the virus. Sometimes they become super spreaders and cause serious virus transmission, so it is particularly important to detect asymptomatic infections early.

Asymptomatic infections in my country have not been listed as "confirmed"

In this COVID-19 outbreak, the initial focus on "asymptomatic infections" came from a paper published in the top medical journal "New England Journal of Medicine" on January 30, which stated that an asymptomatic female infected person from Shanghai, China caused four people in Germany to be infected with the new coronavirus. However, on February 4, "Science" magazine published an article saying that there were factual errors in the article and that the woman was not completely asymptomatic.

This group of people was again in the spotlight after Wuhan was "cleared". On March 19, according to the COVID-19 updates released by the Wuhan Municipal Health Commission, there were no new confirmed cases in Wuhan that day. However, on March 20, a "public notice" circulated online showed that there was a new confirmed case in a community in Qiaokou District on the 19th, sparking controversy over whether the number of confirmed cases in Wuhan was zero. The Qiaokou District Prevention and Control Command responded that the patient Zhang XX, who was circulated online, was an asymptomatic infected person, not a confirmed case. Subsequently, many "asymptomatic infected people" appeared across the country.

In fact, in our country's official diagnosis and treatment plan, asymptomatic infections, confirmed cases, suspected cases, etc. have always been listed separately.

The term "asymptomatic infected person" first appeared in the "New Coronavirus Pneumonia Prevention and Control Plan (Third Edition)" issued by the National Health Commission on January 28, and appeared alongside suspected cases, confirmed cases, mild cases, and close contacts.

The sixth edition of the prevention and control plan released on March 7 clearly stated that "if asymptomatic infected persons show clinical symptoms, they should be promptly revised to confirmed cases." Asymptomatic infected persons should be isolated for 14 days. After the isolation period expires, in principle, those who have two consecutive negative nucleic acid test results (with at least 24 hours between sampling times) can be released from isolation. If symptoms appear during the isolation period, they should be admitted to the hospital immediately.

The "New Coronavirus Pneumonia Diagnosis and Treatment Plan (Trial Version 7)" released on March 3 clearly stated that asymptomatic infected persons may also become sources of infection. Suspected and confirmed cases must have clinical manifestations. Asymptomatic infected persons need to be isolated for 14 days and undergo further testing to make a judgment because they have no clinical manifestations.

It can be seen that since January 28, "asymptomatic infections" have never been included in the category of confirmed or suspected cases. Only when symptoms appear during the quarantine period will they be included in the published figures. Starting from April 1, the official figures of asymptomatic infections were announced.

"Asymptomatic" is not entirely subjective

According to the latest definition released by the National Health Commission on March 31, asymptomatic infections refer to those who have no self-perceived clinical symptoms such as fever, cough, and sore throat, and no clinically identifiable symptoms and signs, but the pathogen testing of respiratory and other specimens for the new coronavirus is positive.

So, what does "asymptomatic" mean? Is it completely determined by subjective feelings? Is it that if someone feels that they have no physical symptoms but tests positive, they are "asymptomatic"?

Yang Gonghuan, a Chinese public health and epidemiology expert and former deputy director of the Chinese Center for Disease Control and Prevention, said that even if a nucleic acid-positive patient has no physical discomfort, but a CT scan shows ground-glass lesions in the lungs, this is a symptom of infection and the patient can no longer be counted as an asymptomatic infected person. This is also the case for confirmed cases in our country.

▲ CT scan of the lungs of patients with COVID-19 shows ground-glass shadows (picture from the Internet)

Asymptomatic infections can be divided into two situations: one is that the infected person tests positive for nucleic acid, and after 14 days of incubation period observation, there are no self-perceived or clinically identifiable symptoms and signs, and the infection remains asymptomatic; the other is that although the infected person tests positive for nucleic acid, there are no self-perceived or clinically identifiable symptoms and signs at the time of sampling, but certain clinical manifestations appear later, that is, the person is in the latent "asymptomatic infection" state.

▲The proportion of asymptomatic infections (Photo source: Huashan Infection)

What about single positive?

Recently, the term "single positive" has appeared in reports from some places. What does this mean?

At present, the main method for detecting nucleic acid of the new coronavirus is the real-time fluorescence RT-PCR method, which targets the open reading frame 1ab (ORF1ab) and nucleocapsid protein (N) in the genome of the new coronavirus.

Generally, positive patients have positive ORF1ab and N genes at the same time, but there may be cases where one of ORF1ab or N gene is positive, which is called single positive. For the above-mentioned cases with single positive nucleic acid test of new coronavirus, it is still necessary to take samples again for real-time fluorescence RT-PCR test to determine whether the case is positive.

For the above-mentioned cases with single positive nucleic acid test of the new coronavirus, it is still necessary to take samples again for real-time fluorescence RT-PCR test to determine whether the case is positive. Asymptomatic people infected with the new coronavirus may have single positive and double positive nucleic acid test results, and there may also be false positives, which is an issue that needs to be paid attention to in the test.

There are differences in the statistics of asymptomatic infections between China and foreign countries

Under WHO guidelines, all people who test positive are classified as confirmed cases, regardless of whether they show symptoms.

South Korea uses this statistical method in its epidemic statistics. The United States, Britain and Italy do not provide testing services to asymptomatic people, except for medical workers who have long-term contact with the virus and officials in important positions.

Recently, many provinces in my country have recorded zero new infections for several consecutive days, which has caused concern among many people and experts. "It is impossible for an epidemic as big as Wuhan to be completely eradicated all at once, and this does not conform to the law of the development and change of the epidemic," said Yang Gonghuan. Now the country has increased the statistics of asymptomatic infections to fill this loophole.

Asymptomatic infections may be underestimated

On March 31, the latest data from the National Health Commission showed that as of 24:00 on March 30, 2020, there were 1,541 asymptomatic cases under medical observation in my country, including 205 imported cases. According to current research, there are still many asymptomatic cases in China that have not been discovered.

A report released by a World Health Organization (WHO) international mission in China in February estimated that asymptomatic infections accounted for 1% to 3% of total cases. But the latest data shows that the proportion of asymptomatic infections may be significantly underestimated.

On March 19, a data model constructed by Hong Kong researchers in a paper published in the journal Nature Medicine showed that the mortality rate of symptomatic patients infected with COVID-19 in the Wuhan population was about 1.4%, much lower than the 4.5% mortality rate shown in current statistics.

Research suggests that during the outbreak, the squeeze on medical resources resulted in a large number of patients with mild symptoms not being tested, including a large number of asymptomatic infections.

The samples from the Diamond Princess cruise ship are also an important reference. After repeated testing and close monitoring of the 3,711 passengers and crew members on the cruise ship, Professor Gerardo Kaul, a mathematical epidemiologist at Georgia State University in Atlanta, published a study in the academic journal Eurosurveillance on March 12 showing that about 18% of the approximately 700 infected people on the Diamond Princess never showed symptoms.

▲"Diamond Princess" cruise ship

In addition, the Korea Centers for Disease Control and Prevention revealed at a press conference on March 16 that based on nearly 300,000 tests conducted by South Korea on close contacts of previously confirmed cases, more than 20% of the infection cases were asymptomatic before discharge.

Through comparison of these studies, many people believe that the proportion of asymptomatic infections reported in China is too low, which is also the main reason for some people's recent concerns.

Asymptomatic infections do not exist in isolation

However, asymptomatic infections must be accompanied by more symptomatic people at the same time, and a large number of asymptomatic infections will not exist in isolation.

Academician Zhong Nanshan said in an interview recently that the current situation of "asymptomatic infections" in China is very limited: there are no specific figures and no detailed research. He believes that some inferences can be made based on known facts. For example, generally speaking, asymptomatic infections have a high rate of infection for people who have close contact with them, but the number of newly confirmed cases of COVID-19 in China has not only not increased, but has continued to decline. This shows that there are not yet a large number of "asymptomatic infections" in China, and the general public does not need to be overly nervous.

Jin Yongtang, a professor at the Department of Public Health at the School of Medicine of Zhejiang University, also publicly stated that there is no evidence that there is a secondary outbreak in my country and epidemic problems caused by asymptomatic infections. Otherwise, the current outbreak and pandemic in my country will not be smoothly controlled as scheduled.

There is no final conclusion on the infectiousness

On February 3, the National Health Commission issued the "Diagnosis and Treatment Plan for Pneumonia Infected by the New Coronavirus (Trial Fifth Edition)", which first clarified in terms of epidemiological characteristics that "asymptomatic infected persons may also become sources of infection." This is mainly based on the close contact monitoring data conducted by the country and some provinces. There are secondary cases among close contacts of asymptomatic infected persons, and epidemiological investigations have found individual clustered epidemics caused by asymptomatic infected persons.

However, there is still some debate in the scientific community about the infectiousness of asymptomatic COVID-19 patients. Some researchers believe that asymptomatic patients are less infectious because they do not sneeze or cough, and the chance of pathogens being excreted from the body is relatively lower than that of confirmed cases, so they are less contagious.

However, some studies have shown that people infected with the new coronavirus are already contagious 2.5 days before they develop symptoms, and their contagiousness peaks 0.6 days before they develop symptoms, reminding people of the risk of infection from asymptomatic carriers.

▲ Schematic diagram of the virus transmission risk of imported asymptomatic infections (Photo source: Huashan Infection)

An article published in the New England Journal of Medicine (NEJM) by the Guangdong Provincial Center for Disease Control and Prevention on March 19 stated that some infected people never showed symptoms, but tests showed that the amount of virus they released was comparable to that of patients with symptoms.

Yang Gonghuan said that humans have only known about the new coronavirus for a few months, and many things have not yet been figured out. Further scientific research is needed on the length of its infectious period, the strength of its infectiousness, and the mode of transmission. It is normal that the scientific community has different understandings of the transmission risks of asymptomatic people infected with the new coronavirus.

Before a definite conclusion is reached, we cannot categorically confirm or deny it, but from the perspective of prevention and control, our country must currently do a good job of tracking and managing this population, cannot turn a blind eye to the related reports that have appeared, and must do its utmost to prevent the spread of virus infection and lead to a secondary outbreak of the epidemic.

Asymptomatic infections are not "letting go"

According to the National Health Commission's Q&A, the prevention and control of asymptomatic COVID-19 infections faces three major transmission risks: hidden transmission, subjective symptom judgment, and limitations in detection.

Liu Fuqiang, director of the emergency office and chief physician of the Hunan Provincial Center for Disease Control and Prevention, said that although asymptomatic COVID-19 patients have not been included in the case statistics in my country for more than two months, they are not in a "sheep-free" state as some people imagine. In fact, all those who can be traced are in centralized isolation and medical observation. People who have close contact with them have also been isolated, which is also an important reason why the national prevention and control has achieved good results in recent times.

Liu Fuqiang stressed that currently asymptomatic infections imported from abroad are the biggest threat to epidemic prevention and control. If they are not strictly screened and tracked, the risk of community transmission will be high. Because in areas where the epidemic has broken out abroad, as the number of new cases increases explosively, the number of asymptomatic infections will also increase. If these asymptomatic infections are imported into my country and directly enter the community, it will be more difficult to trace these asymptomatic infections.

He also believes that as long as you take precautions as required, you generally don't need to worry too much. Infectious diseases must have a source of infection. If there is no source of infection around you, you don't have to worry about being infected. However, you must take precautions when going to public places such as hospitals where the risk is higher.

Yang Gonghuan believes that although there is a risk of infecting others through occasional missed asymptomatic infections, as long as the current epidemic prevention and control measures are not relaxed, they can be properly handled.

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