Two-thirds or more of people infected withCOVID-19who infect others may do so before ever showing symptoms themselves, a prospect that is prompting intense activity to understand the so-called asymptomatic nature of some carriers.
Many, perhaps most asymptomatic patients will never actually develop symptoms, some researchers believe, making them a silent population of the infected, a covert cohort that is undercounted by typical COVID-19 genetic tests.
One study out of China this week argues that so many asymptomatic people go undetected that it may be time to have a new definition of infectious people -- one that relies not only on genetic tests but possibly on serological tests that find antibodies in the blood even when a person tests negative for the disease.
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Qing Lei and colleagues from China's Tongji Medical College screened 177 people in the city of Wuhan, where the virus started, from February to April, they report this week in a paper posted on the medRxiv pre-print server. The study matched the 63 asymptomatic people with 51 people who showed mild symptoms of COVID-19, and 63 people who were healthy control subjects. All of the participants were followed for 65 days.
Among the asymptomatic, 12 people who had no symptoms tested positive for COVID-19 according to the widely used RT-qPCR genetic test, the so-called asymptomatic carriers. Another 51 asymptomatic people came up negative on the genetic test but were found to have antibodies to COVID-19 in their blood, meaning they were infected. Antibodies are particles that form in the blood as the body's response to the virus.
In other words, 81% of people with the disease in this sample who had no symptoms appeared negative on typical tests -- all false negatives.
"Asymptomatic infection has clear infectivity," one of the scientists, Xionglin Fan, toldZDNetin an email, citing past studies by the Chinese Health Commission. For that reason, said Fan, "early identification of asymptomatic infection is urgently needed."
Researchers from many institutions have pointed out for months now that people who show no symptoms of COVID-19 -- no fever, no cough, no shortness of breath -- can nevertheless infect others. The Tongji work is part of a broad trend in COVID-19 research to more sharply delineate just how big the asymptomatic population is.
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If most asymptomatic people go undetected, it could be many more than generally believed, and if many of those undetected infect others, than a whole part of the transmission of the disease might be obscured.
Fan and colleagues propose that the definition of people who are infected with COVID-19 be extended beyond the definition of merely those who have tested positive via the genetic test, a so-called nucleic acid test, or NAT for short.
Instead, "asymptomatic infection should be defined as a person [who] has positive NAT or/and antibodies without clinical symptoms," write Lei and colleagues in the paper, titled,Antibody dynamics to SARS-CoV-2 in Asymptomatic and Mild COVID-19 patients.
The paper has not yet been peer-reviewed, and so its findings should be taken with a degree of caution.
Asked about the definition, Fan toldZDNet: "We think this definition more reasonable and practical."
"If only NAT detection [is used] for identification, 81% of asymptomatic infection can not be found out," wrote Fan. That would mean "the proportion of asymptomatic infections might be much higher than the current rate reported in China."
Fan cites support for the importance of asymptomatic cases in researchpublished inNaturemagazine last weekby fellow researchers at Tongji, led by Xingjie Hao. That study looked back at 32,583 cases in Wuhan and found that 87% of infections prior to March 8 were cases that were "unascertained, potentially including asymptomatic and mild-symptomatic cases," a phenomenon the authors call a "high covertness."
The scope of asymptomatic infection and transmission is widely debated. Asymptomatic cases of COVID-19 have been notoriously difficult to identify and count, leading to controversy about the term.
For example,a review of the literature posted on June 4 on medRxivby Oyungerel Byambasuren and colleagues at Bond University in Australia looked at nine different primary studies of COVID-19. The authors concluded that asymptomatic patients made up on average 15% of total cases of COVID-19, "lower than many highly publicized studies."
Lei and colleagues at Tongji say the data show otherwise.
"I don't agree with the perspective that the truly 'asymptomatic' may be rare," Fan toldZDNetvia email.
Fan directedZDNettoa statement by China's National Health Commissionon April 15 that reported 6,764 cases of asymptomatic infection in China up until that time. Only 1,279 of those asymptomatic cases were ultimately confirmed via nucleic acid test. "These 1,297 cases might be thought of as pre-symptomatic," Fan toldZDNet. "The others really remain asymptomatic."
If asymptomatic people are truly a group that never develop symptoms and don't even show up on a genetic test, and therefore are not confirmed cases, then that means the transmission by people without symptoms may be much higher than believed.
For example,a studyby Tapiwa Ganyani and colleagues at I-BioStat, part of Belgium's Hasselt University, concluded that upwards of 62% of transmission may be pre-symptomatic. However, that study only looked at symptomatic and pre-symptomatic transmission and explicitly excluded asymptomatic transmission.
Besides pointing out the scope of asymptomatic transmission, it's conceivable serological studies of the kind conducted by Lei and team may lead to a more nuanced understanding of infection. Because serological tests can measure different kinds of reactions, they can classify people into sub-groups.
The serological test used by Lei et al. to detect the asymptomatic patients' antibodies is a marvel of modern technology known as bio-printing.
Proteins of the virus are loaded in solution into a kind ofinkjet printer from British firm Arrayjet. The printer emits those proteins through its nozzles onto the surface of a thin strip of film. The film with the dots of protein, known as aprotein microarray, is then exposed to the blood sera of individuals. If an individual's blood forms a reaction to any of the proteins, that means that the individual's blood may contain antibodies that have formed in response to exposure to the virus. The reaction can be seen based on the hue and intensity of a color change in the film when it's run through a laser scanner.
There are 23 different virus proteins printed on the assay used by Lei and the team. Depending on the kind and number of dots that show up, people can be positive for one type or antibody, negative for another, in ways that show specificity for each protein.
Those variations are so specific they can reveal where some people have been misdiagnosed, Fan toldZDNet.
"Our proteome array really demonstrated there are several misclassifications [of] healthy contacts, asymptomatic infections, and mild patients in clinic," said Fan.
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Somewhat ominously, the scientists also observed the possibility that the neutralizing antibodies in a person's blood, the kind that fight the disease, seem to go away over time. Lei and team found that antibodies began to erode 25 days after the infection began. Within a couple of months, they were generally gone from individuals' bloodstreams.
That echoesanother study last week of serological testsfrom Jeffrey Seow and colleagues at the Department of Infectious Diseases, School of Immunology and Microbial Sciences at King's College in London.
If antibodies disappear within months, then immunity to COVID-19 after recovery may not last long.
As a consequence, "Both papers do not think immunity passport is okay," Fan toldZDNet, rejecting the notion of a special exemption for someone to avoid lockdown and masks after having recovered.
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