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Approximately 20% of asymptomatic people who test positive for COVID-19 will remain symptom-free over time, according to two studies published September 22 in different journals. The researchers propose, therefore, that most asymptomatic patients should be considered presymptomatic.
“Only a minority of people with SARS-CoV-2 have a truly asymptomatic infection. Most patients with SARS-CoV-2 who are asymptomatic at the time of testing will go on to develop symptoms,” study author Nicola Low, MD, head of the Research Group at the Institute of Social and Preventive Medicine at the University of Bern in Switzerland, told Medscape Medical News.
The result also suggests expanded testing for SARS-CoV-2 infection is warranted, especially among those at higher risk, and supports use of control measures including masks, physical distancing, and isolation.
“People with asymptomatic infection are infectious. All should be isolated and contact tracing should be started,” Low added.
Low and colleagues performed a living systemic review and meta-analysis evaluating the occurrence and transmission of asymptomatic and presymptomatic patients. They published their findings in PLOS Medicine.
Sung-Han Kim, MD, PhD, and co-investigators conducted a study comparing levels of SARS-CoV-2 in the nose and throat of asymptomatic vs symptomatic individuals published in the journal Thorax.
The research teams out of Switzerland and South Korea point to a need for more clarity on which patients with COVID-19 are asymptomatic vs presymptomatic. Most previous researchers tested people for SARS-CoV-2 infection at a single time, preventing identification of the percentage who subsequently developed symptoms.
The previous work also has been heterogeneous. “Researchers have investigated the proportion with asymptomatic infection in a wide range of settings, including hospitals, as part of outbreaks, through contact tracing, and through screening,” Low said. The variability between estimates was “very high,” from 3% to 83% in individual studies, she added.
Main Meta-Analysis Findings
Low and colleagues searched PubMed, Embase, bioRxiv and MedRxiv for relevant studies. The “living” meta-analysis reflects ongoing updates in March, April, and June of this year. They used reverse transcriptase polymerase chain reaction (RT-PCR) testing for SARS-CoV-2.
The data included a statistical modeling study of all 634 passengers from the Diamond Princess cruise ship with RT-PCR positive test results.
Overall, in 79 studies conducted in a range of different settings, 20% of people with SARS-CoV-2 infection remained asymptomatic during follow-up.
When confined to seven studies that screened defined populations with follow-up, a higher proportion (31%) remained asymptomatic over time.
The researchers caution their asymptomatic estimate was limited by biases in study designs. Furthermore, they found it difficult to identify the proportion of asymptomatic and presymptomatic patients who contribute to the overall transmission of SARS-CoV-2.
A subset of five studies include detailed contact tracing. From this data, the investigators calculated the risk of asymptomatic people transmitting SARS-CoV-2 was lower (summary risk ratio, 0.35, compared with symptomatic people at 0.63). More trials are needed to confirm these findings, they note.
“The findings from systematic reviews, including ours, do not support the claim that a large majority of SARS-CoV-2 infections are asymptomatic,” they add. Furthermore, because SARS-CoV-2 can be transmitted a few days before an infected person develops symptoms, “presymptomatic transmission likely contributes substantially to overall SARS-CoV-2 epidemics.”
Similar Viral Loads Found in South Korea
Kim and colleagues found almost the same proportion, 19% of 213 patients, without severe symptoms of COVID-19 remained asymptomatic through potential exposure, lab confirmation, and hospital admission.
The upper respiratory tract viral load did not differ significantly between asymptomatic and symptomatic individuals in upper respiratory tract samples in South Korea.
“Our data adds to the recent growing body of evidence that asymptomatic individuals with SARS-CoV-2 infection are indeed contributing to the ongoing community spread of COVID-19, senior study author Kim told Medscape Medical News.
The mean cycle threshold (Ct) values of SARS-CoV-2 genes, which reflect the viral load, “were highly similar between asymptomatic individuals and symptomatic patients,” added Kim, professor of infectious diseases and chief of the Office of Infection Control at Asan Medical Center in Seoul, South Korea.
The findings suggest that asymptomatic individuals have “a comparable potential for spreading the virus as much as symptomatic patients,” he said. “To prevent the transmission from asymptomatic individuals with SARS-CoV-2 infection, the use of face masks by the general public — regardless of the presence of symptoms — is highly recommended.”
The study was feasible because of a unique situation — a COVID-19 outbreak in Daegu City was traced to a single religious group. The 3000 close contacts identified reported symptoms from none to severe, and the asymptomatic people were isolated and monitored in dedicated facilities.
“We were able to assess many asymptomatic individuals who were otherwise unlikely to be identified as cases of COVID-19,” the investigators note.
A subset of 183 patients, including 39 asymptomatic people and 144 who were symptomatic, underwent follow-up RT-PCR testing. Swab samples from the nasopharynx and oropharynx were combined in a single assay.
As most asymptomatic people with COVID-19 continue to live in a community setting, the researchers note, “such individuals may act as an essential driving force for the community spread of COVID-19 and the ongoing pandemic state.”
A limitation of the study was a population largely composed of individuals in their 20s and 30s, so the generalizability to other age groups is unknown.
“These studies represent valuable contributions, but also underline how much uncertainty remains. Neither says much about asymptomatic transmission,” Jonathan Dushoff, PhD, professor, Department of Biology, McMaster University, Hamilton, Canada, told Medscape Medical News when asked to comment on the research.
“They don’t seem to me to change the consensus that people without symptoms, whether asymptomatic or presymptomatic, should be seen as potential spreaders, even though there is weak evidence that they are less contagious than people with symptoms,” added Dushoff, who coauthored a study on the timing of asymptomatic SARS-CoV-2 transmission published in June in the journal Epidemics.
Not an Easy Task
“It would be actually difficult and challenging to provide a real estimate of the asymptomatic transmission rates,” Lei Huang, MD, told Medscape Medical News when asked to comment. People without symptoms may be unaware that they were exposed to someone else during the virus incubation period, Huang added.
Studying a randomly selected population, one that is representative and generalizable to settings where disease transmission is known to occur, would be a more ideal approach, Huang said.
The current research “suggests that in places where transmission has occurred, it would always be helpful to pay special attention to self-protection, even when facing someone who appears to be perfectly healthy,” said Huang, lead author of a prospective, contact-tracing study that revealed rapid transmission of COVID-19 in asymptomatic people aged 16 to 23 years.
“While the chance of transmission from asymptomatic cases may be lower than from symptomatic ones, the importance of asymptomatic transmission should never be ignored considering the uncertainty of the real proportion of asymptomatic cases,” said Huang, who is affiliated with the Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Anhui Province, China.
Low is a member of the PLOS Medicine editorial board. Kim, Dushoff, and Huang have disclosed no relevant financial relationships.
The Swiss National Science Foundation, the European Union Horizon 2020 research and innovation programme, a Swiss government excellence scholarship, and a stipend from the Swiss School of Public Health Global P3H funded the PLoS Medicine study.
A grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea, supported the study in Thorax.
PLOS Med. Published online September 22, 2020. Full text
Thorax. Published online September 22, 2020. Full text
Damian McNamara is a staff journalist based in Miami. He covers a wide range of medical specialties, including infectious diseases, gastroenterology and primary care. Follow Damian on Twitter: @MedReporter.