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An international team of researchers, led from Centre for Evidence-based Medicine based in the Nuffield Department of Primary Care Health Sciences, University of Oxford, and funded by the World Health Organization and the National Institute for Health Research School for Primary Care Research, have today announced the findings from the most complete analysis of high-quality covid transmission studies in asymptomatic and pre-symptomatic people to date.

The results suggest that PCR ‘Cycle thresholds’ could be the key to determining if someone who is asymptomatic may be able to infect others or not, and therefore deciding what measures should be put in place to prevent further transmission.

Unique to this systematic review was its combination of clinical, epidemiological, molecular, and laboratory evidence to identify high-quality evidence and limit uncertainty in how the virus was transmitted; a framework that is lacking in similar studies.

For example, the researchers only included evidence where secondary infections were laboratory confirmed by genome sequencing and/or by being able to grow the ‘live’ virus, rather than assumed based on being positive or not. Thereby adding confidence that the asymptomatic carrier did infect a second person.

The findings confirm that a proportion of asymptomatic and pre-symptomatic people can pass on COVID-19 to others, while remaining apparently unaffected themselves, but this is far more likely to happen in people who have a low PCR ‘cycle threshold’.

In most commonly used COVID PCR tests, a positive result is given if a fluorescent signal develops after a number of ‘amplification’ cycles. The cycle threshold (Ct) is the number of amplification cycles required for the fluorescent signal to become strong enough to confirm a positive result. Because of the way PCR works, the more virus in a sample to start with, the fewer cycles are needed for a signal to be detected – the lower the Ct value.

A low Ct value is associated with a high viral load. This means the amount of virus in a given sample was high, and therefore the infected person is more likely to go on to infect others.

Carl Heneghan, Professor of Evidence-based medicine at the Nuffield Department of Primary Care Health Sciences, University of Oxford, Director the Centre for Evidence-based Medicine and practicing GP said:

“In the UK, by design, we carry out a large amount of asymptomatic testing, but we rarely ,if ever, report on an individual's Ct numbers of  these tests. If we look at these findings in the context of reducing the amount of testing done in the UK, for example, it could be that by reporting people’s Ct numbers, we could better determine if someone should isolate or not.

This would have multiple positive effects on both people, such as saving them the worry of being notified they may have been in contact with someone infected, and society, by stopping people needlessly having to isolate and all the problems this  causes people and communities as they go about their daily lives.”

The proportion of asymptomatic people who may have been transmissible ranged from 18% (in cruise ship passengers) to 86% (in army barracks), depending on the study population. As some of the studies focussed on ‘captive’ populations, such as cruise ships or care homes, these levels are likely to vary depending on a number of population and environmental factors.

It was not possible from the studies included to estimate how long a person might remain contagious.

Another important finding was that few studies or data sets actually follow up on asymptomatic people to determine if they did subsequently show symptoms of COVID, or whether they show the traditional symptoms of COVID-19. The authors note that this may be particularly important for elderly people.

Three of the studies examined in the review reported uncommon or subtle symptoms of infection in the elderly, including, for example, new confusion, reduced alertness, fatigue, lethargy, reduced mobility, and diarrhoea.

Also, as this was typically a population with chronic health problems, some studies reported difficulty in determining whether a person was truly asymptomatic as it was hard to distinguish short term COVID symptoms from symptoms of pre-existing illnesses.

Epidemiologist and former GP Tom Jefferson said:

“This finding may go some way to explain the apparent paradox of why the number of people with COVID in care homes rose after lockdowns began. These could well have been people who were infected before the lockdown began, it just took longer for symptoms to manifest or be recognised, and the person be tested.”

This also illustrates, say the authors, that labelling someone as ‘asymptomatic’ based on a single observation can be misleading.

Dr Jefferson continued:

“The problem with calling someone asymptomatic, i.e., no symptoms at the time of a positive test, is that in most studies and data sets available there is rarely a reliable follow up to say if that person actually did or did not go on to develop symptoms. Our research suggests that this may often be the case in elderly populations.”

The results from this systematic review are part of a larger project supported by the World Health Organization and the NIHR School of Primary Care Research (SPCR) , providing regularly updated summaries and evaluations of the data and evidence on SARs-CoV-2 transmissibility, including areas such as airborne, contact and droplet, orofecal, and fomite transmission (inanimate objects that might pass on infection, like door handles and phones).

Dr Heneghan said:

 “As these are ‘living’ reviews, each update we make narrows the sphere of uncertainty a bit more, meaning we can be increasingly confident in what the data says, and what it’s real-world implications may be. The overall aim of this ongoing research is to enable policy makers to make reasonable and reliable decisions around transmission probabilities.”

The authors would also like to thank the authors of the original work included in this systematic review, who together had a response rate to questions greater than 90% to their queries – unusually high for a systematic review.

Limitations of the study:

  • Limited number of studies available to include (18)
  • Of the 18 studies included in the analysis, 14 were classified as high risk of bias and 4 studies at moderate risk of bias.
  • Different populations may still show different transmission characteristics and rates. E.g., young vs elderly.
  • Whether someone remained asymptomatic or not, depending on ‘self-reporting’ on individuals’ symptoms, rather than clinical analysis, for a number of studies.

PUBLICATION:

Transmission of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) from pre and asymptomatic infected individuals. A systematic review.
Tom Jefferson, Elizabeth A. Spencer, Jon Brassey, David H. Evans, John M. Conly, Carl J. Heneghan, et al
DOI:https://doi.org/10.1016/j.cmi.2021.10.015

Carl Heneghan has been PI on WHO funded transmission work and received funding from the University of Calgary and funding support from the NIHR School of Primary Care Research.