A new paper written by Stanford affiliates looks into the science behind the presymptomatic and asymptomatic transmission of COVID-19. Authors Christina Savvides ’19 MS ’21 and professor Robert Siegel explain that they found shortcomings in the existing studies on the issue, and emphasize the need for studies that can provide a more definitive answer on whether or not these kinds of transmissions take place. The paper was published as a preprint on June 13 on medRxiv, a site that distributes complete unpublished manuscripts in the field of medicine.

In presymptomatic cases, the patients have been infected by COVID-19 but are not yet showing symptoms, and in asymptomatic cases, people are infected by COVID-19 but show no symptoms. While some things are known about these types of cases, the existence and extent of transmission by patients like these has yet to be determined.

“What’s been really well established in COVID is you can have an asymptomatic case,” Savvides said. “The problem we haven’t established is [whether] you can asymptomatically transmit that infection.” 

According to Savvides, understanding presymptomatic and asymptomatic transmission is important in creating effective public health measures, such as contact tracing. An increased understanding of these cases will be “instrumental to developing the most informed policies on reopening our cities, states, and countries,” Savvides and Siegel wrote in their paper.

Savvides and Siegel’s paper is a systematic review, intended to give an overview of the existing research on presymptomatic and asymptomatic transmission.

“It’s easy to pick and choose one study that says one thing, but the hope with doing a systematic review is that you get the broader picture,” Savvides said. To find studies, Savvides and Siegel searched PubMed, a database of articles, for articles that collected data on presymptomatic and asymptomatic transmission, and screened the studies before including them in the paper. 

After analyzing the studies, Savvides and Siegel were unable to come to a conclusion about whether presymptomatic and asymptomatic transmission takes place.

“In aggregate, these data offer compelling evidence of asymptomatic and presymptomatic transmission, but individually these studies have notable shortcomings that undermine their conclusions,” Savvides and Siegel’s article says. For example, the article explains that many of the studies did not start collecting data until after subjects already had symptoms, and in some of studies the subjects received treatments, like antivirals, that may have interfered with the results. 

However, Siegel emphasizes that their findings do not mean that asymptomatic and presymptomatic transmission does not take place.

“Absence of evidence is not evidence of the absence,” Siegel said. “Our study doesn’t show that there’s no asymptomatic or presymptomatic transmission. Our study shows that we need good science to underlie those conclusions.” 

To produce more definitive evidence, the authors proposed a study that would address many of the limitations they saw in existing studies. Their proposed research would investigate the progression of the infection by testing members of a population at regular intervals to collect data about the progression of the virus in the body before, during and after an infection. They suggest that an ideal population would be at “high risk of infection and low risk of complications, such as workers in a factory at the start of an outbreak, or individuals identified through contact tracing.” Since those people would be less likely to seek therapies, the progress of the virus in the body could be monitored without interference. 

In addition to finding experimental shortcomings, Savvides has also had transparency issues with some of the articles she looked at.

“In the chaos and the pressure to put out information I think science has kind of fallen on a couple of shortcuts in terms of there’d be times where I’d be looking at the data, and I couldn’t access that data, or the paper would mention see attached data but that data wouldn’t be available,” Savvides said. “In the midst of a pandemic it’s kind of hard to fault people for not dotting their Is and crossing their Ts, but I think that it’s crazy we’re this far along, we have this many cases, this many deaths and we’re still not getting the data we need to answer these really fundamental, really basic questions.” 

Siegel believes that despite the pandemic scientists still need to produce high quality studies.

“The crisis is never too big to do good science,” he said. “If you do bad science you’re not going to get the right answer, if you do good science it might take a little bit longer but in the long run it will save you time, it will save you money, and it will save lives.” 

By writing the paper and outlining what an ideal study would look like, Siegel hopes to motivate the medical community to conduct a study that will provide a much clearer answer, something he thinks should have happened a long time ago.

“We still haven’t really done the proper studies, and that’s just unacceptable,” Siegel said.

Savvides agreed, saying she believes “it’s problematic because we know what kind of studies have to be done to answer this question and unfortunately they just haven’t really been done yet.”

The issue of good science is also an emphasis in Siegel’s class, “The Vaccine Revolution,” which Savvides took this spring. The class encourages students to analyze scientific articles to become “hypercritical about the methodologies, the results, the conclusions of scientific papers to see whether they prove what they said they proved,” Siegel said. In the spirit of the class, Savvides began to look at the evidence behind asymptomatic and presymptomatic transmission, and eventually decided to write the paper. 

Additionally, the paper was an opportunity for Savvides to continue to do scientific research while her lab was shut down. “I think something that’s really cool and really special about Stanford is that I was able to sort of pick up with this other project that isn’t necessarily my primary research field,” Savvides said. 

In mid-July, Savvides and Siegel, along with three new authors, will be publishing an updated preprint, which will include studies that were published too late to be included in the original paper. The new version will be sent out to be peer reviewed. In the meantime, Siegel hopes that the paper may motivate people with the resources to conduct a better study that will provide more definitive evidence.  

Contact Io Gilman at ioyehgilman ‘at’ gmail.com.