I just want to preface this post by noting how amused I was yesterday at how people who have castigated the World Health Organization for its handling of the COVID-19 pandemic, who say the WHO is too beholden to China, who tell us that we shouldn’t take anything the WHO says seriously about the pandemic suddenly shifted to portraying the WHO as the font of scientific truth on COVID-19. The reason, as you might imagine, is that there was a news story. This time around, it was on CNBC, and it was entitled Asymptomatic spread of coronavirus is ‘very rare,’ WHO says. The reason these particular people learned to love the WHO again, as you might imagine, is because they are COVID-19 deniers, people who have downplayed the severity of the pandemic, who promote conspiracy theories about it, who refuse to wear masks or engage in social distancing, and the like. You’ll see why in this passage:
Coronavirus patients without symptoms aren’t driving the spread of the virus, World Health Organization officials said Monday, casting doubt on concerns by some researchers that the disease could be difficult to contain due to asymptomatic infections.
Some people, particularly young and otherwise healthy individuals, who are infected by the coronavirus never develop symptoms or only develop mild symptoms. Others might not develop symptoms until days after they were actually infected.
Preliminary evidence from the earliest outbreaks indicated that the virus could spread from person-to-person contact, even if the carrier didn’t have symptoms. But WHO officials now say that while asymptomatic spread can occur, it is not the main way it’s being transmitted.
“From the data we have, it still seems to be rare that an asymptomatic person actually transmits onward to a secondary individual,” Dr. Maria Van Kerkhove, head of WHO’s emerging diseases and zoonosis unit, said at a news briefing from the United Nations agency’s Geneva headquarters. “It’s very rare.”
Van Kerkove then went on to say that government responses should focus on detecting and isolating people with symptoms and then identifying and tracking their contacts. She then did an amazing thing. After having made such a strong statement, she said that more research and data are needed to ‘truly answer’ the question of whether SARS-CoV-2, the coronavirus that causes COVID-19, can spread widely through asymptomatic carriers. My reaction was: Wait, what? How do you know it’s “very rare” then, particularly given the data we have already?
Here’s how, apparently:
“We have a number of reports from countries who are doing very detailed contact tracing,” she said. “They’re following asymptomatic cases. They’re following contacts. And they’re not finding secondary transmission onward. It’s very rare.”
A lot of those of us who follow the COVID-19 pandemic closely were appalled, mainly for two reasons. First, it’s irresponsible to make a statement as seemingly definitive as this if the data used to make the statement aren’t published, particularly when the WHO admits that the answer hasn’t truly been answered yet. Second, the WHO seemed to be conflating asymptomatic COVID-19 with presymptomatic COVID-19. The difference? Asymptomatic means that the person with COVID-19 is infected but never develops symptom, while presymptomatic means that the infected person doesn’t have symptoms now but goes on to become ill. We’ve known from early on in the pandemic that there is presymptomatic COVID-19 transmission, and it wasn’t until later that it even became clear that a significant percentage of people infected with COVID-19 remain completely asymptomatic or so mildly symptomatic that they don’t suspect that they are infected.
A biologist named Carl Bergstrom noted:
The distinction is incredibly important, but let’s look at the actual text of the WHO’s new statement. Again, Dr. Bergstrom pointed me to the relevant passage in the WHO’s current document:
Among the available published studies, some have described occurrences of transmission from people who did not have symptoms.(21,25-32) For example, among 63 asymptomatically-infected individuals studied in China, there was evidence that 9 (14%) infected another person.(31) Furthermore, among two studies which carefully investigated secondary transmission from cases to contacts, one found no secondary transmission among 91 contacts of 9 asymptomatic cases,(33) while the other reported that 6.4% of cases were attributable to pre-symptomatic transmission.(32) The available data, to date, on onward infection from cases without symptoms comes from a limited number of studies with small samples that are subject to possible recall bias and for which fomite transmission cannot be ruled out.
This is pretty thin gruel. A study of 63 people? A study of 91` contacts of the 9 asymptomatic patients who infected another person? Oddly enough, reference 33 concludes:
In this study, high transmissibility of COVID-19 before and immediately after symptom onset suggests that finding and isolating symptomatic patients alone may not suffice to contain the epidemic, and more generalized measures may be required, such as social distancing.
Actually, the study did suggest that the time of highest transmissibility around the time of symptom onset, but also noted:
Our analysis revealed a similar clinical attack rate between the contacts who only had presymptomatic exposure and those who had postsymptomatic exposure.
The key question is whether the bulk of the transmission from asymptomatic people comes from people who later go on to develop symptoms or whether those who never develop symptoms can transmit the virus, as this population biologist points out:
Rephrasing the question, are asymptomatic or mild cases less infectious than people currently in the presymptomatic phase of COVID-19 infection. As you might imagine, that’s a really difficult question to study, as it requires very widespread testing and followup. One study cited above out of Italy concluded:
We found no statistically significant difference in the viral load (as measured by genome equivalents inferred from the cycle threshold data) of symptomatic versus a asymptomatic patients (p-values 0.6 and 0.2 for E and RdRp genes, respectively, Exact Wilcoxon-Mann-Whitney test). Contact tracing of the newly infected cases and transmission chain reconstruction revealed that most new infections in the second survey were infected in the community before the lockdown or from asymptomatic infections living in the same household.
We will look at this study more later in this post.
There’s also bias in contact tracing methodology due to delays between infection and testing. First of all, a negative swab test does not rule out infection even if you don’t have symptoms:
She further notes that most people who are tested have had at least mild symptoms for several days and were infected 5-6 days before that, meaning that the person who infected them was infectious 8-11 days ago, and, if that person was asymptomatic there’s a decent (although not precisely known) chance that they would test negative when traced, as the virus can be cleared in two weeks (which is why the usual self-quarantine period recommended for those who are thought to have been exposed to the coronavirus is two weeks). It’s possible that asymptomatic people clear the virus faster than presymptomatic people and are thus more likely to test negative at, say, 10 days. If that’s the case, though, this could happen:
Eric Topol also weighed in. The advantage of citing him is that he recently co-authored a review article on the prevalence of asymptomatic SARS-CoV-2 infection. Noting that it’s been suspected that infected persons who remain asymptomatic play a significant role in the pandemic, he and Daniel Oran tried to quantify the percentage of asymptomatic COVID-19 cases. First, they note:
In the early months of the coronavirus disease 2019 (COVID-19) pandemic, an iconic image has been the “proned” patient in intensive care, gasping for breath, in imminent need of artificial ventilation. This is the deadly face of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which as of 26 May 2020 had claimed more than 348 000 lives worldwide (1). But it is not the only face, because SARS-CoV-2 now seems to have a dual nature: tragically lethal in some persons and surprisingly benign in others.
Since February 2020 (2, 3), there have been reports of persons who were infected with SARS-CoV-2 but did not develop symptoms of COVID-19. In some cases (4, 5), the viral load of such asymptomatic persons has been equal to that of symptomatic persons, suggesting similar potential for viral transmission. The prevalence of asymptomatic SARS-CoV-2 infection, however, has remained uncertain. We sought to review and synthesize the available evidence on testing for SARS-CoV-2 infection, carried out by real-time reverse transcriptase polymerase chain reaction using nasopharyngeal swabs in all studies that specified the method of testing.
To this end, they examined 16 cohorts from all over the world where COVID-19 outbreaks occurred, including, for example, cohorts from Europe, the Princess Cruise Ship, the aircraft carrier USS Theodore Roosevelt and the French aircraft carrier Charles de Gaulle, nursing home residents in Washington, and inmates in Arkansas, North Carolina, Ohio, and Virginia among others. They estimated that asymptomatic infections might account for 40-45% of COVID-19 cases and that these asymptomatic patients can also transmit the virus for up to 14 days:
At the beginning and end of a 14-day lockdown imposed by authorities in the northern Italian town of Vo’ (7), researchers collected nasopharyngeal swabs from 2812 residents during the first sampling effort and 2343 during the second; this represented 85.9% and 71.5%, respectively, of the entire population. In the first group, 30 (41.1%) of 73 persons who tested positive for SARS-CoV-2 had no symptoms. In the second, 13 (44.8%) of 29 who tested positive were asymptomatic. According to the researchers, in the roughly 2-week period between the sampling efforts, none of the asymptomatic persons developed any symptoms of COVID-19. In addition, through contact tracing, they confirmed that several new cases of SARS-CoV-2 infection that appeared during the second sampling had been caused by exposure to asymptomatic persons.
Then, the USS Theodore Roosevelt:
The first case of SARS-CoV-2 infection aboard the American aircraft carrier U.S.S. Theodore Roosevelt was diagnosed on 22 March 2020 (24). As of 24 April, 4954 crew members had been tested for the virus; 856 (17.3%) tested positive (12). According to a news report, about 60% of those with positive results were asymptomatic (25). After an extended period of isolation, many of these asymptomatic persons continued to test positive for SARS-CoV-2. An internal U.S. Navy document stated, “Results of out-testing portions of the [Theodore Roosevelt] crew following 14 days of quarantine leads us to reevaluate our assessment of how the virus can remain active in an asymptomatic host” (26).
The Charles de Gaulle:
On 8 April 2020, crew members aboard the French naval vessel Charles de Gaulle first began showing symptoms of COVID-19, 24 days after last having had contact with those outside the ship while docked on 15 March (27). On 10 April, 50 crew members received positive test results for SARS-CoV-2. The entire crew of 1760 was subsequently tested. As of 18 April, 1046 (59.4%) had tested positive, and of these, nearly 50% were asymptomatic (13).
Overall, the authors conclude that asymptomatic transmission is a major factor in the spread of COVID-19. It’s obviously not perfect. For one thing, some of the cohorts did not have longitudinal data; i.e., the cohorts weren’t followed long enough to tell how may asymptomatic patients developed symptoms. In other words, how many asymptomatic people were actually presymptomatic? It is thus possible that Oran and Topol significantly overestimated the percentage of COVID-19 infections that are asymptomatic, although
Confusing the issue was the observation from the Diamond Princess cruise ship that among 104 passengers who tested positive for coronavirus but never developed symptoms and underwent CT scans of the chest, lung opacities were detected in 54% of these asymptomatic patients, suggesting subclinical changes to the lung in a high proportion of “asymptomatic” patients, as was published in this study. This is what we refer to as subclinical disease.
The bottom line is simple. It’s possible that asymptomatic patients don’t transmit the virus as much as symptomatic or presymptomatic people with COVID-19. However, even if that’s true, all it would mean is that the percentage of infected patients without symptoms who are truly asymptomatic would constitute less of a risk of infection. Those who are presymptomatic would still be infectious while they don’t have any symptoms. Even if asymptomatic COVID-19 patients are much less likely to transmit the virus (a contention that goes against a fair amount of evidence that we already have and about which the kindest thing we can say is that it’s unproven), we already have abundant evidence that presymptomatic people can transmit the virus. Even if asymptomatic COVID-19 patients are much less likely to transmit the virus, conflating them and presymptomatic patients, as the WHO appears to be doing, does not mean that concentrating only on symptomatic persons with contact-tracing will effectively shut down transmission, both because of the time bias in contact tracing and testing but also because presymptomatic people will continue about their normal lives.
What do we need to get a handle on this question? Oran and Topol tell us:
As noted earlier, the data and studies reviewed here are imperfect in many ways. The ideal study of asymptomatic SARS-CoV-2 infection has yet to be done. What might that study look like? Most important, it must include a large, representative sample of the general population, similar to the U.S. serosurvey for which the National Institutes of Health is currently recruiting (31). In contrast to the narrowly defined cohorts here, it will be illuminating to have data that accurately reflect the population at large. In addition, longitudinal data must be collected over a sufficiently long time to distinguish between asymptomatic and presymptomatic cases.
It’s a bit puzzling that a study like this hasn’t yet been done, but it has only been recently that we’ve had enough testing capability to undertake such a large scale study. Absent such a study, it’s really irresponsible of the WHO to make a recommendation like this based on so little data and communicated so poorly.