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It has been two months since China announced a previously unknown virus had been identified as the cause of a new outbreak in the city of Wuhan. In the weeks since then, the coronavirus — now called SARS-CoV2 — has raced around the globe, igniting major outbreaks in Iran, South Korea, Italy, Japan and now, it seems, Seattle.

There are still many, many questions about this virus and the disease it causes, Covid-19. But in a matter of mere weeks, a number of features of the disease have come into focus, through extraordinarily rapid sharing of research.

“Eight weeks into Covid-19, there’s quite a lot that we are learning,” Maria Van Kerkhove, who heads the World Health Organization’s emerging diseases and zoonoses unit, said in a recent interview. (Zoonoses are diseases that jump to people from animals.)

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Kerkhove spoke to STAT after returning to the agency’s headquarters in Geneva after two weeks in China, where she was part of an international mission to learn about China’s response to its outbreak.

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You can read the mission’s report on the WHO’s site. But interviews with Kerkhove and others help illuminate some of the most interesting findings. Of note: For now, they pertain to the outbreak in China. Some may change as the virus spreads to locations that use different approaches to try to limit its spread. 

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People are infectious really early in the course of their disease.

When the world saw a SARS outbreak in 2002-2003, one of the reasons it could be contained was because people were most infectious about seven days after they started to be sick — by which point they were generally already in isolation and their contacts were in quarantine. The same has been true in the case of some other related viruses. But Van Kerkhove said early studies on Covid-19 suggest people who have contracted the coronavirus are emitting, or “shedding,” infectious viruses very early on — in fact sometimes even before they develop symptoms.

“We do know from shedding studies that people can shed in the pre-symptomatic phase,” Van Kerkhove said, adding that while the data are still preliminary “it seems that people shed more in the early phases rather than the late phases of disease.”

If people can infect others before they know they themselves are ill, it makes it much more difficult to break the chains of transmission.

“If you are feeling a little bit unwell and you’re in your early stage of disease, you’re not necessarily in hospital. It takes a few days for you to develop more severe disease and you wouldn’t necessarily seek health care. So it does make sense in terms of what we’re seeing with the epidemiology” of the outbreak, Van Kerkhove said.

People can shed virus for weeks after they have recovered. But that doesn’t mean they are infectious.

There have been a number of studies that suggest Covid-19 patients may shed virus in stool or from their throats for some time after they’ve recovered. That naturally raises concerns about whether they are still infectious.

It’s too soon to draw that conclusion.

Testing for these viruses is based on what’s known as PCR — polymerase chain reaction. It’s a process that looks for tiny snippets of the genetic code of the virus in sputum from a throat or nasal swab, or in stool.

Finding that recovered patients are emitting virus fragments does not mean they are shedding whole viruses capable of infecting others. To determine if they are, scientists need to try to grow viruses from the sputum or stool of recovered Covid-19 patients, Van Kerkhove said.

The report from the WHO mission that traveled to China concluded that viable — i.e. potentially infectious — virus has been isolated from stool in some cases, but it questions whether that means much for spread of a virus that attacks the respiratory tract. Those mainly spread by coughs and sneezes.

Van Kerkhove said researchers should follow recovered patients over time to map out whether and how long they remain infectious, testing them at intervals of seven days, 14 days, and 21 days to see if they can grow virus from their sputum.

Truly asymptomatic Covid-19 infections are probably rare.

An early report on a cluster of cases in Germany caused a huge stir when the authors claimed a woman from China who was asymptomatic had infected several colleagues in Germany when she visited her company’s headquarters there.

It was later revealed the woman had had some symptoms while she was in Germany, but sloughed them off as jet lag. Despite that, the authors continue to describe her as having infected others before she became ill.

People infected with Covid-19 who are truly asymptomatic are rare, Van Kerkhove said. Studies in China estimate that about 1.2% of confirmed cases are asymptomatic. But Van Kerkhove said when the scientists on the WHO mission to China pressed for more detail, it became clear that most of the people who were first described as asymptomatic actually were pre-symptomatic — they’d been detected through contact tracing before their symptoms manifested.

“So, very, very few,” she said. “And [asymptomatic cases are] definitely not a major driver of transmission.”

People probably aren’t being re-infected after recovery.

There has been concern on social media about reports of people getting infected, recovering, and then later developing symptoms again. Some scientists from China have suggested the virus is able to re-infect people after a very short time.

Van Kerkhove said this probably is not what is happening. In fact, it would be unusual if an immune system that had just fought off a viral invader would forget how to recognize it and fend it off within a period of days or a few weeks.

What more likely, Van Kerkhove said is this: In order for hospitalized Covid-19 patients to be released after an infection they have to test negative for the virus twice, in tests conducted 24 hours apart. In some cases, people have had the two negative tests — but then tested positive again later.

Van Kerkhove said those results likely reflect more about the way the tests were conducted than about the status of the patient — how a throat swab was taken, for instance. “I don’t think that they’re actually truly negative and then they get re-infected again. It’s likely that they’re still positive for some time.”

Transmission in China happened among family members and close contacts. True “community spread” was less common.

“This virus is not circulating in the community, even in the highest incidence areas across China,” Van Kerkhove insisted.

What’s the difference between spread among close contacts and community spread, you might wonder? Van Kerkhove said the data the mission saw in China pointed to the virus finding its way into households and transmitting there. One family member gets infected and infects others. The “secondary attack rate” — the percentage of people in a household who got infected after someone brought the virus into the home — was between 3% and 10%.

Van Kerkhove said true community spread involves transmission where people get infected in a movie theater, on the subway, or walking down the street. There’s no way to trace back the source of infection because there’s no connection between the infected person and the person he or she infects. That’s not what the Chinese data show, she said.

Marc Lipsitch, an infectious diseases epidemiologist at the Harvard School of Public Health, found this claim puzzling. “I have reached out to the World Health Organization to understand the basis of some of those statements. My perception is that there is significant community transmission, especially when you aren’t aware that someone is sick, because there’s not enough testing,” he said.

China’s Covid-19 outbreak isn’t driven by spread in hospitals.

The SARS outbreak mainly occurred in hospitals. Sick people who weren’t recognized as cases infected other patients nearby or the health workers looking after them. Large hospital outbreaks have also been a feature of MERS infections.

With this new disease, more than 2,000 health workers have become ill. But Van Kerkhove said it seems like most of them were infected at home — something she acknowledged came as a surprise.

“Given our experience with SARS and MERS, I was expecting that there would be large hospital outbreaks,” she said. “But even among the health care worker infections that have been reported to date, when they went back and did interviews with them and then looked at exposures, it’s likely that most of those exposures were in the community rather than in health care facilities.”

That pattern may not hold. With global supplies stretched thin of of N-95 respirators and other equipment needed to protect health workers, there is a real risk of shortages that could put the front line workers at risk, the WHO has warned.

China’s Covid-19 outbreak isn’t driven by spread in schools.

Children and teens make up a smaller proportion of China’s cases than adults do, accounting for just 2.1% of nearly 45,000 cases reported in a study from the China CDC. The WHO report said that in China, about 2.5% of children and teens who became infected developed severe disease and 0.2% developed critical disease. None of the infected children 9 and younger died; only one teenager succumbed to infection.

South Korea, which is grappling with an explosive outbreak, has likewise seen small numbers of infections in children and teens and no deaths in those age groups. Of 6,284 cases, only 0.7% were under the age of nine; 4.6% were ages 10 to 19. A bigger chunk of the total cases, 29.9%, were ages 20 to 29. Even in that age group, South Korea reported no deaths.

“Even when we looked at households, we did not find a single example of a child bringing the infection into the household and transmitting to the parents. It was the other way around,” Van Kerkhove said. “And the children tending to have mild disease.”

If that pattern holds true elsewhere, it would question the value of closing schools to slow spread. But that could happen regardless, if teachers fall ill or families are worried about letting their children attend school.

The big unknown: How deadly is this outbreak?

In order to answer that question you need to know how many people have been infected and how many have died. The assumption before the WHO-led team went to China was that there were probably mild cases that hadn’t come to light.

In the report, the team indicated it couldn’t find much evidence of undetected cases. But the only way the world will know for sure is when researchers start testing the blood of people who were not confirmed cases in places where the virus has circulated.

If they find antibodies to the virus in the blood of people who never made the case list, that will change the math. This week the WHO said the case fatality ratio currently looks like 3.4% — which is not a reassuring number.

Researchers have been working feverishly to develop the tests needed to do this kind of research. China has recently licensed a couple of serology tests and Singaporean researchers have developed one as well. More will come on board soon.

Any country or location that has cases should be conducting this type of research, Van Kerkhove said.

“These types of studies should be conducted now,” she said. “This is one of the major things that needs to be done now. And everywhere. Not just in China. In the U.S., in Italy, in Iran — that would give us a better understanding of where this virus is and if we’re truly missing a large number of cases,” she said.

“Until we have population based sero-surveys, we really don’t truly know.”

Andrew Joseph contributed reporting.

  • How long is an infected person sick? How long is he/she contagious? What is the average age of persons who died?

  • all you need to do is the same thing covid-19 did, upgrade itself. all you need to do is upgrade the vaccine for SARS

    • There is no SARS vaccine.
      Best estimate for a deployable Covid-19
      Vaccine is 18 months

    • Seems you are putting cart before the horse. Article speaks intelligently to need for research to understand the disease and contagiousness.
      Public health is an issue NOW, even if a vaccine is a year away.

  • HMGB1 is a strong effector molecule that is involved with a great number of pathologies that include inflammation, but occurs rather late in a disease like sepsis when major organ dysfunction often occurs after sepsis resolution. Now HMGB1 is a primary contributor to the inflammation of ARDS by upregulating IL33 now appreciated as likely a major factor in ARDS. Several compounds such as EGCG are strong inhibitors of HMGB1. So just maybe: EGCG or other candidates inhibits HMGB1 which inhibits IL-33, which lessens or prevents ARDS (a major cause of death with late-stage coronavirus)? There are other known inhibitors to HMGB1 and perhaps they should be looking at those as treatment for late-stage disease as an emergency therapy.

    ‘. . . Acute respiratory distress syndrome (ARDS) developed in 17–29% of hospitalized patients, and secondary infection developed in 10%. [2,4] In one report, the median time from symptom onset to ARDS was 8 days.[3]’
    https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html

  • I think that the effect and role of Health workers did not come out properly in the article. My hunch is that Health Care Worker (HCW) is a major driver of this disease.

    Excluding Pediatric and Obstetric departments, the average age of staff (all below retirement age) is lesser than the average age of Patients (most patients have co-morbid conditions too).

    HCW due to the exposure to multiple patients and sharing of common areas among themselves have a higher likelihood of getting illness (usually milder due to lesser age, but may become seriously ill due to strain of work in outbreak areas). They can transmit the disease to more older patients who come to the hospital for their usual care needs and sometimes for elective surgeries. In these older patients, the mortality rate can be high.

    It seems that Singapore had given attention to this aspect. I saw the news that came from Singapore that advised HCWs not to attend work if they felt sick. Also, they had stopped elective surgeries.

    This driver may be active only in the early phases of the outbreak, when much is not known about the disease. Later, after every HCW have become affected and later recovered then they may contribute much less in hospital-based transmission.

  • Adjusting for women and HCW smokers should account for ~20% of all infected, assuming equal risk.

    They actually account for ~2% of patients where smoking is declared. This is true across all studies Eg last week

    https://journals.lww.com/cmj/Abstract/publishahead/Analysis_of_factors_associated_with_disease.99363.aspx

    It predicts more severe illness if contracted (by a pretty wide margin) but predicts pretty strongly against infection by all appearances.

    Why? What would you attribute this to?

    • As an addendum looking through the data, asthmatics are also wildly underrepresented.

      Could it be chronic lung inflammation reducing effective transmission?

      Also interesting, nicotine and cotinine seem to downregulates ACE2 in the upper respiratory tract, but upregulate it everywhere else. Would explain reduced incidence but higher severity.

      Can’t find anything on asthma and ACE2.

      Something definitely needs explained here.

  • As a general lay person who has been following the outbreak since early January; I find your articles extremely reassuring and perfectly articulated for the general public. I have been reading all the data, looking at the evidence base from researchers across the globe. I commend the work , you are all putting in tirelessly to ensure public health is understood. I have so many questions and find your articles, research and analysis answer so many of my questions that mainstream media don’t answer. I am curious about how countries like Germany and Switzerland have been able to maintain public health , without any loss of life (so far) . What are they doing differently from the UK? How can we learn from this? Why can’t we stop all travel or put measures in place to test passengers before they enter a country? If we know there are patterns of non aggressive symptoms, can’t we pre-test? As Trevor Bedford discovered that 2 days prior to showing symptoms people’s heart rates increase significantly, surely other changes are occurring? I am fascinated by the patterns and rate of infections . Thank you for making something so hard to understand accessible to the general public. Whilst my peers and friends think I am obsessed, I think knowledge is key. Evidence is far more valuable than media hype. I share your journals with everyone . I just wish politicians would put their egos aside and take public health seriously. It’s very scary to think we could have more prevention and control, but sadly we can’t make the world listen. Thank you for sharing these articles.

  • From the South China Morning Post on March 4, 2020 : there are 2 strains of this new coronavirus (L and S) – maybe that explains different reactions. That the Covid-19 occurrence is so much lower in children could very well be due to their vaccinations being far more recent than for adults. Likewise, recent vaccinations in older Covid-19 adults (such as for the flu, shingles, pneumonia, other boosters, etc) might explain the greater resilience of some in that age group. Seems to me that this certainly warrants investigation.

    • If the L/S type dichotomy is real, it looks like Iran may have gotten the “L”. We know that health care there is overstretched and underfunded, but it’s known to be fairly good. Smoking isn’t that common in Iran. Regime officials and medical personnel are dying, and they would presumably be receiving top flight cars. It must be something else.

  • Truth, justice and the American way..In other words we need a comet to land carrying Superman then wait till he comes of age.. That’s convenient..

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