Amid the rush to unpick the mysteries of Covid-19 and its effects, clinicians are scrambling to understand the information they have and prioritise what needs to be looked at next. By Elizabeth Flux.

Researching SARS-CoV-2

Associate Professor Michael Beard  of the University of Adelaide.
Associate Professor Michael Beard of the University of Adelaide.

About five weeks ago, the National Covid-19 Clinical Evidence Taskforce website went live. Its main goal during the pandemic is simple yet ambitious. “To provide a trusted, up-to-date and consistent national voice for clinicians around Australia,” explains Dr Julian Elliott, an infectious diseases physician at Melbourne’s Alfred Hospital, and the taskforce’s executive director. “[It’s] a set of national guidelines that are a one-stop shop – a place where people can come to and be guided and reassured that the care they’re providing is the best possible care for people with Covid-19.”

It sounds like an obvious measure but, as with so many things in 2020, these rapidly updated “living” guidelines are unprecedented. Normally in medicine, doctors and researchers have years to untangle knotty questions. But, as Covid-19 dominates our lives, time is of the essence.

Traditionally, once medical guidelines are developed they are updated every three to five years. The National Covid-19 Clinical Evidence Taskforce guidelines, however, get updated weekly. Despite the fact we are constantly hearing about Covid-19, the disease occupies that strange space of generating both too much data and not enough. We know the common symptoms. We know the mortality rate is higher in men than women. We know it is caused by a coronavirus. However, as the situation evolves and new information rolls in, treatment options shift and change – and so the guidelines need to evolve as well.

From the outside it could look as if the medical profession is feeling around in the dark. In terms of understanding, Covid-19 has quickly gone from an unusual pneumonia, to a new respiratory condition causing a flu-like illness with fever and cough, to a disease being linked to all kinds of specific but rare complications. So, what is true and what isn’t? How does medicine keep up when the goalposts are constantly moving? And, is Covid-19 particularly mysterious, or are we mistaken in our expectations of where we should be at this stage of investigating a novel virus?

The fact is, we are actually in a pretty good position in terms of understanding both the disease itself, Covid-19, and the virus that causes it – SARS-CoV-2.

While it is impossible to predict how long it will take to develop a vaccine, Dr Mohammed Alsharifi, head of the vaccine research group at the University of Adelaide’s Research Centre for Infectious Diseases, is optimistic. His area of specialty is influenza and, as he explains, each year it takes eight months to develop the newest flu vaccine. “That’s how long it takes to make a vaccine when we know everything’s been approved for that vaccine – the protocol is well known, the system is well established.”

We don’t have such protocols in place for SARS-CoV-2 yet – there are a lot of questions to be answered, a lot of research to be done and many approvals to be secured. It’s unlikely we will have a vaccine within two years. And yet, he points out, “five months since the outbreak and [there are] vaccines in clinical trials. That is unheard of in any scenario … so that’s a positive message.”

“I don’t think Covid-19 is particularly mysterious compared with other emerging infectious diseases,” says Dr Andrew Stewardson, senior research fellow at Monash University’s Department of Infectious Diseases, and an infectious diseases physician at The Alfred. “While it’s true that we still have much to learn, we already know a remarkable amount for a disease that was first diagnosed four months ago.”

“I think the majority of the symptoms we’ve captured rather early, if we assume that what we’re seeing at the moment is everything,” says Dr Sanjaya Senanayake, associate professor of medicine and infectious diseases physician at the Australian National University. “But as you say, things might evolve further and new clinical features might appear.”

He points to some of the more unusual potential variations being reported: rashes in patients in Italy; “Covid toe”, which “is almost a form of chilblains in the hands and feet”; and possible links with Kawasaki disease – an illness most commonly occurring in children and infants that causes inflammation of the blood vessels. “I don’t think the association has been fully demonstrated, but it looks like it’s a possibility,” he says. There are also increasing reports of clotting abnormalities in Covid-19 patients, which could be linked to reports coming out of the United States of strokes in younger, otherwise healthy patients.

“It does seem to be that it has particular effects that are, I would say, more unusual than you might have expected,” says Julian Elliott. “It comes from this family of coronaviruses including … the original SARS, and MERS [Middle East respiratory syndrome, first identified in 2012], and if you’d just looked at those two viruses and made predictions about what the next coronavirus would look like, I think you would have been wrong.”

Associate Professor Michael Beard is the molecular and biomedical science head of department at the University of Adelaide. For the past couple of months he has been researching SARS-CoV-2. His projects include generating a biobank of samples that will allow scientists to study the immune response to the virus, and attempting to see if Covid-19 is detectable in waste water. If the latter is true, it could turn out to be a valuable surveillance tool used to guide management of the pandemic.

Asked how researchers approach novel viruses, he explains “you can begin by going back and looking at what’s been done previously with similar viruses”.

“We are lucky in a little respect that we do have some knowledge of coronaviruses from the previous pandemic such as SARS-CoV-1 and MERS … but this virus is different to those other viruses, enough to cause significant problems.” Beard points specifically to the fact that there is an asymptomatic phase where people, not knowing they are infected, can pass the illness on to others. As a result, he says, “It’s very difficult to short-circuit the transmission of this virus.”

The more information we get, the more questions are raised. Every “what” inevitably begs a “how” and the fact is there hasn’t been enough time to get answers. Even if we confirm that Covid-19 is linked to some of the new symptoms being reported, it may be years until we know why. This isn’t because SARS-CoV-2 is more complicated than other viruses – it’s simply because it’s new. As medicine works on the run, researchers and clinicians are now doing a balancing act – sorting out what information has the most value, and prioritising where focus needs to go.

“We’re still at a very early phase in terms of learning about immunity, reinfection and the long-term outcomes. There have been several studies reporting early reinfection. But an important limitation of many of these is that the diagnostic test usually used doesn’t distinguish between live and dead virus,” says Stewardson.

“You’ve got to remember this has only been going for a couple months or so, and so the scramble now is to get therapeutic [outcomes] whether that be an antiviral or a vaccine,” adds Beard. “The studies on how the virus causes the disease will start to follow, and they’re coming through now, but these studies do take a long time to do.”

“There’s obviously pressure to publish data quickly in medical journals early in the pandemic so that we can make evidence-based recommendations. However, it’s hard to know how much weight to place on this type of evidence for a few reasons,” explains Stewardson. “First, early publications also tend to not have particularly strong study design … [and] these reports can be vulnerable to various types of bias. Second, early studies may be based on findings in a laboratory – there’s a big difference between seeing that a drug kills a virus in a laboratory and knowing whether it will improve patient outcomes. Third, it’s not always appropriate to extrapolate the experience in another country to our own situation, particularly when we’re in a very different phase of the pandemic.”

“There’s been this traditional tradeoff between high-quality synthesis of evidence and currency or the timeliness, and the living-evidence model essentially breaks that tradeoff,” says Elliott. “But we can have both. We can have high quality but also keep it up to date with the latest research – and obviously Covid-19 is the perfect example of when you need to break that tradeoff.”

It’s undeniable that there are big gaps in our knowledge about both Covid-19 and SARS-CoV-2, but this isn’t necessarily a correspondingly big problem. We don’t need all the answers at once – and as time passes we will get both more information and more in-depth studies.

“What we’re trying to do is really focus our research around the clinical need,” says Michael Beard. “And the clinical need at the moment is antivirals, vaccine and understanding how this virus causes disease, so that’s what we’re doing.”

This article was first published in the print edition of The Saturday Paper on May 16, 2020 as "A novel approach".

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