An analysis in early February by news agency Reuters found that 153 studies on the novel coronavirus we all know as Covid-19 had been published. At the time, just 40 per cent of those were in peer-reviewed journals, while 60 per cent were published on pre-print servers. By early May, the literature had exploded much like the virus. A simple PubMed search for peer-reviewed studies with Covid-19 in the title alone returned close to 8,000 entries. LKCMedicine Assistant Professor and Provost's Chair in Molecular Medicine Sanjay Chotirmall has contributed to this publication tally both through his work and as an associate editor of American Journal of Respiratory & Critical Care Medicine, also known as The Blue Journal.
In addition, he serves on an international taskforce set up by the American Thoracic Society that provides regular guidance assessing the available evidence on managing Covid-19 for clinicians around the world. Enjoying both a bird’s eye view of the publication landscape and an on-the-ground perspective, he talks to The LKCMedicine about what it is like working amid this frenzy and hunger for definitive answers during this ongoing outbreak.
The LKCMedicine: Starting with a bird’s eye view, how has this outbreak affected science?
Sanjay Chotirmall (SC): I think [the pandemic] has changed both clinical medicine and science in big ways. For example, this pandemic has made everybody embrace Digital Health and the use of digital technology and digital consultations within a couple of weeks.
From a more basic scientific perspective, it’s taught us about the way we publish and the responsibilities of publishing data. Pre-print servers, where people can put unpublished non-peer-reviewed research articles into the public domain for quick dissemination, are one example. While people visiting those sites are warned that these are not peer-reviewed papers, this pandemic has shown that most of the press stories about Covid-19 science were based on pre-print papers. And the problem with that is that it spreads information that may subsequently be found to be inaccurate.
The other lesson, which I think is very positive, is that people have come together in a multinational and international way. This has happened so quickly, sharing experience, sharing data, having webinars all towards a single cause.
The LKCMedicine: With so much data out there now, can we say that we understand the virus? And if not, what are the key areas we need to focus on?
SC: We are a long way off understanding the virus. In that way, we are all still students. But there are six key areas we need to focus on.
The first key issue is diagnosis. Lots of people are asymptomatic, but not all asymptomatics are the same. Some will go on to develop symptoms. But these pre-symptomatic individuals shed viral loads at several-fold higher and they could be the super-spreaders we’re talking about. How do you, at a population level, decipher the asymptomatic from the pre-symptomatic ones? That is a big unknown and that’s why we are seeing problems in closed quarters and vicious spread.
Unknown and issue number two is that we’re starting to see different phenotypes. So, two people infected with the same virus react very differently on a ventilator. Each needs very specific treatments. But are these true phenotypes, or are these different stages and severities of the same disease? And do they really need different treatments?
The third is getting the right treatment to the right patient at the right time of the illness. The illness comes in phases. The first part of the illness is very viral and affects the upper respiratory tract. A lot of the symptoms are based on the virus. The middle phase is where the virus moves into the lower respiratory tract, not in everybody, but in some, triggering a pneumonic phase where you may or may not need hospitalisation, oxygenation, etc. And then the critical phase, which is largely dependent on two things: systemic dissemination of the virus and its inflammatory consequence coupled, as some have proposed, to the host immune response rather than the virus itself. We need to understand the transition between these phases, the speed of transition and how to intervene at various phases with the right intervention.
The next one is recovery, shedding and immunity. We know people [who have recovered] shed for a long time, but nobody’s been able to grow this as a live virus, which suggests that they’re only fragments of RNA that are being shed. Are these people truly infectious? What does that mean for immunity? Understanding this plays a huge role in how you control cessation of the lockdowns and how you control this disease in the longer term.
The fifth key issue is probably long-term preventive strategies. Everyone wants a vaccine. But to date, we don’t have a single vaccine that is successful against any coronavirus or any upper respiratory tract infection and unfortunately, this virus seems to be affecting the upper respiratory tract in its early stages. An RNA vaccine is likely most promising but simply, it’s just too early to tell.
The final unknown is where people are looking at specific aspects of at-risk people, we need a ranking of risks. So, when you cease a lockdown you can advise those most at risk.
The LKCMedicine: How will your research contribute to our understanding of these key issues?
SC: We have established a lung organoid model in our lab through which we can reproduce upper and lower airways. So, it’s a lung in a dish. The grant proposal that has been recently awarded in collaboration with colleagues at Duke-NUS, the National Centre of Infectious Diseases and Tan Tock Seng Hospital will use these models and expose them to SARS-CoV-2 so we can isolate mechanisms and the pathways induced by this infection. We can do that in both the upper and lower airways as we have both nasal and bronchial organoids. I imagine you’re going to see different responses in different pathways. The bad outcomes come from the bronchial organoids or lower airways in general.
Then, we’ll extend that to diseased organoids developed from patients with severe asthma and chronic obstructive pulmonary disease (COPD).
The other studies we will perform will use leftover lung washes from some of the most critically ill Covid-19 patients and place them on organoids to determine the contribution of the virus and the contribution of the host immune system [to the illness] because we don’t really understand those transitions and why and when they happen. The organoid model may provide those insights.
We have no idea what we are going to find because it is a new virus. But with our systematic scientific approach using the best technology available and with the best people gives us a chance. What’s really powerful here is that the organoid model gives us a precision medicine look at how individual samples react to the virus.
The LKCMedicine: You’re also looking at the relationship between air quality and severity of Covid-19 illness. Can you tell us more?
SC: I have a big interest in the environmental influence on lung disease and the content of air in general. Together with Professor Stephen Schuster from the Singapore Centre for Environmental Life Sciences Engineering at NTU, we have looked at air quality and Covid-19 fatalities in 46 global cities. We have interesting evidence that air quality may play a role in Covid-19 outcomes. And we may be able to pinpoint it down to the microbial content specifically in polluted air.
The LKCMedicine: What do you hope is the legacy of this pandemic?
SC: One of the top three threats to mankind is another pandemic. So, pandemic preparedness is extremely important, but so many countries in some of the best health systems were very poorly prepared, which means they just didn’t listen. So, I hope they [governments and societies] will listen better to the other major challenges that we’re facing which include climate change and antimicrobial resistance because those aren't far behind.
The LKCMedicine: Thank you, Sanjay, for sharing your insights.