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AAN 2022 | Disentangling the concept of post-acute COVID-19 sequalae

Jennifer Frontera, MD, New York University Grossman School of Medicine, New York, NY, describes difficulties in understanding the burden of post-acute COVID-19 sequelae. Firstly, there are issues in understanding the true extent of COVID-19 infection, with many asymptomatic cases likely going undetected. Post-acute sequelae also depend on the population looked at, with 90% of the hospitalized population having objective abnormalities, whilst an exact number is yet to be determined for non-hospitalized individuals. Additionally, post-acute sequelae are a heterogenous set of syndromes, some which are related to COVID-19, but others likely not. In February 2021, a survey of 999 participants addressed anxiety, depression, sleep, cognition and fatigue, and stressors faced by individuals (e.g., financial insecurity, conflict in household) to determine how people who felt that they are suffering from post-acute COVID-19 sequelae performed. The survey found that stressors were stronger predictors of test performance compared to the speculation of having prolonged COVID-19 symptoms. Ultimately, questions remain whether the symptoms usually connected to post-COVID are due to the biological effects of COVID-19 or living situations. Onwards, the RECOVER initiative (https://recovercovid.org/) is planning on enrolling 18,000 individuals to gain more information on what post-acute COVID-19 is, including phenotypes and biology mechanisms. This interview took place at the American Academy of Neurology 2022 Congress in Seattle, WA.

Transcript (edited for clarity)

So one issue is understanding the denominator of people who’ve had COVID when you talk about burden of disease. And frankly, in this country, because we don’t have a systemized way of testing everybody to know what the denominator is like, how many people had asymptomatic COVID and never knew it and they never got tested. We don’t have good ways of making those estimations. And frankly, in publications, it looks like up to a third of people are asymptomatic when they have COVID...

So one issue is understanding the denominator of people who’ve had COVID when you talk about burden of disease. And frankly, in this country, because we don’t have a systemized way of testing everybody to know what the denominator is like, how many people had asymptomatic COVID and never knew it and they never got tested. We don’t have good ways of making those estimations. And frankly, in publications, it looks like up to a third of people are asymptomatic when they have COVID. So the denominator’s probably really large, larger than we understand right now when you look at a data set that says, the CDC website that says 100 million people have had COVID in the United States, it’s probably much larger than that. We just don’t have a great system of understanding that denominator. So when you talk about burden of disease, we can only look at the numbers that we know of.

So for post-acute sequelae, it matters partially on which population you’re talking about. If you’re talking about hospitalized patients, as I said, 90% of them have something abnormal on their actual objective testing. Not their symptoms, 50% say they still have symptoms. But 90% have objective abnormalities which is perhaps even more concerning than the symptoms they might complain about. And that’s a very sick population, okay? So that does not mean everybody who at COVID is going to have these serious problems. The sickest patients have a high risk of having something. The non-hospitalized patients, if you look at the literature, it looks like it’s anywhere from probably around 25% or 10 to 25%, we don’t really know exactly the numbers right now. But if you translate that into the numbers of people who have tested positive that we actually know had COVID, it’s probably on the order of six to 10 million people in the United States, and much higher numbers if you looked globally, who could have post-acute sequelae.

The problem with post-acute sequelae is that it’s a heterogeneous type of syndrome or collection of syndromes. Some of which are related to COVID, some of which are probably not at all related to COVID. We did a study where we did a survey, this is back in February 2021, and it was a survey that the platform that supported it looks basically at patients across the country and they’re matched by age, gender and race, ethnicity to the demographics of the United States. So you’re getting this little slice that’s demographically similar to the population of the U.S. And so we surveyed 999 patients. And we didn’t tell them we were asking about COVID, we said we’re asking about your medical conditions. So we had them complete neuro-QOL batteries on cognition, fatigue, sleep, depression, anxiety. And then we also asked them other questions about what are your stressors right now? Now keep in mind, this is February 2021, we’re right in the middle of the pandemic. So, things like financial insecurity, food insecurity, conflict in your household, education disruption, whatever it may be.

And then we asked them at the very end did you have COVID and do you feel that you have prolonged symptoms lasting more than four weeks or a month from your diagnosis, which at the time and still is technically the CDC definition of post-acute sequelae, is more than four weeks of symptoms. And so we looked at how do the people who feel that they have post-COVID, how does that correlate with their testing for anxiety, depression, sleep, fatigue, cognition, et cetera? And what we found was that a lot of people had a lot of stressors, even people who were COVID-negative were stressed out, had financial insecurity, had a lot of pandemic related issues. And it turns out that those stressors were stronger predictors of how you did on tests of anxiety, depression, and sleep, fatigue and cognition. The only area where having COVID itself predicted having some abnormality was in the realm of cognition. So the people that had COVID or even prolonged COVID scored themselves worse on the cognitive batteries. So there might be something there.

But even still, even within the domain of cognition, the stressors that people were reporting were still bigger predictors of having abnormal cognition. So there was 20% of the general U.S. population who said, “I never had COVID and I have brain fog.” So how much is actually related is hard to know, given the environment that we’re living in, you have to take these other factors into account when you’re looking at this. So it’s not all biologically necessarily related to COVID, it’s secondarily related, based on the things that have happened in the context of pandemic that have really caused disruption in people’s lives. So I think at this moment, it’s hard to know the burden. The RECOVER Initiative, which is an OTA-NHLBI-NIH study, large study, they’re planning on enrolling 18,000 people in the adult cohort, more in the pediatric and autopsy and real-world data cohorts. But the point of that particular study is to really get at what is post-acute COVID anyway in terms of phenotypes or biological underpinnings of what we’re seeing? And try to just pull apart or disaggregate what’s been lumped into this one post-acute sequelae category.

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Disclosures

NIH funding, WHO Brain Health Taskforce