COMMENTARY

Is Long COVID Even Real?

F. Perry Wilson, MD, MSCE

Disclosures

November 09, 2021

This transcript has been edited for clarity.

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I'm Dr F. Perry Wilson of the Yale School of Medicine.

Postacute COVID-19 syndrome, better known as long COVID or long-haul COVID, has been described since the very beginning of the pandemic. But, as syndromes go, this one is really hard to define. On October 6, the WHO released a consensus case definition for long COVID that is woefully vague. It defines a syndrome that:

  • Occurs in those with a history or probable history of SARS-CoV-2 infection;

  • Involves symptoms that occur or persist 3 months from infection;

  • Has symptoms that last at least 2 months; and

  • Cannot be explained by an alternative diagnosis.

What symptoms might count? Virtually everything, as you can see here. The list includes brain fog, abdominal pain, palpitations, anxiety, and new allergies, among others.


 

And this week, a new article in JAMA Internal Medicine shows data that, frankly, calls into question the very existence of long COVID.

I'll show my cards now: I think this study is fairly problematic, and I'll walk you through the problems in a minute. But first, a reminder that no one is saying that symptoms do not occur after COVID. The biological question of interest is twofold. Does COVID cause these symptoms, and, if so, does COVID uniquely cause these symptoms?

In other words, does long COVID occur because people survived a really bad illness? After all, prepandemic studies show that two thirds of people who survive an intensive care unit (ICU) stay have persistent symptoms. But is COVID uniquely bad — uniquely harmful to a variety of organ systems, out of proportion to severity of illness?

The unique finding in the JAMA Internal Medicine study? The presence of long COVID symptoms was more strongly associated with the belief you had COVID than whether you actually had COVID. The implication, left unsaid, is: It's all in your head. Here's how it worked.

Researchers in France leveraged an existing population-based cohort study that had been running since around 2012. From May to December 2020 — right during the peak of the first wave in France — they asked around 36,000 participants to volunteer to send in a blood sample to detect anti–SARS-CoV-2 antibodies. These seroprevalence data tell us whether those individuals had prior infection.

From December 2020 to January 2021, they asked those same people to tell them about their persistent symptoms and, critically, whether they thought that they had contracted COVID.

What this created was four groups of people:

  1. The negatives (those without serologic evidence of infection who didn't think they had been infected) — these were the overwhelming majority.

  2. The positives — people who thought they had been infected and, indeed, had serologic evidence to that effect.

  3. The asymptomatics — people with serologic evidence of infection who never knew they were infected.

  4. The people who thought they had been infected but had no serologic evidence to that effect.


 

Now, if long-COVID is caused by and is unique to COVID, you would expect that the prevalence of long-COVID symptoms would be higher in people with serologic evidence of COVID infection than those who merely thought they had COVID infection. But that's not what was seen here.

A couple of symptoms illustrate the difference.


 

In each case, you were more likely to report the symptom if you thought you had had COVID, regardless of whether the serologic evidence supported it or not.

The researchers put both belief you had COVID and serologic evidence of COVID into a multivariable model, allowing them to compete, as it were, to see which, independent of the other, would associate more strongly with symptoms. Across the board, belief bested serology as a predictor of long COVID symptoms. Again, the implication: If thinking you had COVID is a better predictor of long COVID than actually having COVID, is long COVID even real?

But, as I alluded to earlier, there is a real problem with this analysis that was, I think, inadequately addressed in the paper. It has to do with the serologic test itself. The authors report that the serologic test they used had a sensitivity of 87% for detecting prior infection and a specificity of 97.5% — good numbers. But at the time this study was conducted, very few people in France had been infected — just 4% by the study accounting. Let's do some math to figure out how the test characteristics interact with the disease prevalence.

The study included 26,823 individuals. Let's assume that 4% had a prior COVID infection — that's 1073 people. Given a sensitivity of 87%, only 933 of those people would be detected by the test. That leaves 140 false-negatives.


 

They would live somewhere in the serologically negative group. The authors, to their credit, point out that the false-negatives represent about 1% of the total serologically negatives — not enough to move the needle.

But no mention is made of false-positives. With 97.5% specificity, we can estimate that 644 individuals would test positive on serology despite never having COVID.


 

They would be found in the bottom row, and you can see that they are a big group relative to the size of this row overall. In fact, more than half of the serologic-positive group was probably a false-positive in this study.

That's a real problem if we're going to argue that serologic positivity is not a good predictor of long COVID — after all, half of our seropositive group never had COVID. That's going to dilute your effect somewhat, no?

This wouldn't be a problem if the prevalence of prior COVID infection was higher, so maybe a follow-up study would shed more light. But for now, I am in no way ready to say that long COVID is all in your head. Rather, this study may just be telling us that serologic testing for COVID is not as good as a patient's recollection whether they had COVID or not — many of them had PCR tests at the time proving it, in fact — that's something that you're likely to remember.

To be honest, I'm a bit frustrated with how we're handling long COVID right now. The case definition is bad, we have zero diagnostic tests, and papers like this may be used to argue it isn't even a real problem. The truth is that long COVID definitely exists; I know many patients and friends who weren't deathly ill from COVID and yet had long, lingering, debilitating symptoms. But we don't know how common it is. We need to recognize that vague symptoms lead to vague diagnoses — and without clearer criteria, we risk labeling a bunch of people with "long COVID" when that's not what they have at all. And that does a disservice to everyone because it makes it that much harder to make progress on this disease...whatever it is.

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale's Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and here on Medscape. He tweets @fperrywilson and hosts a repository of his communication work at www.methodsman.com.

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