Is it Long COVID or Long Everything?
When a patient presents with symptoms of a viral respiratory infection these days, we can usually know which virus is to blame within hours, thanks to lab testing that has become fairly routine. But it doesn’t stop us — nor should it — from guessing beforehand. We’ve all learned that viruses have tells, after all. Flu, which announces its presence with deep muscle aches. RSV, with the wheezing. But COVID, to me at least, always felt a bit apart from these other pathogens. The sometimes permanent loss of the sense of smell; that is such a specific, and bizarre finding. And then of course, there is long covid. A syndrome that has been devilishly difficult to define clearly, but seems to crystallize our modern, post-vaccine-era concerns about the virus.
But is Long COVID unique to covid? Or rather — have we simply failed to understand that in reality, there is long everything?
The study we are looking at this week acknowledges a host of post-covid conditions that occur with some frequency after a COVID hospitalization. But the heart of any epidemiologic study is the control group. Should we compare individuals hospitalized with COVID to healthy people from the general population?
And they give us three potential control groups against which to compare people hospitalized with COVID: individuals hospitalized with influenza in the pre-COVID era, individuals hospitalized with sepsis in the pre-COVID era, and individuals hospitalized with sepsis during COVID, but who were not COVID-infected.
The study leverages the remarkable universal electronic health record system of Ontario, Candada to have what amounts to complete data capture on nearly 400,000 adults who were hospitalized with one of the conditions of interest and, importantly, survived that hospitalization. Can’t get long COVID if you don’t survive COVID, after all.
Now, patients hospitalized with COVID are quite different from those hospitalized with flu or sepsis. They are substantially younger, with mean age 61 compared to 74 or 75. They are less likely to be female — it has become quite clear that men tend to do worse with COVID than women, after all. It’s worth noting that only 15.3% of the COVID group had received a dose of vaccine, compared to 35% of the sepsis group hospitalized during the pandemic. COVID patients were markedly less likely to carry a cancer diagnosis, to have hypertension, and had a lower frailty score. In other words, the COVID patients, prior to getting COVID, were healthier.
Nevertheless, patients with COVID were more likely to end up in the ICU and require mechanical ventilation. So I want to be clear on this as we move forward — COVID is worse than flu, even worse than sepsis — at least for hospital survivors.
We need to take that severity of illness into account when we think about long COVID. The syndrome may represent the unique pathophysiologic consequence of COVID itself or it might represent the sequela of any severe illness — it’s just that COVID happens to be a particularly severe illness.
OK the researchers used something called “propensity score overlap weighting” to account for those baseline differences among patients as well as for the stuff that happened during the hospitalization — accounting for the particular severity of COVID, essentially. This is a rather novel method to account for traditional confounders which I really like and my lab has used in a few papers before — you get very balanced groups after the process. Sorry for the inside baseball.
Ok — the big question. If we account for the fact that people who get hospitalized with COVID tend to be healthier than people hospitalized for flu and sepsis, and also the fact that people hospitalized with COVID tend to have a worse course than people hospitalized for flu and sepsis, who would have worse outcomes after discharge?
Rather than creating some arbitrary long covid definitions, the researchers looked at a variety of specific disease outcomes, which is much more informative.
And here’s the rub — there was almost no difference between those who survived a hospitalization with COVID and those who survived the other conditions. They had similar long-term rates of heart attack, dementia, depression and stroke.
The risk of venous thromboembolism was higher among COVID patients compared to those hospitalized with influenza which may be real — COVID does seem to be a relatively pro-thrombotic infection. But overall, the message of this study is — yeah — bad things happen after COVID, but bad things happen after any severe illness.
It’s of course critical to mention that the outcomes the authors looked at here were things you could easily extract from the electronic health record — hard outcomes like stroke — we don’t have data on more subtle presentations of long covid — think fatigue, brain fog.
And, of course, the study doesn’t say anything about patients who had COVID that never required hospitalization. There may well be a long-covid syndrome in that population, but finding an appropriate control group for outpatients with COVID is incredibly difficult.
I do have one niggling concern about this study though. The overall 1-year mortality rate was dramatically higher in the control groups than the COVID groups.
Around 6% of those who survived their COVID hospitalization died within the following 12 months. Around 12% of those who survived a flu hospitalization, and 25% who survived a sepsis hospitalization died in the next 12 months. That makes sense, of course — the COVID group was much younger and healthier overall. But the authors treated death as a “competing risk” in their analysis — which means that people who die don’t contribute to the rate of other conditions. You can’t have a stroke if you die of something else before you have a stroke. It’s like saying that ingesting cyanide reduces the risk of getting struck by lightning. Sure it does, but not really in the way you want.
I think this framework would bias the results against COVID, by deflating the rate of events in the control groups. Censoring for death, rather than treating it as a competing risk, would reveal this difference, but the authors don’t report that analysis.
So — does long covid exist? Yes — absolutely. Is long covid different than long flu? Long sepsis? That is less clear. The real question is whether there is a syndrome unique to COVID that we can identify. That has proven somewhat difficult. Future research should certainly investigate clotting phenomena, but should also consider whether the higher death rate of those hospitalized for other conditions makes COVID look worse than it should.
A version of this commentary first appeared on Medscape.com.