SARS-CoV-2 is a Very Weird Virus

Once again, a study shows that the effects of COVID are weirder than what we’d expect from “really bad flu”.

In the early days of the pandemic, before we really understood what COVID was, there were two specialties in the hospital that had a foreboding sense that something was very strange about this virus. The first was the pulmonologists, who noticed the striking levels of hypoxemia – low oxygen in the blood – and the rapidity with which patients who had previously been stable would crash into the Intensive Care Unit.  The second, and I mark myself among this group, were the nephrologists.  Because the dialysis machines stopped working right.  I remember rounding on patients in the hospital receiving dialysis for kidney failure in the setting of severe COVID infection and seeing these clots forming on the dialysis filters. We had some patients that could barely get in a full treatment because the filters would clog so quickly. 

We knew it was worse than flu because of the mortality rates – but these strangenesses made us realize it was different too – not just a particularly nasty respiratory virus – but one that had effects on the body that we hadn’t really seen before.

That’s why I’ve always been interested in studies that compare what happens to patients after COVID to what happens to patients after other respiratory infections. And this week, we’ll look at an intriguing study that suggests that COVID may lead to autoimmune diseases like rheumatoid arthritis, lupus, and vasculitis.

The study we’re discussing this week appears in the Annals of Internal Medicine and is made possible by the universal electronic health record systems of South Korea and Japan, who collaborated to create a truly staggering cohort of over 20 million individuals living in those countries from 2020 to 2021.

The exposure of interest? COVID infection – experienced by just under 5% of those people over the study period. (Remember, there was a time when COVID infections were relatively controlled, particularly in some countries).

Source; Worldometer

The researchers wanted to compare the risk of autoimmune disease among these COVID-infected individuals with two control groups – the first is just the general population. This is interesting, but a difficult analysis, because people who become infected with COVID might be very different from the general population. As a second control group? People infected with influenza.  And I like this a lot better – the risk factors for COVID and Flu infection are quite similar and the fact that this group was diagnosed with flu means at least that they are getting medical care and are sort of “in the system” so to speak.

But it’s still not enough to just identify these folks and see who ends up with more autoimmune disease. The authors used propensity score matching to pair individuals infected with COVID with individuals from the control groups who were very similar to them.  I’ve talked about this strategy before but the basic idea is that you build a model predicting the likelihood of infection with COVID based on a slew of factors – and the slew these authors used is pretty big as listed here – and then stick people with similar risk of COVID together, with one member of the pair actually having got the disease and the other having eluded it (at least for the study period).

Statistical balancing done, the authors looked at the risk of a variety of autoimmune diseases.

Compared to those infected with flu, those infected with COVID were more likely to be diagnosed with any autoimmune condition and with connective tissue disease, and, in Japan at least, inflammatory arthritis.

The authors acknowledge that being diagnosed with a disease might not be the same as actually having the disease, so in another analysis they only look at people who received treatment for the autoimmune conditions – the signals were even stronger in that group.

This risk seemed to be highest in the six months following the COVID infection – which makes sense biologically if we think it’s the infection screwing up the immune system somehow.

And the risk was similar with both COVID variants present at the time of the study.

The only factor that reduced the risk?  You guessed it… vaccination.  This is a particularly interesting finding because the exposure cohort was defined by having been infected with COVID – therefore the mechanism of protection is not prevention of infection – it’s something else. Perhaps vaccination helps to get the immune system in a state to respond to COVID infection more… appropriately?

Yes, this study is observational – we can’t draw causal conclusions here. But it does reinforce my long-held belief that COVID is a weird virus – one with effects that are just different from the respiratory viruses we are used to. I can’t say for certain if COVID causes immune system dysfunction that puts you at risk of auto-immunity – not from this study. But I can say it wouldn’t surprise me.

A version of this commentary first appeared on Medscape.com.