What's causing long COVID?

What’s the mechanism behind why some people are developing these syndromes? Chris Smith spoke to Yale Immunologist Akiko Iwasaki...

Akiko - So there are a couple of theories that are now posed to explain long COVID. One is a lingering virus or a viral reservoir that persists in a person that can stimulate chronic inflammation. The other possibility is autoimmunity; that even a mild viral infection can trigger autoimmunity, which has long-term consequences.

Chris - So when you say long-term infection, this would be that although the virus has, say, disappeared from the lungs, it could be loitering somewhere else in the body, and it's the physical presence of it turning over gently and indolently somewhere that's continuing to drive the immune system and cause some of the symptoms that people describe?

Akiko - Right. So that's one of the theories of lingering virus or viral reservoir. And data from studies have already shown that the gastrointestinal tract of people who recovered or who had COVID months ago still contained viral antigens and RNA. And so it's possible that a reservoir like that, where we cannot capture the virus from the nasal pharyngeal swabs or saliva may still exist somewhere.

Chris - The surprising thing though, is that it's not everybody. Why would that happen to just a magic 10 to 20% of people who catch the infection and the rest would get rid of it?

Akiko - That's a critical question that many of us are trying to answer. Some of it has to do with the demographics that Lawrence just discussed, which has to do with, you know, women of middle age or ages between thirties, forties, fifties. These are also the age group that is at high risk for developing autoimmune diseases. And so if COVID is triggering autoimmune diseases, it might explain why that's predominant in these, this age group of women.

Chris - And when you say auto-immune disease, this is the immune system being persuaded to turn on itself. Instead of defending us, it starts attacking us. Why would coronavirus infection do that though?

Akiko - Well, we don't really know why it would do that. We've certainly seen evidence of auto-antibodies that develop in COVID patients. And there are many theories out there as to why a viral infection can trigger autoimmunity, but there's a lot of autoimmune diseases that have known links to a viral infection. How exactly a viral infection induces autoimmunity still unclear.

Chris - You therefore have two theories. One is that the virus loiters for longer than you'd like in some people, the other is that it does nasty things to the immune system. Or it could be both, I suppose, couldn't it going on at the same time. How are you trying to find out which it is?

Akiko - Right, so long COVID is likely a collection of distinct diseases. And we're trying to understand the underlying cause by casting a wide net, looking at immune phenotype and metabolic phenotype in people with long COVID. And so we are trying to understand how the immune response differs between long COVID patients versus those who had acute COVID, but recovered completely.

Chris - And does it?

Akiko - Well so far, the evidence is still very premature, but we are seeing some distinct differences in people who have long COVID versus acute COVID and studies have already come out showing presence of auto-antibodies, different cytokines that are elevated, activation of different cell types. So we are getting a early glimpse into how the long COVID is being driven.

Chris - And do those changes that you're detecting, these antibodies that recognise us rather than foreign invaders, inflammatory signals and so on. do they actually marry up with the sorts of symptoms that people are describing? Do you see more of those sorts of things in people with worse symptoms? Do you see those things disappear as people's symptoms improve and how do you disect away what's cause and what's effect because could it not be that if someone's got problems in a certain part of their body that's making the symptoms, they get the antibodies because of that, not causing that?

Akiko - Right. So the cause and effect issue is a little bit more difficult to untangle. Currently a lot of the evidence is correlative. But we are seeing symptoms that may be consistent with the type of autoreactive reactions that people are making. For instance, if a person is making antibodies against, you know, cells of the brain that could result in inflammation within the brain that can trigger fatigue or brain fog or memory loss.

Chris - A question which is surfacing a lot, and I think with very good reason, and it's even as an argument being used to justify why we should target vaccination at certain groups is vaccination could reduce your risk of long COVID. Would you agree?

Akiko - Vaccination in general will reduce the risk for getting infection as well as subsequent diseases. So definitely, you know, it's very important that we all get vaccinated. However, vaccination may not guarantee a person from not getting long COVID. In fact, there is some evidence that's arising that shows that people who are fully vaccinated can get long COVID from breakthrough infections.

Chris - The other thing just since we're talking about vaccines, there have been a number of people saying I've had the vaccine, my long COVID got better. What do you think?

Akiko - So there are a couple of groups, mostly patient led groups that are reporting about 40% of long haulers who get the vaccine feel better, whereas about 15% feel worse after the vaccine. And so we think this is a very interesting phenomenon and that the immune response to the vaccine may be causing this difference in the symptoms. We're actually starting a study where we are collecting blood and saliva from long haulers before and after the vaccine to try to understand how immune changes that result from vaccination might contribute to symptom improvement or worsening.

Chris - Do you think it's just the coronavirus vaccine or is it the immune modulation that's conferred by having a vaccine? And so it could be a flu jab that would achieve much the same outcome.

Akiko - So that all depends on which of the two hypotheses are true. So if the viral reservoir is what's causing long COVID, then it has to be a specific coronavirus vaccine in order to eliminate that reservoir. Whereas if it's auto-immune disease, any vaccine that could trigger the right kinds of cytokines may be helpful. And in fact, I have heard from people who've gotten other types of vaccines and also feeling better. So we have yet to discover which of these hypotheses are true, but there are some early signs of indicating that it could be the autoimmune disease.

Chris - So it'll be interesting to see what happens with the forthcoming flu season.

Akiko - Yes, it's a great opportunity, actually, to monitor how long haulers might respond to flu jabs and whether that could be helpful, and if so, why.