What We Know—or Mostly Don’t Know—about Long COVID Steven Deeks, M.D. Professor of Medicine, University of California, San Francisco There are many remaining immunological questions about COVID-19. How does SARS-CoV-2 trigger severe disease or even death in some and cause sniffles in others? Another still unanswered question is what gives rise to the lingering symptoms of COVID-19 known as long COVID, or, more formally, as post-acute sequelae of SARS-CoV-2. Researchers may not have a definitive answer to this question, but they are homing in on a handful of factors that correlate with the onset of long COVID in certain individuals. To learn more about this, HVP Editor Kristen Jill Abboud recently spoke with Dr. Steven Deeks, Professor of Medicine at the University of California, San Francisco, a veteran HIV/AIDS researcher. An edited version of the conversation appears below. Maybe we should start by defining long COVID. What is the clinical definition? The biggest issue right now in this area of research is the fact that we lack a standard definition for long COVID. In fact, we don’t even have a standard name. There is a battle going on as to whether to use long COVID, PASC for post-acute sequelae of SARS-CoV-2, or even PACS for post-acute COVID-19 syndrome. In the scientific literature, PASC seems to be preferred. This reminds me of the early days of the AIDS epidemic when the virus was referred to as LAV, ARV, and HTLV-III before people finally agreed on HIV. Everything about long COVID right now is very vague, and this is limiting our ability to describe the epidemiology, the natural history, and the biology of this phenomenon. As we have yet to figure out what the syndrome is, there is no widely accepted definition. Even though it is vague, I like the one by the WHO [World Health Organization], which is anybody who is three months past their initial infection and has new symptoms which impact their daily lives and persist for at least two months has long COVID. Is part of the reason that it is difficult to define because the symptoms vary so much from person to person? This is the fundamental problem. Everybody experiences long COVID differently, and most of the problems we are dealing with are very subjective and cannot be easily diagnosed—there’s no biomarker or imaging or way to test for them. It’s essentially about how you feel. I am not diminishing the subjective nature of it, but simply pointing out that it is hard to measure in a clinical and research setting. What do we know about the causes of long COVID? Either virologically or immunologically? We don’t know anything; we just have lots of theories. But there is a lot of research being done. Almost daily now there are papers being deposited as preprints on potential biomarkers, predictors, and mechanisms of long COVID. Broadly speaking there are maybe four major pathways people are pursuing. The first is chronic inflammation. We know from other areas of medicine that infectious diseases can cause persistent immune defects and inflammation and that this can cause end organ disease, so that’s one major area. Another major area of research is on residual defects from the acute infection. SARS-CoV-2 spreads throughout the body and causes tissue damage and this can cause problems. A related area is the issue of persistent virus. The assumption is that after the acute phase all of the virus is gone. But there are emerging data that suggest that in some people the virus, or at least parts of the virus, can persist and that can cause ongoing tissue damage or inflammation. Another potential pathway is coagulation or clotting. There are some studies coming out of South Africa that indicate this and there has been a lot of concern that because of the inflammation and tissue damage we are going to get these small blood clots or microclots forming, which can cause disease. And then finally, something that relates to all of this is the development of autoantibodies. There have been many reports of autoantibodies that emerge in the acute setting that can also persist in the chronic setting. Are individuals who are either immunocompromised or who have autoimmune diseases more prone to developing long COVID? People who are immunocompromised or who have autoimmunity have more inflammation and they are prone to have more inflammation post-COVID. Whether or not they are actually more likely to get long COVID is less clear. We just released a paper online suggesting that people with HIV are at much higher risk of developing long COVID than people without HIV. We would have expected that. And I do expect that once we figure out how to measure all of this stuff and we do the right studies, we’re going to see that people with autoimmunity or any inflammatory predispositions are going to be at much higher risk of developing long COVID. But for now, there aren’t a lot of data, so the HIV story is very informative. What role does vaccination play in long COVID? Multiple papers have been published or deposited online suggesting that if you were vaccinated and then developed a breakthrough infection, your risk of developing long COVID is substantially lower—around 50% lower. That is not unexpected. I assume that if you’ve been vaccinated and then you get acute SARS-CoV-2 infection, the amount of virus will be lower, the amount of tissue damage will be lower, the amount of inflammation will be lower, and the risk of long-term complications will therefore also be lower. I think that that is going to prove to be true. The more complicated question is whether or not a post-infection COVID vaccine will help with long COVID. There have been reports in both directions and right now we do not know if you can use vaccines as a therapy. But there is certainly enough data out there to support doing randomized clinical trials of vaccines in that setting. How long do the autoantibodies triggered by SARS-CoV-2 infection persist and is this something seen with other viral infections? There are reports that suggest you can get these persistent autoantibodies following other acute viral infections. We’ve known forever that with almost any infection, a subset of people can develop sometimes disabling, persistent symptoms—chronic Lyme disease is the classic example, but we also see it after Ebola and many other acute viral illnesses. It just hasn’t been well studied. I’m not an immunologist, but the way this can be explained is that acute infection can be such an inflammatory disaster that you end up overwhelming all the breaks on the immune system. B cells that produce harmful autoantibodies are no longer kept under control and they start causing harm, and then getting them under control is not easy. Could individuals who experience long COVID as a result of residual virus benefit from the SARS-CoV-2 antivirals that are now available? We have absolutely no idea, but it is an important question. We don’t know whether treating with antiviral drugs or monoclonal antibodies during the acute infection will prevent long-term consequences, though I suspect they will. The second question is whether months after an infection you can suppress any virus that is still around with the antivirals. That study has to be done. Does age play a role in your risk of developing long COVID? The two biggest risk factors are the acuity of the disease during the first few weeks—if you were in the ICU [intensive care unit], versus hospitalized, versus symptomatic, versus asymptomatic, your risk of developing long COVID goes down. The other big risk factor is biologic sex. Being female consistently increases your risk of developing many of these issues, which isn’t too surprising because many of the autoimmune diseases and inflammatory disorders are much more common in women than men. Older age is also a risk factor, but the data are less clear in my opinion. Certain co-morbidities such as obesity and diabetes mellitus seem to set you up for more serious long-term complications. Given the severity of acute infection is a major predictor of developing long COVID does that mean it is less likely to occur following omicron infection? That is certainly my hope. There was so much more omicron infection than what occurred in the previous waves that if omicron causes disability in even a small proportion of infected individuals, then we will need to get prepared. The medical and social security systems are going to have to deal with millions of affected individuals. We just don’t know yet, but my guess is that given omicron doesn’t get as widely distributed in the body, it’s not going to have the same impact. And many people who gotten omicron were already vaccinated or previously infected, so that makes a difference too. How has the research on long COVID been driven by patients advocating for this issue? That is a fascinating story. In March and April of 2020, reports of persistent symptoms emerged in social media online. Soon after that large advocacy groups formed, and soon after that we started getting reports of this in the media driven entirely by these online forums and these advocacy groups. All that attention led to governments getting involved. Up to that point, the biomedical establishment did not pay that much attention to this stuff. Obviously, everyone was busy dealing with the acute infections and vaccine development at that point. But it took a while to get people to pay attention to this and give it the respect it is due. That is happening now. This is becoming a very well-resourced area of research. This is very similar to how the HIV community worked with the NIH [U.S. National Institutes of Health], the FDA [U.S. Food and Drug Administration], industry, and others in the 1980s to build what eventually became a very sustained and productive collaboration.