Since the early days of the coronavirus pandemic, some patients have recovered from an acute bout of Covid-19 but then experienced months or even years of profound fatigue, brain fog, headaches, dizziness, and other disabling symptoms. Formally called post-acute sequelae of SARS-CoV-2 (PASC) but more commonly referred to as long Covid, this illness—or, more accurately, this set of illnesses—has emerged as a medical and scientific conundrum as well as a major public health issue.
Akiko Iwasaki, PhD, a professor of immunobiology at the Yale School of Medicine, is among those leading the search for answers to long Covid. Dr. Iwasaki’s research focuses on the mechanisms of immune defense against viruses and the development of effective vaccine strategies. At Yale, she has been tapped to head the new Center for Infection & Immunity, which officially opened last August.
Based on a review of the evidence, Dr. Iwasaki and her colleagues proposed in a major article last September in the journal Nature that four mechanisms likely underlie the various manifestations of long Covid. She spoke with the Wellness Letter about these recent developments.
Wellness Letter: First, what is the focus of the Center for Infection & Immunity?
Akiko Iwasaki: The Center was created to focus on two things. One is to study the pathobiology of post-acute infection syndromes, a category that includes long Covid and ME/CFS [myalgic encephalomyelitis/chronic fatigue syndrome], among others. The second aim is to prevent these types of diseases from occurring by developing effective vaccines. We have a number of members already on board and starting to investigate a variety of aspects of these diseases.
WL: You just referred to post-acute infection syndromes as opposed to the standard terminology, which has been post-viral illness or post-infectious illness. Can you clarify that distinction?
AI: We are calling long Covid a post-acute infection syndrome because we don’t really know the etiology of the disease. It might be caused by a chronic infection, or it might be caused by some process or cascade triggered by the original infection even though the infection has already been resolved. Because we don’t really know what the drivers of these diseases are, we’re using a term that can encompass a variety of possibilities. Also, it’s important to emphasize that long Covid itself is not one disease but multiple diseases under one umbrella.
WL: In your work you have outlined four hypotheses of what might be causing what we’re calling long Covid. Can you explain each of these?
AI: Right, there are four main hypotheses that we believe could be the root causes of the symptoms. The first is persistent virus. There is a wealth of literature now demonstrating the presence of viral antigen in many different tissues. And I think there is enough evidence to suggest that there is chronic replication of the virus going on deep in some tissues. This persistent virus hypothesis includes a second branch, which is the possibility that even if there may not be an intact viral genome left, there are bits and pieces of defective virus that are not themselves replicating but could still be causing damage.
WL: And the other hypotheses?
AI: The second hypothesis is autoimmunity. We know that many infections can lead to autoimmunity and contribute to the development of autoimmune diseases. In this case, it’s possible that acute Covid leads to activation of self-reactive T-cells and B-cells [classes of immune system cells], which could be leading to these very long-term consequences. The result could be one of the known categories of autoimmune disease, or it could be something that’s not yet defined in the rheumatology field at this point.
The third hypothesis is that the infection triggers the reactivation of latent viruses that many of us carry. We are seeing evidence of that—for instance, the reactivation of Epstein-Barr virus [the virus that causes mononucleosis] has now been reported repeatedly in people who develop long Covid, and other viruses as well seem to be reactivated. This suggests that there’s some kind of immune dysregulation. These latent viruses are known to be suppressed because of pressure from the immune system, so the fact that they’re reactivating suggests that some sort of immune pressure has been lifted in these people. The reactivation of those viruses could be causing symptoms, or whatever is itself causing the reactivation could be causing the symptoms. We’re trying to develop animal models to study whether this reactivation is the cause of symptoms or is just a bystander effect of having dysregulated immune responses.
The last hypothesis involves the dysregulation of tissue function because of inflammation. Along with a group at Stanford University, we tested the impact of very mild respiratory infection in mice. Seven weeks after this very mild infection, the mice exhibited significant damage in different regions of the brain even though we found no virus in the brain. So the infection was limited to the respiratory tract, but it still led to measurable brain damage that could account for neurocognitive deficits. What this means is that the inflammation happening in the lungs is able to transmit some kind of inflammatory signal to the brain through circulating cytokines.
WL: Are these processes mutually exclusive? Or is it likely that many people have multiple things going on that are interconnected?
AI: These four areas are not mutually exclusive by any stretch. They all could be interacting, or some patients could be impacted by some of them but not by the others. It is also possible that A triggers B and B triggers C, and so on. Whatever it is, we need to understand which of these things are being triggered in different individuals because the kinds of treatment that you would offer to people with autoimmunity, for example, are very different from those you would give to people who are having persistent infection.
It’s very difficult at this point to dissociate these subtypes of long Covid. One way to do that is through clinical trials coupled with biological analyses. So, for example, we have an ongoing trial to see if a 15-day course of Paxlovid reduces long Covid symptoms and makes people feel better. We’re also testing major immunological factors to see what markers correlate with positive responses. Paxlovid is a drug that narrowly targets the virus itself. If we can identify those biomarkers, not only does that give us a tool to screen for people who might need treatment, but it also would give us a kind of marker for persistent viral infection.
WL: What are the prospects for treatments at this point?
AI: We’re still in the early phase of research. Understanding the underlying causes of something so complex could take years. But because of ongoing efforts throughout the world, I am hopeful that we will be able to find biomarkers for subsets of long Covid as well as come up with treatments that will help people on a much faster timeline.
What we’re trying to do at the Center is to compare head-to-head the biomarkers that we find from people with long Covid versus those who have ME/CFS versus those who have chronic Lyme disease, for example—to be able to understand the overlapping similarities and the differences. That way we’ll be able to say, “Okay, with these types of markers for long Covid, X, Y, and Z treatments work, and maybe we can translate that to treatment of ME/CFS and other conditions.” If we can find a biomarker for autoimmunity, for example, we might be able to apply that same marker for people with ME/CFS and do clinical trials to see if they improve. So I think there is a lot of cross-talk between these diseases.
WL: In a paper you coauthored last year, you wrote that it wasn’t “clinically or scientifically valid” to classify long Covid as a psychosomatic condition. Why did you feel the need to include that statement?
AI: We were feeling frustrated about the multiple articles that have portrayed long Covid as psychosomatic. We felt it was harmful to patients to paint this class of diseases as being psychosomatically driven. Of course people are feeling a lot of anxiety and depression as a result of having to deal with serious disability, but it’s simply not true to suggest that these conditions are caused by anxiety or depression or other psychiatric conditions.
We know from our research that this disease is driven by something related to the immune response to the infection or something else that’s triggered by the infection, and we don’t need to invoke other hypotheses to explain it. If the functional hypothesis is true, I’d be happy to see the evidence of whether their parameters can explain what’s going on with accuracy and whether that’s going to lead to some kind of therapy. But that’s not what we’re seeing.
WL: So why do you think that patients reporting these symptoms of long Covid and related illnesses are often told that there’s nothing wrong with them?
AI: One of the issues is that often the standard tests simply do not show the kinds of dysfunctions that we’re talking about. People go to the doctor and get a standard panel of tests, and they don’t pick up the differences that we’re seeing in our research, and the doctor says, “Hey, nothing wrong.” Ultimately what we want to do is to develop diagnostic biomarkers that doctors can order to see whether someone has long Covid, and if so what kind—is it autoimmune driven, or is it persistent virus, or is it something else? We’re not there yet, but that’s where we want to be.
WL: Is there anything people can do to stave off the prospects of getting long Covid if they do get Covid? What advice would you give patients struggling with it?”
AI: Once you get Covid, there are some things you can do to prevent getting long Covid. Taking Paxlovid to reduce the viral burden may help. And if you can afford to do so, take extra days off work and rest as much as possible.
For patients struggling with long Covid, scientists are working hard to find causes and therapies. We are uncovering several possible root causes, and based on that insight, starting to do clinical trials. I wish things moved forward a lot faster for people suffering, but I remain determined and hopeful we will get there.
