Those mysteries include what the syndrome even is. The long-term fatigue and brain fog some people report after recovering from an acute infection are the symptoms most commonly associated with long Covid, but more than 200 distinct symptoms have been reported. The novel coronavirus may also change people’s cardiovascular systems permanently in ways that could lead to long-term health problems, even strokes and heart attacks. Is it all long Covid?
There are other elusive questions: How frequently do people get long Covid? Who is at the highest risk of developing it? And what is causing these long-term symptoms in the first place?
The remaining uncertainties can mask the scientific progress of the past few years. Scientists have a better idea of how long Covid works, and why it might cause a wide array of seemingly unconnected symptoms.
But — and this is more important than it might seem — we know what we don’t know. We have a stronger sense of what the most important unanswered questions are and where there is genuine debate among even the experts about this bedeviling condition.
The highly charged public discourse over long Covid can be overwhelming. There is a plethora of research being released at all times, some of it well-vetted, but some of it not. If you or someone you love has long Covid — or you’re worried that you might get it — it can be hard to get even basic answers.
One of the clearest takeaways of the past three years is this: Long Covid does not look the same in every patient.
”I think that consensus exists at this point to say, there is no one underlying cause of long Covid,” said David Putrino, who is leading research efforts at Mount Sinai. “Because there are many types of long Covid.”
But scientists are getting closer to resolving some of these debates. Everyone I spoke to agreed long Covid is a real physiological syndrome. The physical evidence that some people’s bodies function differently in the long term after a Covid infection is too strong to chalk up to psychosomatic symptoms or some kind of neurological disorder.
“If you’re someone who follows really high-quality research, you have to acknowledge that there are organic causes for illness in long Covid,” Putrino said. “It is not psychosomatic.”
Still, the lack of consistency has been confounding for researchers, doctors, and patients alike. Even so, evidence is growing that antiviral medication and other treatments may go a long way to reducing and even eliminating long Covid symptoms, regardless of their cause. Doctors and researchers might not have to fully understand the disease in order to successfully treat it. For patients, none of these questions matter as much as what can be done to make them feel better.
That future is finally getting closer. It is a sign of how far the science has come in the past three years. But there is still much work to do. The ongoing research and debate over long Covid can be broken down into at least four buckets.
1) The most obvious question: How common is it?
Post-viral syndromes are not new, but given the number of people infected over the past three years, long Covid has been recognized as a distinct public health threat. The scale of the crisis depends, at least in part, on how many people end up with long-term symptoms. But that is a surprisingly difficult question to answer.
That is partly because of how varied the symptoms are; most studies rely on patients self-reporting symptoms, so results will vary based on the respondent. A meta-analysis out of the UK published last year in Nature reviewed nine studies that collectively included more than 1 million reported Covid cases in that country. Not all of the studies used the same definition, some including any symptoms and others counting only those that prevented the patient from doing their everyday activities. But, in general, they defined long Covid as symptoms that were still present 12 weeks after the initial infection.
Even experts who believe long Covid is quite prevalent can give wide ranges, anywhere from 10 to 30 percent of patients. The UK meta-analysis found that between 8 and 17 percent of patients said they still had symptoms 12 weeks after their initial infection; between 1 and 5 percent said that they were experiencing debilitating symptoms. Women, people who were older, and people who were in worse health prior to the pandemic were more likely to say they were experiencing long Covid.
That study still left plenty of uncertainty about exactly how common the syndrome actually is; the top end of the range would be twice the rate of the low end.
The frequency of long Covid may also be occurring less frequently as more people gain immunity through vaccination and natural infection, and as the virus itself evolves. Another UK-based study published in the Lancet last year compared reports of long Covid during the summer 2021 wave of the delta variant to reports after omicron became the dominant variant in the winter of 2022. It found a 10 percent rate of long Covid during delta that dropped to a 4 to 5 percent rate once omicron took over.
While much of the public discourse has focused on such calculations, they would be irrelevant if doctors had the tools to treat long Covid.
2) The first-order question: What actually causes long Covid?
More than 100 million Americans have had a recorded case of Covid-19. Most of them do not end up reporting having long-term symptoms. So why do some people develop this syndrome and others don’t? And for the first group, what is happening in their body to make them feel this way?
It likely starts with the health of the patient. People who have a severe case of Covid and are admitted to the hospital are much more likely to have symptoms that persist for months. People who have a milder initial infection are more likely to experience long Covid if they are older, or if they were in poorer physical and mental health prior to being infected. Women also report higher rates of long Covid than men.
But knowing who may be more susceptible to long Covid is not the same as knowing why these people have long-term symptoms. A few theories are particularly popular with people who study long Covid.
One leading candidate is the idea that some people fail to fully eliminate the virus after infection, leaving remnants to hide away in their bodies only to later cause havoc. It is known as viral persistence and most (but not all) of the long Covid experts I spoke with said that it is likely a factor in many, maybe even most, people having long-term symptoms.
“There is not the one long Covid driver, the one long Covid marker,” Amy Proal at the PolyBio Research Foundation, whose team has been examining viral persistence in long Covid patients, told me. “But what does seem the most straightforward to anyone really reading the literature is that some patients are not fully clearing the virus.”
A February 2023 study published in Clinical Infectious Diseases found that people with long Covid had the coronavirus’s telltale spike protein in their blood 12 months after their infection.
The idea of viral persistence could be a skeleton key that unlocks the mystery of all the various and seemingly unrelated symptoms that long Covid patients report. Proal pointed to autopsy-based research published in Nature in December 2022 that found the coronavirus lurking all over the body months after infection.
The symptoms that an individual experiences could be related to where exactly the virus has taken up residence, she said. If it’s in your brain, you may experience more confusion and brain fog. If it hunkers down in your muscle tissue, you might feel the chronic fatigue heavily associated with long Covid.
But some experts are not as sure about the link between viral persistence and long Covid, without stronger evidence that the virus is still actively replicating, which Proal and others said is the subject of study. Some people who do not report long-term symptoms have also been found to have the coronavirus’s spike protein in their blood, complicating the picture even further.
And there could be other drivers of long Covid in play. For example, there is growing evidence that a coronavirus infection can lead to latent viruses that people already have in their bodies, such as the herpes virus, being reactivated.
At this point, some candidates for long Covid’s causes have stronger evidence than others. Researchers floated other theories earlier in the pandemic, such as the idea that Covid could contribute to auto-immune diseases, in which white blood cells attack healthy cells in a person’s body because they can no longer distinguish between good and bad cells. This now appears less likely, although it can’t be fully ruled out.
Akiko Iwasaki, a long Covid researcher at Yale University, summarized the current understanding of long Covid’s causes like this: “I wouldn’t say we’ve ruled in or ruled out anything yet.” Proal shared a similar sentiment: “In science, we never say we’re sure. Things may change.”
But, according to Iwasaki, scientists have still learned a lot. Viral persistence is clearly happening; the question is whether and how that could be a mechanism for long Covid. There’s also evidence for the reactivation of other viruses, though it is an open question whether that is a driver of long Covid or merely a symptom of a person’s immune system functioning poorly after being battered by the virus.
3) The most puzzling question for scientists: What is going on with the micro-blood clots?
There is another common feature of long Covid that still cannot be classified as either a cause or a symptom of the syndrome: tiny blood clots found in people after they have a coronavirus infection. After some people have a coronavirus infection, they can develop tiny blood clots. People who have had Covid have a higher risk of heart attack and stroke for months after their infection, and researchers posit that the micro-blood clots could be a cause. The role of the micro-blood clots is among the most confounding questions that researchers are exploring.
What makes it one of the most crucial areas of study is that Covid’s disruption of a person’s cardiovascular system could be a “silent killer,” in the words of South African researcher Resia Pretorius.
Most people may think of Covid-19 as a respiratory disease, but one of the key lessons of the past few years is the havoc the virus wreaks on a patient’s cardiovascular system. Various studies have found people in the middle of an acute Covid-19 infection can experience injuries to their heart muscle, the kind that can portend a heart attack or pulmonary embolism. And studies have found that heart injury during an infection was associated with a higher risk of death from Covid itself.
As Pretorius put it, though most people associate the coronavirus with respiratory issues, “we learned very early on that this is also a vascular disease.”
That has led researchers to probe whether that disruption is also contributing to people experiencing long-term symptoms. Multiple studies have found that people face a higher risk of heart attack or stroke after a Covid-19 infection, whether or not they had a severe case and regardless of whether they experience chronic symptoms after recovering from their initial infection.
But the science on the role of these micro-clots in explaining other symptoms commonly associated with long Covid is still unsettled.
The existence of these clots in people who have recovered from an acute infection is substantial. Pretorius led a study published in Cardiovascular Diabetology in August 2021 that found “large, anomalous” deposits of amyloid proteins — micro-clots — in people with long Covid.
But even she acknowledged that the connection between those clots and long-term symptoms remains a mystery. Different patients have different pathologies. Some appear to have small clots during their acute infection, but their body recuperates and they can go on and live their lives without side effects. Others seem to have persistent clots and symptoms that eventually go away on their own after a few months. A third group develops problems with blood clots that start during their Covid infection and then never go away. That is the group Pretorius worries about most.
“In the patients who struggle the most, their whole vasculature is compromised,” she said.
But scientists still haven’t reached a consensus on how these clots may contribute to long Covid symptoms. Some believe they may not be important at all. Others, such as Proal, wonder if they are connected to viral persistence; perhaps these clots are the result of the virus still circulating in a person’s blood.
But that is just a theory, for now. Science still needs more time to reach a satisfying answer.
4) The most important question for patients: How do we treat long Covid?
These unanswered questions about causes, prevalence, one syndrome or multiple, all lead to the biggest question of all: What can medicine do about it?
The pandemic itself has changed. Most people now have some exposure to the virus, whether from vaccination, infection, or both, and that immunity appears to be associated with fewer reports of long Covid, experts told me. That effect may be compounded if the more recent evolutions of the virus have also made it less severe, as people who end up in the hospital are at a much high risk to have long-term symptoms.
But those developments should not breed complacency. Scientists are still learning about the longer-term risks for people who have milder infections. As Proal put it to me, even if 1 percent of cases lead to long Covid, “that’s still a disaster because so many people are still getting infected all the time.”
But with treatment, as with the understanding of the mechanics of long Covid, medicine has made important progress in the past three years. There is promising but still preliminary evidence that taking Paxlovid, the antiviral medication, is associated with lower rates of long Covid. That would make sense if some of the problem can be traced back to viral persistence. If people are struggling to clear the coronavirus out of their bodies of their own, Paxlovid could help them finish the job — and that would in turn make them less likely to experience lasting symptoms.
If the mechanics of long Covid are more multifaceted, then patients may need more personalized treatments, with each patient getting a cocktail tailored to their symptoms. Physicians might prioritize anticoagulation for cardiovascular symptoms. Iwasaki noted evidence that some long Covid patients have low levels of the hormone cortisol. Prior to the pandemic, giving cortisol to patients with chronic fatigue syndrome — which has been suggested by some experts as a useful analogue to long Covid — hadn’t panned out in clinical trials. But it’s too soon to say it wouldn’t work and more investigation is warranted, she said.
Thinking outside the box may also be necessary. Just as researchers discovered that existing drugs, such as dexamethasone, could improve outcomes during an acute case, now scientists are experimenting with a variety of existing treatments to see if they help with long Covid. One pre-print paper, released this week, found the diabetic medication metformin had appeared to reduce the risk of long Covid for patients who received it after contracting the virus.
In the end, some of the unanswered questions about long Covid may not need to be answered in order to find effective treatments, and researchers are getting closer to knowing how best to treat it. Doctors are desperate for more information as they struggle to help patients who are still reporting health problems long after their initial infection.
There may not be a single study, a single discovery that resolves all of these debates. But with time, long Covid is becoming less of a mystery.
“I don’t think there will ever be a long Covid breakthrough,” Proal said. “It’s going to be a growing understanding.”