More than three years into the Covid pandemic, there are a host of important unanswered questions about long Covid, which significantly limit healthcare providers’ ability to treat patients with the condition, according to US physicians and scientists.
That vacuum of information remains as much of the US has moved on from the pandemic, while Covid long-haulers continue to face stigma and questions over whether their symptoms are real, providers say.
But while there has only been a trickle of new information about long Covid, doctors say that they remain confident that researchers will find answers to fundamental questions about the disease, such as: aside from contracting the virus itself, what actually causes long Covid?
“We don’t quite have our finger on the pulse of what’s wrong, what biologically is causing it, and that’s a big problem,” said Dr Marc Sala, co-director of the Northwestern Medicine Comprehensive Covid-19 Center. “It’s hard to direct drugs or treatments without having the biological underpinnings for why someone is feeling so fatigued with exercise.”
In addition to the ambiguity around the root causes of long Covid, there are also challenges in research because of how Covid can produce so many different symptoms. The Centers for Disease Control and Prevention list includes fatigue, respiratory issues and difficulty thinking or concentrating but also states that “post-Covid conditions may not affect everyone the same way”.
“Everyone has a different constellation of symptoms,” said Dr Steven Deeks, an infectious disease specialist at the University of California, San Francisco. “Some people get better over time, some people wax and wane, some people get worse,” and so it is difficult for researchers to determine when a study should end and compare a drug versus a placebo.
That ambiguity creates something of a Catch-22 for efforts to advance research. Pharmaceutical companies want to have biomarkers – meaning a defined characteristic used to measure a condition – before investing in research to find a drug to treat long Covid, and since there are none, they won’t conduct the expensive studies that could help identify biomarkers.
“We are struggling in academia to come up with a definition [of the condition] that will work, and we are hoping to engage people who regulate clinical trials and hope to engage industry once we have made some progress,” said Deeks, who is also considered an expert in HIV.
The medical field also does not have a clear understanding of long Covid in part because the National Institutes of Health (NIH) initially focused on its symptoms rather than the addressing the underlying problem, said Dr Ezekiel Emanuel, a bioethicist at the University of Pennsylvania.
That “was exactly the wrong approach”, Emanuel said. “This is a major, major problem, and what we were initially going to try is Band-Aids.”
Answering questions about the fundamental problems with long Covid could take years, researchers said.
The virus has been around for three years, which compared with other diseases is a very short amount of time to understand the condition and develop treatments, Sala said.
But for those with the condition, it does not matter that three years is not that long in terms of scientific research. Hannah Davis, a co-founder of the Patient-Led Research Collaborative, a group of researchers who also have long Covid, contracted the virus in March 2020 and remains disabled because she has neurocognitive problems and chronic fatigue, among other symptoms. She previously worked in machine learning and artificial intelligence.
She argues that there has not been significant urgency about conducting trials for drugs that could treat the condition. The co-chair of a $1.2bn NIH initiative to study long Covid cases acknowledged frustration with the pace of research and said starting enrollment of patients “took way too much time”, according to Stat.
“Those clinical trials really need to start immediately because we won’t see results from them for years and people are reaching the three-year mark and are suffering,” Davis said.
In the meantime, Sala continues to see about the same number of patients at the Northwestern center as compared to earlier in the pandemic, though these are now more often people who are continuing to suffer from symptoms such as brain fog or unusual fatigue after exercising rather than people who were on a ventilator for months in an intensive care unit.
Long Covid patients are often the most upset about the cognitive effects of the condition, Sala said.
“In their social circles, they noticed that they are having difficulty with just finding words and remembering things. That is very frustrating for them to have other people see,” Sala said.
The physical symptoms of long Covid also continue to disrupt people’s lives.
In Sala’s city, Chicago, Jonathan Toews, the star and captain of the Blackhawks, recently announced that he was stepping back from the NHL team because he continues to suffer from long Covid and chronic immune response syndrome.
“This is the kind of person who I think it surprises people most,” Sala said. “Someone who was athletic, ran marathons, and then suddenly cannot get back on their feet or do what they wanted to, athletically, before. That’s the individual who really has that stigma associated with it.”
That lack of biomarkers also not only stymy research but also can have a harmful effect on patients’ mental health, Sala said. The only way to determine whether a person has long Covid is to ask people how they feel.
With something like iron deficiency anemia, “it’s very visible on your labs and you can have a good explanation for your friends. Here, all your tests pan out normal, and you start to think: ‘Is it all in my head’?” Sala said.
While patients and providers are frustrated with the pace of research, people who study the virus say they are making progress. For example, researchers reported in June that they detected a fragment of the virus in the blood of people with long Covid up to a year after the original infection. That finding could serve as a biomarker for the condition, Deeks said.
Once researchers discover how the virus can affect a person’s immune system, it could also provide answers to questions about other chronic and acute illnesses, Emanuel said.
“I do think a breakthrough here is going to be profound for our understanding of human immunology,” Emanuel said. “I think we will understand very clear what can go wrong in the immune system.”
