How Scientists Explain the Biology of Long COVID | Science

By Jennifer Couzin-Frankel13 April 2021, 12:50

ScienceThe COVID-19 reporting is supported by the Heising-Simons Foundation.

After the first surge of COVID-19 cases in the spring of 2020, a new concern arose: some people did not get better. For those with so-called Long COVID, persistent symptoms ranged from brain fog and intense fatigue to shortness of breath and loss of smell and taste. So far, there is little clarity about the causes or how to treat this constellation of symptoms. Some surveys suggest that between 10% and 30% of people infected with the pandemic coronavirus are struggling to recover, but these data are preliminary.

Emilia Liana Falcone, an infectious disease specialist at the Montreal Clinical Research Institute, and Michael Sneller, an infectious disease specialist at the National Institute of Allergy and Infectious Diseases (NIAID), each lead a large-scale COVID clinical trial. They recruited volunteers who had COVID-19 – some with persistent symptoms and others without – along with a control group of people who had never contracted the virus. Volunteers come in regularly for medical tests, and scientists examine their blood for immune disorders. The goal: a biological explanation of chronic symptoms after COVID-19. The couple spoke to Science about their work, their thoughts on Long COVID and their efforts to lead the data. This conversation has been edited for brevity and clarity.

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Q: We have long known that many infections – and not just COVID-19 – can cause lasting and inactive symptoms in some people, such as fatigue and brain fog. Is Long COVID just another example of this?

Michael Sneller: Maybe it’s new, maybe not. There are precedents for this type of post-infectious, non-critical disease, such as Lyme disease after treatment. And there are people with chronic fatigue syndrome, some of whom determine the onset of their symptoms as a viral infection. During polio outbreaks in the fifties, there was another syndrome that developed in people: fatigue, concentration problems, aches and pains. I thought early on that given tens of millions of people who would probably become infected with COVID, we would see it.

Emilia Liana Falcone: In terms of fatigue, some of the neurological complications, brain fog, lack of concentration, are certainly common after other infections. That said, I think there are certain characteristics that are not so common now – the loss of smell and taste that I have seen in the clinic for at least six months. There is also this new onset of endocrinopathies, such as thyroid problems. Maybe it happens in the context of other viral infections and we are not looking for it. But it could be something more characteristic of COVID.

Q: How did you become interested in Long COVID?

ELEVEN: I was at the National Institutes of Health for almost 9 years, where I looked at long-term inflammatory complications in patients with congenital immune defects. It seemed very plausible to me that there would be long-term consequences due to the intense inflammatory processes in the acute phase of COVID-19.

MS: About 6 years ago I was asked to help lead a study of Ebola survivors in West Africa. In the outbreak of 2014, it infected hundreds of thousands of people. Of those who survived, persistent symptoms such as headache and joint pain emerged. We enrolled about 1,000 Ebola survivors and about 2,300 Ebola-negative people in Liberia – it was a NIAID-Liberia collaboration. I knew we needed to have a control group to really determine if any of the things we were seeing were related to Ebola per se, or just life in Africa, which could be difficult. I learned a lot that I could apply to studying post-COVID syndrome.

Q: Why do we not yet have a clear definition of Long COVID?

MS: A year ago it did not exist. So that’s why.

ELEVEN: Many of the first studies were based on questionnaires and map reviews, especially in patients admitted to the hospital. Many symptoms have been described. There is a lack of mechanical data.

Q: How was your study set up to deepen biology?

MS: We have a COVID group of 18 years and older, at least 6 weeks after the onset of symptoms. We enrolled about 150 survivors, and about 55% had no symptoms after COVID. As was the case with the Ebola study, we knew it was important to have a control group. We ask participants to identify people with whom they have had contact who have not received COVID, and we ask them to participate in the study. We try to match them for age, and if you do, you will get a good match for other comorbidities, including hypertension, diabetes, obesity, and so on. We have about 100 checks entered now.

Both groups undergo basically the same evaluations, which include lung function, exercise testing, and cardiac MRIs. Cortisol and thyroid functions are measured to work out reasons for various things such as fatigue. We conducted an extensive evaluation of mental health with neurocognitive tests and psychiatric interviews. And then we have a whole lab component that looks at aspects of the immune response, evidence of persistent virus, persistent inflammation. This is a longitudinal study for 3 years. We see people every 6 months, sometimes sooner.

ELEVEN: This is very similar to our study. We also start with a number of questionnaires that contain information on diet, wellness, etc. There are neuropsychiatric or neuropsychological tests by a separate team. We look at every organ system. And then there is the collection and analysis of blood and tissue samples – we have laboratories right upstairs. We also have a team of specialists that we refer to for deeper exercises for anyone with a real organ weakness.

Q: You include both control groups of people who did not have COVID-19. Why is this important?

ELEVEN: You need to control the background noise. We are in a pandemic and it creates anxiety, stress, insomnia, depression. We need to include people who are alive to be able to bother who is really related to the infection.

MS: With the Ebola study, by having a control group, we showed that many symptoms considered post-Ebola syndrome occurred at the same frequency in the control group.

I can give you two examples from our current study. There have been published reports of tinnitus as a problem after COVID. About 12% of our COVID group complain of tinnitus, and about 14% of the control group have tinnitus. This is the same with a slight abnormality in a lung test that measures how well lungs transfer oxygen to the bloodstream. About 50% or 60% of the COVID group have it with an average age of 50. If I did not have a control group, I would say, ‘It comes from COVID.’ Well, exactly the same percentage of the age-, comorbidity-adjusted control group has the defect. You need a control group to assign any abnormality to the virus infection. Without a control group, this is difficult, if not impossible.

ELEVEN: Exactly.

Q: Can your findings help explain who is susceptible to long COVID?

MS: Potential. This may give some clues as to what may be causing these symptoms. If you had detailed bio-samples of the stage of acute diseases in the same patients, this would be ideal, but it is very difficult to do. In my group, 90% COVID-19 drove out at home. So they have no bio samples.

ELEVEN: The development of predictive models is very attractive, and people have been interested in it. But it is about patients who are not admitted to the hospital; you just have no samples from before or during the illness to compare with the current one.

Question: It will take time before your studies and others tease you. Are there now ways to help people with Long COVID?

ELEVEN: There is no clear treatment route. You can treat the obvious reversible problems – someone who is anemic, someone who is vitamin D deficient. Many revolve around rehabilitation, depending on the patient.

Q: What does rehabilitation involve?

ELEVEN: If it is pulmonary, there are exercises you can do to improve shortness of breath, some of which are related to the exercises that singers do. We approached the Montreal Opera House to develop a rehabilitation program for patients, as many of these exercises work to improve lung function.

MS: I find that when they talk to patients, they are afraid to exercise because they think they have heart damage or lung damage. I tell them we test a lot. If we find no evidence of serious damage to the lungs, I encourage them to exercise gradually. There are many issues about mental health, and also in the control group. There is much room for better mental health evaluation in the community and treatment.

ELEVEN: The only thing I would like to add is if you think the patient has chronic fatigue syndrome, then it is rather a conservative approach in terms of their energy, rather than forcing an exercise.

Q: Do you think some of these cases are chronic fatigue syndrome?

ELEVEN: I think there is a subgroup of post-COVID patients where they might fall into that category, but there may be others who have something different.

Q: There are anecdotal reports of people with long COVID getting better after vaccination. What do you think of this?

ELEVEN: It is very challenging; it’s intriguing. With the control group, you need to look closely. It can only be patients’ natural healing rate.

MS: We asked people to let us know when they get vaccinated. In a subset, we try to draw blood at a certain point in time to study the response of B-cell and antibodies in both groups after vaccination.

ELEVEN: We also take patients after the first dose and the second dose, although they get COVID here in Quebec, but only get one dose.

MS: As for the symptoms, most people in my vaccinated protocol have not said one thing or another. We’ll just see what happens.

Q: Long COVID is constantly in the news. What do you think about how it is described to the general public?

MS: There is a lot of misinformation out there that does not provide context. There will be a headline that says that psychosis is a new symptom of Long COVID, and it seems that the story is only about one person. My patients, some of them, tell me that they spend 6, 8 hours a day on social media pages related to Long COVID. I think this is not always a good thing.

Q: But maybe they do it because they do not get the support of the health system, right?

MS: It’s true.

ELEVEN: There are people who feel that it is not recognized. The reports started with doctors in the UK on infectious diseases, such as: ‘Hey, after a few months, I’m not performing like a normal doctor.’ It beats for me. It is important that we listen, that we acknowledge that something is going on. But, as Mike said, there is misinformation. This is where research projects play a role. We have some concrete, objective data to put it all into perspective.