How Scientists Investigate the Biology of Long COVID | disassemble Science

A COVID-19 survivor in Caracas, Venezuela, practices at a rehabilitation center for patients like him.

Pedro Rances Mattey / picture-alliance / dpa / AP Images

By Jennifer Couzin-Frankel

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

After the first wave of COVID-19 cases in the spring of 2020, a new concern emerged: Some people did not get better. For those with the so-called Lung COVID, the 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 research suggests that between 10% and 30% of people infected with the pandemic coronavirus struggle 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), are each leading a large, long clinical COVID study. They recruit volunteers who have had COVID-19 – some with persistent symptoms and others without – along with a control group of people who have never contracted the virus. Volunteers visit regularly for medical tests and scientists test their blood for immune abnormalities. The goal: a biological explanation of chronic symptoms after COVID-19. The pair spoke with Science about their work, their opinion of Long COVID and their efforts to be guided by the data. This conversation has been edited for brevity and clarity.

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

Michael Sneller: Maybe it’s new, maybe it’s not. There are precedents for this type of post-infectious non-critical illness, such as post-Lyme disease treatment. And there are people with chronic fatigue syndrome, some of whom point the onset of their symptoms to a viral infection. During polio outbreaks in the 1950s, there was another syndrome that developed in humans: fatigue, difficulty concentrating, aches and pains. I thought early on that given the tens of millions of people likely to be infected with COVID, we would see this.

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 features that are not as common as we see now – the loss of smell and taste that I have seen in the clinic from at least six months. There is also a new onset of some endocrinopathies, such as thyroid problems. Perhaps this is happening in the context of other viral infections and we are not looking for it. But it may be a little more distinct from COVID.

Question: How did you get interested in Long COVID?

ELF: I spent nearly 9 years at the National Institutes of Health looking at long-term inflammatory complications in patients with congenital immune deficiencies. It seemed to me very likely that, given the intense inflammatory processes in the acute phase of COVID-19, there would be long-term effects.

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

Q: Why don’t we have a clear definition of Long COVID yet?

MRS: This did not exist a year ago. So that’s why.

ELF: Many of the early studies were based on questionnaires and chart reviews, especially in hospital patients. Many symptoms have been described. There is a lack of mechanistic data.

Q: How is your study designed to dig into biology?

MRS: We have a COVID group, at least 6 weeks from the onset of symptoms, ages 18 and older. We enrolled about 150 survivors and about 55% have no post-COVID symptoms. As with the Ebola study, we knew it was important to have a control group. We ask participants to identify people they have been in contact with who have not received a COVID, and we ask them to participate in the study. We try to match them by age, and doing that will give you a pretty good match for other comorbidities, including hypertension, diabetes, obesity, and so on. We now have about 100 checks.

Both groups undergo basically the same evaluations, including lung function, exercise testing and heart MRIs. Cortisol and thyroid functions are measured to find out reasons for various things, such as fatigue. We have a comprehensive mental health evaluation with neurocognitive tests, psychiatric interviews. And then we have a whole laboratory component, looking at aspects of the immune response, evidence of persistent virus, persistent inflammation. It is a 3-year longitudinal study. We see people every six months, sometimes earlier.

Hélène Lambin / Montreal Clinical Research Institute

ELF: This is very similar to our study. We also start with a whole series of questionnaires that contain information about nutrition, well-being, etc. There are neuropsychiatric or neuropsychological tests by a separate team. We look at every organ system. And then there’s the collection and analysis of blood and tissue samples – we have labs up there. We also have a team of specialists we refer to for deeper studies of anyone with actual organ dysfunction.

Q: You are both control groups of people who have not had COVID-19. Why is that important?

ELF: You need to control the background noise. We are in a pandemic and it causes anxiety, stress, insomnia and depression. We need to involve people who live that life in order to tease out what is really related to the infection.

MRS: With the Ebola study, by having a control group, we showed that many symptoms that were believed to be post-Ebola syndrome symptoms were in fact equally common in the control group.

I can give you two examples from our current study. There are published reports of tinnitus as a post-COVID problem. About 12% of our COVID group complains of tinnitus and about 14% of the control group has tinnitus. It’s the same with finding a mild abnormality in a lung test that measures how well the lungs are carrying oxygen into the bloodstream. About 50% or 60% of the COVID group has that, with an average age of 50 years. If I hadn’t had a control group, I would say, “This is from COVID.” Well, the exact same percentage of the age-matched, co-morbidity-matched control group has the defect. You need a control group to really attribute any abnormality to the viral infection. This is difficult, if not impossible, without a control group.

ELF: Exactly.

Q: Could Your Findings Help Explain Who Is Susceptible to Lung COVID?

MRS: Possibly. It can provide some clues as to the cause of these symptoms. If you had detailed biospecimens from the acute disease phase of the same patients, that would be ideal, but it is very difficult to do. In my cohort, 90% COVID-19 drove home. So they don’t have any biospecimens.

ELF: Developing predictive models is very attractive, and people are interested in that. But the problem is with those patients who aren’t hospitalized, you just don’t have samples from before or during the illness to compare with the present.

Q: It will take time for your studies and others to tease this. Are There Ways To Help People With Lung COVID Now?

ELF: There is no clear treatment process. You can treat the obvious reversible problems – someone with anemia, someone with a vitamin D deficiency. Much revolves around rehabilitation, depending on the patient.

Q: What is rehabilitation?

ELF: If it’s pulmonary, there are exercises you can do to improve shortness of breath, some of which are related to the exercises opera singers do. We have been approached by the Opera House of Montreal to develop a patient rehabilitation program because many of these exercises work to improve lung function.

MRS: When I talk to patients, I find that they are afraid to exercise because they think they have heart or lung damage. I tell them we test a lot. If we don’t find any evidence of serious damage to the lungs, I encourage them to start exercising gradually. There are many psychological problems, and also in the control group. There is a lot of room for better mental health evaluation in the community and for treatment.

ELF: All I would add is that if you think the patient has chronic fatigue syndrome, it is more of a conservative approach in terms of their energy, rather than forcing an exercise progression.

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

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

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

ELF: It’s very provocative; it’s intriguing. You have to take a good look at the control group. It could just be the patient’s natural healing rate.

MRS: We asked people to let us know when they were getting a vaccine. We try to draw blood at specific times from a subgroup to study the B cell and antibody response in both groups after vaccination.

ELF: We, too, sample patients after the first dose and the second dose, although here in Quebec, if they have had COVID, they only get one dose.

MRS: As for the symptoms, the majority of the people in my protocol who have been vaccinated have not said one or the other. We will just see what happens.

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

MRS: There is a lot of misinformation that does not provide context. There comes a headline saying that psychosis is a new symptom of Lung COVID, and it turns out that the story is only about one person. My patients, some of them, tell me they spend 6.8 hours a day on social media pages related to Long COVID. I think that’s not always a good thing.

Q: But maybe they are doing that because they are not getting the support they need from the health system, right?

MRS: That’s true.

ELF: You are right, there are people who feel that it is not recognized. The reports started with infectious disease doctors in the UK saying, “Hey, after a few months I’m not working like a normal doctor.” That struck a chord for me. It is important that we listen, that we recognize that something is going on. But, as Mike said, there is misinformation. Research projects play a role there. We get some concrete, objective data to put it all in perspective.