This week we talked to Dr. Benjamin Krishna from the Cambridge Institute of Therapeutic Immunology & Infectious Disease. He was part in a study led by the University of Cambridge that has discovered that the protein interferon gamma (IFN-γ) might be a key indicator of Long COVID fatigue. This finding could help develop treatments and offer a clear diagnosis for some patients.

“Do you classify Long Covid as a neurological condition, for everyone, regardless of their symptomatology?”

“Absolutely yes, I think a major component of Long Covid is neurological, and by neurological I don’t mean only central neurological, peripheral neurological….”

“I estimated those costs all together… for the US would be about $3.5 trillion dollars which is a huge amount of money, which just tells you kind of the scale of the number of people who have Long Covid, and how disabling it can be both in terms of their health and in terms of their incomes, their ability to work, and how much medical spending is involved.”

“So here comes the immune system. What are we doing for it? Well, it's inflammatory. It's over activated. And it's basically in hyperdrive. One of the 10 commandments of immunology is the immune system is antigen driven. It doesn't just turn on because it wants to turn on, it is turned on because something pushed the ‘on’ button.”

“We saw really big differences between the patients and our controls in the way that the muscle is able to generate energy using mitochondria. We know that that normally exercise is good for you and the exercise improves the mitochondrial function, but in our patients we saw the opposite happening - that it worsens.”

“You have this chronic central nervous system influence on the body, such that there's inadequate return of blood to the brain… but the problem is not with the not with the veins, the problem is not with the blood return, the problem is not even with the nerves… The problem is with the central command system… so in this model, the idea would be that Covid is the trauma and that's it's turned on this switch, and Long Covid is the failure to turn off the switch.”

“The number one symptom that people present with when they've got Long Covid or pernicious anaemia or iron deficiency is fatigue. So that is across the board in all three conditions. And then the second most common symptom is shortness of breath, palpitations, dizziness, fainting, difficulty sleeping, brain fog, pins and needles joint pain, depression and anxiety…”

“They found that the strongest signal was coming from serotonin. Peripheral serotonin levels were very similar between those who are acutely active with Covid and those who had Long Covid and much lower than those who had recovered from Covid and did not have persistent symptoms.”

“We are seeing viral persistence in tissues over many years after initial infection and the immune system is not able to completely clear this out. And so now we have to figure out how either we a) can get the immune system to clear this all out, or can we use other modalities - antivirals, monoclonal antibodies, immune-boosting modification, things like that, that will actually help purge these kind of persistent infected cells that we're observing in tissue.”

“60 to 70% of the Long Covid patients with that specific people phenotype - that type of pattern of symptoms - got quantifiable, abnormal pain PET scans, which puts the problem, I think, really in the brain.”

“We're going to look at our antibody spectrum to do a diagnostic accuracy study. What I expect to find is there'll be groups of patients where some of them have holes around the onset of the of the Long Covid symptoms. “

“When we talk about Long Covid on planet Earth, I think the lower estimates are about 60 million and the upper estimates are at 400 million globally. It's not a disease of the wealthy worried well in the UK or the US or whatever, it's a disease of six to 10% of everybody on planet earth has ever had COVID-19, no matter where they are. So if the stakes are that high, why on earth can't we regain some of that battle spirit and momentum? I think it does come into kind of policy and politics.”

Microbiologist Dr. Amy Proal spearheaded the Long Covid Research Initiative (LCRI) at the Washington state–based nonprofit PolyBio Research Foundation. A privately funded venture hoping to raise 100 million dollars and direct it into trials. So far they have raised 15 million. Of course the fund pales in comparison to the 1 billion in the hands of the RECOVER Long Covid initiative at the National Institutes of Health (NIH).

“The first year of this was recognising the problem and getting people to buy into that... The second year of this was describing who was most likely to get this condition. The third year of this was laying out potential biology. The current era of this now needs to be proving that each of those mechanisms is or is not driving this and… you actually have to intervene on those pathways to see if you can change either a biological measurement or change how people feel. What that means to us is doing trying to do these intense proof of concept, experimental medicine type studies, where we identify a target pathway that we think it is contributing, then we try to alter it by giving an investigational treatment and we see what happens and whether our hypothesis was correct.”

“If we’ve learned anything, this is not something anyone wants to get… The fact that there's a genomics that underlie Long Covid tells you how real it is, right? And then the fact that we will get treatments to people, all these things reinforce how big an issue.”

“Our reward system is - how many papers, how many citations, how many grants… and what enamoured me as I got started in my career was the idea that none of that really matters if you haven't made a difference in people's lives. So the question really is - what's the value of the information you're producing? And how can you do it in a way that that makes a difference?”

“The conventional model is trying to identify what disease does this person have, and then you treat the disease. Well, that may work in some situations… but there are many situations involving chronic illness in which that doesn't work. And I've evolved and taught other approaches to diagnosis, something that I call person-centred diagnosis.”

“We’re trying to develop clinical trials ourselves, to look at this combination of clinical point testing, where we can actually do that very robust analysis of saying, what's going on in terms of blood gases, what's going on in terms of bicarbonate, what's going on in terms of pH? How is that affecting patients at rest and in movement, and how does that correlate with symptoms?”

“I would word this as a massive public health problem… crisis that most of the world is yawning through and sleepwalking through. I think people are sleepwalking through this because it's too invisible.”

Publishing in scientific journals is a challenging process due to fierce competition, limited resources, lack of networks and mentorship, bias and subjectivity in peer review, leading to high rejection rates. Addressing these obstacles requires collective efforts to foster inclusivity, collaboration, and support systems for all researchers.