Poorly defined and understood, the far-reaching impact of long COVID is emerging as the next battleground of the COVID-19 pandemic.

More than a year on from the beginning of the pandemic, the success of the first generation of vaccines is weakening the link between COVID-19 infections and deaths.

But researchers at Imperial and elsewhere are now turning their focus on the lasting effects of the virus, which may linger for months and even years. 

For many who have long recovered from the initial infection, COVID-19 has had lasting, life-changing impacts on their health, affecting their ability to resume normal life and even their ability to work. The emerging pattern of the condition, called long COVID, features a list of symptoms: from fatigue, breathlessness and brain fog, to aching joints and depression.

Scientists describe working in ‘uncharted territory’ as they race to define a condition that may affect many millions of people around the world, drastically reducing their quality of life and increasing the burden on healthcare systems.

Ryan O’Hare spoke to Professor Danny Altmann, from the Department of Immunology and Inflammation at Imperial, about efforts to pin down this new disease, in the hope that better understanding will help to treat and mitigate its effects. 

Listen to the full interview, recorded in July 2021. Abridged answers below edited for style and clarity.

Q - Most of us will be familiar with the acute effects of COVID-19, which have unfortunately lead to many losses of life. But many of us are probably less familiar with long COVID. What are we talking about here? And how does it affect people?

Danny Altmann: Long COVID obviously has been talked about a great deal. And the point that I'd emphasise is that this is a new disease process, in uncharted territory, that we're trying to describe in real time.

It's a real thing. So I'm very impressed when I look around the world, at different cohorts of people in different countries who've been infected, that they're all describing the same kind of thing. They're saying that they may have had quite mild COVID-19 infection, or severe infection, or even asymptomatic infection, and yet for several weeks, or months, or now years afterwards, many of them are describing the same kind of pattern of symptoms.

They're describing fatigue, breathlessness, wheeze, chest pain, brain fog, a list of symptoms that goes on in different combinations, through 40 or 50 symptoms, that's out there in the world and the many millions of people that have had COVID.

Q - Do we know at the moment if it can affect anyone? Or are certain people more at risk?

DA: There's an enormous data set that comes out of many heroic groups of sufferers around the world who've organised themselves into very large online groups. There's a sense from those data sets that females [may be more affected] than males.

At one stage, there was a question about whether that was a kind of ascertainment bias, because perhaps women are more likely to express how they feel to online groups and things like that. But I suspect, if you look across the datasets, it's not just that. I think it is a real thing, and there are there are even immunological reasons why women might be more affected.

Beyond that, I think it's hard to say. The other point I'd add to that, is that, you know, we're all trying to debate and decode what it is and what the pathophysiology of it is. And sure, you could argue ways in which somebody who's been extremely ill on intensive care for a long time with a viral load might, for example, have lung damage that you could see on a CT scan or an MRI, and we know that that's one subset of long-COVID. But that's not the whole story. It's perhaps partly that, but it's also much more than that.

Q - Obviously, the picture is still emerging. But is there any evidence that there's a long term risk associated with long COVID as well, that may predispose you to other health conditions?

DA: I think one of the reasons I worry so much for people with long-COVID is the kind of uncharted aspect of it. And without straying into politics, it's one of the reasons why I do worry, when I see people being laissez faire, saying ‘Well, if we've got the stage where people aren't dying, and aren't filling up the intensive care units, do we need to care?’. And the answer is, I think, until we've got more data, we don't know how much we need to care.

At the moment, we have an awful lot of people reporting long-COVID from the first wave, so in other words, well beyond a year. And in many cases, these are people who have life-changing illness. These are people who used to cycle to work who can no longer cycle, these people who now find it difficult to go up and down stairs, and people used to be full time full on workers, who now find it hard to turn up for a full time job and gone part time. This is the real thing, and at the time of speaking, it's more than a year. I don't know, and nobody can tell them, what the long term future holds for them.

One of the reasons I became interested in this is that in our lab we have a lot of collaborations in Brazil. And one of the diseases we're especially interested in there is another totally different viral infection, an infection called Chikungunya, which is spread by mosquitoes.

The reason that we're so interested in that, in addition to our interest in related diseases, like Zika, or Dengue, is that if you have Chikungunya, there's a moderately large minority of infected people who will go on to get a kind of autoimmune arthritis that can stretch on for three, four, five years or more. And so it's the long term after effects that devastates their lives, not the initial fever, because many of them lose their jobs or become suicidal, and that's the real burden to the Brazilian healthcare system. So you can see where I'm going with this in terms of the analogy, that's the thing that worries us.

Q - You've mentioned Chikungunya, but has it been of any surprise really, that we're seeing this with COVID-19? And did we see anything similar with other coronaviruses like SARS, or MERS?

DA: There were glimmers of this kind of stuff with SARS and MERS. But really, COVID has come at us like a juggernaut, hasn't it? And everything about it has been unexpected and bigger than we expected and worse than we expected. So no, we weren't really ready for it.

We should have been ready for it, because there are many viral infections that have weird disruptive effects on the immune system and long term consequences. Think about Epstein Barr virus, glandular fever, think about Ebola virus, or Cytomegalovirus. So many, many examples like that. But I guess like so many other things that surprised us and caught us off guard, we thought of Coronavirus as being a bit like the common cold and not in that set.

Q - Obviously the science in this area has been advancing at a tremendous pace. But do we have any idea yet if the vaccines which have been rolled out are having an impact on long COVID or curtailing it at all?

DA: There are some quite good surveys out there, again, from the support groups, both here and in the United States, as well as a big research programme on this out of Yale University, so it's kind of work in progress.

The way that I probably guesstimate the results off the top of my head is there's a fairly consistent picture, at least in the short term, where in people who have long COVID, who've been vaccinated, perhaps half of them report feeling better or quite a lot better, perhaps a quarter of them report feeling no different, and perhaps a quarter report feeling worse. It’s hard to know what to make of that until more work is done.

But that would perhaps be compatible with there being just different immune mechanisms at play – some of them are improved by having more anti-spike [protein] antibodies on board, and some not.

Q - Your team is just about to undertake some new research in this area with funding from the NIHR. Can you tell us a little bit about what that will involve? And what you're hoping to find out?

DA: What we really want to do is do something slightly new for our lab and really reach out to people in the UK who have long COVID symptoms, and get them into the lab to give a blood sample and really throw at that blood sample everything we know about analysing the immune response.

That's both looking at autoimmunity, looking at the array of antibodies to different proteins in the human body, and to see whether there are patterns of autoimmunity that correlate with those symptoms. We also want to look at RNA, look at the things that lymphocytes are making in those people, and see if programmes of immunity are turned on differently in people with long COVID.

One of the ways that I've tried to imagine this process when people have asked me about it, is kind of by analogy to things like glandular fever. If you know any teenager who has ever had glandular fever, it can take them years to feel normal again, and they become susceptible to minor infections for a long time.

I describe it as a bit like somebody throwing a hand grenade into our immune system, that all the populations [of immune cells?] are completely topsy turvy and unsettled for years. And, that's a guess, but we've got the technology to look at that in quite a lot of detail. And that's the third strand that we want to look at.

Q - As an immunologist, you're working to uncover what's happening to our body's defences when we come into contact with Coronaviruses. Do we know why this particular virus, SARS CoV-2, may be having this longer lasting impact?

DA: I think it's really, really hard to say without doing more work. As I said, every single thing that I've come across about SARS CoV-2 has surprised me.

As somebody who's been giving so-called expert opinions to policymakers and the press for a year and a half now, it always has potential to embarrass us because something that we thought of as a certainty six months ago, isn't a certainty today and the story keeps on rolling along with massive amounts of data around the world, in real time.

We simply have to do the studies – finally, I feel very kind of overdue, really, I've been anxious to do this for many months – and work out what on earth is going on.