By Elizabeth Cooney Jan. 24, 2024 Reprints

You’ve heard of long Covid, a condition in which the acute infection subsides but troubling symptoms persist. Less well known is chronic Covid: The virus just doesn’t leave, sometimes staying in patients’ bodies long enough to mutate into new variants. This happens to people whose immune systems are compromised, whether through disease or treatment, leaving them vulnerable to infections that last weeks, months, or, in one known case, a year.

New research published Wednesday in Science Translational Medicine analyzed how long it took for people with different levels of immune compromise to clear the virus, and how that virus evolved along the way. The work highlights the spectrum of risk for Covid becoming chronic — from high levels for people with blood cancers requiring bone marrow transplants, lower risk for people taking immune-suppressing drugs for autoimmune illness, and little risk for those with intact immunity. The 56 immunocompromised people in the study had a variety of conditions, but they all fall into a category of people overlooked as many in the world have moved on from the pandemic in its fifth year.

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Study co-authors, infectious disease physician-scientists, and Harvard Medical School faculty members Jacob Lemieux of Massachusetts General Hospital and Jonathan Li of Brigham and Women’s Hospital spoke to STAT about their research. The two interviews have been edited and condensed for length and clarity.

Back in 2020, you wrote in the New England Journal of Medicine about one of the first cases of chronic Covid-19 in an immunocompromised man infected for five months before he died. What did you learn?

Li: In that case we saw all these mutations that eventually became hallmark mutations for Delta and Omicron and all these variants of concern, so it had a lot of public health implications. Immunocompromised patients are the folks who are at greatest risk, so they can be a driver of evolution. But an immunocompromised state is not a yes-no situation. It represents a broad spectrum of disorders and you need a large enough cohort to really be able to categorize these individuals into the varying strata for risk.

With that cohort, what does your new study say about the spectrum of risk?

Lemieux: It’s reassuring in the sense that patients with mild or moderate immunocompromise do seem to clear the virus quite well. And that’s many patients. On the other hand, it seems clear that in the severely immunocompromised patients, in some cases, something very different is going on. And that’s something that we need to understand in better detail how to diagnose and how to treat. Those patients who were classified as having severe immunosuppression had a malignancy, or had a [bone marrow] transplant.

What does your research tell us about what these patients face?

Lemieux: Immunocompromised groups seem to have both higher numbers and higher rates of viral evolution, particularly in the spike gene. Some of that evolution clearly impacted the efficacy of monoclonal antibody therapies.

Related: Could long Covid’s signs of immune dysregulation in the blood lead to a diagnostic test?

Are there other lessons for treatment?

Li: This study helps put risk into context. It will help our patients and their clinicians figure out who are the patients at greatest risk of not being able to clear the virus — of chronic infection — and focus our treatment attention on those patients. At this point, folks at my institution and others are sometimes using combination treatments, even though we don’t have great studies on those yet, but just because some of these patients require stronger, longer treatment regimens than we need otherwise.

Lemieux: I think it’s really important to try to identify the best ways to eradicate infection from persistently infected patients so that they can get better. But also so that the risk of transmission is eliminated.

How does this play into the evolution of new variants?

Lemieux: There has been and I think it remains a concern that some patients harbor these persistent infections, which are basically the breeding grounds for future viral variants. So there’s both a medical concern, of course, for the health of those patients and their contacts. But there’s also a public health concern that by failing to detect and abort those infections, we may be missing an opportunity to improve public health and prevent future variants.

Related: Researchers try to tease out possible ties between long Covid and menopause

Any other lessons learned?

Lemieux: One of the big stories from the pandemic is just this virus essentially outrunning antibodies. We’ve seen this time and time again: Scientists create strongly binding, potent antibodies that are active against the virus. And then mutations occur and then all of a sudden, the virus with those mutations spreads across the world, and the antibodies are useless, basically.

Why is that happening?

Lemieux: Well, it seems like the virus kind of knows which antibodies are coming. And in fact, it does, because the viruses that take over are viruses that have evolved under these settings, we think, in which they’ve kind of evolved to become good at escaping antibodies. And those settings are what’s happening in these severe immunocompromised patients, or a subset of them.

What’s next?

Li: There’s still so much we don’t know. I think we need more data about the best way to treat these patients with immunosuppression, especially if they have chronic infection, especially in those who have failed first-line treatment with Paxlovid or with remdesivir, should we be giving longer courses? Combination therapy? There’s so much that we don’t know yet about the best practices on how we can take care of these patients.

Lemieux: What the field doesn’t know for sure is to what extent these individuals transmit the viruses that are evolved to the general population. There’s circumstantial evidence for that because of this eerie connection between the mutations that evolve in patients with persistent infections and then the mutations that appear. But in only a handful of cases has the transmission of these evolved variants from index cases that have been well characterized been observed. But there are examples.

Related: Paxlovid is not fully accessible to those who need it most: the immunocompromised

What is life like now for immunocompromised people as Covid continues?

Li: Most people in this country feel that the pandemic is largely over. The one population that feels left behind is the immunocompromised. They’re the ones who come and see me in clinic and tell me that they’re still very careful. They’re still scared to go outside, especially during times when the numbers are up. These are the patients who feel like all their friends or family have moved on. They’re not as protected by the vaccines. They have a hard time moving on.

These are the patients who are still being seen in the hospitals. Immunocompromised patients admitted for Covid-19 represent one of the largest populations of Covid hospitalizations, at this point. Still.