April 20, 2021

Why do some patients develop 'long Covid'—and others don't? Here are 5 top theories.

Daily Briefing

    Research suggests that as many as 10% of Covid-19 patients suffer long-term symptoms, a phenomenon that remains poorly understood by researchers. Reporting for Vox, Julia Belluz outlines five leading hypotheses to explain so-called "long Covid."

    Recovery clinics for Covid-19 long-haulers

    5 hypotheses on long Covid

    1. Remnants of the virus are still in the body

    According to experts, one reason Covid-19 symptoms may persist is because, even after testing negative for the new coronavirus, patients may still have reservoirs of the virus or its components in their body.

    This phenomenon occurs after infections with other viruses, Belluz reports, including the Ebola virus, which has been found to linger in the eyes and semen, and the Zika virus, which evidence suggests may be sexually transmitted even after an infection appears to have resolved.

    "It's out of the blood but gets into tissue in a low level—the gut, even maybe the brain in some people who are really sick—and you have a reservoir of the virus that remains," Amy Proal, a microbiologist at the PolyBio Research Foundation, said. "And that drives a lot of inflammation and symptoms."

    A related possibility is that, even after the body has cleared an acute infection, there may remain what Akiko Iwasaki, an immunologist at the Yale School of Medicine, calls "viral ghosts."

    "[T]here may be RNA and protein from the virus that's lingering and continuing to stimulate the immune system," Iwasaki said. "It's almost like having a chronic viral infection—it keeps stimulating the immune system because the virus or viral components are still there, and the body doesn't know how to shut it off."

    According to Belluz, studies in Nature and The Lancet have found RNA and protein from the new coronavirus in a number of systems in the body.

    2. The infection awakens other, previously dormant pathogens

    It's also possible that, after Covid-19 strikes, other pathogens already in the body could take advantage of a weakened immune system, Belluz reports.

    "So, for example, 90% of people in the world already have herpes viruses," Proal said. "But in those patients, the immune system keeps them in a place where they can't replicate, where they can't express proteins. They're kind of controlled."

    However, when a patient develops Covid-19, formerly dormant viruses could awaken and cause long-term symptoms, Belluz reports.

    3. The immune system begins fighting the body itself

    Another hypothesis posits that long-haul Covid-19 patients have developed an autoimmune disorder. Under this hypothesis, researchers theorize that the virus may cause the body's immune system to malfunction, so that antibodies that typically attack foreign entities—such as viruses—start attacking the body instead.

    According to Nature, these "rogue antibodies," or autoantibodies, "attack either elements of the body's immune defenses or specific proteins in organs such as the heart."

    In these cases, the immune system tries to attack the virus, but "if it has a similar size and shape to a human tissue or protein," then the "human tissue or protein" gets attacked "as well," Proal said.

    4. A person's microbiome gets thrown off

    A separate theory suggests that the coronavirus may kill off beneficial microorganisms in the gut microbiome, Belluz reports.

    For instance, one study in which researchers tracked the blood and stool samples of 100 Covid-19 patients found that the disease was linked to a "dysbiotic gut microbiome," even after the virus had left the respiratory tract. This could potentially contribute to the long-term symptoms some Covid-19 patients experience.

    "Under conditions of health, those communities are in a state of balance," Proal said. "It's like a forest, like different organisms are doing different things, but it's in a harmonious state."

    But if Covid-19 causes a microbiome imbalance, Proal said, that could potentially disrupt "a huge number of symptoms [that] are tied to microbiome dysbiosis."

    5. The body is simply suffering a long-term injury

    Another hypothesis theorizes that over the course of Covid-19, the virus may cause scarring in the lungs or damage to the heart, and those injuries could lead to long-lasting symptoms, Belluz reports.

    For example, one recent preprint study of 201 patients found that 70% had at least one organ impairment four months after their initial Covid-19 symptoms started. Meanwhile, another unpublished study looked at the lung recovery of hospitalized Covid-19 patients and found that, over a month later, one-third had scars caused by tissue death.

    For patients who were treated in ICUs for their Covid-19 infections, their lingering symptoms might be "post-intensive care syndrome," Belluz writes. People who go to the ICU for any reason frequently experience long-running symptoms after they are discharged, such as brain fog, fatigue, and muscle weakness. These symptoms could be related to being relegated to a hospital bed for an extended period of time or to the side effects of the treatments they received, as such intubation.

    What can help long Covid patients?

    As of now, there's no "silver bullet" for long Covid, Belluz reports. Although some patients report that they've begun feeling better after receiving a Covid-19 vaccine, others say their symptoms have persisted.

    Proal suggests health care providers simply listen to their patients, even if their symptoms are medically unexplained and easy to dismiss or minimize. "It's time for medicine to be rooted in just believing the patient," Proal said (Belluz, Vox, 4/14).

    Recovery clinics for Covid-19 long-haulers

    Download the case study

    Recovery Clinics for Covid-19 Long-haulers

    Several health systems have set up dedicated recovery clinics to help treat and coordinate care for long-haulers. This resource provides an overview of Covid-19 recovery clinic models pioneered by two early adopters—The University of Iowa Hospitals and Clinics and the University of Pennsylvania Medicine—and considerations for assessing whether it is a model you should pursue.

    Download now

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