Most COVID-19 patients recover from their acute infection within two weeks, but parts of the virus do not always clear patients’ bodies immediately. Now a new study, one of the largest, focusing on hospitalized COVID-19 patients shows that some patients harbor this residual virus for weeks to months after their primary COVID-19 symptoms have resolved.

The study suggests that when the virus’s genetic material, called RNA, stays in the body for more than 14 days, patients have worse disease outcomes, experience delirium, stay in hospital longer and are at greater risk of dying from COVID. 19 compared to those that eliminated the virus quickly. The persistence of the virus may also play a role in Long COVID, the debilitating array of symptoms that can last for months. It is estimated that between 7.7 and 23 million people are now affected by long COVID in the United States alone.

Without immunity from vaccination or previous infection, SARS-CoV-2 — the virus that causes COVID-19 — replicates and spreads throughout the body and is cleared through the nose, mouth and intestines. But in most infected people, levels of the virus in the body peak between three and six days after the initial infection, and the immune system eliminates the pathogen within 10 days. Virus shed after this period is generally not contagious.

Even after accounting for disease severity, whether patients were intubated or had underlying medical comorbidities, “there is something here that suggests patients who are persistently PCR positive have poorer outcomes,” says Ayush Batra, a neurologist at Northwestern University Feinberg School of Medicine who led the new study.

Batra’s study shows that patients who had prolonged shedding during an acute infection have more severe consequences from COVID-19, says Timothy Henrich, a virologist and immunologist at the University of California, San Francisco, who was not involved in the new research . However, the study does not examine whether this stubborn virus is directly responsible for long COVID.

“There are several leading hypotheses about the cause of a long COVID, including virus persistence, and it may be that multiple pathways are at play, perhaps to varying degrees in each person,” says Linda Geng, a Physician at Stanford Health Care, who is one newly opened post-acute COVID-19 syndrome clinic to treat patients with long-term COVID-19 illness.

Persistent virus causes worse COVID-19 outcomes

Batra and his team began investigating ongoing coronavirus infections after noting that some patients who returned to hospital were still testing positive for the virus four or five weeks after the initial infection was diagnosed.

For their new study, the team analyzed 2,518 COVID-19 patients hospitalized at Northwestern Medicine Healthcare between March and August 2020. They focused on PCR tests, which are considered the gold standard because such tests detect genetic material of the virus and so on, are highly sensitive and less likely to return false negative results.

The team found that 42 percent of patients continued to test positive for PCR two weeks or more after their initial diagnosis. After more than 90 days, 12 percent of persistent shedders still tested positive; one person tested positive 269 days after the original infection.

Viral persistence has been identified in previous smaller studies. The researchers showed that even patients with no obvious COVID-19 symptoms carried SARS-CoV-2 for a few months and beyond. In some immunocompromised patients, the virus may not clear for a year. Four percent of COVID-19 patients in a study of chronic COVID-19 infection at Stanford continued to shed viral RNA in feces seven months after diagnosis. However, Batra’s study shows that a larger number of patients are taking longer to clear the virus than previously thought.

“Sustained RNA shedding would mean there was still a virus reservoir somewhere in the body,” says Michael VanElzakker, a neuroscientist with affiliates with Massachusetts General Hospital, Harvard Medical School and Tufts University. It is believed that such reservoirs could allow the virus to persist for a long time and trigger the immune system to act abnormally, potentially leading to a long COVID.

“Some patients are unable to clear this reservoir for various reasons, or their immune system responds in an abnormal way, resulting in these persistent symptoms called long COVID,” says Batra.

Still, many scientists believe there is still insufficient evidence to link viral RNA persistence to long COVID.

Dormant Viruses

The list of human tissues in which SARS-CoV-2 hides long after initial infection is growing. Studies have identified the virus or its genetic material in the gut of patients four months after initial infection and in the lungs of a deceased donor more than a hundred days after recovering from COVID-19. A study that has not yet been peer-reviewed also found the virus in appendix and breast tissue 175 and 462 days after coronavirus infection, respectively. And research from the US National Institutes of Health, also yet to be peer-reviewed, has detected SARS-CoV-2 RNA remaining at low levels in multiple tissues for more than seven months, even when undetectable in blood .

“It’s not surprising to find viruses that you encounter throughout life” that survive in human tissue, says Kei Sato, a virologist at the University of Tokyo. In fact, Sato’s work has shown that humans commonly accumulate viruses such as Epstein-Barr virus, varicella-zoster virus (which causes chickenpox), and many herpesviruses in dormant forms. These persistent viruses are typically present in low concentrations, so they can only be identified by extensive genetic sequencing.

This shows how complicated it is to prove or disprove the link between persistent SARS-CoV-2 and long COVID. Shingles, for example, occurs decades after chickenpox infection when the latent virus is reactivated during immune stress.

Likewise, prolonged SARS-CoV-2 could cause long-term health problems. Henrich believes that if the virus is seeded into deep tissue, it may cause the immune system to go into a dysregulated inflammatory state. Such a condition is “probably evidence that the virus is capable of surviving and perhaps entering into some sort of uneasy truce with the body,” says VanElzakker.

However, to link an ongoing virus to a long COVID requires extensive studies. “We still don’t know enough to draw any meaningful conclusions about the currently proposed mechanisms, but research is actively being done to answer these questions,” says Geng.

Eliminating stubborn viruses could long cure COVID

Both Geng’s and Henrich’s groups have reported preliminary case studies showing improvement in long-term COVID symptoms after patients were treated with Pfizer’s oral antiviral COVID-19 drug Paxlovid. Paxlovid stops the virus from replicating, which is why some experts believe it can eliminate any remaining virus. However, both authors advise caution before assuming that Paxlovid will be safe, effective, or sufficient and therefore a reliable cure for long COVID.

“There are some interesting hypotheses about how Paxlovid might be useful in treating long-term COVID, but we need more research and clinical trials before we can come to any conclusions,” says Geng.

The US Food and Drug Administration has warned against off-label uses of Paxlovid, which is not approved for long-term COVID treatment. The agency has granted Paxlovid emergency use authorization to treat mild-to-moderate COVID-19 in people at risk of serious illness, twice a day for five days shortly after testing positive.

“It would be important to consider the optimal duration of treatment [of Paxlovid] to ensure long-term and sustainable results,” says Geng.

President Joe Biden has directed the Secretary of Health and Human Services to create a national long-COVID action plan, and the NIH has launched a multi-year study called RECOVER to understand, prevent, and treat long-term health effects related to COVID. 19

Meanwhile, not only do vaccines continue to protect against serious illnesses, but there is evidence they can prevent many long-standing COVID symptoms. A new study compared 1.5 million unvaccinated COVID-19 patients to 25,225 vaccinated patients with breakthrough infections and found vaccines significantly reduced the risk of developing long-lasting COVID symptoms 28 days after infection. The protective effect of the vaccination became even greater 90 days after infection.

“Although the majority of people don’t develop long-term COVID, it’s certainly a risk, and COVID doesn’t stop after the first 10 days of infection,” says Henrich. “For those who don’t take COVID seriously, it can be life-changing.”

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