By Sanjay Mishra

Most COVID-19 patients recover from their acute infection within two weeks, but bits of the virus don’t always disappear from patients’ bodies immediately. Now a new study, one of the largest focusing on hospitalized COVID-19 patients, shows that some patients harbor these viral remnants for weeks to months after their primary COVID-19 symptoms resolve.

The study suggests that when the genetic material of the virus, called RNA, lingers in the body longer than 14 days, patients may face worse disease outcomes, experience delirium, stay longer in the hospital, and have a higher risk of dying from COVID-19 compared with those who cleared the virus rapidly. The persistence of the virus may also play a role in long COVID, the debilitating suite of symptoms that can last for months. Estimates suggest between 7.7 and 23 million people in the United States alone are now affected by long COVID.

Without immunity from vaccination or a previous infection, SARS-CoV-2—the virus that causes COVID-19—replicates and spreads throughout the body and is shed through the nose, mouth, and gut. But for most infected people, virus levels in the body peak between three and six days after the original infection, and the immune system clears the pathogen within 10 days. The virus shed after this period is generally not infectious.

Even after accounting for disease severity, whether the patients were intubated, or had underlying medical comorbidities, “there is something here that signals that patients who are persistently PCR positive have worse 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 risk more severe outcomes 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. But the study doesn’t investigate whether this persistent virus is directly responsible for long COVID.

“There are multiple leading hypotheses out there about the cause of long COVID, including viral persistence, and it may be that there are multiple pathways at play, perhaps to some varying degree in any one person,” says Linda Geng, a doctor at Stanford Health Care who co-directs a newly opened Post-Acute COVID-19 Syndrome Clinic for treating long COVID sufferers.

Persisting virus causes worse COVID-19 outcomes

Batra and his team began studying persistent coronavirus infections after observing that some patients who were returning to the hospital were still testing positive for the virus four or five weeks after they were diagnosed with the initial infection.

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

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

Viral persistence has been noted before in previous smaller studies. Researchers showed that even patients without obvious COVID-19 symptoms harbored SARS-CoV-2 for a couple of months and beyond. In some immunocompromised patients, the virus may not be cleared for a year. Four percent of COVID-19 patients in a trial on chronic COVID-19 infection at Stanford continued to shed viral RNA in feces seven months after diagnosis. However, Batra’s study illustrates that a larger number of patients take longer to clear the virus than previously realized.

“Persistent RNA shedding would mean that there still is a reservoir of virus somewhere in the body,” says Michael VanElzakker, a neuroscientist affiliated with Massachusetts General Hospital, Harvard Medical School and Tufts University. Such reservoirs are thought to allow the virus to persist over a long period of time and could trigger the immune system to act aberrantly, perhaps causing long COVID.

“Some patients, for variety of reasons, are not able to clear this reservoir, or their immune system reacts in some abnormal way that results in these persistent symptoms that have come to be termed as long COVID,” says Batra.

Still, many scientists don’t think there is sufficient evidence yet to link the persistence of viral RNA to long COVID.

Sleeping viruses

The list of human tissues where SARS-CoV-2 hides long after the initial infection is growing. Studies have identified the virus, or genetic material from it, in the intestines of patients four months after initial infection, and inside the lung of a deceased donor more than a hundred days after recovery from COVID-19. One study that’s not yet peer reviewed also detected the virus in the appendix and breast tissues 175 and 462 days, respectively, after coronavirus infections. And research from the U.S. National Institutes of Health that’s also not yet peer reviewed detected SARS-CoV-2 RNA persisting at low levels across multiple tissues for more than seven months, even when it was undetectable in blood.

“It is not surprising to find viruses encountered during the lifetime” surviving in human tissues, says Kei Sato, a virologist at the University of Tokyo. Indeed, Sato’s work has shown that humans frequently accumulate viruses such as Epstein-Barr virus, varicella zoster virus (which causes chicken pox), and many herpes viruses in dormant forms. These persisting viruses are typically present at low levels, so only extensive genetic sequencing can identify them.

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

Likewise, lingering SARS-CoV-2 could cause long-term health problems. Henrich thinks when the virus is seeded in deep tissues, it potentially causes the immune system to shift into a dysregulated inflammatory state. Such a state is “probably evidence that the virus is capable of persisting, and maybe getting down into sort of an uneasy truce with the body,” says VanElzakker.

Still, associating any lingering virus with long COVID will require extensive studies. “We still don't know enough to make strong conclusions about any of the current proposed mechanisms, but research is actively underway to answer those questions,” says Geng.

Clearing up persistent virus might cure long COVID

Both Geng and Henrich’s groups have reported preliminary case studies that show an improvement in long COVID symptoms after patients were treated with Pfizer's COVID-19 oral antiviral Paxlovid. Paxlovid stops the virus from replicating, which is why some experts think it can clear any lingering virus. But both authors urge caution before assuming that Paxlovid will be safe, effective, or sufficient and thereby a reliable cure for long COVID.

“There are some interesting hypotheses about how Paxlovid may be useful in the treatment of long COVID, but we’d need further investigation and clinical trials before coming to any conclusions,” says Geng.

The U.S. Food and Drug Administration has warned against off-label uses of Paxlovid, which is not approved for long COVID treatment. The agency has given Paxlovid an emergency use authorization to treat mild to moderate COVID-19 in those who are at risk of developing severe disease, twice daily for five days soon after a positive test.

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

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

In the meantime, vaccines not only continue to protect against severe disease, but evidence is also emerging that they can prevent many long COVID symptoms. One new study compared 1.5 million unvaccinated COVID-19 patients to 25,225 vaccinated patients with breakthrough infections, and it found that vaccines significantly reduced the risk of developing long COVID symptoms 28 days after an infection. The protective effect of vaccination got even larger at 90 days post-infection.

"Although a majority of people do not develop long COVID, it's certainly a risk, and COVID doesn't stop after the first 10 days of becoming infected,” says Henrich. “For those who don't take COVID seriously, it can be life changing."