Most COVID-19 patients recover from acute infection within two weeks, but virus fragments do not always immediately disappear from the body of patients. Now a new study, one of the largest looking at hospitalized COVID-19 patients, shows that some patients harbor these viral remnants for weeks or months after their primary COVID-19 symptoms resolve.
The study suggests that when the genetic material of the virus, called RNA, persists in the body for more than 14 days, patients may face worse disease outcomes, experience delirium, stay hospital and have a higher risk of dying from COVID-19. 19 compared to those who quickly cleared the virus. The persistence of the virus may also play a role in the long COVID, the debilitating series 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 the long COVID.
Without immunity from vaccination or previous infection, SARS-CoV-2 – the virus that causes COVID-19 –replicates and spreads throughout the body and spreads through the nose, mouth and intestines. But for most infected people, virus levels in the body peak between three and six days after the initial infection, and the immune system eliminates the pathogen within 10 days. the virus shed after this period is usually not contagious.
Even after accounting for disease severity, whether patients were intubated or had underlying medical comorbidities, “there is something here that signals that patients who are consistently PCR positive have less good results,” says Ayush Batraneurologist at Northwestern University Feinberg School of Medicine, who led the new study.
Batra study shows patients who had prolonged shedding during acute infection risk more severe COVID-19 outcomes, says Timothee Henrich, a virologist and immunologist at the University of California, San Francisco who was not involved in the new research. But the study does not investigate whether this persistent virus is directly responsible for long COVID.
“There are several main hypotheses about the cause of the long duration of COVID, including viral persistence, and there may be multiple pathways at play, perhaps to varying degrees in a single individual,” says Linda Genga Stanford Health Care physician who co-directs a new post-acute COVID-19 syndrome clinic for the treatment of long-term COVID patients.
Persistent virus leads to worse COVID-19 outcomes
Batra and his team began studying persistent coronavirus infections after observing that some patients returning to hospital still tested positive for the virus four or five weeks after being 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 testing, which is considered the gold standardbecause these tests detect the genetic material of the virus and are therefore very sensitive and less likely to return false negatives.
The team found that 42% of patients continued to be PCR positive two weeks or more after their initial diagnosis. After more than 90 days, 12% of persistent shedders were still positive; one person tested positive 269 days after initial infection.
Viral persistence has already been noted in previous smaller studies. Researchers showed that even patients without obvious symptoms of COVID-19 harbored SARS-CoV-2 for a some months and beyond. In some immunocompromised patients, the virus may not be allowed for a year. Four percent of COVID-19 patients in a chronic COVID-19 infection trial at Stanford continue to excrete viral RNA in feces seven months later diagnostic. However, Batra’s study shows that more patients take longer to clear the virus than previously thought.
“Persistent shedding of RNA would mean that there is still a reservoir of virus somewhere in the body,” explains Michel Van Elzakker, 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 an aberrant action of the immune system, possibly causing a long COVID.
“Some patients, for various reasons, are not able to eliminate this reservoir, or their immune system reacts in an abnormal way that leads to these persistent symptoms that are now called long COVIDs,” says Batra.
Yet many scientists don’t think there’s enough evidence yet to link viral RNA persistence to long COVID.
The list of human tissues where SARS-CoV-2 lurks long after initial infection is growing. Studies have identified the virus, or genetic material from it, in the the intestines of the sick four months after the initial infection, and inside the lung of a donor who died more than one hundred days after recovering from COVID-19. A yet to be peer-reviewed study also detected the virus in the appendix and breast tissue 175 and 462 days, respectively, after coronavirus infections. And research from the US National Institutes of Health that has not yet been peer-reviewed detected persistent SARS-CoV-2 RNA at low levels in several tissues for more than seven months, even when it was undetectable in blood.
“It’s not surprising to find viruses encountered in life” surviving in human tissue, 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 chickenpox) and many herpes viruses in dormant forms. These persistent viruses are usually 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 persistent SARS-CoV-2 and long COVID. Shingles, for example, comes decades after a chickenpox infectionwhen the latent virus is reactivated during immune stress.
Likewise, persistent SARS-CoV-2 could cause long-term health problems. Henrich believes that when the virus is seeded in deep tissue, it potentially causes the immune system to shift to a dysregulated inflammatory state. Such a state is “probably proof that the virus is able to persist, and perhaps engage in some sort of uneasy truce with the body,” says VanElzakker.
Still, associating any lingering virus with long COVID will require careful study. “We still don’t know enough to draw strong conclusions about any of the currently proposed mechanisms, but research is actively underway to answer these questions,” says Geng.
Eliminating the persistent virus could cure the long COVID
Both geng and Henry’s groups have reported preliminary case studies that show a improvement in long COVID symptoms after patients were treated with Pfizer’s COVID-19 oral antiviral Paxlovid. Paxlovid prevents the virus from replicating, which is why some experts believe it can eliminate any lingering virus. But both authors urge caution before assuming that Paxlovid will be safe, effective, or sufficient and therefore a reliable remedy for the long COVID.
“There are some interesting hypotheses about how Paxlovid may be useful in the treatment of long COVID, but we would need further investigation and clinical trials before drawing any conclusions,” says Geng.
The US Food and Drug Administration has warned against off-label uses of Paxlovid, which is not approved for long COVID treatment. The agency gave Paxlovid a emergency use authorization to treat mild to moderate COVID-19 in people 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 sustainable, long-term results,” says Geng.
President Joe Biden led the Secretary of Health and Human Services to create a national long COVID action planand the NIH has launched a multi-year study called RETRIEVE to understand, prevent and treat the long-term health effects of COVID-19.
In the meantime, vaccines not only continue to protect against serious illnesses, but evidence is also emerging that they can prevent many prolonged symptoms of COVID. A new a study compared 1.5 million unvaccinated COVID-19 patients to 25,225 vaccinated patients with breakthrough infections, and he found that vaccines significantly reduced the risk of developing long COVID symptoms 28 days after an infection. The protective effect of vaccination became even greater 90 days after infection.
“While a majority of people don’t develop COVID for long, it’s definitely a risk, and COVID doesn’t stop after the first 10 days of infection,” Henrich says. “For those who don’t take COVID seriously, it can be life changing.”
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