Friday, March 13, was an unlucky day for Fiona Lowenstein. Over the weekend, the 26-year-old spiked a fever, then she started coughing, and soon she was so short of breath she had trouble speaking. At the hospital, Lowenstein tested positive for COVID-19. She was admitted and put on supplemental oxygen. After two days, she improved enough to go home—but her symptoms didn’t stop there.
She started to have intense diarrhea, lost her sense of smell, and was plagued by a sore throat and hives. Most troubling, about a month after her initial symptoms, she developed intense fatigue and severe headaches. Lowenstein started scrambling her words and struggled to focus, forgetting what she meant to say in the middle of speaking.
“It felt like I’d just been hit by a truck,” she says. “I had days where I would manage to do work, and then the next day I’d not feel like getting out of bed.”
Scientists are still trying to understand why some COVID-19 patients like Lowenstein are having these kinds of relapses—sometimes weeks or months after they first got sick.
It’s possible that long-term patients are struggling because some of the coronavirus sticks around in their tissues. Researchers are now figuring out how long the germ stays alive inside the body, a situation known as viral persistence. That may be different from the length of time that someone who had COVID-19 can shed viral fragments, which can sometimes cause false positives on diagnostic tests.
It’s important to understand COVID-19 persistence, as this knowledge determines how long someone is contagious, how long patients should stay in isolation, and even whether it’s possible to be re-infected.
“Persistence is a tricky word,” says Mary Kearney, a senior scientist who studies HIV drug resistance at the National Cancer Institute’s Center for Cancer Research. It’s especially tricky, she says, because scientists don’t know how coronavirus persistence might vary by individual or even by organ.
The coronavirus has a genome made of RNA rather than DNA, Kearney says. In other families of RNA viruses, such as Hepatitis C, persistent infections can lead to liver disease or cancer, even decades after the original infection. “Where there’s long-term persistence, there can be long-term consequences,” she says. So although these outcomes are not yet evident for COVID-19 given its novelty, they should be investigated.
Persistence versus reinfection
Scientists use three general categories to define persistence. With acute viral infections—such as the stomach-churning norovirus—people develop symptoms quickly and then fully recover within days. Other tiny invaders stick around—among them, the varicella-zoster virus which initially causes chickenpox but then becomes latent in neurons for the rest of a patient’s life. Others still, such as poliovirus, are acute in most people but persistent in a few who have trouble clearing the virus from their bodies.
One complicating factor for COVID-19 is that many of the tests used by doctors tracking patients—or by researchers swabbing hospital light switches—use the polymerase chain reaction (PCR) method. This test searches for genetic fragments of the virus that are expelled by a person’s breath or sampled in their stool, urine, or other secretions. A PCR test can tell you whether someone has recently caught the disease, but it can’t distinguish between the live replicating virus and non-infectious viral debris.
“Even when the virus is no longer infectious, there’s a period of time when you can still detect its RNA,” explains Andrew Karaba, an infectious disease fellow at Johns Hopkins University. (Learn why some rural hospitals may not survive COVID-19.)
To test for live viruses, researchers must grow them from samples in cell culture flasks or petri dishes. That’s not easy; nasal swabs can dry out too much, or they can miss grabbing an infected cell. In other cases, the sample may not hold enough virus particles to seed growth. What’s more, the U.S. Centers for Disease Control and Prevention advise that the SARS-CoV-2 virus should only be isolated and studied in secure laboratories with a biosafety level of 3 or higher.
While the number of live virus studies on SARS-CoV-2 has been limited, a few have emerged that offer clues to how long the virus may last. One study in Germany looked at nine mild cases and found that live viruses could not be grown from throat swabs or sputum samples eight days after symptoms started. The work also found that people emit high amounts of viral RNA during the early days of infection.
Another study in Nature isolated the live virus from nine COVID-19 patients during their first week of symptoms. One had virus that still could be cultured after nine days; researchers also found viral RNA fragments in multiple samples after 31 days. A third study on 89 nursing home residents, published May 28 in the New England Journal of Medicine, also found that patients can shed the live virus for up to nine days.
Relapse redux
Working out the true windows of viral persistence will help resolve whether people are being re-infected with COVID-19, whether they develop lasting immunity—and, ultimately, how long sick people need to stay isolated.
So far, for cases of what appear to be long-lasting symptoms, reinfection seems not to be the explanation. South Korea's Centers for Disease Control and Prevention recently traced the contacts of 285 patients who had re-tested positive after a negative PCR result. The study found no evidence that any of the patients could transmit the virus to others, or that they had they been reinfected by the contacts around them.
“Usually, when people recover from acute viral infections, their immune response kills the cells affected to eliminate the virus,” says Diane Griffin, a virologist at the John Hopkins Bloomberg School of Public Health. But when viruses infect long-lived cells, such as neurons, the immune system can’t afford to destroy them. That means “you don’t actually get rid of all the virus genome,” she says; instead, the virus might hide in parts of the body for long periods.
If so, this persistence may actually be key to long-term immunity. Griffin says that even if the virus isn’t spreading profusely, if its proteins are still being produced in a small number of cells, its fragments may force your body to maintain an immune response—keeping you from getting sick again.
That’s true even for infections such as measles, where long-living neurons aren’t a major target. In monkey studies, Griffin found viral RNA in immune system cells called lymphocytes for six months after apparent recovery. The virus could last even longer in human cells, she says. Meanwhile, measles produces life-long immunity, and Griffin suspects persistent RNA may help explain that effect.
Others agree with her. “Some aspects of the immune system exist as they are because we are chronically infected,” says Skip Virgin, executive vice president and chief scientific officer of the biotechnology company Vir.
Avindra Nath, the clinical director of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health, says that a “possible persistent immune function” may be detrimental to COVID-19 patients, and may play a role in so-called cytokine storms where the immune system kicks into damaging overdrive. Such immune responses may help explain the potential relapses and some of the emerging long-term complications, says Nath, who has begun developing a long-term study on the topic.
However, individuals may exhibit myriad levels of viral persistence and immunity, which could make vaccine development and deployment more challenging. “The same viral particle won’t have the same effect in every person,” says Santosh Vardhana, a medical oncologist at Memorial Sloan Kettering Cancer Center. That’s why few vaccines provide universal immunity, says Vardhana, who’s researching how adaptive immunity might help COVID-19 patients.
This variety in responses can also make it harder to recommend how long sick people should stay isolated. The U.S. CDC currently recommends COVID-19 cases isolate for 10 days after they start feeling ill, and three days after their fever dissipates. If you never have symptoms, the 10-day window starts after you get a positive result on a COVID-19 test.
Both for vaccine efforts and to better treat patients, Vardhana says, “we have to think about the immune response with COVID with more complexity.”
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