For 500 days, a Connecticut patient has had COVID – and three unknown variants

For more than 500 days, there’s a patient in Connecticut who has tested positive for COVID-19.

At least, Yale’s Chrispin Chaguza and his team think it’s likely the patient has crossed the 500-day threshold. They have reason to believe that’s the case, since the patient they studied tested positive for 471 days before they stopped testing.

“It’s just that we stopped collecting samples, because of the worsening condition of the patient,” he said of the patient who has also been diagnosed with cancer.

“We haven’t had a negative test from this individual yet,” said Nathan Grubaugh, who runs the genomics lab in which Chaguza works. He said though there have been other chronic infections studied, this one is “one of the longest chronic infections ever documented.”

The pandemic began in late 2019, so no chronic COVID infections could be longer than two-and-a-half years, and the patient Chaguza and Grubaugh studied caught COVID in 2020.

“This started in the first year of the pandemic,” Grubaugh said. “So I’d imagine that there are still some out there that are longer, but they can’t be that much longer.”

The patient has, over all that time, been asymptomatic and due to a cancer diagnosis has been largely isolated. That means they haven’t likely infected anyone else, but have been unable to receive treatment that might knock the COVID out of their system.

“This person actually took very good care to stay isolated because there’s not just COVID. When you have lymphoma, you are susceptible to all sorts of diseases,” Grubaugh said.

Over the 471 days Chaguza and his team were conducting their study, the patient’s infection bred three new, completely as-yet unobserved COVID variants, though those variants have not infected anyone other than the study subject.

“To our knowledge, they haven’t emerged,” Grubaugh said. “We haven’t found any of these viruses outside of this individual.”

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Every virus replicates and their descendants change form in a never-ending attempt to become more “fit” — more ineffective, or better at evading immunity.

But these new variants that Chaguza and his colleagues identified in this patient were siblings, not descendants. Chaguza speculated that perhaps patients with chronic infections are like variant factories, producing major new branches of the virus’ genetic tree.

“They have the same parent. They’re more like twins,” he said. “When we draw the tree, the branches for all these different genotypes dated back to the base of the tree, meaning that they started evolving once the infection started in this individual.”

It’s possible that the major variants like delta and omicron — though possibly not the sub-variants like BA.5 — all began in a person with a chronic infection.

“During chronic infection, what we see is that evolution is accelerated compared to the evolution that occurs when the virus is spreading between people,” Chaguza said. “The fact that evolution is accelerated, it means that the virus can diverge over a short period of time and can accumulate so many mutations over a short period of time and that by accident, some of these mutations may promote transmission”

“So the hypothesis for omicron is that there was a chronic infection,” he said.

All of the variants that were found were not out-competing each other for dominance, as variants and sub-variants tend to do. If one is more ineffective, or better at evading immunity, it will very quickly become the dominant strain.

In this case, all three variants were in the same patient at the same time.

“What we saw with this individual is that the evolutionary rate of the virus is twice as fast as what we would normally see,” Grubaugh said. “That’s how multiple genotypes could develop within an individual. We were shocked to see that they were co-circulating.”

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It’s possible, Grubaugh said, that chronic infection — particularly in immunocompromised patients — is not all that rare.

“A fair number of them that had infections probably develop some level of persistent infection and things like monoclonal antibodies and vaccines can clear those infections,” he said.

What made this patient different is that a bad reaction to a monoclonal antibody treatment.

“A lot of these persistent infections aren’t nearly as long as this one because eventually we’re able to get that under control with treatments,” Grubaugh said.

Exactly how many infections result in a chronic case is perhaps not knowable. There are parts of the world where immunocompromising conditions like HIV are far more common than they are in the United States, and vaccines and treatments are not always as easily obtainable as they are here.

“How many of these infections that have been going on for more than a year exist? It’s more than one,” Grubaugh said. “But I don’t know what the upper end is.”

COVID, of course, is not the only virus that can cause a chronic infection. HIV, Grubaugh said, is a good example.

“People are infected for decades. We haven’t come close to those levels yet,” he said. “What happens in HIV infected individuals, the virus evolves resistance to the drugs they would give them and we have to give them drug cocktails.”

That further suggests that persistent viral infections are different beasts.

“Evolution doesn’t abide by the same rules as it does during routine transmission,” Grubaugh said.

There’s a theory, Grubaugh said, that evolution happens quickest when there is pressure to adapt, but not so much pressure to be an existential threat.

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“When you have a very strong immune response, there’s very little opportunity for evolution because the body gets rid of the virus, or pathogen or whatever,” Grubaugh said. “When you have no absolutely zero immune response, there’s no opportunity for evolution because either you die or what is there to adapt to?”

With this patient, there was some attempt to fight the virus, but not enough to clear it out of their system.

“This individual has antibodies, but they’re low level. There’s some immune response. It’s not completely obliterated, it’s just weakened,” Grubaugh said. “They have some immune response, and that makes it so it’s not enough to control the virus, but it’s enough there that the virus can adapt.”

“I think this is why we see the accelerated evolution, including acquiring mutations that have been found in other known variants, including delta and omicron,” he said, though that doesn’t mean every immunocompromised patient will spawn new, more dangerous variants if they get infected.

“An immunocompromised individual that gets infected, on the whole, has a very low probability of creating the next omicron,” Grubaugh said. “My evidence for that is that there’s only been a handful of variants that have actually emerged.”

But Chaguza and Grubaugh’s study does support the idea that chronic infection, particularly in immunocompromised patients accelerate viral evolution.

“This has been a hypothesis for a while now, that this is the origin of variants,” Grubaugh said. “Our study certainly supports that and might be the best evidence yet of this rapid rate of evolution and creating the ability to generate not just one variant but multiple different variants from a single infection.”

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