A 25-year-old Nevada man was the first American confirmed to have caught COVID-19 twice, and his second infection was worse than the first. USA TODAY

By medical standards,Nicole Worthley is considered extraordinarily rare. She was diagnosed with COVID-19 on March 31 and again in September.

She was walloped both times, with a fever for six weeks and side effects all summer before round two kicked in.

But she can't prove she had COVID-19 twice. That requires genetic testing of both infections, which has only happened a few dozen times in the world, and never in South Dakota where she lives.

Many states are keeping track of claims of reinfection South Dakota, for example, is studying at least 28, while Washington state is investigating 120 but they are still considered extremely unusual, according to health experts, including the World Health Organization.

In Colorado, 241 people have had a second positive PCR test more than 90 days after the first one. "All are investigated as cases, including isolation instruction for the case and quarantine instruction for their close contacts," according to a Colorado Department of Health and Environment spokesperson.

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The Centers for Disease Control and Prevention said in a statement that it is investigating some possible reinfections but has not yet confirmed any. It only considers infections more than 90 days apart to be possible reinfections; otherwise, someone's illness is likely a lingering infection.

Worthley said she's not sure which is worse: Being able to be reinfected, or having a lingering virus that could flare up anytime.

Nicole Worthley believes s he's been infected twice with COVID-19, forcing herself and three kids, ages 6, 8 and 10, to isolate at home for months.(Photo: Courtesy Nicole Worthley)

"Whether or not I personally have a proven reinfection isn't to me as important as it's possible that you can get it again," she said. "Or, if you don't believe that, then it's possible that for six straight months you can have COVID-19, still test positive for COVID-19 and still be actively ill from it because I don't think there's a lot of understanding of that right now."

No one knows how long the immune system can keep someone safe from COVID-19 after infection.

Some diseases like measles are one and done. Once a person is infected or vaccinated, the immune system typically provides protection forever. With other viruses, like the common coldsome of which are closely related to the coronavirus that causes COVID-19protection might not last a year, or even a season.

COVID-19 was discovered less than a year ago, so scientists don't yet know how long the body can fight it off.

The answer has implications for the longevity and effectiveness of vaccines, the possibility of communities developing so-called herd immunitywhere the virus no longer spreads because so many people have already been infected, and how those infected once should feel and behave.

Worthley, 37, could be considered a "long-hauler"someone whose COVID-19 lasted for months after infection.

She was diagnosed on March 31 after suffering sharp chest pains. A few days later, she was so short of breath thatshe could barely walk across her apartment.

A single parent to three kids, ages 6, 8 and 10, Worthley struggled to function. "The room would be spinning and I'd be wheezing and stuff. Sometimes I could feel my teeth tingling," she said.

She had a fever for four straight weeks, then had a break for a day or sonot enough to meet the 72-hour window to be declared healthy and then spiked again for two more weeks.

She and her kids were stuck in their Sioux Falls apartment from late March until early June.

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The children never got more than a few tired days and a yucky cough. But she knows her illness affected them. During his bedtime prayers, her oldest son often said he was thankful she was still alive.

In early June, the family was finally allowed to go out. Worthley was told she didn't need another test; she was no longer considered infectious.

She went back to work at the day care center where she's an assistant teacher but only part time because the pandemic had driven away some families.

Still, all summer, Worthley, previously healthy though admittedly overweight, had weird symptoms. Her doctor prescribed a beta blocker for heart palpitations and an anticonvulsant for nerve pain in her legs.

She donated convalescent plasma in September, hoping the antibodies her immune system had developed could help someone else fight off COVID-19.

Nicole Worthley had a fever for six weeks during her first bout with COVID-19, but "only" 17 days with her second.(Photo: Nicole Worthley)

Then, at the end of September, about a month after her kids started in-person school, her 10-year-old came down with strep.

Worthley was feeling lousy, too, so she got tested for strep. Negative.

A few days later, still feeling weak, she called her doctor. Can you smell anything, the doctor asked.

"I got the Vicks out," Worthley said. Nothing.

Four days later, she got a positive COVID-19 test result.

"It was easier this time," she said. "I was only feverish for 17 days."

She had diarrhea, upset stomach, loss of taste and some respiratory issues, but not as bad as the first infection. More than a month later, though, she still can't smell and a half-hour phone call was punctuated with her coughs.

Worthley believes she is among the 28 people that the South Dakota Department of Health has said it's investigating for reinfection, although she's yet to hear from anyone at the state.

So far, only a few dozen people worldwide have been confirmed to have been infected twice with SARS-CoV-2, the virus that causes COVID-19.

One man in Hong Kong didn't know he'd been infected a second time. He only found out when he was routinely tested on his return home from a trip to Italy. Another man, just 25, in Nevada, was sicker the second time.

In both cases, genetic analysis of the infections proved that they were infected twice, with slightly different versions of the virus not just long-suffering. The WHO has received reports of reinfections, but they are relatively rare so far.

"Our current understanding of the immune response is that the majority of people who are infected mount an immune response within a few weeks of infection," a WHO spokesman said via email. "We are still learning about how long the antibodies last. So far, we have data that shows that the immune response lasts for several months."

In a statement, a CDC spokesperson said the agency is actively investigating a number of suspected cases of reinfection, though none has been confirmed.

"CDCs investigation of the reinfection phenomenon is in its early stages," he said.

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Jeffrey Shaman, a professor at the Columbia University Mailman School of Public Health, who has been investigating reinfections, said scientists still have a lot of open questions.

Among other things, he said, they want to know: How often reinfection can happen, are people contagious with the second infection and for how long, and do people who are reinfected have less severe cases the second time or are they worse off?

To answer those questions, researchers like him have to figure out what's behind these reinfections, Shaman said.

People might fail to generate immune memory with the first infection, and need repeated exposure to build up immunity. If so, a vaccine might have the same problem, and it won't bevery effective.

Or people might get antibodies to the virus and then lose them, Shaman said. In that case, a vaccine's benefit might not last long.

The worst-case scenario would be what happens with dengue.In the case of that mosquito-borne tropical disease,someone can get sicker if infected a second time, or infected after getting a vaccine.Then, a vaccine could actually be harmful though theres no evidence thats the case with COVID-19.

Sometimes diseases that start as outbreaks can become endemic, returning year after year.

The 1918 flu, for instance, was so devastating because it was new and no one had built up resistance, Shaman said. It came back repeatedly but "didn't have the huge pulses of people dying," he said, possibly because their bodies had built up some immunity to it.

If that's the case with COVID-19, then a vaccine, even a partially effective one, could have a big benefit by exposing people to the virus and helping them build up a tolerance, he said.

It's not yet clear how long someone is contagious with COVID-19 if their symptoms linger or recur.

A study published Thursday in JAMA Internal Medicinefound that 18% of COVID-19 patients in an Italian hospital tested positive again after recovering from symptoms and having a negative test.

Only 1 of the 32 patients tested showed signs of replicating virus in their bloodstream, suggesting that they were either still infectious or reinfected but that couldn't be confirmed because no genetic testing was done. That patient was still suffering symptoms 39 days after the initial diagnosis, though the others who tested positive again were unlikely to be contagious, the study concluded.

Until scientists learn the answers to these questions, people who have been infected once shouldn't assume they're protected indefinitely, and should continue to wear masks, wash hands, maintain distance and avoid crowds, Shaman said.

"The only way we're going to get a sense of it is over time," he said.

Worthley admits she could have been more careful about wearing a mask. When she first caught COVID-19 in March, few people were wearing them, and Worthley didn't know of anyone at church, work, her kids' schools who had COVID-19.

In the summer and early fall, she wore a mask at work, but not at church. She assumed she'd be protected because she'd been sick for so long.

Now, Worthleysaid she's not confident of being protected against the virus, so she always wears a mask.

"I have a whole bunch of them in my van," she said.

Contact Karen Weintraub at kweintraub@usatoday.com.

Health and patient safety coverage at USA TODAY is made possible in part by a grant from the Masimo Foundation for Ethics, Innovation and Competition in Healthcare. The Masimo Foundation does not provide editorial input.

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