July 7, 2022 – People who become reinfected with the virus that causes COVID-19 are at greater health risk with each round of reinfection, a large national database study shows.

Researchers saw worse health effects during active infection, but some symptoms lasted up to 6 months, suggesting a direct link between reinfection and a long COVID.

“Reinfection adds or contributes to additional health risks. It’s not entirely benign, and people should try to avoid reinfection,” says the study’s lead author Ziyad Al-Aly, MD.

The risks remained whether people were fully vaccinated or not. In some cases, people could have been previously infected with the Delta strain and now be exposed to Omicron or its BA.5 subvariant, which may be better at evading vaccine protection, he says.

“It’s also possible that the first infection weakened some organ systems and made people more vulnerable to health risks if they get a second or third infection,” adds Al-Aly, clinical epidemiologist at Washington University and director of research and development at VA St .Louis Health Care System. “There are many variables at play, but it is clear that reinfections carry additional risks and should be avoided.”

Al-Aly and his colleagues compared 257,427 people with a first infection with the virus that causes COVID-19 to a group of 38,926 people who had a second or later infection, and then to 5.4 million people who were never infected . Information for the study came from veterans in a health database maintained by the Department of Veterans Affairs.

The results were published online on June 17th as a pre-print study, meaning it has not yet been peer-reviewed, an important step in evaluating and validating the clinical research. The study is currently being reviewed by the journal nature portfolio.

Experts decide

Three COVID-19 experts not involved in the research expressed some reservations, including whether or not a study on veterans might apply to the general population.

“It’s the first study to characterize the risks of reinfection,” says Eric Topol, MD.

He points out that a second infection was associated with twice the death rate of people, as well as twice the risk of heart or lung problems, compared to a first.

The additional risks have also increased with each infection, says Topol, executive vice president of Scripps Research and editor-in-chief of Medscape, WebMD’s sister site for healthcare professionals.

“Obviously, these results are concerning because reinfection prior to the arrival of the Omicron wave was fairly rare at 1% or less during the delta variant wave. But now reinfections have become much more common,” he says.

Higher risks, especially for some

The study was “well done,” says Dr. Ali Mokdad when approached for comment. Al-Aly and colleagues “have access to good data and they’ve done several studies.”

He says the added risks are more likely in the elderly, the immunocompromised, and those with other medical conditions.

“It makes sense, and let me explain why,” says Mokdad. “If you have someone who got COVID-19 for the first time and was affected by it, maybe someone who was older or had a chronic condition, the next blow would also do more damage.”

“Therefore, one would expect that some people would be more likely to have a more severe second infection,” says Mokdad, associate professor of epidemiology and professor of health metrics at the University of Washington in Seattle.

“The best thing for you and the community at large – healthy or not, chronically ill or not – is not to get infected,” he says. “Get your vaccines and boosters and wear a mask if you’re in a crowded place and can’t keep a safe distance.”

Different Risk Factors for Veterans?

“The big caveat when you look at this study is that veterans don’t resemble the general population,” says Amesh Adalja, MD, a senior researcher at the Johns Hopkins Center for Health Security at the Bloomberg School of Public Health in Baltimore.

“I don’t think you can generalize about that [the study] for everyone, but really for people who have risk factors for serious illnesses,” he says, because veterans tend to be older and have more health problems.

He says many people who become reinfected test positive at home. As a result, their cases don’t make it into research. In contrast, the veterans in the study were “people who wanted to take a formal test for some reason.”

Because the virus has mutated away from the vaccines, the immunizations can still protect against serious illness, hospitalization and death, but they are less able to protect against infection, Adalja says. “This is also the case with prior immunity. For example, if you were infected with someone BA.1 or Delta, your ability to block the new BA.4 and BA.5 variants might not be very high.”

The study shows why “it’s important to stay current with your vaccines,” he says, “and why we need to get better vaccines that target variants currently in circulation.”

Despite these caveats, Adalja says the researchers used “a robust database” and a large study population, which “gives us all confidence in the strength of the result.”

Look at longer-term effects

Whether reinfection contributes to an increased risk of long COVID was unknown, so researcher Al-Aly and his colleagues followed the veterans for over 6 months. They compared people who had one, two, three or more infections to the uninfected group.

Among those with reinfection, approximately 13% had two infections, 0.76% had three infections, and 0.08% or 246 people had four or more infections.

Compared to veterans with a first coronavirus infection, those who got re-infection had more than double the risk of dying from any cause.

Although “the mechanisms underpinning the increased risk of death and health outcomes upon reinfection are not fully understood,” say the authors, “the results highlight the consequences of reinfection and emphasize the importance of preventing reinfection of SARS-CoV 2, “The virus that causes COVID-19.

When asked about the next step in her research, Al-Aly said, “BA.5 appears to be the biggest challenge ahead and we are focused on understanding it better.”

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