From “Immunity Debt” to “Immunity Theft”—How COVID-19 Might Be Tied to Recent Respiratory Disease Surges | Allergy and Clinical Immunology | JAMA

Last fall, children in China were coming down with respiratory illnesses earlier and in greater numbers than usual.

Ditto for respiratory syncytial virus (RSV) infections in the US and elsewhere in 2021 and 2022. And the current winter season doesn’t appear to be much different as far as higher-than-usual case numbers, according to CDC surveillance data.

The surging case numbers and their out-of-whack timing have fueled an ongoing debate about how the COVID-19 pandemic contributed to rates of other infectious diseases. No one yet knows for sure.

“Right now, this is phenomenology,” Wolfgang Leitner, PhD, chief of the Innate Immunity Section at the National Institute of Allergy and Infectious Diseases, told JAMA in an interview. “People are assuming a lot about the mechanism.”

Much of the discussion has centered around immunity debt and immunity theft, terms born of the pandemic and not found in textbooks.

The former generally refers to the reduced spread of other pathogens because of nonpharmaceutical interventions (NPIs) imposed to curb the spread of SARS-CoV-2, such as school closures and mask mandates. In early January of this year, a PubMed search for immunity debt resulted in only 22 hits, the earliest reference published online by French researchers in May 2021.

“The lack of immune stimulation due to the reduced circulation of microbial agents and to the related reduced vaccine uptake induced an ‘immunity debt’ [that] could have negative consequences when the pandemic is under control and NPIs are lifted,” the authors predicted.

Indeed, Chinese authorities have attributed the increase in influenzalike illnesses in their country to the lifting of COVID-19 restrictions and the circulation of known pathogens such as influenza and Mycoplasma pneumoniae, not some new infectious agent, according to a November 22, 2023, statement from the World Health Organization.

And as Leitner pointed out, echoing the first article to mention immunity debt, some vaccines have a dual benefit. They protect against their specific targeted disease, but they also induce nonspecific immunity against other, unrelated pathogens, which is called heterologous immunity. During the pandemic, declines in vaccinations against diseases such as measles and reduced exposure to circulating viruses was “kind of a double whammy” that could also have left children more susceptible to infectious diseases, including RSV, Leitner noted.

Some scientists have suggested that something else is also going on. They call the phenomenon immunity theft, a term that is nowhere to be found on PubMed, although it makes frequent appearances on X, formerly known as Twitter. T. Ryan Gregory, PhD, an evolutionary biologist at the University of Guelph in Ontario, Canada, is widely credited with having coined the term in late 2022.

While immunity debt refers to the ramifications of reduced exposure to a variety of pathogens resulting from efforts to rein in SARS-CoV-2, immunity theft refers to the notion that SARS-CoV-2 itself steals immunity, leaving some people who’ve had COVID-19 more susceptible to other infections.

Immunity theft seemed like a logical financial counter-metaphor to immunity debt, Gregory explained in an interview.

Neither term is scientific, though, he noted: “They’re both rhetorical devices.” They’re not mutually exclusive either, Gregory said.

“I think both can be taken too far, and both have been,” he said. One example is “this claim that immunity debt explains everything we’re still seeing 3 years after lockdowns,” he explained. “We’ve had RSV surges 3 years in a row now. How long does it take for the debt to be repaid?”

It’s unlikely that immunity debt, or immunity gap, as some prefer to call it, completely explains recent surges in respiratory infection, Leitner acknowledged. “Reduction in immune status is contributing to rebound, but I don’t think it’s the whole story,” he said.

Population vs Personal Immunity

When it comes to protecting against viral infections, people can’t have their cake and eat it, too.

“In 2020, we needed lockdowns absolutely desperately,” epidemiologist William Hanage, PhD, associate director of the Center for Communicable Disease Dynamics at Harvard T.H. Chan School of Public Health, emphasized in an interview.

He takes issue with those who suggest “that we would have been able to somehow come up with an optimal solution that would have both minimized the pandemic and these consequences for other infections.”

That notion, he says, “is utterly, utterly false.”

The effects on other infectious diseases of implementing and then lifting COVID-19 mitigation measures are not at all surprising, Hanage noted.

“Do you expect fewer infections in this season to end up leading to more infections next season? Yeah,” he said. “That’s the way it works. The interventions that were put in place and were extremely effective in bringing [COVID-19] surges under control also stopped other things. It’s basic infectious disease epidemiology.”

Just don’t call it immunity debt, Hanage urged. “I dislike the term. It suggests you’ve been sort of profligate, that you have not been taking care of your immunological finances. Immunity gap, I think, is a less-loaded term.”

There’s precedent for the concept. Although immunity gap and immunity debt hadn’t yet been coined at the time, a dip in respiratory infections due to social distancing followed by a rebound when people resumed normal activities occurred in France nearly 30 years ago, Leitner pointed out.

During a Paris public transport workers strike that began on November 30, 1995, many people in the region—including children who normally went to daycare centers—stayed home to avoid getting stuck in widespread traffic jams. Cases of bronchiolitis, a respiratory infection that commonly occurs in infants and children during the winter and is usually caused by RSV, started declining shortly after the strike began. But after the 3-week strike ended, respiratory diseases surged in the region, Leitner said.

One of the most important influences on the usual patterns of seasonal viruses is population immunity, which declines over time as immunity wanes in previously infected people, as some of them die, and as immunologically naive infants are born, pointed out a 2022 editorial coauthored by Alasdair Munro, MD, PhD, a senior clinical research fellow in pediatric infectious diseases at the University of Southampton in the UK. But without the annual waves of seasonal viral infections to bolster it during the COVID-19 pandemic, population immunity continued to decline, the editorial noted.

However, Munro said in an interview, immunity debt “has been misinterpreted by some people to mean…if you’re not exposed to certain pathogens in general that is bad for your personal immunity.”

That may sound like the hygiene hypothesis, first proposed in 1989 to explain a parallel decrease in infectious diseases and a steady increase in atopic diseases such as asthma and food allergies and immune dysregulation disorders, such as type 1 diabetes and inflammatory bowel disease.

But they’re not the same thing, Munro pointed out. The hygiene hypothesis attributes the rise in atopic diseases and immune dysregulation disorders—which are not viral respiratory infections—to a lack of exposure to friendly intestinal bacteria and parasitic worms, or helminths, not to a lack of exposure to pathogenic viruses.

With little RSV in circulation early in the pandemic, antibodies specific to the virus, which protect against severe disease, dropped precipitously, especially in adults, Leitner noted. “It was an unintentional side effect because the lockdowns had to last so long…to bide time for the vaccines to come out,” he said.

However, Leitner explained, “the problem is with newborns.”

That’s because newborns depend on their mother’s RSV antibodies, which are transferred through the placenta during the third trimester of pregnancy and provide some protection for infants up to 3 to 6 months of age. (In August 2023, the US Food and Drug Administration approved the first RSV vaccine for pregnant people, which is designed to prevent the disease in their infants.)

A recently published brief report describes a small study that found the functions of RSV-specific antibodies in women of childbearing age in British Columbia waned while COVID-19 mitigation measures were implemented. The researchers reached that conclusion after analyzing 18 paired serum samples collected between May and June 2020 and from February to May 2021 from women aged 18 to 51 years.

“These data add to the growing body of evidence supporting that protective RSV antibody immunity is short-lived,” the researchers concluded. However, they noted, how these changes are correlated with symptomatic RSV infection isn’t clear, and they acknowledged that their study lacked information about clinical outcomes that would have enabled them to analyze the relationship between decreased antibody functions on the severity of RSV cases in infants.

Not only have RSV infections surged in recent years, but a study published in a December research letter in JAMA Pediatrics suggested that children hospitalized with them have been sicker than before the COVID-19 pandemic. The “COVID-19 pandemic provides a unique scenario with which to explore the shift in RSV epidemics and age of hospitalization because of lack of previous RSV exposure,” the authors noted.

The scientists analyzed hospitalization trends and disease severity in children younger than 5 years with RSV infection at Nationwide Children’s Hospital in Columbus, Ohio. They included 6 prepandemic RSV seasons, from November to April, in 2012 to 2018, as well as 1 pandemic RSV season, from June to December 2021, and 1 postpandemic season, from September 2022 to January 2023. They left out 2020 because there was no RSV season that year.

Disease severity, characterized by the need for oxygen administration and intensive care as well as the length of stay, gradually increased from prepandemic to 2021 and 2022-2023. In addition, the median age of children hospitalized with RSV increased from 5.3 months before the pandemic to 6.3 months in 2021 to 8.2 months in 2022-2023.

But COVID-19 mitigation measures also appear to have had beneficial effects besides reducing SARS-CoV-2 infections and deaths. For example, the Yamagata lineage of influenza B viruses, first identified in the 1980s, hasn’t been isolated since March 2020, leading scientists to assume it is now extinct.

And from 2019 to 2022, asthma attacks among US Black adults, who have higher rates than Hispanic or White adults, decreased from 29.3% to 22.1%, according to a national survey study published recently as a research letter. The authors noted that decreasing chronic airway disease exacerbations have been attributed at least in part to reduced circulation of common respiratory viruses.

Since the beginning of the pandemic, many people have either dismissed COVID-19 as nothing worse than a cold or, at the opposite end of the spectrum, have referred to it as airborne AIDS.

“We work with children with HIV, and it’s just offensive to see people make those kinds of statements,” Munro said of comparing COVID-19 with AIDS.

Reality lies somewhere between those extremes, experts say.

Almost all viral respiratory infections, especially when they are severe, cause immune system disturbances, Munro said. “There’s nothing that we’ve seen with COVID that seems extraordinary compared with any other respiratory viruses.”

After an acute viral respiratory infection, “your immune system is in repair mode,” Leitner explained. “During that repair cycle, your immune system is suppressed.” People who die from influenza typically die from a secondary bacterial infection taking advantage of that immune suppression, not from influenza itself, he noted.

Immunity theft “doesn’t mean anything—that’s the problem,” infectious disease specialist Nathaniel Erdmann, MD, PhD, an associate professor at the University of Alabama at Birmingham Heersink School of Medicine, told JAMA in an interview.

“The idea of having a period of increased vulnerability following an acute process is not only possible but probable,” Erdmann said. However, he said, postviral infection “ripples in the immune system” are transient, usually resolving in 20 to 30 days.

Erdmann noted that immunity theft doesn’t explain post–COVID-19 condition (PCC), commonly known as long COVID. A 2023 review article he coauthored concluded that some long COVID symptoms may be due to chronic immune activation and the presence of persistent SARS-CoV-2 antigen.

A small study published in Cell in August 2023 found that severe COVID-19 can cause long-lasting immune system changes, but the alterations were related to persistent activation, not suppression.

The researchers compared blood samples from 57 people, some who were recovering from severe COVID-19 or other severe illnesses and some who were healthy. They found gene expression differences in hematopoietic stem and progenitor cells (HSPC)—long-lived precursors to diverse immune cells—between the patients recovering from severe COVID-19 and the other study participants that persisted for up to 1 year after the patients became ill.

In the recovering patients, those differences were associated with a higher production of white blood cells that seemed to produce more inflammation-triggering chemicals. The scientists speculated that interleukin-6 caused the gene expression changes. But their study was too small to link the changes to clinical outcomes, such as PCC, the authors pointed out.

A recent study found that US children who’d had COVID-19 were significantly more likely to contract RSV.

The researchers analyzed data from a nationwide multicenter database of electronic records that included 1.7 million infants and children up to 5 years old. Of that group, the scientists analyzed RSV infections in about 229 000 children with no prior RSV infection who saw a physician in late 2022.

The authors found that the risk of RSV infection in children with prior COVID-19 infection was 6.4%, compared with 4.3% for matched children without prior COVID-19. They also conducted a separate study, with similar results, involving about 371 000 children with no prior RSV infection who saw a physician in July 2021 and August 2021. That analysis, reported in the same article, found a 4.85% risk of RSV infection among children who’d had COVID-19, compared with 3.68% in the matched children who hadn’t.

The researchers based the children’s COVID-19 status on the clinical diagnosis code or positive laboratory test results in the electronic health records, which didn’t capture those who had tested positive on a home test and had mild symptoms that didn’t require medical attention. For that reason, their study might have underestimated the relationship of COVID-19 with RSV infection, the authors noted.

But Munro speculated that confounding bias, not COVID-19, likely explained the difference in RSV rates between the children. An increased likelihood of RSV in children who’d had COVID-19 “is absolutely what we would expect,” because parents who had their children tested for COVID-19 would also test them for RSV, he explained.

In addition, some children are predisposed to repeated viral respiratory infections, whether they be COVID-19 or RSV, Munro noted. “They don’t fight off viral respiratory infections as well as other children” do.

Contrasting with the results of the study of young children, a recently published cohort study of Danish adults aged 50 years or older found no increased risk of hospitalization overall for other infectious diseases in people who’d recovered from COVID-19 compared with those who hadn’t been infected with SARS-CoV-2. Vaccination status at the time of their COVID-19 infection didn’t appear to make a difference, the researchers found.

“We chose 50 years as a cutoff because older individuals are more likely to get infections that are severe enough to warrant hospitalization” compared with younger adults, the study’s first author Niklas Andersson, MD, a PhD candidate in the department of epidemiology research at the Statens Serum Institut in Copenhagen, explained in an email.

Andersson and his coauthors cross-linked data from the Danish COVID-19 test and surveillance system with the country’s nationwide health care and demographic registers to establish a cohort of more than 2.4 million people with no evidence of SARS-CoV-2 infection before entering the study. Their average age was about 67 years. From January 1, 2021, to December 20, 2022, 930 000 cohort members acquired COVID-19.

“Our study does not support an increased susceptibility to non-COVID-19 infectious disease hospitalization following SARS-CoV-2 infection,” the authors concluded.

Their study didn’t answer the question of whether COVID-19 infections might be linked to increased susceptibility to less serious non–COVID-19 infections, Andersson acknowledged in the email. “We do not include milder infections seen in primary care or those not requiring medical attention, and, as such, we cannot exclude that the risk of these infections could be increased,” he wrote.

He and his coauthors did find that people who’d been hospitalized for COVID-19 were more likely to be hospitalized for another infectious illness than those who’d never had COVID-19. “Not surprisingly, those individuals who had been hospitalized for one type of infection would tend to have higher odds of later being hospitalized for another infection,” Andersson explained.

No question, SARS-CoV-2 “messes with your immune system,” Leitner said. “It kills T cells…What I don’t know, and it hasn’t been shown, is how much does that contribute in what we’re seeing in terms of outbreaks? My theory is it contributes, but it’s certainly not the only reason.”

Published Online: January 10, 2024. doi:10.1001/jama.2023.26608

Conflict of Interest Disclosures: Dr Hanage reported serving as a paid scientific advisor to Merck Vaccines, Shionogi Inc, Pfizer, and Biobot Analytics, a company in which he holds stock options. Dr Erdmann reported serving as an investigator for the National Institute of Allergy and Infectious Diseases’ Adaptive COVID-19 Treatment Trial and COVID-19 Prevention Network and the National Institutes of Health’s Researching COVID to Enhance Recovery Initiative and COVID-19 Therapeutic Interventions and Vaccines public-private partnership. Dr Erdmann also reported receiving payment for serving as a member of Perspectum’s Scientific Advisory Board and having a patent for human neutralizing antibodies against SARS-CoV-2 and COVID-19 that has been licensed to the PlantForm Corp. No other disclosures were reported.

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