Since 2021, children, globally, have been afflicted with respiratory illnesses earlier and in greater numbers than usual, the surging case numbers fuelling an ongoing debate about how the Covid pandemic has contributed to rates of other infectious diseases.
While no one yet knows for sure, much of the discussion has centred 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 non-pharmaceutical interventions (NPIs) imposed to curb the spread of SARS-CoV-2, like school closures and mask mandates.
Early this month, 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, reports JAMA Network, Chinese authorities have attributed the increase in influenza-like illnesses in their country to the lifting of Covid-19 restrictions and the circulation of known pathogens like influenza and Mycoplasma pneumoniae, not some new infectious agent.
Wolfgang Leitner, PhD, chief of the Innate Immunity Section at the US National Institute of Allergy and Infectious Diseases, said some vaccines have a dual benefit – protecting against their specific targeted disease, but also inducing non-specific immunity against other, unrelated pathogens, which is called heterologous immunity.
During the pandemic, declines in vaccinations against diseases like measles and reduced exposure to circulating viruses was “a double whammy” that could also have left children more susceptible to infectious diseases, including RSV, Leitner noted.
Some scientists have suggested something else is also going on, calling the phenomenon immunity theft, a term found nowhere on PubMed.
T Ryan Gregory, PhD, an evolutionary biologist at Canada’s University of Guelph is widely credited with having coined the term in late 2022.
While immunity debt refers to the ramifications of reduced exposure to various 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 said, although “neither term is scientific”.
“They’re both rhetorical devices. They’re not mutually exclusive either. I think both can be taken too far, and both have been. One example is this claim that immunity debt explains everything we’re still seeing three years after lockdowns. We’ve had RSV surges three 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 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.”
Although immunity gap and immunity debt hadn’t yet been coined during Covid lockdowns, 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 said.
During a Paris public transport workers strike starting on 30 November 1995, many people, including children who normally went to day-care centres, stayed home to avoid getting stuck in widespread traffic jams.
Cases of bronchiolitis, a respiratory infection common in infants and children during the winter and usually caused by RSV, started declining shortly after the strike began. But after the three-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, according to a 2022 editorial co-authored by Alasdair Munro, MD, PhD, a senior clinical research fellow in paediatric infectious diseases at the University of Southampton, UK.
But without the annual waves of seasonal viral infections to bolster it during the pandemic, population immunity continued to decline, the editorial noted.
However, Munro said, 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 like 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 added. 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.
Repaying a debt?
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 said. “It was an unintentional side effect because the lockdowns had to last so long…to bide time for the vaccines to come out.”
However, 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 three to six-months-old.
One study 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 analysing 18 paired serum samples collected between May and June 2020 and from February to May 2021 from women aged 18 to 51.
“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 acknowledged that their study lacked information about clinical outcomes which would have enabled them to analyse 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 research letter in JAMA Paediatrics suggested that children hospitalised with them have been sicker than before the Covid-19 pandemic. “The pandemic provides a unique scenario with which to explore the shift in RSV epidemics and age of hospitalisation because of lack of previous RSV exposure,” the authors noted.
They analysed hospitalisation trends and disease severity in children under five with RSV infection at Nationwide Children’s Hospital in Ohio. They included six pre-pandemic RSV seasons, from November to April, in 2012 to 2018, as well as one pandemic RSV season, from June to December 2021, and one post-pandemic season, from September 2022 to January 2023. They left out 2020 because there was no RSV season that year.
Disease severity, characterised by the need for oxygen administration and intensive care as well as the length of stay, gradually increased from pre-pandemic to 2021 and 2022-2023. In addition, the median age of children admitted 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.
A thieving virus?
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.
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 we’ve seen with Covid that seems extraordinary compared with any other respiratory viruses.”
Immunity theft “doesn’t mean anything – that’s the problem”, said infectious disease specialist Nathaniel Erdmann, MD, PhD, an associate professor at the University of Alabama at Birmingham Heersink School of Medicine.
“The idea of having a period of increased vulnerability after an acute process is not only possible but probable,” he said. However, post-viral infection “ripples in the immune system” are transient, usually resolving in 20 to 30 days.
Erdmann said immunity theft doesn’t explain post–Covid condition (PCC) – or long Covid. Some long Covid symptoms may be due to chronic immune activation and the presence of persistent SARS-CoV-2 antigen, he said
A small study published in Cell 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 haematopoietic stem and progenitor cells (HSPC) – long-lived precursors to diverse immune cells – between the patients recovering from the Covid-19 and the other study participants that persisted for up to a 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, they said.
Conflicting findings
In another study, scientist found that US children who’d had Covid-19 were significantly more likely to contract RSV.
The researchers analysed data from a nationwide multi-centre database of electronic records that included 1.7m infants and children under five. Of that group, they analysed RSV infections in about 229 000 children with no prior RSV infection who saw a physician in late 2022.
The risk of RSV infection in children with prior Covid infection was 6.4%, compared with 4.3% for matched children without prior infection. 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 found a 4.85% risk of RSV infection among children who’d had Covid-19, compared with 3.68% in those who hadn’t.
The researchers based the children’s Covid 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, they noted.
But Munro said confounding bias, not Covid, probably explained the difference in RSV rates between the children. An increased likelihood of RSV in children who’d had Covid “is what we would expect”, because parents who had their children tested for the virus would also test them for RSV, he said.
Additionally, some children are predisposed to repeated viral respiratory infections, whether they be Covid-19 or RSV. “They don’t fight off viral respiratory infections as well as other children do.”
Contrasting with the results of the study of children, a cohort study of Danish adults aged over 50 found no increased risk of hospitalisation overall for other infectious diseases in people who’d recovered from Covid-19 compared with those who hadn’t been infected.
Vaccination status at the time of their Covid infection didn’t appear to make a difference, the researchers found.
“We chose 50 as a cut-off because older people are more likely to get infections severe enough fpr hospitalisation compared with younger adults,” said first author Niklas Andersson, MD, from the Statens Serum Institut in Copenhagen.
Andersson and co-authors 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 2.4m people with no evidence of SARS-CoV-2 infection before entering the study. Average age was 67. From 1 January 2021 to 20 December 20 2022, 930 000 cohort members acquired Covid-19.
“Our study does not support an increased susceptibility to non-Covid infectious disease hospitalisation after SARS-CoV-2 infection,” the authors concluded.
Their study didn’t answer the question of whether Covid infections might be linked to increased susceptibility to less serious non–Covid infections, Andersson said.
However, they did find that people hospitalised for Covid-19 were more likely to be admitted for another infectious illness than those who’d never had Covid.
“Not surprisingly, those who had been hospitalised for one type of infection would tend to have higher odds of later being admitted for another infection.”
SARS-CoV-2 “definitely 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 to what we’re seeing in outbreaks? My theory is it contributes, but it’s certainly not the only reason.”
See more from MedicalBrief archives:
Viruses paused during COVID pandemic are on their way back
Did Covid ‘viral interference’ keep common flu away?
‘Walking pneumonia’ may be causing rise in paediatric illnesses worldwide
One in every eight adults likely infected with long COVID, large study finds
Respiratory virus killing 100,000 children a year – systemic analysis