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It has been more than a decade, but Rachael Thomas still remembers the early hours of 5 February 2010 as if it was yesterday. She was standing against the wall in a hospital room in Kent, UK, watching a team of doctors fighting to save her 13-week-old child, Alexander. “They were putting tubes in him and silently crying,” she says. “I remember thinking: ‘It must be really bad if the doctors are crying.’”
The previous week, Alexander had been the “happy, calm baby” he usually was. But he soon developed a cough and a runny nose, which the local doctor dismissed as a minor cold when Thomas took him for a check-up. However, the next night, Alexander woke up with a high-pitched scream, and quickly “went white and floppy”. Thomas rang for an ambulance, and began resuscitating her baby in a panic.
At the hospital, doctors worked furiously to save Alexander, but stopped after 2.5 hours of trying to revive him. “I held him while they turned the machines off. I sang to him because I didn’t want him to be scared,” she recalls.
Part of Nature Outlook: Respiratory syncytial virus
It was only three weeks later, when the post-mortem results came through, that Thomas found out that what had snatched Alexander from her was respiratory syncytial virus (RSV). The virus causes a highly contagious infection of the lungs and respiratory tract. It can strike at any age, but young children are most at risk. In most instances, the virus passes with minimal consequences after a week or two. However, for some children — particularly those younger than six months, those born prematurely or who have an underlying illness — RSV can lead to severe complications, such as pneumonia and bronchitis.
Thomas is now a part of the non-profit Respiratory Syncytial Virus Foundation’s patient network, ReSViNET, and says she speaks to many parents whose babies have survived an RSV infection but continue to experience long-term effects, such as asthma. “The children just seem more susceptible.”
When these post-infection symptoms persist for weeks, months or even years, the question arises whether they amount to a disease in its own right — as with long COVID. But for now, scientists are unsure how much credence they should give to the idea of ‘long RSV’.
How these infections affect children in the long run has aroused intense interest — especially given that an estimated three million children aged five or younger are hospitalized with RSV complications globally every year1. For now, protection for at-risk children remains limited to two prophylactic antibody drugs, palivizumab and nirsevimab. And an RSV vaccine, approved in the United States in May, is for use only in those aged 60 or older. Once an infection occurs, “it’s one of the important human viral pathogens with no treatment”, says virologist Larry Anderson at Emory University in Atlanta, Georgia, who has studied RSV for nearly four decades.
One pressing question that researchers, physicians and anxious parents are keen to answer is: does RSV lead to asthma in the long run? Proving such a causality would be like striking medical gold for the 22 million children and teenagers worldwide who develop asthma every year2.
But unravelling a firm connection has been difficult. It’s a chicken-and-egg conundrum, says Nathaniel Justice, a paediatrician at the University of Iowa Stead Family Children’s Hospital in Iowa City. “The challenge is answering the question: does infection with RSV trigger an underlying predisposition to developing asthma? Or does a predisposition to asthma increase the likelihood of having a severe illness from RSV?”
Tracing a definitive link between RSV and asthma would require uncovering the biological mechanism. And that would first need controlled clinical studies in which a vaccine or drug can eliminate the virus in one group of patients — something that, unfortunately, remains out of reach for now. However, researchers are edging closer to an answer.
With RSV comes wheezing
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For a long time, studies focused mainly on the severity of the disease — “so mainly hospitalizations”, says Xavier Carbonell-Estrany, a paediatrician in Barcelona, Spain, who has been treating RSV for more than 50 years. “But later, we started to realize that those patients had problems in the follow-up.”
“That made us think that we should include long-term follow-up in our studies,” he says. Such research only really kicked off after palivizumab entered the market in 1998, he adds.
Since then, several studies have explored RSV’s lingering impacts on lung health in childhood, throughout adolescence and into adulthood. In one of the earliest papers3, US researchers in 1999 determined that children who contracted an RSV infection in the lower respiratory tract in the first three years of life quadrupled their risk of wheezing at age six, compared with those with no RSV infection. Wheezing is a common sign of asthma in children.
In a 2015 study, Carbonell-Estrany and his collaborators in Spain found that almost 47% of premature infants who had been hospitalized with RSV experienced recurrent wheezing in the first six years of their lives, compared with about 27% of babies in the control group4.
And a 2020 meta-analysis of 41 studies conducted by Louis Bont, a paediatric infectious-disease specialist at the University Medical Center Utrecht in the Netherlands, and his collaborators found that infants with RSV infections were three times more likely than healthy infants to experience recurrent wheezing up to the age of 36 months5. At 144 months, the risk decreased but remained high, at 2.14 times.
In general, most studies come to similar conclusions on RSV and long-term wheezing — they “say yes” to the link between preschool wheezing and the virus, says Bont.
But when it comes to asthma, clinical-trial evidence remains inconclusive, says Bont.
Some studies point to an association between RSV and asthma. For instance, when a team of Swedish researchers followed 46 participants who had been hospitalized with RSV bronchiolitis before age one for 18 years, they discovered the risk of developing allergic asthma in later life was 43%, compared with 17% in the control group6.
In a study in Bangladesh, 535 children were observed for six years. For those who had an RSV infection in the first two months of life, “we observed some association” with asthma, says study coordinator Harish Nair at the University of Edinburgh, UK. The study ended in June 2021, and results are expected to be published by the end of this year.
Mouse models, too, support a link between RSV and asthma. At the American Thoracic Society International Conference in Washington DC in May, US researchers revealed that a severe RSV infection in early life resulted in sustained upregulation of interleukin-33, a protein found in a type of lung cell involved in airway hyper-responsiveness and inflammation in asthma7. This suggests “a mechanism of asthma predisposition in infants after RSV infection”, concluded the authors.
There’s a good reason, however, why no one has been able to say definitively that RSV causes asthma in the long term, says Changfa Fan, who studies RSV in mice at China’s National Institutes for Food and Drug Control in Beijing. All of the studies so far have been observational.
“There’s some very good data that link early RSV infection to later reactive airway disease,” says Anderson. “But an association doesn’t mean it’s causal.”
One of the biggest confounders is genetics. Does RSV lead to asthma, or are those who get infected genetically predisposed to asthma? Complicating matters further, previous studies focused mostly on severe RSV infections, which usually require hospitalizations.
Keenly aware of these limitations, Anderson and his collaborators designed a study using serology and molecular testing to ascertain RSV infection status, rather than relying on hospitalization data. The study, which included more than 1,700 infants in Tennessee, concluded that those infected with RSV were 26% more likely than were those without RSV infection to develop asthma within five years8.
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Still, this doesn’t prove that RSV causes asthma in the long run, caution the authors. Doing so would require ‘probe studies’ — long-term randomized clinical trials involving interventions that can “take out the disease to see what happens”, says Anderson. This would mean having an RSV vaccine or treatment on hand — neither of which are currently available for infants or young children.
In August, however, the US Food and Drug Administration approved a vaccine from Pfizer, which, when injected into pregnant people, can protect newborns from RSV for up to six months. But the drug, called Abrysvo, reportedly has some troubling side effects, such as an increased risk of premature birth.
There’s also another catch to probe studies: the sheer number of participants required for the results to be statistically significant. In one analysis, Bont, Nair and their co-authors estimated that a study evaluating the effect of an RSV maternal vaccine on a wheeze-associated disorder would require a minimum of 6,196 mother–infant pairs per study arm9. That’s a tall order.
Despite these challenges, the field must persevere, says Justice. Anything researchers can do to deduce RSV’s potential long-term impacts on asthma, as well as on other airway complications, will go a long way towards shrinking its outsized burden on children. “It’s difficult talking about Alexander even 13 years on,” says Thomas. “But I hope for some education around RSV so that we can try and prevent deaths in the future or even [stop] people being seriously ill.”