Burden of disease of respiratory syncytial virus in infants, young children and pregnant women and people

Background Passive immunization products for infants and pregnant women and people have sparked interest in understanding Canada’s respiratory syncytial virus (RSV) burden. This rapid review examines RSV burden of disease in infants, young children and pregnant women and people. Methods Electronic databases were searched to identify studies and systematic reviews reporting data on outpatient visits, hospitalizations, intensive care unit admissions, deaths and preterm labour associated with RSV. We also contacted Canadian respiratory virus surveillance experts for additional data. Results Overall, 17 studies on infants and young children and 10 studies on pregnant women and people were included, in addition to primary surveillance data from one Canadian territory (Yukon). There were higher rates of medical utilization for infants than older children. Hospitalization rates were highest in infants under six months (more than 1% annually), with 5% needing intensive care unit admission, but mortality was low. Severe outcomes often occurred in healthy full-term infants and burden was higher than influenza. Respiratory syncytial virus attack rate was 10%–13% among pregnant women and people. Only one study found a higher hospitalization rate in pregnant women and people compared to non-pregnant women and people. Limited evidence was found on intensive care unit admission, death and preterm birth for pregnant women and people. Conclusion While risk of severe outcomes is larger in high-risk infants and children, healthcare burden is greatest in healthy term infants. The RSV severity for pregnant women and people appears to be similar to that for non-pregnant women and people.


Introduction
Respiratory syncytial virus (RSV) is a common respiratory virus, affecting nearly all children younger than two years of age (1).Globally, RSV contributes to 31% of pneumonia cases, causing 33 million acute respiratory infections (ARI), 3.1 million hospitalizations and 118,200 deaths annually (2).Respiratory syncytial virus ranks as the third leading cause of lower respiratory deaths in children younger than five years of age, after Streptococcus pneumoniae and Haemophilus influenzae type b (3).
The RSV vaccine landscape has evolved.Previously, only one passive immunization product (palivizumab; a monoclonal antibody) was available for high-risk infants.Canada anticipates at least two new products; nirsevimab, a long-acting monoclonal OVERVIEW CCDR • January/February 2024 • Vol.50 No.1/2 antibody, and an RSV stabilized pre-fusion subunit protein vaccine for pregnant women and people (Pfizer RSVpreF vaccine, Abrysvo), offering both active and passive immunity for newborns.As the indication for the new passive immunization product includes healthy infants, and as the vaccine for pregnant individuals would protect both healthy and higher-risk infants, there is a need for an understanding of RSV's burden in infants, young children and pregnant women and people.
Throughout this article we will refer to "pregnant women and people" and intend it to be an inclusive term to include people of all gender identities who are pregnant.We recognize this language is evolving and our aim is to use language that removes barriers to care.
While a recent review focused on high-risk infants (including prematurity, cardiopulmonary disease and immunocompromised), less data exists on RSV's burden in healthy infants and young children in Canada (4).To inform recommendations for RSV prevention, we conducted literature reviews on RSV's burden focusing on healthy infants (younger than 12 months of age) and young children (12-24 months of age).Since one approach involves vaccinating pregnant women and people, we also explored RSV's burden in this group.This rapid review aims to summarize the available evidence on RSV burden of disease in infants, young children and pregnant women and people in Canada and other high-income countries.

Search strategies
Three search strategies were developed by a research librarian from Health Canada and the Public Health Agency of Canada.One focused on systematic reviews (SR) of RSV burden in infants and young children (Supplemental material S1).Two targeted RSV burden in pregnant women and people, with one concentrating on primary evidence studies and the other on SRs (Supplemental material S2).Embase, MEDLINE, Global Heath and ProQuest Public Health databases were searched for studies published from January 1, 1995, to April 10, 2023.We also contacted Canadian respiratory virus surveillance experts for additional data.After removal of duplicates, references were uploaded in DistillerSR online software (Evidence Partners, Ottawa, Ontario).

Study selection
Two reviewers (for pregnant women and people and for infants and young children) screened titles and abstracts for study eligibility.The articles pertaining to infants and young children focused on healthy infants younger than 12 months and healthy young children 12-24 months of age but did not exclude articles that captured high-risk infants.Full texts of selected articles were then evaluated.A second independent reviewer assessed citations marked for exclusion, with disagreements resolved through discussion.The reference lists of included studies were also screened for relevant articles on RSV burden in high-income countries including Canada and the United States (US) for infants and young children; due to a paucity of data, we did not restrict articles pertaining to pregnant women and people to high income countries.

Eligibility criteria
Observational studies, randomized controlled trials (RCTs) and SRs that met the criteria outlined in Table 1 were included.Inclusion was limited to studies conducted after 1995 to capture the most recent evidence.The evaluation of RSV burden focused on clinical outcomes of interest in infants, young children and pregnant women and people and considered emergency department (ED) or outpatient visits, hospitalizations, intensive care unit (ICU) admissions, death and preterm labour associated with RSV.

Infants and young children
Study selection: After deduplication, 389 references underwent screening (Figure 1).Seventeen articles, including five SRs, were incorporated into the narrative synthesis of RSV burden in infants and young children (Table 2).
Medically attended RSV respiratory tract infection: Three prospective observational studies demonstrated a high incidence of medically attended RSV infections.A US-based surveillance system from 2002 to 2004 found that RSV accounted for 18% of ED visits and 15% of office visits for ARI from November through April with higher rates in infants (5).More than 70% of the outpatients were previously healthy.Another US study from 2003 to 2005 reported 21.5 RSV-related ED visits per 1,000, higher than influenza (n=10.2 per 1,000), particularly in children younger than 24 months (n=64.4visits per 1,000) (6).A European birth cohort in healthy term infants from 2017 to 2020 found a 26.2% (95% confidence interval [CI]: 24.0-28.6)RSV infection incidence and 14.1% (95% CI: 12.3-16.0)medically attended RSV incidence during the first year of life (7).Global data for children younger than five years aligned with these findings, reporting 38.5 (95% CI: 21.6-68.8)RSV-associated ARI per 1,000 children younger than one year of age in high-income countries (8).
Over five respiratory seasons, from 2018 to 2023, in Yukon, there were a total of 73 RSV infections in children 24 months and younger, which was higher than the number of influenza infections (n=20).Among infants younger than 12 months of age, the highest number of RSV infections occurred in those younger than three months of age.In summary, medically attended RSV infections are significant during infancy and early childhood, with approximately 10%-20% of infants seeking care for RSV in a season, surpassing medically attended influenza.
International data align with this rate.A European birth cohort study in healthy term infants found 5.5% of RSV-associated hospitalizations led to ICU admissions (7).An SR of RSV disease in the US identified ICU admission proportions ranging from 6.3% to 71.4% and linked risk factors to younger age, prematurity, congenital heart disease and chronic lung disease (16).In summary, Canadian research suggests approximately 5% of RSV-hospitalized children required ICU admission, with higher rates among those with risk factors.In comparison to influenza, there is some evidence that RSV leads to more ICU admissions.

Death associated with RSV respiratory tract infection:
Existing literature suggests a low risk of RSV-related mortality in both Canada and the US.An overall mortality rate of 0.  13).In the US, an infant cohort followed from 1999 to 2018 showed an RSV mortality rate of 6.9 (95% CI: 6.4-7.5) per one million live births, with preterm infants at the highest risk ( 21); however, the majority of deaths occurred in full-term infants (53.7%), primarily those between one and four months of age (63.8%).Globally, a systematic analysis reported a 0.1% (95% CI: 0.1-0.3)case fatality rate for in-hospital RSV deaths in children 0-12 months of age (8).

Pregnant women and people
Study selection: After removing duplications, 474 primary evidence studies and 28 systematic reviews underwent screening (Figure 2).In total, two SRs and eight studies were included in the narrative synthesis of RSV burden in pregnant women and people (Table 3).No data on RSV-related mortality was identified in pregnant women and people.
Medically attended RSV respiratory tract infection: Two US cross-sectional studies by Hause et al. investigated RSV infection rates in pregnant women and people in their second or third trimester during the 2015-2016 RSV season.In one study, with combined PCR and serological data, the RSV attack rate among ambulatory pregnant women and people receiving routine prenatal care was estimated at 10%-13% (22).In the second study, approximately 10% of acute lower respiratory tract illness cases in pregnant women and people were confirmed as RSV (23).

Hospitalization associated with RSV respiratory tract infection:
The literature on RSV-associated hospitalizations presents a broad range of rates.A retrospective study within the Pregnancy Influenza Vaccine Effectiveness Network (PREVENT) 2010-2016 found a 2.5% RSV-positive rate, contrasting with a 51% influenza-positive rate (24).A US population-based study from 2015 to 2018 revealed higher hospitalization rates among pregnant women and people compared to non-pregnant adults (average rate of 620 vs. 320 per 100,000) (25).Additionally, one retrospective case series documented adverse pregnancy outcomes in ten pregnant individuals hospitalized with RSV, including pneumonia, respiratory failure and sepsis, with six experiencing obstetrical complications during hospitalization, including preterm contractions, coinfections and preeclampsia (26).In summary, the literature suggests a wide range of possible RSV hospitalization rates among pregnant women and people, with one study indicating a higher burden compared to nonpregnant adults.
Intensive care unit admission associated with RSV respiratory tract infection: Evidence on RSV-related ICU admissions is limited.In a retrospective case series focusing on adverse pregnancy outcomes, one of 10 pregnant women and people required ICU admission and mechanical ventilation (26).Another case series of three pregnant women and people with RSV found that two required ICU admission and mechanical ventilation, while the third was monitored as an outpatient (27).
A case report describes a pregnant person admitted with RSV pneumonitis and sepsis, requiring ICU admission, mechanical ventilation and emergency C-section (28).However, data regarding the risk of ICU admission among pregnant women and people remain scarce.Average burden from 2015 to 2018 of 620/100,000 in pregnant women and people which was higher than the burden for nonpregnant adults 18 years and older (n=320/100,000)  Outcome for both infants and pregnant women and peoplepreterm labour/birth: Three studies reported data on the risk of preterm labour/birth associated with RSV infection.In the Pregnancy Influenza Vaccine Effectiveness Network study, no difference was observed in preterm, small for gestational age, and low birth weight births between RSV-positive and RSVnegative pregnant women and people (24).However, among ARI admissions without delivery during the hospital admission, RSV positivity was associated with subsequent preterm birth (29% vs. 15%).A study from Nepal showed a higher rate of preterm birth with RSV illness episodes during pregnancy (29% vs. 13%) (29).
In a case series of ten pregnant women and people hospitalized with RSV, one had preterm birth (10%) (26).In summary, available evidence is insufficient to assess the risk of preterm labour/birth due to RSV infection during pregnancy.

Discussion
This rapid review offers insight into RSV burden in predominantly high-income countries, with a focus on Canada, the US and Europe.More robust evidence was available for infants and young children, with Canadian studies contributing significantly, while evidence for pregnant women and people primarily stemmed from small observational studies outside Canada.In infants and young children, medically attended RSV was common, and RSV hospitalization rates varied but generally decreased with age.Most hospitalized children had no underlying medical conditions.Approximately 5% of RSVhospitalized children in Canada required ICU admission, and the risk of death was low.Respiratory syncytial virus caused a higher burden of disease than influenza in this population.Novel and previously unpublished data from the Yukon support the conclusions of this literature review, noting a higher burden of RSV than influenza and the highest burden in younger age groups.For pregnant women and people, RSV severity appeared to be similar to non-pregnant women and people, with an attack rate of 10%-13% during the respiratory virus season.One study reported higher RSV hospitalization rates than those for nonpregnant women and people.Data on ICU admission, death and preterm birth related to RSV in pregnancy were limited, although two studies suggested an association with preterm birth.
This rapid review highlights limitations in characterizing RSV burden in Canada.Studies often focused on RSV-associated hospitalization and ICU admission, which are critical outcomes for assessing severe clinical consequences.However, it is also essential to grasp the significance of other outcomes in the Canadian context, in particular medically attended RSV and death related to RSV infection.Currently, Canada has limited enhanced national RSV surveillance data.Recent research initiatives have leveraged existing healthcare administrative databases to characterize RSV burden; however, those data are expected to underestimate RSV disease especially in the community and outpatient setting due to undertesting in routine clinical care, the lack of generalizability to the Canadian population and healthcare coding systems that do not capture all possible contributors to RSV-related complications (30).

Limitations
This rapid review has limitations.It primarily focused on shortterm outcomes and did not consider potential long-term effects such as asthma, which may be associated with early-life RSV infection (31,32).Detection of RSV infection was not limited to laboratory confirmation; some studies relied on clinical diagnostic codes, potentially inflating RSV incidence.Estimates were imprecise.Robust data on severe RSV outcomes in pregnant women and people were lacking; however, historically, pregnant women and people have not been known to specifically be at higher risk of RSV infection.Although the goal of forthcoming RSV immunization products is to reduce complications of RSV in infants, it is essential to also consider the potential benefits of an RSV vaccine for pregnant people, given their increased susceptibility to certain respiratory pathogens such as influenza resulting from pregnancy-related changes in anatomy and the immune and cardiovascular systems.This review did not specifically focus on RSV burden during the coronavirus disease 2019 (COVID-19) pandemic.The public health measures in place during the early phase of the pandemic led to a significant reduction of seasonal respiratory virus circulation (33).
In recent seasons, there has been a substantial increase in RSV cases, with changes in age distribution and atypical seasonality patterns compared to prior to the COVID-19 pandemic, attributed to larger populations of RSV-naive children (34,35).For example, a recent publication from 13 paediatric centres in Canada noted a significant burden of RSV hospitalizations, with a significant increase in hospitalizations in 2021-2022 compared to pre-pandemic (36).Despite these limitations, the data presented here provide a foundation for understanding the typical RSV burden in infants and young children.

Conclusion
A high incidence of medically attended RSV is observed in infants and young children, with hospitalization rates decreasing with age.Approximately 5% of hospitalized infants and young children with RSV required ICU admission.The risk of death appears to have been low.Pregnant and non-pregnant women and people showed similar RSV severity, although data were limited for pregnant individuals.With the introduction of interventions, RSV's disease burden is expected to change; robust surveillance systems at the provincial, territorial and national levels will be crucial for evaluating the public health impact of RSV immunization programs.This review contributes to the literature, aiding in characterizing RSV's burden in Canada and guiding RSV immunization strategies for infant protection.

Figure 1 :
Figure 1: Study selection PRISMA flow diagram of infants and young children

Figure 2 :
Figure 2: Study selection PRISMA flow diagram in pregnant women and people

Table 1 :
Study inclusion and exclusion criteriaOne reviewer extracted data from each article, verified by a second reviewer.Disagreements were resolved through discussion.Data included event number, sample size and effect measures.Results were synthesized narratively based on the study population and outcomes.Due to the value of Canadian data on RSV's burden in healthy infants and young children, surveillance data from one territory (Yukon Communicable Disease Control) were included in this literature review.
Systematic reviews and/or meta-analyses Any primary evidence studies (i.e., experimental, quasi and non-experimental studies) Abbreviations: ICU, intensive care unit; N/A, not applicable; PICOS, population, intervention, control, outcome and study design; RSV, respiratory syncytial virus Data extraction and data synthesis

Authors of systematic reviews and meta-analyses have also examined RSV hospitalization rates in infants and young children. McLaughin et al. reported US rates of 26.2 (95% CI: 24.2-28.2) and 19.4 (95% CI: 17.9-20.9) per 1,000 infants younger than six months and younger than 12 months, respectively (14).
(17)nzer et al.'s pan-Canadian study showed RSV as a major cause of hospitalization (n=130 per 100,000), with the highest rates in infants younger than six months (9).Papenburg et al.'s Québec-based study found RSV was the most common virus (63.6%) in children hospitalized for ARI, with higher severity linked to age under six months and prematurity(10).In Nunavik, RSV hospitalization rates were higher in high-risk infants (147.6 per 1,000 live births) compared to healthy term infants (n=64.8 per 1,000)(11).An Ontario study by Pisesky et al. reported RSV hospitalization rates of 10.2 per 1,000 children younger than one year and 4.8 per 1,000 in children one to three years of age(12).Buchan et al.'s Ontario cohort study revealed varying RSV hospitalization rates across age groups, with the highest in one-month-olds (n=29.55 per 1,000) and declining with age, with rates highest among children born at younger gestational ages(13).Over five respiratory seasons from 2018 rates varied by a factor of 2-3 over seasons, they decreased significantly with increasing age.The majority (more than 70%) of children hospitalized had no underlying risk factors.Compared to influenza, RSV caused up to 16 times more hospitalizations in children younger than five years of age(17).

Table 2 :
Summary of included studies on the burden of disease of respiratory syncytial virus in infants and young children (continued) OVERVIEW CCDR • January/February 2024 • Vol.50 No.1/2

Table 2 :
Summary of included studies on the burden of disease of respiratory syncytial virus in infants and young children (continued)

Table 2 :
Summary of included studies on the burden of disease of respiratory syncytial virus in infants and young children (continued) Intensive care unit admission associated with RSV respiratory tract infection: Canadian studies indicate that approximately 5% of RSV-hospitalized children required ICU admission.

Table 3 :
Summary of included studies on the burden of disease of respiratory syncytial virus in pregnant people

Table 3 :
Summary of included studies on the burden of disease of respiratory syncytial virus in pregnant people (continued)