The risk of cardiac disease events after respiratory syncytial virus a systematic literature review and meta-analysis

Authors: Jehidys Montiel, Elizabeth Williams, William Gildardo Robles-Rodríguez, Konstantina Chatzikonstantinidou, Elvira Carrió, Suzie Seabroke, Cassandra Hall-Murray, Kashmira Date, Ann R. Falsey, Edward E. Walsh, Elizabeth Begier, Bradford Gessner

Abstract

Background

Respiratory syncytial virus (RSV) infection has been associated with an increased risk of cardiac events. This systematic review aims to synthesise the evidence on the absolute and relative risks of cardiac events in adults with RSV disease.

Methods

We searched Embase, PubMed and grey literature sources for studies published between 1 January 2000 and 6 March 2024, reporting on cardiac events in adults with RSV disease. Study quality was assessed using a validated checklist. Absolute and relative risks of cardiac events following RSV disease were summarised and pooled estimates using random effects meta-analysis were calculated.

Results

Of 3887 publications, 28 met the inclusion criteria. Among hospitalised patients with RSV disease (25 studies), the pooled estimates showed that 19.2% (95% CI 15.1–24.2) experienced any cardiac event (including specific and unspecific events and combinations of cardiac events), 15.7% (95% CI 14.8–16.5%) heart failure (HF) and 5.4% (95% CI 3.1–9.5%) acute coronary syndrome (ACS). Cardiac event-related mortality ranged from 1.1 to 9.8%. Compared to influenza patients, those with RSV disease had a risk ratio of 1.2 (95% CI 1.1–1.4) for any cardiac event, 1.3 (95% CI 1.1–1.6) for HF and 1.2 (95% CI 0.9–1.5) for ACS.

Conclusion

RSV disease poses significant risks beyond respiratory illness, including cardiac events, among older adult patients. RSV was associated with a higher risk of HF compared to influenza. Further research is needed to more precisely define the risk period of cardiac events following RSV disease.

Introduction

Respiratory syncytial virus (RSV) is increasingly recognised as a significant viral pathogen in adults with acute respiratory illness, with a disease burden comparable to that of influenza [1, 2]. Older adults, along with patients with weakened immune systems or chronic comorbid conditions, are more susceptible to developing severe complications related to RSV disease leading to hospitalisation, sequelae and death [3–6].

Beyond the respiratory system, studies have suggested a link between respiratory viral infection and increased susceptibility to cardiovascular events [7–9]. A literature review from 2018 showed that 14–22% of adults hospitalised due to RSV disease experienced cardiovascular complications, including worsening congestive heart failure, acute coronary syndrome and arrhythmias [10]; a more recent (2024) review specifically focused on long-term sequela among patients in high-income countries showed similar findings [9]. Additionally, previously recognised underlying cardiovascular disease was associated with hospitalisation in 45–63% of adults with confirmed RSV disease [10]. Chronic inflammation, disruption of endothelial function, hypercoagulability and immune dysregulation are proposed to be involved in the occurrence of cardiovascular complications during or after RSV disease [11].

While the cardiac impacts of other respiratory viral pathogens, such as influenza, are well described, the connection between RSV and acute or subacute cardiac disease is less recognised [10, 11]. Understanding the relationship between RSV disease and cardiac events is crucial for a comprehensive assessment of the burden of RSV disease in adults and for determining the potential clinical and economic benefits of RSV vaccination for this population. For influenza, and when compared to a placebo, vaccination has shown protective effects against infection-related cardiovascular events, including acute coronary syndrome (ACS), myocardial infarction (MI) and the recurrence of such outcomes [12].

To better understand the relationship between RSV disease and the occurrence of cardiac events in adults with and without pre-existing cardiac conditions, we conducted a systematic literature review (SLR) and meta-analysis. Here, we aimed to summarise the available evidence on 1) the absolute risk of cardiac events associated with RSV disease and 2) the relative increase in risk of cardiac events after RSV disease versus a control group.

Methods

Systematic literature review

We performed an SLR in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [13]. We prospectively registered the SLR protocol in PROSPERO, with registration number CRD42024519100.

Case definitions

RSV disease cases were defined in two ways, as 1) patients with symptomatic laboratory-confirmed RSV infection by serological tests (e.g., indirect fluorescent antibody, ELISA and direct fluorescent antibody), molecular tests (e.g., PCR), viral culture, rapid antigen tests, or a combination of these methods, or 2) patients with at least one of the following three RSV-specific International Classification of Diseases (ICD)-10 clinical codes in their medical record J12.1 RSV pneumonia, J20.5 acute bronchitis due to RSV and J21.0 acute bronchiolitis due to RSV disease) [14].

A cardiac event was defined as the occurrence of any of the following ACS (including heart attack, unstable angina, MI or myocardial ischemia), heart failure (HF) (including new-onset, exacerbations, acute HF, unspecified and congestive HF events), arrhythmias (including atrial fibrillation (AF)), myocarditis and/or pericarditis, valvular disease, unexplained sudden death, or other cardiac events.

To assess the overall cardiac burden of patients with RSV, the category of “any cardiac event” was defined as either 1) any specific or unspecified cardiac event or 2) any combination of specified events (e.g., MI plus HF reported together) without indication of which event was primary.

“Pre-existing cardiac disease” was defined as cardiac disease in the study population diagnosed before the RSV disease (e.g., MI, HF and arrhythmias). Patients both with and without known pre-existing cardiac disease or patients in studies where the presence or absence of pre-existing disease is not described were reported as the “overall population”.

We included only cardiac events occurring after RSV disease diagnosis. Only one of the included studies provided information on the specific timing of the cardiac event following RSV and no time restriction was applied.

Selection criteria

We included publications reporting on absolute risk (proportion) and relative risk of cardiac events in patients ≥18 years old following RSV disease. Studies on patients with and without pre-existing cardiac disease were included. Detailed inclusion and exclusion criteria are listed in population, intervention, comparison, outcome, timing and setting (PICOTS) table S1.

Search methodology

We searched Medline (through PubMed) and Embase to identify peer-reviewed publications from 1 January 2000 to 6 March 2024 using pre-defined search terms, as listed in table S2. We searched for unpublished manuscripts in the medRxiv database (2022–2024) and for grey literature in the following Centers for Disease Control and Prevention (CDC) RSV working group presentations (www.cdc.gov/rsv/index.html), the Respiratory Syncytial Virus Foundation, including Respiratory Syncytial Virus Vaccines for the World conference abstracts (https://resvinet.org), Infectious Disease Week abstracts (https://idweek.org), the American Thoracic Society (www.thoracic.org), the European Respiratory Society (www.ersnet.org), the European Academy of Allergy and Clinical Immunology (https://eaaci.org), the American Academy of Allergic Asthma and Immunology (www.aaaai.org), the American College of Chest Physicians (www.chestnet.org), the Congress of the European Society of Clinical Microbiology and Infectious Diseases (www.escmid.org), the RSV symposium (www.efcni.org/event/12th-international-rsv-symposium-rsv2022/) and the CDC RSV Advisory Committee on Immunization Practices (www.cdc.gov/vaccines/acip/index.html). Additionally, snowballing techniques were applied to identify further relevant references by reviewing reference lists of selected systematic reviews and included studies.

After removing the duplicated articles using EndNote (Clarivate), unique studies were transferred to DistillerSR (Evidence Partners) to proceed with the selection process. Two reviewers (J. Montiel and W. Robles-Rodríguez) independently screened in duplicate all titles and abstracts and agreed on the selection of studies to be screened in full text. J. Montiel and W. Robles-Rodríguez screened the full text and S. Seabroke reviewed in duplicate 30% of the full-text publications for quality control.

Data extraction and bias assessment

The data extraction form was created and piloted in DistillerSR, and datasets were exported to Microsoft Excel. Data extraction was conducted by multiple reviewers and an independent researcher reviewed 30% of the extracted data to assess quality. Extracted items included the country, study design, setting, period, population, sample size, population age, gender, inclusion and exclusion criteria, clinical outcomes (pre-existing cardiac disease, RSV infection definition, ICD code version, tests used for RSV detection, type of sample, follow-up time, comparative study and comparative control group), cardiac event proportion (numerator, denominator, proportion lower and upper 95% confidence interval), relative risk measures (relative measure units, ratio, ratio adjustment, 95% confidence intervals and p-value), and type of stratification (pre-existing cardiac disease, cardiac event type, cardiac event time, age group, setting and other strata).

To assess the risk of bias (ROB) of the included publications, we used the critical appraisal tool developed by the Joanna Briggs Institute at the University of Adelaide, Australia (https://jbi.global/critical-appraisal-tools). For each study design, we used a specific set of criteria and incorporated a scoring system (tables S4 and S5). We applied a higher weight to certain criteria identified as indicators of robustness in the study design. We assessed as low ROB those studies with more than eight criteria rated as “yes” or “not applicable (NA)”, all higher-weight criteria rated as “yes” or “NA”, clear evidence of robust study design, conduct, and reporting, and minimal or no major methodological flaws. We assessed as moderate ROB those studies with five to seven criteria rated as “yes” or “NA”, some limitations or concerns regarding study design, conduct or reporting, and moderate confidence in the validity of the study results. We assessed as high ROB those studies with 0–4 criteria rated as “yes” or “NA”, significant methodological flaws, limitations or biases, and low confidence in the validity of the study results.

Data analysis and meta-analysis

We processed the data using Microsoft Excel and generated summary tables and forest plots using R v. 4.2.0. We focused our analysis on data from hospitalised patients grouped by cardiac event. When data on absolute risk (presented as proportions, %) or relative risk measures (such as relative risk, odds ratio and prevalence ratio) were missing, but could be derived from other available information, the corresponding calculations were performed. When missing, 95% confidence intervals were estimated using the exact method [15].

For outcomes reported by five or more comparable studies, we conducted a meta-analysis and calculated pooled estimates using the most comprehensive data available, excluding values from stratified subgroups. To ensure comparability, we only pooled outcomes from studies reporting on hospitalised patients and excluded the few studies reporting on other settings or specific populations (such as intensive care unit (ICU) patients, outpatients, post-discharge patients, or transplant recipients).

To estimate the pooled absolute risk, we used the random intercept logistic regression model of the generalised linear mixed models family [16], which accounts for within-study variability and tends to give greater weight to studies with larger sample sizes. To estimate the pooled risk ratio, we conducted a random-effects meta-analysis using the inverse variance method, which assigns more weight to studies with smaller standard errors. We used the maximum likelihood method [17] to estimate the variance of the true effect sizes across studies (τ^2^) and the Clopper–Pearson (exact) method [15] to estimate the 95% confidence interval for the individual studies. We assessed heterogeneity using the I^2^ statistic [18]. For the meta-analysis, we used the R package “meta” [19].

To express the proportional increase in the risk of cardiac events following RSV disease compared to the risk of cardiac events in a control group (other respiratory viruses), we estimated the relative risk increase using extracted measures (relative risk and prevalence ratio), whenever feasible. Alternatively, if the necessary measures were not available, the relative risk increase was estimated using raw data extracted from the manuscripts (number of cardiac events in each group).

Results

Our search identified 3887 publications (3811 from databases and 76 from the grey literature), of which 28 met the inclusion criteria (figure 1). The included publications comprised 27 cohort studies and one cross-sectional study [20], with sample sizes ranging from 19 to 175 113 participants, and from 18 to 175 113 RSV cases. Most studies were conducted in the United States (n=8) [20–27], China (n=5, including Hong Kong) [28–33], France (n=4) [34–38] and Thailand (n=2) [39, 40]. Other contributing countries included Australia [41], Canada [6], Chile [42], the Czech Republic [43], Israel [44], Portugal [45], Sweden [46], Switzerland [47] and Taiwan [48], each with one study. Additionally, one study was conducted across several countries, including Belgium, the Netherlands and the United Kingdom [39, 40].

The included studies mainly concern hospitalised patients (25 studies out of 28) and we therefore focused our analysis on in-hospital events. Studies reporting on nonhospitalised patients [43, 49] or with unspecified settings [23] were not analysed. Among studies on hospitalised patients, one was a cross-sectional study, five were prospective studies and 19 were retrospective studies. For RSV case identification, 22 studies used laboratory confirmation, two used ICD codes [27, 38] and three did not report the method [22, 34, 45]. A complete description of the analysed study characteristics is presented in table S3. Among all analysed studies, 11 were classified as having low ROB, 11 as moderate ROB and three as high ROB (tables S4 and S5).

All studies on hospitalised patients reported the absolute risk of cardiac events among patients with RSV disease (table S6). Additionally, 16 studies provided data on the relative risk or included information to calculate the relative risk of cardiac events among patients with RSV disease compared to those with other infections (table S7). Only one study provided information on the timing of cardiac events in relation to RSV infection, reporting a proportion of patients experiencing any cardiac event at 30 days and 365 days post-infection (16.4 and 20.9%, respectively) [41].

Across studies, the participants’ average age ranged from 64.1 to 79.5 years, with females accounting for 40.9–67.5% of the total (table S3, average age range provided per figure).

Meta-analysis of the absolute risk of cardiac events in patients with RSV disease results

Any cardiac events

The risk of any cardiac events in patients with RSV was reported by 18 studies (figure 2). All studies reported on hospitalised patients from the general population, with one study also reporting on individuals with pre-existing cardiac disease [20]. In the overall population, the absolute risk of any cardiac event among hospitalised patients with RSV disease ranged from 1.1 to 51.0% and the pooled estimate was 19.2% (95% CI 15.1–24.2%) (figure 2) with considerable heterogeneity among the pooled comparable studies (I^2^=87.0%, p<0.0001).

In patients with RSV disease and pre-existing cardiac conditions, the absolute risk of any cardiac events varied by type of pre-existing cardiac disease and the specific cardiac event, ranging from 0.0 to 66.7% between patients with HF (figure S1), ACS (figure S2) and other cardiac events (figure S3).

Heart failure

Overall, HF was the most reported cardiac event following RSV disease (n=17 studies) (table S6). Of these, 13 studies specifically reported HF outcomes in hospitalised patients, with 11 of these in an overall population and four for patients with pre-existing cardiac disease. Three studies by Chen et al. [28–30] included patients from the same setting and time period and therefore only one result was included in the pooled estimate to avoid duplicate results.

In the overall population, the absolute risk of HF among hospitalised patients with RSV ranged from 12.9 to 33.1% (n=11 studies) (table S6) and the pooled estimate was 15.7% (95% CI 14.8–16.5%, n=9 studies), without substantial heterogeneity across the pooled comparable studies (I^2^=0.0%, p=0.4489) (figure 3).

In hospitalised patients where a history of cardiac disease was reported, those with at least one documented pre-existing cardiac event had an absolute risk of HF after RSV disease ranging from 23.4 to 66.7% (n=4 studies) (figure S1). One study reported on patients without any pre-existing cardiac disease, showing a proportion of heart failure after RSV disease of 3.6% [21] (table S6).

Acute coronary syndrome

The risk of ACS after RSV disease was reported in 11 studies (table S6). Nine studies reported data on in-hospital cardiac events, with all providing data for the overall hospitalised population, and two focused on hospitalised patients with pre-existing cardiac disease.

In the overall population, the absolute risk of ACS among hospitalised patients with RSV disease ranged from 0.0 to 19.0% (n=9 studies) and the pooled estimate was 5.4% (95% CI 3.1–9.5%, n=9 studies), with substantial heterogeneity between the pooled comparable studies (I^2^=94.5%, p<0.0001) (figure 4). One study reported on patients with RSV admitted to the ICU, showing a risk of ACS of 11.1 (95% CI 1.4–34.7) [34].

In patients with a pre-existing cardiac condition (n=2 studies), the absolute risk of ACS following RSV disease ranged from 0.0 to 9.8% [20, 47] (figure S2). One of these two studies reported no ACS events, likely due to the small sample size or the focus on subgroups with specific pre-existing conditions.

Absolute risk of arrhythmias in patients with RSV disease

Arrhythmias, including atrial fibrillation, after RSV disease were reported in four studies (table S6).

In the overall population, the absolute risk of arrhythmia in hospitalised patients with RSV disease ranged from 0.0 to 51.1% (n=5 studies). Only one study provided data on cardiac arrhythmias in patients with pre-existing cardiac disease, with an event rate of 1.6% (95% CI 1.2–2.1%) [20]. Due to the wide array of conditions that are classified as arrhythmias (including atrial fibrillation, atrioventricular block and unspecified arrhythmias such as sinus bradycardia), a pooled proportion was not estimated.

Absolute risk of myocarditis and/or pericarditis in patients with RSV disease

Only one study reported the frequency of myocarditis and pericarditis following RSV disease and stated that no patients experienced an event [44]. A total of 85 individuals participated in this study, including those with and without pre-existing heart disease conditions.

Absolute risk of death related to a cardiac event in patients with RSV disease

Four studies reported that the absolute risk of cardiac event-related deaths following RSV disease ranged from 1.1 to 9.8% in the overall population (figure S4). One study also reported the number of cardiac deaths as a proportion of all deaths following RSV infection (11.8%) [40]. Pre-existing cardiac disease diagnosis was not specified for any of the results.

Relative risk of cardiac events among patients with RSV disease compared to controls

A total of 17 studies provided data on the relative risk of cardiac events in patients infected with RSV compared to those infected with other viruses. Among those reporting in-hospital cardiac events following RSV infection, 13 studies compared with influenza virus, one with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [46], one with parainfluenza [29] and two with human metapneumovirus (hMPV) [28, 29] (table S7). Compared to influenza, the relative risk of in-hospital cardiac events following RSV disease varied significantly. The relative risk ranged from 0.4 (95% CI 0.1–1.6) to 6.9 (95% CI 1.2–40.5), the PR ranged from 1.4 (95% CI 0.9–2.1) to 1.5 (95% CI 0.9–2.3) and the odds ratio was reported in a single study as 2.7 (95% CI 1.2–6.2). Overall, the relative risk increase ranged from −60 to 590 (table S7).

Pooled estimates showed that patients with RSV disease compared to patients with influenza had a risk ratio of 1.2 (95% CI 1.1–1.4; n=13 studies) for any cardiac event, 1.3 (95% CI 1.1–1.6; n=8 studies) for HF and 1.2 (95% CI 0.9–1.5; n=5 studies) for ACS (figure 5). Heterogeneity for the pooled results was low, with I^2^ estimated at 0% for all comparisons. One study reported on patients with RSV admitted to the ICU, showing a risk ratio of ACS of 1.2 (95% CI 0.3–5.0) [34].

A single study reported that patients with RSV disease had an odds ratio of 0.6 (95% CI 0.5–0.8) for developing acute MI (AMI) compared to those infected with SARS-CoV-2 (table S7) [46]. Another study reported that, compared to patients with parainfluenza, the relative risk of HF exacerbation in inpatients with RSV was 4.0 (95% CI 2.0–7.9) [29]. When compared to patients with hMPV, the relative risk of experiencing a cardiac event after RSV disease varied from 0.2 (95% CI 0.0–1.2) to 2.6 (95% CI 0.3–24.9) in three studies [28, 29, 38].

Discussion

This SLR and meta-analysis synthesises the available evidence on the risk of cardiac events following RSV disease in adults with and without pre-existing cardiac disease. The results show that RSV disease poses significant risks beyond respiratory illness, with cardiac events, particularly HF and ACS, being common among hospitalised older patients.

The absolute risk of any cardiac event following RSV disease among hospitalised patients was substantial, estimated at 19.2% (95% CI 15.1–24.2). These data showed considerable variability, which is unsurprising given the different outcomes included in this broad category. Additionally, sample sizes ranged widely from 19 to 6248 subjects. A limited number of studies reported on arrhythmias and myocarditis/pericarditis in patients with RSV disease, with data for arrhythmias displaying wide variability due to the inclusion of different types of events.

The absolute risk of HF amongst hospitalised patients with RSV disease from the overall population was estimated at 15.7% (95% CI 14.8–16.5%), with data suggesting that patients with pre-existing disease were at higher risk, ranging from 23.4 to 66.7% [6, 37, 50–52]. Compared to HF, the risk of ACS after RSV disease was smaller, estimated at 5.4% (95% CI 3.1–9.5) among hospitalised patients with RSV disease. Only two studies reported results of ACS following RSV disease for patients with pre-existing cardiac disease with conflicting results. The study with the larger sample size (n=3564) showed a significant increase in the risk of ACS [20], while the other study, with stratified sample sizes ranging from two to 47 participants, showed no or a reduced risk of ACS [47].

The observed rates of cardiac death amongst patients with RSV, ranged from 1.1 to 9.8%, with one study reporting that 11.8% of all deaths following RSV infection were cardiac-related. Interestingly, no events of unexplained sudden deaths were reported, suggesting that cardiac complications related to RSV may be more predictable, identifiable and potentially preventable. However, the absence of data in patients with pre-existing cardiac conditions limits our understanding of how increased background cardiac risk factors may contribute to mortality risk. Moreover, the small sample size of the studies reporting on this outcome (ranging from 51 to 141 individuals in five studies) should be acknowledged.

The comparison of cardiac event risk following RSV disease with influenza suggests that RSV may lead to a higher risk of any cardiac events (relative risk 1.2, 95% CI 1.1–1.4) and specifically of HF (relative risk 1.3, 95% CI 1.1–1.6). Heterogeneity was low for both meta-analyses, reinforcing the robustness of these findings. Although relative risk estimates were not adjusted for differences in baseline risk, the risk of cardiac events after RSV appears comparable to the risk after influenza and possibly higher. Given that influenza is a well-known risk factor for cardiac conditions [53], this result suggests comparable morbidity for the two pathogens. Although the risk ratio for ACS in patients with RSV disease compared to influenza did not reach statistical significance (relative risk 1.2, 95% CI 0.9–1.5), the elevated risk ratio point estimate also suggests a possible increased risk.

Most of the identified studies reported on hospitalised patients. Several studies have shown that including RSV-attributable cardiovascular disease significantly increases the incidence rate of RSV-related hospitalisation among adults [54–57]. Estimated RSV-attributable cardiorespiratory hospitalisations increased with age and were substantially higher in people with risk factors compared to those without risk factors.

This study has several notable strengths. A comprehensive literature search was conducted across established databases and grey literature, supplemented by snowballing techniques to identify additional references. To ensure inclusivity, we incorporated abstracts and conference posters, acknowledging that this approach may introduce some methodological uncertainty. Additionally, all references were rigorously assessed for ROB, without excluding those with moderate or high bias, underscoring our commitment to a thorough analysis. Finally, the majority of the included studies relied on laboratory testing data for RSV case identification (n=20, 80% of all studies), which provided a more robust diagnostic measure than reliance on ICD codes.

However, several limitations of this SLR should be acknowledged. The reliance on publicly available studies may have led to omission of relevant data due to publication bias or inadequate reporting, particularly from under-represented regions. Most studies originated from North America, Europe and developed countries in Asia, raising concerns about global representativeness. At the time of the review, no data were available from younger adults, despite the presence of risk factors in this population. The included studies did not report on how the cardiac events were diagnosed which might be a source of bias, especially for conditions difficult to distinguish clinically (e.g., acute decompensated heart failure versus chronic progression). Furthermore, while the review aimed to assess the timing of cardiac events following RSV disease, only one study provided this data, preventing any conclusions from being drawn and highlighting a key research gap.

In large database studies that rely on ICD-10 codes, it is often unclear whether the recorded diagnosis was truly acute during hospitalisation, potentially affecting the accuracy of case identification. Although most studies reported using laboratory-confirmed RSV diagnoses, some included studies were based on a diagnosis of RSV without specification of the type of diagnostic test used [22, 34, 45]. Although these patients exhibited symptoms consistent with RSV at the time of analysis, the lack of test type confirmation introduces a degree of uncertainty. In one study, some cases were detected using serology test and it remains unclear whether one or two antibody measurements were used to differentiate between the convalescent phase and the acute phase. Overall detection methods other than molecular tests were minimally used [20]. Crude unadjusted relative risks were calculated for several studies using reported proportion data, thus confounding factors may have influenced the results. There was limited data comparing the cardiovascular impact of RSV to other viral infections. Also, substantial heterogeneity was observed between ACS studies, mostly driven by one study that reported a high proportion of events [27]. This difference was largely explained by a higher prevalence of patients with underlying conditions compared to other studies, limiting data interpretation. Finally, as most of the studies identified reported on hospitalised patients (25 out of 28) who generally have underlying diseases or are older, the increase in cardiac complications following RSV may not be generalisable to a younger or baseline healthier population.

These findings emphasise the importance of monitoring patients with RSV disease, particularly older populations and those with pre-existing cardiac conditions, for potential cardiac complications. Enhanced clarity in identifying cardiac events could facilitate improved risk stratification and prevention recommendations for patients, ultimately leading to improved outcomes. Given the contribution of cardiac events to the overall RSV disease burden, they should be considered when evaluating RSV prevention programmes, such as vaccination. Moreover, cardiac events following RSV could serve as meaningful end-points in RSV vaccine effectiveness studies [58] and should be incorporated into health economic evaluations to fully capture the impact of RSV. Future research should focus on proposing standardised reporting practices, particularly concerning the definition and timing of events, and on elucidating the underlying mechanisms linking cardiac events to RSV disease among adults, including older adults and those with high-risk pre-existing conditions. Improved understanding of these relationships is essential to guide clinical approaches and public health strategies aimed at mitigating these risks.