Estimated Respiratory Syncytial Virus-Related Hospitalizations and Deaths Among Children and Adults in Spain, 2016–2019

Respiratory syncytial virus (RSV) causes a substantial disease burden, typically with an annual seasonality, peaking during the autumn/winter months in temperate climates [1]. High-risk groups for severe infection include young children and older adults, particularly those with underlying cardiorespiratory conditions [2, 3]. Approximately 33 million annual RSV cases occur globally in children < 5 years, of which 11% are hospitalized [4]. Among older adults, an estimated 787,000 RSV-related hospitalizations are projected to be occurring annually in high-income countries alone [5]. In Spain, RSV-related hospitalization rates were reported to be between 2500 per 100,000 population [6] in children aged < 1 year and 1.7 per 100,000 population [7] in adults aged ≥ 60 years, based on the count of RSV-specific hospital discharge codes. However, these estimates are likely many fold below the true burden for older children and adults due to methodological limitations [8, 9]. Although RSV infection is frequently diagnosed in infants, the disease burden in older children and adults is mostly underestimated due to nonspecific symptoms, limited standard-of-care testing among adults, inadequate diagnostic capacity and lower sensitivity of tests compared to infants [8, 10‐17]. In addition, several studies reported that RSV infection not only causes respiratory diseases but often generates new events or acute exacerbations of chronic cardiovascular diseases (such as congestive heart failure, acute coronary syndrome, and arrhythmias) [18‐20], which are not typically considered when assessing RSV burden. Therefore, the estimates based on laboratory-confirmed RSV cases generally underestimate the incidence.

To overcome this limitation, several retrospective statistical model-based approaches have been developed to estimate the burden of RSV disease using secondary data sources [21‐31]. These models indirectly estimate the proportion of a health outcome attributable to RSV by examining the relationship between changes in the viral activity indicator (e.g., laboratory-confirmed cases or virus-specific hospitalizations) and the corresponding changes in the incidence of the health outcome. Studied outcomes ranged from very broad (e.g., all-cause hospitalizations, all-cause mortality) [26, 32] to more specific (e.g., bronchitis/bronchiolitis hospitalizations, influenza/pneumonia deaths) [25, 33]. These estimates are substantially closer to prospective study estimates than incidence estimates based on standard-of-care testing and RSV-specific ICD-10 codes [34].

In this study, we aimed to estimate the RSV-attributable incidence of cardiorespiratory hospitalizations and deaths in Spain between 2016 and 2019 by applying comprehensive statistical modeling.

Time-series studies compare the variability in pathogen-indicators (here RSV and influenza) to variability in broad all-cause health outcomes that are could be related to these pathogens (e.g., all-cause respiratory hospitalizations), to estimate the proportion of these all-cause events that can be attributed to these pathogens. Our model-based study found a high burden of RSV-attributable hospitalizations in Spain, with incidences substantially higher than those reported based on RSV-specific codes in all ages, particularly among older children and adults. We also found that a considerable burden of adult cardiovascular hospitalizations and deaths, specifically for chronic heart failure and arrhythmias, was attributed to RSV by the time-series model.

As expected, our estimates diverged substantially from results in another Spanish study that used the same database but did not incorporate time-series modeling to account for untested/undiagnosed events. The annual RSV-specific hospitalization rate in adults aged ≥ 60 years was 1.7 per 100,000 for the 2012–2020 period [7], while our estimates ranged from 257–283 per 100,000 (if we only consider respiratory hospitalizations) and 438–476 per 100,000 (if we consider cardiorespiratory hospitalizations). Our estimates in turn were comparable to prospective study results from two recent systematic literature reviews and meta-analyses that adjusted for diagnostic testing based under-ascertainment: a United States study with a pooled annual incidence estimate of 282 cases per 100,000 population [34] and a global study of high-income countries with a pooled estimate of 347 cases per 100,000 population [5] in those aged ≥ 65 years. By contrast, two model-based studies from the United Kingdom reported lower incidences [11, 49], a result that may be explained primarily by two methodological differences. First, we observed that using surveillance data as RSV indicator (as these studies did, rather than pediatric RSV-related hospitalization) can reduce peak outcome estimates and decrease capture of RSV activity outside of the influenza season, when testing is more frequent [9]. Deriving the RSV proxy from the same dataset as the outcomes ensures an exact match regarding geographic representation of the proxy and outcome data, which may not be present when using sentinel viral surveillance data as the proxy. Second, our respiratory and cardiorespiratory disease outcomes groupings used both primary and secondary diagnosis codes. This allows for events with other primary codes (e.g., viral illness or sepsis) to be included in the modeling. This approach has been used in other recent publications [11, 29]. Nevertheless, our calculated proportions of RSV-attributable cases of hospitalizations were comparable to these studies, ranging from 4 to 10%, depending on age [11, 34].

We found that under-ascertainment based on standard-of-care diagnostic codes increased as age increased. This observation can be explained by the increased use of nonspecific lower respiratory tract infection codes –such as unspecified bronchiolitis, bronchitis or pneumonia– as age increased [51], exacerbated by infrequent testing. Studies from Spain and other countries also support lower testing frequency and reporting in older children [52, 53] and adults [8]. The opposite was seen for children aged 2–5 years, among whom the estimated incidence rates (11–13 cases per 100,000) were lower than those based on RSV-specific codes (39–80 cases per 100,000). This is likely due to the fact that the observed respiratory hospitalizations frequency in this age group did not have a clearly seasonal pattern, which prevents the model from accurately attributing a percent of the outcome to RSV. The reason for the lack of seasonality is not clear but it may be that more respiratory hospitalizations are associated with chronic disease exacerbations which can have non-infectious triggers, e.g., asthma exacerbations can have allergic and infectious triggers. Similar limitations were also observed in other modeling studies, where estimates for RSV-attributable hospitalizations in children aged 5–17 years were negative [33] or equal to zero [22, 54].

As expected, the RSV-attributable hospitalization rates of respiratory events in children obtained from our model were slightly higher than those reported in other Spanish observational studies using RSV-specific codes [6, 55, 56]. Nevertheless, although comparisons must be made with caution since the study periods and regions were not the same, our estimates are in line with results from other countries, such as the United Kingdom, where the modeled incidence for 0–5 months was 4184 per 100,000 [54] (range of 3998–5453 in our study). In the United States, modeled results were slightly lower (1500–2800 cases [29] and 1,896 per 100,000 [28] in children < 1 year of age).

Based on the literature establishing that some cardiovascular outcomes can be provoked/related to RSV infections [19, 21, 22, 30, 31], we included cardiovascular and respiratory diseases in our modeled outcomes. This study’s definition included only selected specific cardiovascular outcomes since not all of them showed marked seasonality. The seasonal variation allows the linkage between the season viral activity and the variability in the all-cause outcomes through time-series modeling. We estimated that in adults ≥ 80 years, RSV may have been related to approximately 6%, 4% and 5% of all hospitalizations for chronic heart failure exacerbations, ischemic heart diseases, and arrhythmias, respectively. This finding from our model is supported by previous literature that has established that respiratory viruses, including RSV, can exacerbate chronic cardiovascular diseases, such as coronary artery disease, and trigger new cardiovascular events [20, 57]. It has been described that inflammation, prothrombotic imbalance, and increased metabolic demands of the myocardium can worsen or trigger myocardial ischemia and arrhythmias [19, 42, 58]. Respiratory viruses were also found to be one of the most common etiological factors of myocarditis [59]. However, myocarditis hospitalizations did not show a clear seasonal pattern in our study.

As expected, RSV-attributable mortality rates were highest in the oldest age group, among whom RSV was related with 4–5% of selected cardiorespiratory deaths. Although our estimates were slightly lower than those reported in the United Kingdom (1, 8, 37, and 198 deaths per 100,000 in people 18–49, 50–64, 65–74, and ≥ 75 years, respectively), the proportion of deaths attributable to RSV in older adults was similar for cardiorespiratory and respiratory causes (ranged between 2 and 5%) [11]. This might be also related to a different definition of cardiorespiratory deaths, as we selected more specific outcomes than all cardiorespiratory causes (i.e., J00-J99I00-I99) [11]. Spain has the second highest life expectancy in Europe [60], which may in part account for the lower mortality rate. However, our estimates (14.6–17.1 deaths per 100,000 person-years) of RSV-attributable mortality rate of underlying respiratory deaths in adults ≥ 60 years were comparable to results of a model-based study in the United States (14.7 deaths per 100,000 in people ≥ 65 years of age) [61]. Due to a low number of deaths among children, data were not modeled.

The main strength of our study was the inclusion of two population-based, nationally representative databases, which reduced the risk of selection bias. In addition, primary and subgroup outcome definitions, including cardiovascular causes, allowed us to explore a wider spectrum of conditions described in the literature associated with RSV infection. Our final statistical model was based on an extensive literature review and experts’ input.

However, several limitations can be described. Firstly, we captured only severe cases (hospitalizations and deaths) and thus likely underestimated the total burden of RSV disease in the population. Secondly, we could not stratify by risk groups due to data limitations. Thirdly, as an RSV activity proxy, we used hospitalization data from children aged < 2 years (consistent with other publication [29]), which may not reflect the exact temporality of circulation of the virus in the adult population. To account for this, we selected the best lag between the proxy in children and the outcome in adults to reflect the sequential pattern of infection, usually starting in children and spreading to older age groups [62]. In addition, we only included RSV and influenza in our analysis, implicitly assuming that these are the only two pathogens that show a relevant association with the outcome of interest. Nevertheless, even without explicitly modeling other potentially relevant pathogens, they are indirectly accounted for in the model through the periodic component and the overdispersion parameter to a great extent. Lastly, by using a modeling approach, we cannot confirm causal inference.

In conclusion, our study suggests that a high number of RSV-related hospitalizations and deaths may not have been correctly identified in Spain, largely due to low rates of standard-of-care RSV testing and diagnosis outside of the infant/toddler period. This underestimation, which is higher in older children and older adults, should be considered when assessing the potential benefit of preventive measures such as vaccination. Our study also indicates that, like other respiratory viruses such as influenza and SARS-CoV-2, RSV may contribute to both respiratory and cardiovascular complications. In these age and risk groups, implementation of preventive measures such as vaccines and effective RSV antivirals would have a substantial impact on health.