Infection by respiratory syncytial virus (RSV) is a significant global public health challenge and one of the leading causes of child morbidity and mortality, particularly in children aged less than 5 years.1,2 This virus is the leading pathogen associated with hospital admissions for lower respiratory tract infection (LRTI) in this age group. It is estimated to be responsible for 33 million cases of acute LRTI annually, and for 3.6% of deaths among infants aged 28 days to six months.3 In Europe, between 2006 and 2018, there were nearly 250 000 pediatric admissions per year associated with RSV, 75% of which were in infants aged less than one year.4 In Spain, two out of every 100 children aged less than 2 years are hospitalized due to RSV infection, with a mean length of stay of six days and an estimated annual cost of 49.6 million euros to the public health system.5,6

Although risk factors like preterm birth or chronic illnesses increase the risk of serious complications, most cases occur in healthy full-term infants.6–8

The burden of disease caused by RSV extends beyond the hospital setting: approximately 90% of bronchiolitis cases in children aged less than 2 years in Valencia are managed at the primary care (PC) level.5 Despite this, there are limited data on its impact on the primary care system.7

The impact of RSV is not limited to acute episodes; in fact, the probability of developing recurrent wheezing and asthma triples following a severe RSV infection.8,9 This is likely why prophylaxis against RSV with a monoclonal antibody was associated with a 61% reduction in the number of days with wheezing during the first year of life.10 In recent years, new preventive tools have been approved in Europe to protect infants, such as long-acting monoclonal antibodies (nirsevimab, clesrovimab) and maternal vaccination.11–14 In 2023, Spain was one of the first countries in the world to introduce nirsevimab as part of its official immunization program.15,16 The evaluation of its effectiveness requires reliable data on the actual burden of RSV disease, particularly in PC.

The ComNet RSV III multicenter study analyzed the disease burden and societal impact of RSV infections in children aged less than 5 years managed at the PC level in five European countries (Belgium, Italy, Spain, the Netherlands, and the United Kingdom).17,18

In the present study, we compiled and analyzed the data on the burden of disease caused by RSV in children younger than five years in Spain at the PC level, a subject that has received little attention to date. This knowledge is essential for optimizing strategies for prevention, management, and treatment.

We conducted a prospective, observational, descriptive, and analytical study of cases documented by 37 pediatric researchers who were members of the Primary Care Pediatrics Research Network (PAPenRED)19 in eight of the autonomous communities (ACs) of Spain.

The initial objective was to collect data on 800 cases of suspected RSV infection in children aged less than five years (the estimated minimum sample size, for a 95% level of confidence, a 3% margin of error, a 20% expected prevalence, and accounting for attrition, was 804 Spanish children). The study was interrupted twice by different SARS-CoV-2 epidemic waves. The enrollment period was from November 2021 to January 2024. Fig. 1 shows the study flowchart.

Figure 1.

Flow chart of patient recruitment and follow-up.

Inclusion criteria: children aged less than 60 months presenting to their primary care pediatrician with respiratory symptoms suggestive of RSV infection. In this study, we applied the WHO definition of acute respiratory tract infection for community-based RSV surveillance (ie, sudden onset of at least one of the following symptoms: dyspnea, cough, sore throat, or coryza).

Exclusion criteria: insufficient understanding of study information by caregivers due to language barriers or intellectual disabilities.

After the legal guardians signed the informed consent form, and following a physical examination and the collection of demographic and clinical data related to the episode, a nasopharyngeal swab was taken from the patient. Swabs were transported in a standard transport medium to a laboratory (one hospital in each autonomous community), where the molecular testing process started within 24 h (polymerase chain reaction, primarily the Allplex Respiratory Full Panel Assay for the detection of 17 different viruses, including RSV A and B).

Each collaborating pediatrician prospectively collected (at 14 and 30 days after enrollment) follow-up clinical and treatment data for patients who tested positive for RSV on the day of enrollment, as well as data regarding the household and caregivers.

We defined a categorical variable: testing positive for RSV A, for RSV B, or for both.

We collected baseline descriptive data in the initial visit when the patient was recruited, including data on presenting symptoms, relevant history, including personal history of chronic conditions, and physical examination findings, in addition to demographic characteristics. In patients who tested positive for RSV, at 14 and 30 days, we collected data on the outcomes of interest: clinical manifestations and laboratory findings, complications, use of medication, duration of illness, school absences, health care visits at any level of care, parental work absence, and current general health of the child on the scale from 0 (worst possible) to 100 (best possible) used in the multicenter study.17

Of all the patients included in the study, one received palivizumab, and during the most recent season (October 2023 through January 2024), 32 received nirsevimab for prophylaxis.

For quantitative variables, we calculated measures of central tendency and dispersion and assessed the normality of the distribution (Kolmogorov-Smirnov test); for qualitative variables, we calculated percentages with 95% confidence intervals (CIs). Depending on the type of variable, we used the χ2 test, Student t-test, ANOVA, or, when appropriate, nonparametric tests (Fisher exact test, Mann-Whitney U test, Kruskal-Wallis test) in the comparative analysis.

Direct healthcare costs (primary care visits, medications, and emergency department visits) were calculated in euros using official rates adjusted to 2022 prices.20 Indirect costs were estimated based on parental work absences based on average wages in Spain.

Each participated pediatrician entered the anonymized questionnaire and laboratory data into a custom study database (REDCap tool).

Compared to the European study in which it originated,17,18 this study included an additional 96 patients (30 RSV-positive) recruited between October 2023 and January 2024.

In Spain, the study was approved by the Ethics Committee of the Principality of Asturias (reference 2021.457 from September 30, 2021).

A total of 517 children aged less than 5 years were recruited and screened, of whom 206 (39.8%) tested positive for RSV. Table 1 shows the distribution of patients in the eight autonomous communities that participated in the study, showing significant differences in the percentage who tested positive for RSV (P =  .012).

Fifty percent of the RSV + patients were female (95% CI, 43.2–56.7 %).

Table 2 presents the data collected on the day of recruitment, both for the overall sample and for the RSV + and RSV − groups. There were differences between the groups, as the RSV + group had a greater proportion of patients with dyspnea (50.0% vs 31.8%) and wheezing (63.1% vs 53.4%). The probability of testing positive was significantly lower among patients who had received palivizumab or nirsevimab (15.2% vs 41.5%; P =  .004).

The RSV subtype was established in 127 of the 206 patients who tested positive: 64.5% were positive for RSV A, 35.4% for RSV B, and 2.4% for both. Coinfections were detected in 48.3% of the total sample (95% CI, 44.5%–53.1%). In the RSV + group, coinfections were detected in 35.92% of patients, primarily with rhinovirus, bocavirus, and enterovirus (37, 18, and 9 cases, respectively).

Table 3 shows the changes in study variables between the date of recruitment and the 14- and 30-day follow-ups. Fourteen cases of acute otitis media (7.7%) and eight of pneumonia (4.4%) were diagnosed during the month of follow-up.

Sixty-one patients (31.0%) visited the emergency department; 16.7% of participants required hospitalization, and 1.5% were admitted to the intensive care unit (ICU). There were no deaths. Table 4 compares the characteristics of infants aged less than 12 months and older children.

There were differences in resource utilization among the autonomous communities. The percentage of patients managed in emergency departments differed significantly (47.6% in Extremadura; 28.6% in Aragón; 28% in Murcia; 21.7% in Castilla-La Mancha; 15.8% in the Valencian Community; 15.4% in Madrid; 15% in Asturias; and 12.5% in the Canary Islands; P =  .038). However, there were no significant differences in the percentage admitted to hospital (23.8% in Extremadura; 21.4% in Aragón; 19.5% in Madrid; 15.8% in the Valencian Community; 15.0% in Asturias; 12.5% in the Canary Islands; 10.0% in Murcia; and 4.34% in Castilla-La Mancha; P =  .504).

We found no differences in clinical presentation, health care utilization, or duration of illness between patients infected with RSV A versus RSV B.

With regard to medication, 54.3% of children received acetaminophen, 28.3% ibuprofen, 58.4% inhaled bronchodilators, 9.7% inhaled corticosteroids, 11.9% oral corticosteroids, 3.1% cough syrups, and 18.3% antibiotics. Ibuprofen was used significantly less frequently in infants under 12 months compared to older children (7.6% vs 25.7%; P =  .001), as were inhaled bronchodilators (50.0% vs 64.7%; P =  .036). Also, the proportion of infants who received antibiotics was 10.9%, compared to 20.0% of older children (P =  .079). At the autonomous community level, we only found differences in the use of inhaled bronchodilators (64.3% of children in Aragón; 10% in Asturias; 30.4% in Castilla-La Mancha; 66.6% in Extremadura; 62.5% in the Canary Islands; 69.2% in Madrid; 64.0% in Murcia; and 68.4% in the Valencian Community; P <  .001) and inhaled corticosteroids (Aragón, Asturias, Madrid, Murcia, and Valencia: 0%; Castilla-La Mancha: 4.3%; Canary Islands: 12.5%; and Extremadura: 6.7%; P =  .003).

Only children included between November 2023 and January 2024 had the option to receive nirsevimab for prophylaxis. Of this total (33 children), only five (15.2%) tested positive, which makes it impossible to draw comparisons with this subgroup.

Among the patients enrolled in school, 69.2% missed at least one day (median days of absence, 8 days; IQR, 5−14). One or both parents missed at least one day of work in 26.7% of cases (median days of absence: 8; IQR, 4−12).

The direct health care costs per RSV episode amounted to a mean of €301 (95% CI, 288–313), primarily due to primary care visits (54%) and emergency department visits (43%). Indirect costs averaged €157 (95% CI, 137–180) per episode (Table 5). Overall, the mean total cost per episode was €458, with significant variations between age groups: €507 for infants aged less than 1 year and €419 for older children (mean difference, €88; 95% CI, 76–99; P <  .001).

This was a study conducted at the national level, integrating data from a multinational study (ComNet RSV III)17,18 in five European countries (Italy, Spain, Belgium, the Netherlands, and the United Kingdom). Following the COVID-19 pandemic and the restrictive measures imposed on its account, RSV did not circulate during the usual time of the year in the 2020–2021 season, and the RSV season did not return to the prepandemic pattern until 2022.21–23

Spain accounted for 23.5% of the RSV + participants in the European study. The positivity rate (39.8%) was similar to the rates reported in other studies conducted during the RSV season.24–27 Similarly, the positivity rate was higher in infants aged less than 1 year, possibly due to more frequent lower respiratory tract involvement, which may be a source of selection bias. Infants, compared to older children, visited the emergency department more frequently (39.6% vs 22.5%) and a higher proportion were admitted to hospital (25.0% vs. 9.5%), a finding that is consistent with other studies.5,24,28–30

In our study, 16.7% of RSV + patients were admitted to hospital. In the ComNet RSV III study,17 the rate of hospitalization was only higher in Belgium (43.7%) (United Kingdom 5.2%; Italy 4.1%; Netherlands 3.7%). One in four infants required admission, compared to one in ten children aged more than 12 months. Differences in health care systems alone cannot fully explain these discrepancies, and potential selection biases could explain the observed variation among the autonomous communities (with hospitalization rates ranging from 23.8% in Extremadura to 4.34% in Castilla-La Mancha).

There were no differences based on the RSV subtype (some studies found greater severity associated with RSV A, a few found greater severity with RSV B, and others found no differences).31

In our study, viral coinfection was detected in 36.8% of RSV + patients and 60.6% of RSV − patients, in agreement with previous studies,27,28,32 although the reported prevalence of coinfection varies widely, from 6% in the study by Hall et al.27 to 51% in the study by Sankatsing et al. in Italy.32 Variation in study methodology, the age of included patients33 and the sensitivity of the test used for detection of RSV can explain these differences. A recent meta-analysis found no differences between RSV monoinfection and RSV coinfection with other viruses, except for a higher rate of ICU admission associated with metapneumovirus, although this subject is still under debate.34

Only wheezing and dyspnea were significantly more prevalent among RSV + patients. Furthermore, data on disease duration, impact on the frequency of office visits, emergency department visits, and hospital admission confirm, as in other studies, that this infection is more severe than other viral respiratory tract infections.7,23–28,31,32,35

Despite the limited evidence in support of its effectiveness, the excessive use of medication stands out as a clear area for improvement. Antibiotic use in Spain was similar to that in neighboring countries like the Netherlands or the United Kingdom and lower compared to Italy32 and previous studies in Spain.25 The use of bronchodilators, however, was very high (over 50%). In Spain, medication was prescribed more frequently to children aged more than 12 months, possibly on account of a higher frequency of fever and a significantly greater use of bronchodilators overall. Furthermore, the differences between autonomous communities in the use of inhaled bronchodilators (beta-2-adrenergics and corticosteroids) do not seem justified.

However, the use of antibiotics (in 18.3% of patients) appeared reasonable given the complications, such as acute otitis media or pneumonia, with 6.2% of the total prescriptions without a clear justification. Compared to other studies,7,23,25,32 we ought to highlight the infrequent use of antibiotics in infants aged less than 1 year (10.9% in infants, and less than 20% in older children). Bacterial superinfection is considered rare in these patients; therefore, guidelines do not support routine antibiotherapy.36,37 In our study, 7.7% of the children received a diagnosis of otitis, a proportion that was lower compared to other studies (which have reported rates of up to 23% and 30%, particularly in infants).26,34,38,39 This difference could be explained, at least in part, by the difficulty of making an accurate diagnosis with conventional otoscopy, which is the customary practice in Spain. The prevalence of bacterial pneumonia associated with RSV infection (3.7% in the ComNet RSV III study and 4.4% in our study) was not clearly defined in primary care, as most studies were conducted in the hospital setting.36

The cost per patient hospitalized for RSV ranges from €3500 to €4500 in Spain and neighboring countries,30,31,40 although the burden of care is highest at the PC level (90% of cases).5 The mean number of PC visits was 1.97, although higher numbers have been reported in Spain.25 Similarly, the frequency of visits to emergency departments was high (31.0%), comparable to that in Belgium, but much higher than in Italy, the United Kingdom, and the Netherlands.17,18,32 In Spain, percentages as high as 61.6% have also been reported.25 The differences between autonomous communities is striking, ranging from 12.5% in the Canary Islands to 47.6% in Extremadura. These figures are most likely related to the accessibility of both resources in Spain and to inadequate health education, given that there are no substantial differences in epidemiological trends.

The total cost per episode (€458) was significantly higher for infants aged less than 1 year, as is the case in most studies.5,18,26,28,32 The mean direct health care costs in Spain (€301) chiefly stemmed from PC visits (54%) and emergency department visits (43%). In the ComNet III study, 26.7% of Spanish parents missed work hours to care for their children, the lowest percentage among the participating countries, which ranged from 35% in the United Kingdom to 71% in Italy.18 In our study, direct costs were higher than indirect costs (the opposite of what has been reported elsewhere). This distribution appears to be closely related to the characteristics of the different health care systems, parental leave policies, and available family support.

Finally, as observed in other studies, the infection rate was significantly lower among those immunized with nirsevimab.41,42

Our study has several limitations. A number of factors may have introduced selection bias: patients were selected by pediatricians motivated by research and by addressing common diseases like this one; some patients were recruited after presenting to emergency departments with lower respiratory tract symptoms and even after hospitalization (which would explain the high use of these resources observed in the study); conversely, the number of severe cases may have been underestimated because severely ill patients may go directly to the emergency department and not visit a PC center; patients with mild symptoms who did not seek medical care were not included, nor were those with language barriers or comprehension difficulties, those using private health care services, or even those with serious economic disadvantage. In addition, pediatricians participated on a voluntary basis and were likely to be highly motivated, which also constitutes a positive selection bias that may have led to underestimation of resource utilization and drug prescribing.

It is important to note that the sample was not large enough to draw conclusions about at-risk populations. Finally, we calculated costs based on official rates, which do not necessarily reflect actual costs, vary by autonomous community, and do not account for the variation between health care organizations.

Since this project was conducted in the framework of a larger prospective study in several European countries with standardized methodology, and included 8 autonomous communities with different geographical characteristics, we can extrapolate the findings to all of Spain and make comparisons with other studies. In addition, the completion rate was substantial, with high response rates in all questionnaires through day 30 of follow-up. All of this strengthens our findings and their relevance.

It is reasonable to conclude that RSV infection places a considerable economic burden on the primary care system in Spain, chiefly on account of direct health care costs due to high utilization. The high hospitalization rate and the prolonged lengths of stay are also significant. Furthermore, we identified a frequent use of medications considered ineffective for RSV infection. These findings highlight the importance of considering the economic burden beyond the hospital setting and contribute data toward the evaluation (in terms of cost-effectiveness) of effective preventive measures, such as monoclonal antibodies and the recently introduced maternal vaccination program, implemented to mitigate the impact of RSV. In Spain, there is a clear opportunity to improve the management of RSV infection, primarily in terms of health care utilization and the rational use of medications.

This study was conducted in the framework of a collaborative European project (RSV ComNet study) coordinated by the Netherlands Institute for Health Services Research (Nivel), with headquarters in Utrecht, and funded by Sanofi AstraZeneca. The study was designed and planned in collaboration with researchers from the team from Sanofi, but funders had no role in data collection, data analysis, data interpretation, writing of the report, or the decision to submit the paper for publication, which were the responsibility of the RSV ComNet coordination team (Nivel/RIVM) and local country partners. Datasets are held by Nivel and the local country partners, and are not shared with the funding parties.