Respiratory syncytial virus (RSV) causes significant morbidity, mortality and healthcare use worldwide, particularly in pre-term infants, children, the elderly and those with pre-existing conditions such as lung and heart disease. [1–5] Globally, it was estimated in 2015, in children < 5 years of age there were 33.1 million episodes of lower respiratory tract infection due to RSV, with 3.2 million RSV-related hospitalizations and 59,600 in-hospital deaths. [6] There are currently no global estimates for RSV infections in other age groups, or in those with underlying medical conditions.

The burden of RSV on the US healthcare system is not clearly established. Based on the limited available data, RSV causes 57,527–132,000 hospitalizations, 1.5–1.7 million office visits and 402,000–517,747 emergency department (ED) visits in children < 5 years of age, [1, 7, 8] and approximately 177,525 hospitalizations each year in those aged ≥65 years. [2] The estimated annual average number of deaths from RSV in the US between 1997 and 2009 was 11,300, [9] with a substantial number in those aged < 5 years and those ≥65 years. [9, 10]

RSV may also increase use of healthcare utilizations through longer-term effects including recurrent wheezing and new diagnosis of asthma, exacerbation of underlying illnesses such as cardiopulmonary conditions and deaths. [2, 11–15]

Given the high burden of RSV, particularly in the young and elderly, and the associated healthcare utilization with infection, it is expected for RSV to lead to substantial healthcare costs. The currently available evidence for RSV-attributable costs is limited by a lack of a control group in many of the studies, and so the impact of RSV on healthcare burden is not clearly defined. In addition, many of these studies in the US focus on infants alone [7, 16–24] and little is known of the impact of RSV for those who are older, such as young children aged between 1 and 4 years and the elderly. [2, 25]

Recent advances in the development of RSV vaccines and monoclonal antibody indicates that the prevention of RSV will likely to be available in the next few years. [26] Understanding healthcare utilization and costs associated with RSV is therefore essential for guiding the implementation of new vaccines and monoclonal antibodies against RSV in various age groups and high-risk populations. [27] The aim of this study was to provide the most recent and comprehensive data on the economic burden of RSV across all ages in the US.

This is the first comprehensive study of annual healthcare resource use and costs in those with RSV across multiple age groups in the US. Through the use of matched control patients without RSV we were also able to estimate the incremental differences in resource use and costs between those with and without RSV. There was higher annual resource use in the RSV patients across all age groups; when compared to non-RSV matched controls, up to 29% more in the RSV group had ≥1 hospitalization, up to 27% more in the RSV group had ≥1 ED/UC visits and up to 20% more in the RSV group had ≥1 ambulatory visit. The adjusted annual costs for those with an RSV event were also higher when compared to matched controls across all age groups, with incremental differences of $2251 to $23,194. Due to the matching of RSV and non-RSV patients, which controlled for some confounding factors, we can conclude that this higher resource use and higher costs are related to RSV.

Previous studies of healthcare costs related to RSV in the US have generally focused on infants, often comparing full-term and pre-term infants. These studies highlight the higher burden of RSV in preterm infants, with annual hospitalization costs as high as $19,559 to $52,900. [16, 19, 22] In studies in infants with matched controls, those with RSV had higher rates of hospitalization, higher ED use, more ambulatory visits, more prescriptions filled and more antibiotic use. [17, 18, 22] In a study of costs in children aged < 5 years in the US, annual mean hospitalization costs in those with RSV was $4584, with total estimated medical costs of RSV of $341–449 million, with a further $258 million estimated for ambulatory care costs. [7] In our study only those ≥1 year old were included in this analysis. We were also interested in healthcare utilization and costs in infants aged < 1 year, due to the documented burden of RSV in this population, and particularly wished to explore outcomes by age subgroups (< 3 months, 3–5 months, and 6–11 months). However, among the 31,013 infants aged < 1 year with a RSV diagnosis during the 2012–2013 season, the results were not coherent and did not follow the global trend of healthcare costs. We were not able to identify the potential bias or confounding factors for these unexpected results, and so they were not included in the final analyses. One source of the potential bias may have been related to the process used to retrieve the birth date, as date of birth is not available in the MarketScan® databases; the date of the first claim with an ICD-9-CM code for birth was used as a proxy for birth date (Appendix 2), if this was not available then the first enrolment date was used when year of enrolment and birth year were the same. In the process of identifying patients for inclusion, 16.3% (n = 5054) did not have an estimable date of birth and 52.3% (n = 16,390) did not have 1 year of continuous enrollment post-index date in infants aged < 1 year. These issues might have contributed to these unexpected results, or by the step of matching controls in this group.

In studies of RSV-attributable healthcare costs in the elderly in the US, estimates have been made of annual hospitalization costs of $11,000 per hospitalization, with total costs for all elderly aged ≥65 years estimated from $150–680 million [25] to $1 billion. [2] In a study of all adults in the US, mean adjusted costs for RSV hospitalization across age groups was calculated as $38,828. [30] However, that study found the highest hospitalization costs in those aged 45–59 years, and lowest in those ≥60 years; [30] this differs to the findings in our study, where the highest resource use and costs were seen in those aged ≥65 years. Compared to those who were aged 18–49 years, in those ≥65 years, 3–5 times more patients had a hospitalization, 1–2 times more had an ED/UC visit, and twice as many had an ambulatory visit, with a higher mean number of visits for each setting and longer hospital stays. This higher resource use also translated to higher costs, with the highest adjusted annual healthcare costs seen in those with RSV who were aged 75–84 years, almost double the costs seen in those aged 18–49 years. The highest incremental difference in costs between the RSV and matched-control group was also seen in the elderly patients.

The higher resource use and costs in the RSV patients, beyond the costs directly related to the RSV event itself, may be due to the complications and long-term effects that have been suggested to result from RSV infection, such as wheezing, asthma and allergies in children [11, 17, 18, 20], and exacerbation of underlying conditions, such as pulmonary or cardiovascular diseases. [14, 20]

This study also showed a substantial increase in the number of antibiotic prescriptions in patients in the RSV group in the year after RSV infection compared to the baseline period and to those in the non-RSV matched control group. This increase in antibiotic prescriptions may have been due to the inappropriate use of antibiotics for RSV, or may be a further indication of the longer-term impact of RSV. Previous studies have also shown a high level of unnecessary antibiotic use in RSV, [12, 13, 31, 32] with estimates of excess antibiotic prescriptions in RSV of 641 per 1000 in children aged < 5 years in the US. [13] Bacteremia is rarely concurrent with RSV infections, even in those with high-risk for infection, [32, 33] and as such antibiotic use has no clinical benefit and leads to increased costs and the potential for increase in drug resistance. [31]

Generating comprehensive data on healthcare resource use and costs associated with RSV across several age groups will help to provide valuable information for the development of cost-effectiveness models, and help guide prevention strategies against RSV. Protective immunity to RSV induced by natural infection is weak and short-lived, [34, 35] and current prevention strategies are restricted to at-risk infants with repeated doses of the expensive monoclonal antibody palivizumab during the RSV season. However, the cost-effectiveness of palivizumab has not been definitively proven, with studies both for and against its cost-effectiveness. [36] Consequently, new approaches for preventing and treating RSV that are also cost-effective, particularly for at-risk groups such as infants, young children, elderly and those with underlying medical conditions, are needed. Vaccines against RSV are currently in development, with phase 2 and 3 studies ongoing for one vaccine, including for the vaccination of pregnant women in order to confer immunity to newborns. [37, 38] In addition, a late stage phase 2b trial of a highly potent monoclonal antibody, MEDI8897, in pre-term infants is expected to complete in 2018, [39] with plans for a phase 3 study in healthy full-term and late pre-term infants. Current data on RSV infections rates has allowed for modeling studies to identify children aged < 5 years as those most likely to be infected with RSV, and most likely to transmit it, [40] supporting previous suggestion that children are an important source of RSV transmission to adults, [41] consequently those aged < 5 years are the target group for future vaccination. Our data on the economic impact of RSV across age groups can be used to re-evaluate cost effectiveness of new vaccines or monoclonal antibodies, especially in the elderly age groups.

This was a large observational study of over 11,000 patients ≥1 year of age with an RSV event in the US, and with follow-up data for 12 months. This analysis, covering a wide range of ages, allowed assessment of RSV-related costs in children, adults and the elderly; utilizing age ranges chosen to focus on those age groups with the highest risk. The use of matched non-RSV controls allowed for comparison and estimates of the RSV-attributable resource use and costs, which is lacking in many other RSV costs studies. There were, however, several limitations to this analysis. ICD-9-CM codes were used to identify RSV cases and healthcare resource use and costs in the 12 month follow-up period; miscoding or misclassification or missed opportunities for RSV testing may have occurred leading to a misdiagnosis or incorrect utilization or cost to be attributed. Similarly, where a patient did not make an insurance claim the associated healthcare resource use or cost would not have been captured in the database. Some outcomes that may be relevant to this analysis, such as mortality or the severity of disease were not available. The completeness of the data on prematurity in those aged < 5 years in the databases is uncertain; prematurity was identified using ICD-9CM and additional diagnosis-related group codes (Appendix 3), however, the proportion of premature child who are not identified by these codes is unknown. The severity of prematurity was also not assessable for almost 40% of premature children in this study. Palivizumab use during hospitalization was not captured in the databases, so not all patients with palivizumab would have been excluded from the analysis. Only direct medical costs were captured in this analysis, other economic consequences such as out-of-pocket costs or loss of productivity were not included. Assessment of out-of-pocket costs in infants with RSV have been estimated to be between $214–644, with $1921–3873 estimated in lost productivity. [24] The data presented here may not be applicable to the entire US population, as this analysis is based on a commercially insured population.

This study presents the annual healthcare resource use and costs of RSV in the US across age groups, highlighting the particular burden in those aged ≥65 years. These data confirm the significant healthcare burden of RSV and need for the prevention of RSV to be a high priority across age groups, and that additional safe and effective preventative measures are required.