Introduction

Respiratory syncytial virus (RSV) is a leading cause of hospitalization among infants, and is associated with acute lower respiratory tract infections (LRTI) such as bronchiolitis and pneumonia [1–3]. RSV infection among US children younger than 1 year is still associated with approximately 100 deaths annually, posing a greater risk to them than influenza [4]. Acute LRTI remains a significant cause of morbidity and mortality in children under the age of five globally, accounting for approximately 10% of inpatient hospital admissions [5,6]. In the United States, the rate of RSV-associated hospitalizations (RSVH) has been estimated at 19.4 per 1,000 infants annually, with approximately 80,000 RSV hospitalizations occurring within the first six months of life in 2020 [7,8].

Certain subgroups of children, including preterm infants, those with congenital heart disease (CHD), and those with chronic lung disease (CLD) of prematurity, are at greatest risk of developing severe RSV and associated complications [9]. Preterm infants have higher RSV hospitalization rates compared to full-term infants [10]. Similarly, children with CLD of prematurity have increased odds of RSVH, while hospitalizations associated with congenital heart disease (CHD) remain considerable [11,12]. However, approximately 75% of hospitalization occur in healthy term infants [13–15]. Newborns and infants less than six weeks old face a higher risk of complications resulting from RSV infection. These complications can manifest in various developmental, cardiac, clinical, and dermatological issues [1]. Bronchiolitis and pneumonia are the most common manifestations of RSV LRTIs, often accompanied by complications such as cough and chest wall hyper-expansion [9,16–19]. Severe cases of LRTI can result in respiratory failure, necessitating admission to the intensive care unit (ICU) and ventilation support [18].

Preventing RSV LRTI in infants is crucial in order to prevent consequent health complications [20]. RSVH and associated chronic conditions are associated with increased healthcare costs, primarily due to higher service utilization [21,22]. The financial burden of RSV hospitalizations is substantial: each hospitalization costs $12,000, on average, and contributes to an annual aggregate cost of $472 million in the United States in 2020, a majority of which is financed by Medicaid [21]. Furthermore, a significant proportion of total RSV-related costs is attributed to hospitalizations, particularly to associated ICU admissions and mechanical ventilation utilization [23]. In addition to the economic impact, RSV episodes also result in a reduction in quality of life, with an estimated loss of 6.17 net quality-adjusted life days per episode in the first 60 days of life [24]. Until 2023, upon the introduction of nirsevimab-alip [25], no universally effective treatments or vaccines for RSV existed. Targeted prevention options such as palivizumab and ribavirin were restricted to specific high-risk populations [7,9,26].

Acute LRTI is known to be a leading cause of child mortality in the US—3% to 14% of cases necessitate ICU admission—and infants younger than 1 year experience the highest rates of severe infection [27] Nonetheless, an incomplete picture of service utilization during infant RSVH prevails. To fill this gap, our primary objectives were to describe inpatient service utilization and death associated with RSV LRTI hospitalizations in three large insurance claims databases. Specifically, we aimed to estimate the proportion of hospitalizations involving ICU admission, supplemental oxygen use (in-hospital and post-discharge), mechanical ventilation (invasive and non-invasive), and extracorporeal membrane oxygenation (ECMO), and in-hospital mortality, as well as the length of inpatient stay, and number of days spent in the ICU.

Methods

Results

Characteristics of infants hospitalized with respiratory syncytial virus

Under the specific RSV index diagnosis definition, we identified 5,811 hospitalizations in the CCAE database, 13,668 in the MDCD database, and 2,926 in the CDM database, for a total of 22,405 infant hospitalizations. These numbers correspond to approximately 1.3% of infants who were observed through their first RSV season in our prior study [32] having experienced an RSV-related hospitalization. Utilizing the sensitive RSV index diagnosis definition, we identified 8,807 such hospitalizations in the CCAE database, 22,081 in the MDCD database, and 3,621 in the CDM database, respectively. Across index diagnosis definitions and databases, we observed that a higher proportion of hospitalized infants were male, ranging from 55% to 59%, and born at the end of the calendar year (between September and December). Approximately 62%–71% of infants were categorized as healthy full-term infants (Group A), while 6%–11% were considered eligible for palivizumab treatment (Group B), and 23%–27% were identified as having other underlying health conditions (Group C). Census division and payer type varied by commercial database (CCAE versus CDM). Further details about the sample characteristics can be found in Table 1.

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Table 1. Sample characteristics among infants’ first RSV-associated hospitalization during their first RSV season, stratified by RSV index diagnosis definition.

https://doi.org/10.1371/journal.pone.0317367.t001

Outcomes, procedures, and services

Around one-quarter of infants (20.7%–27.2%) were admitted to the ICU, with chest imaging (33.9%–38.1%) and supplemental oxygen (14.7%–15.7%) being the most commonly administered procedures, as detailed in Table 2. The occurrence of ECMO usage or in-hospital mortality was less than one percent. Invasive and non-invasive mechanical ventilation were infrequent, with the highest estimated risk across claims databases and RSV index diagnosis definitions being 3.7% (see Discussion for important context regarding this finding). Following hospital discharge, between 1.5% and 4.9% of infants received supplemental oxygen. The healthcare services provided to infants hospitalized during their first RSV episode within their initial RSV season were generally consistent across databases and did not show significant variation based on the RSV index diagnosis definition.

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Table 2. Proportion of RSV-associated hospitalizations involving a given service/procedure or death, by MA RSV LRTI index diagnosis definition.

https://doi.org/10.1371/journal.pone.0317367.t002

Length of inpatient stay

Infants had hospital stays with median durations of 3–4 days regardless of insurance claims database or RSV index diagnosis definition (Table 3). Interquartile range widths varied from 2 to 5 days for CCAE and MDCD, and from 3 to 6 days for CDM. When infants had an ICU admission, their median inpatient stay was extended by 2–3 days compared to hospitalizations without ICU admission. Among hospitalizations that included an ICU stay, infants spent a median of 4–6 days receiving intensive care, as detailed in Table 3.

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Table 3. Distributions of length of inpatient stay and number of days spent in the intensive care unit (ICU), by MA RSV LRTI index diagnosis definition.

https://doi.org/10.1371/journal.pone.0317367.t003

Variation by comorbidity group

Palivizumab-eligible infants in comorbidity group B exhibited the highest risks of chest imaging, ICU admission, and post-discharge supplemental oxygen (Fig 1). Infants with other comorbidities (group C) also showed increased chest imaging and ICU utilization. All infants had similar in-hospital supplemental oxygen use (numerical values are provided in the supplemental code repository but suppressed in Fig 1 due to suspected underascertainment in claims; see Discussion). The proportion of infants’ utilization healthcare services varied by comorbidity group, with palivizumab-eligible infants and infants with other comorbidities utilizing services more frequently (Fig 1). Palivizumab-eligible infants had the longest average length of stay, especially when ICU admission was involved, and they spent more time in the ICU (Fig 2).

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Fig 1. Select primary binary outcomes by comorbidity group.

Note that y-axis differs for each panel, as informed by the data range. Color scale refers to infant comorbidity groups. Mechanical ventilation and in-hospital supplemental oxygen use are omitted due to likely data quality issues (see Discussion), while in-hospital death and extracorporeal membrane oxygenation are omitted due to the potential to derive small cell sizes in the Clinformatics data. CCAE, Merative MarketScan Commercial Claim and Encounters Database; MDCD, Multi-State Marketscan Medicaid; CDM, Optum’s de-identified Clinformatics® Data Mart Database.

https://doi.org/10.1371/journal.pone.0317367.g001

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Fig 2. Primary continuous outcomes by comorbidity group.

95% confidence intervals calculated using the non-parametric bootstrap percentile method (R = 9,999 replicates). Colors refer to infant comorbidity groups. CCAE, MarketScan Commercial Claims and Encounters; MDCD, MarketScan Multi-State Medicaid; CDM, Optum’s de-identified Clinformatics® Data Mart Database; RSV, respiratory syncytial virus; LRTI, lower respiratory tract infection; LOS, length of inpatient stay; ICU, intensive care unit.

https://doi.org/10.1371/journal.pone.0317367.g002

Discussion

In this study, we sought to understand the patterns of service utilization during RSVH in infants, utilizing three large insurance claims databases representing both privately and publicly insured infants in the U.S. Our findings indicate consistent RSV-related inpatient service utilization patterns across all three insurance claim databases we analyzed. Notably, a higher proportion of hospitalized infants were male, and a significant number were born between September and December. These findings corroborate existing knowledge, underlining RSV’s status as a seasonal respiratory pathogen with a predilection for affecting male infants [13,33]. RSV hospitalizations are not confined to high-risk groups, as a considerable number also occur among healthy term infants. This finding underscores the widespread impact of RSV across infant subgroups with varying comorbidity profiles. This finding could highlight the need for broader RSV therapeutic strategies, as these healthy infants, though less frequently hospitalized, represent a large segment of the affected population [33]. Simultaneously, a substantial portion of infants who were not otherwise eligible for palivizumab prophylaxis had other comorbidities that could increase the complexity of their care and the potential for adverse outcomes [34].

Our study found that approximately one-quarter of infants were admitted to the ICU during their first RSV-related hospitalization during their first RSV season. In-hospital mortality was rare, occurring in only 0.1%–0.2% of cases. Chest imaging (33.9–38.1%), ECMO use (<0.1–0.2%), supplemental oxygen (14.7–15.7%) administration, and mechanical ventilation (3.7%) were low, despite bronchiolitis guidelines [35]. We emphasize, though, that the accuracy of recorded mechanical ventilation and supplemental oxygen use in insurance claims data might be low, especially for ICU stays shorter than a day. If true, one potential explanation might be that billing for extra procedures necessitates the infant spend a minimum amount of time in the ICU, with billing usually starting on the second day after ICU admission. Conceivably, mechanical ventilation use in an infant requiring it for only a brief period (e.g., less than 24 hours) might not be captured if the infant’s stay in the ICU is brief and the child is transferred to a high-dependency unit or even to the general ward. The contrast between our estimated levels of mechanical ventilation use and those of studies which ascertained ventilation using medical record review also suggests that insurance claims may be inadequate for this purpose. For example, Halasa et al. reviewed medical records to identify mechanical ventilation use in 39 pediatric hospitals across 27 US states and reported that 24% of RSV-hospitalized infants received invasive mechanical ventilation, 25% received non-invasive mechanical ventilation, and 51% received low-flow supplemental oxygen, high-flow nasal cannula oxygen, or continuous positive airway pressure as their highest level of oxygen support [36].

Two other recent studies show evidence of reduced ascertainment of ventilation and/or supplemental oxygen use more broadly in payment claims. Lade et al. found that approximately 6% of infants hospitalized for RSV in Germany required ventilation of any kind (inclusive of oxygen support) [37], while Han et al. estimated that around 2% of infants hospitalized for RSV in South Korea needed mechanical ventilation [38]. Direct quantitative comparisons of this sort may be difficult to interpret given the differing patient mixes, time periods, environments, and operational service definitions reflected across analyses, including ours. Taken together, these results nonetheless seem to support our assertion regarding the limitations of payment claims in this context. Arriola et al., however, reported that 27% of hospitalized children younger than 2 were admitted to the ICU in a subset of FluSurv-NET hospitals, and that 6% received mechanical ventilation [14]. This estimate of mechanical ventilation use was based on clinical records [14,39] and appears to be in line with claims-based estimates. It is worth noting, too, that our estimated proportion of ECMO use may represent a slight underestimate. Recent analyses using the Pediatric Health Information System (PHIS) database [40] observed higher rates of hospitalizations and advanced respiratory support needs post-pandemic, with 70% more children requiring high-flow nasal cannula or noninvasive ventilation, suggesting a broader rise in severe RSV cases requiring intensive care at hospitals offering advanced respiratory services.

The length of inpatient stay for RSV hospitalizations in our study is consistent with the literature, which suggests that the severity of illness and the need for ICU care prolonged hospital stays [41]. Palivizumab-eligible infants had notably longer average lengths of stay, especially when ICU care was required, signifying the heightened complexity of their clinical course and the challenges in managing this high-risk population [42]. Our data also shed light on the variation in healthcare experiences among different comorbidity groups. Palivizumab-eligible infants (comorbidity group B) and infants with other comorbidities (comorbidity group C) faced distinct healthcare challenges, and both experienced elevated risks. Palivizumab-eligible infants had higher utilization of healthcare services, longer lengths of stay, and more days spent in the ICU, highlighting the importance of targeted interventions and close monitoring for high-risk infant populations.

The uniformity in the risk of infants requiring supplemental oxygen, regardless of their comorbidity group, emerges as a salient finding, with a notable emphasis that, while higher-risk infants in Group B are a focus of concern, it is the numerically larger Group A—healthy term infants—that contributes substantially to the overall burden of disease. The discrepancy between the supplemental oxygen use reported in claims datasets (around 15%) and retrospective clinical studies (approximately 70%) indicates a significant under ascertainment of this outcome in our data, suggesting caution when comparing its use across different infant comorbidity profiles [43]. Existing research also emphasizes the significance of effective respiratory support in pediatric patients affected by RSV infections [1]. Furthermore, this consistency may be attributed to the fact that RSV infections primarily manifest as respiratory distress, transcending differences in underlying health conditions [44,45]. While infants with diverse comorbidity profiles may face distinct healthcare challenges and outcomes, the uniformity in supplemental oxygen utilization across claims databases highlights its importance in addressing respiratory distress during RSV episodes. These findings should prompt a deeper exploration of the specific determinants influencing the need for supplemental oxygen across varying clinical contexts. Such investigations could potentially inform tailored approaches to optimize the care and outcomes of RSV-infected infants.

Our study has several limitations. First, the data originate from administrative databases and the use of payment claims data may result in measurement bias and the under ascertainment of some outcomes, such as mechanical ventilation [46–48]. The incidence of oxygen supplementation and mechanical ventilation is relatively infrequent in our study, so it is imperative to consider the possible existence of alternative support (such as heated humidified high-flow therapy) as well as the potential nuances in how these alternatives are reflected in the claims data. Second, the gestational ages of infants, as well as their comorbidity diagnoses, are also subject to misclassification in the claims data we used. Third, it’s plausible that certain infants were incorrectly excluded from our analysis. We identified RSV-related hospitalizations based on the presence of ICD-10-CM diagnosis codes on inpatient medical claims rather than relying on RSV laboratory tests (which are available only for small subsets of infants). This methodology may have led to some misclassification of RSV-related hospitalizations or misattribution of services to an RSV-related hospitalization. We also expect that diagnoses made for the purpose of claims payment might miss RSV-related hospitalizations altogether, so our sample of hospitalizations may not be representative of all RSV-related hospitalizations. We do not feel licensed to speculate, however, about whether our sample would lead us to over- or underestimate inpatient service utilization and length of stay. Finally, though difficult to speculate about their exact nature, differing healthcare and/or coding practices between databases could complicate interpretation of our findings, given observed differences in Census division and payer type between databases. Such inconsistencies could either mask or exaggerate differences in service utilization patterns across the infant populations represented by each database. Our findings also may fail to generalize to populations not covered by the insurance data (e.g., uninsured persons), who might exhibit risk factors or service utilization patterns unlike those captured in commercial and Medicaid claims. Moreover, classifying infants into comorbidity groups may ignore the full spectrum of clinical complexity, and potential variations in coding practices between institutions are not reflected in our results.

Despite these limitations, our findings underscore the need to reduce RSV-related hospitalizations. Future work should attempt to quantify the potential for emerging preventive strategies such as nirsevimab [49] and maternal RSV vaccination [50], both of which aim to protect infants across the comorbidity spectrum, to reduce the severity and cost of RSV hospitalization. Improved access to prevention and healthcare among underserved populations could further enhance these health- and cost-related benefits. Furthermore, the limitations of insurance claims discussed in this section should motivate efforts to improve ascertainment of key outcomes, such as mechanical ventilation, either via targeted data collection or observational data sources (e.g., electronic medical records) that identify services of interest explicitly.

Conclusion

In conclusion, our study illustrates healthcare utilization and mortality among infants hospitalized with RSV during their first RSV season. Our findings emphasize the substantial healthcare burden of RSV infections, particularly among high-risk infants. These results have implications for healthcare resource allocation (at the local and systems level), the development of preventive care strategies for RSV, and the need for ongoing research to better understand the epidemiology and clinical course of RSV in infants. Further studies with more comprehensive data sources, explicit identification of healthcare service or procure receipt, and larger sample sizes (particularly for palivizumab-eligible infants) are warranted to refine the understanding of RSV and inform evidence-based interventions.

Supporting information

Acknowledgments

We thank David Diakun for programming support in the Merative analyses and Sarah Naeger for comments regarding capture of mechanical ventilation outcomes in claims.