ABSTRACT
Background
Since the onset of the coronavirus disease (COVID‐19) pandemic, changes in the severity of respiratory syncytial virus (RSV) infection have been reported in Japan. However, few studies have compared the severity of RSV infection before and after the COVID‐19 pandemic. This study aimed to compare the severity of RSV infection before and after the COVID‐19 pandemic in two pediatric hospitals in Hanshin in Hyogo Prefecture, Japan.
Methods
This retrospective study included patients aged ≤ 15 years hospitalized with RSV infection in Hyogo Prefectural Amagasaki General Medical Center and Hyogo Prefectural Kobe Children's Hospital between January 1, 2019, and July 31, 2023. Patient characteristics during the pre‐pandemic (January to December 2019), pandemic (January 2020 to December 2022), and post‐pandemic (January to July 2023) periods were compared.
Results
The pediatric intensive care unit (PICU) admission rate was significantly higher during the post‐pandemic period (26.1%) than during the pre‐pandemic period (13.6%) (p < 0.001). The proportion of patients who received any form of respiratory support (tracheal intubation, noninvasive positive‐pressure ventilation, or high‐flow nasal cannula) was significantly higher during the post‐pandemic period (26.9%) than during the pre‐pandemic period (16.1%) (unadjusted odds ratio: 1.92, 95% confidence interval: 1.23–3.04; p = 0.005).
Conclusions
In children hospitalized with RSV infection, the PICU admission rate and respiratory support requirements were significantly higher during the post‐pandemic period than during the pre‐pandemic and pandemic periods. Ongoing monitoring of clinical severity is needed to ensure effective prevention of RSV infection and optimal medical resource allocation.
Keywords: COVID‐19 pandemic, Hyogo prefecture, Pediatric intensive care unit, respiratory support, respiratory syncytial virus infection
1. Introduction
Respiratory syncytial virus (RSV) infection is an acute respiratory infection that primarily affects children under 2 years of age [1]. Although at least 50% of infants become infected during their first year of life and nearly 100% by their second year, life‐long immunity is not achieved. In infants, approximately 50% of pneumonia and 50%–90% of bronchiolitis cases are due to RSV [2]. Prematurely born infants, young infants, and those with underlying conditions such as hemodynamically significant congenital heart disease, chronic lung disease, chromosomal abnormalities (such as Down syndrome), neuromuscular disease, and immunodeficiency are at an increased risk of severe illness [3, 4], sometimes requiring intensive care with high‐flow oxygen therapy or positive pressure ventilation. While treatment for RSV infection is primarily supportive, such as oxygen administration or infusion therapy [5], high‐risk infants may receive prophylactic treatment with palivizumab or nirsevimab, which are humanized monoclonal antibodies against the RSV F protein [6, 7].
During the coronavirus disease (COVID‐19) pandemic, a dramatic reduction in the incidence of RSV infection and a shift in the seasonality were reported in multiple countries, including Israel, Australia, South Africa, New Zealand, France, United States, and Japan [8].
Few studies have directly compared RSV infection trends and severity rates before and after the COVID‐19 pandemic in Japan. Understanding these trends is crucial for anticipating future RSV outbreaks and estimating potential disease severity. Therefore, this study aimed to compare the characteristics of patients hospitalized with RSV infection during the pre‐pandemic, pandemic, and post‐pandemic periods.
2. Methods
2.1. Study Design and Participants
This two‐center retrospective cohort study was conducted using electronic medical records of children aged 15 years or younger who were diagnosed with an RSV infection and hospitalized at Hyogo Prefectural Amagasaki General Medical Center or Hyogo Prefectural Kobe Children's Hospital between January 1, 2019, and July 31, 2023. RSV infection was defined as having a positive result on a rapid antigen test or respiratory polymerase chain reaction panel. No specific exclusion criteria were applied.
Data on the admission date, age, sex, presence of underlying diseases, length of hospital stay, pediatric intensive care unit (PICU) admission, length of PICU stay, and treatment modality were extracted. The study cohort was divided into three groups according to the admission date: pre‐pandemic (January 1 to December 31, 2019), pandemic (January 1, 2020, to December 31, 2022), and post‐pandemic (January 1 to July 31, 2023). We compared the characteristics and outcomes of children hospitalized in the post‐pandemic period with those of children hospitalized in the pre‐pandemic period.
Patients with underlying diseases were defined as children with any of the following conditions: a preterm birth (before 36 gestational weeks), chronic lung disease, congenital heart disease with abnormal hemodynamics, Down syndrome, or immunodeficiency, according to the Consensus Guidelines for the Use of Palivizumab in Infants and Young Children with Congenital Heart Disease (JSPCCS 2019) [9]. The need for respiratory support was defined according to the most intensive respiratory treatment method used during hospitalization, including tracheal intubation, noninvasive positive pressure ventilation (NPPV), and oxygen administered via a high‐flow nasal cannula (HFNC).
Data on co‐infections with other viruses were not systematically collected and therefore not included in the analysis.
Since no significant data were missing, a complete case analysis was applied.
2.2. Statistical Analysis
Patient characteristics are summarized as frequencies and proportions for categorical variables, and the median and interquartile range (IQR) for continuous variables according to the period. Variables were compared between pre‐ and post‐pandemic periods using Fisher's exact test for categorical variables and Welch's t‐test for continuous variables.
Univariate logistic regression analysis was performed to evaluate differences in the risk of PICU admission and respiratory support requirements between the post‐ and pre‐pandemic periods, treating the period as the exposure variable. Additionally, multivariable logistic regression was used to adjust for potential confounders including age group, sex, and the presence of underlying diseases.
A linear regression analysis was performed to evaluate the differences in the length of PICU stay in the pre‐COVID‐19 period compared with the post‐COVID‐19 period. A multivariable logistic regression analysis was performed to identify factors associated with PICU admission.
Two‐sided p values < 0.05 were considered statistically significant. Statistical analyses were performed using R version 4.3.1.
2.3. Ethical Considerations
This study was approved by the Ethics Committee of Hyogo Prefectural Amagasaki General Medical Center (approval number: 6203) and the Ethics Committee of Hyogo Prefectural Kobe Children's Hospital (approval number: R7‐122). The requirement for informed consent was waived by both committees owing to the retrospective nature of the study and the use of anonymized data.
3. Results
3.1. Patient Characteristics
In total, 942 children were hospitalized with RSV infection during the three periods, of whom 495 were admitted to Hyogo Prefectural Amagasaki General Medical Center and 447 were admitted to Hyogo Prefectural Kobe Children's Hospital. The number of admissions for both hospitals combined was 236 in 2019, 12 in 2020, 262 in 2021, 198 in 2022, and 234 in 2023; therefore, 236, 472, and 234 patients were admitted during the pre‐pandemic, pandemic, and post‐pandemic periods, respectively.
The median age [IQR] was higher during the pandemic period (14 [2–27] months) than during the pre‐pandemic (9 [2–19] months) and post‐pandemic periods (8 [2–22] months; Table 1). The majority (54.7%, 258/472) of patients admitted during the pandemic period were aged 12 months or older. The prevalence of underlying diseases was higher during the post‐pandemic period (21.4%, 50/234) than during the pre‐pandemic (7.2%, 17/236) and pandemic periods (6.6%, 31/472; Table 1).
TABLE 1.
Patient characteristics according to the period.
| Characteristic | Period | ||
|---|---|---|---|
| Pre‐pandemic (N = 236) | Pandemic (N = 472) | Post‐pandemic (N = 234) | |
| Age (months), median (IQR) | 9 (2–19) | 14 (2–27) | 8 (2–22) |
| Age group, n (%) | |||
| < 3 months | 69 (29.2) | 131 (27.8) | 74 (31.6) |
| 3–11 months | 68 (28.8) | 83 (17.6) | 61 (26.1) |
| ≧ 12 months | 99 (41.9) | 258 (54.7) | 99 (42.3) |
| Sex, n (%) | |||
| Male | 137 (58.1) | 262 (55.5) | 127 (54.3) |
| Female | 99 (41.9) | 210 (44.5) | 107 (45.7) |
| Underlying disease, n (%) | |||
| Absent | 219 (92.8) | 441 (93.4) | 184 (78.6) |
| Present | 17 (7.2) | 31 (6.6) | 50 (21.4) |
3.2. Outcomes
The primary and secondary outcomes related to severity are shown according to the period in Table 2. The proportion of patients who required PICU admission was significantly higher (26.1%, 61/234) during the post‐pandemic period than during the pre‐pandemic (13.6%, 32/236) and pandemic (12.9%, 61/472) periods (p < 0.001). The median (IQR) length of PICU stay was longer during the pre‐pandemic period (7 [4–10] days) than during the pandemic (5 [3–9] days) and post‐pandemic (6 [4–10] days) periods (Table 2), but the difference between the pre‐ and post‐pandemic periods was not statistically significant (p = 0.68; Table 3).
TABLE 2.
Incidence of primary and secondary outcomes according to the period.
| Period | |||
|---|---|---|---|
| Pre‐pandemic (N = 236) | Pandemic (N = 472) | Post‐pandemic (N = 234) | |
| PICU admission, n (%) | 32 (13.6) | 61 (12.9) | 61 (26.1) |
| Length of PICU stay a (days), median (IQR) | 7 (4–10) | 5 (3–9) | 6 (4–10) |
| Respiratory support b , n (%) | 38 (16.1) | 60 (12.7) | 63 (26.9) |
| Tracheal intubation | 15 (6.4) | 32 (6.8) | 28 (12.0) |
| NPPV | 10 (4.2) | 5 (1.1) | 8 (3.4) |
| HFNC | 13 (5.5) | 23 (4.9) | 27 (11.5) |
| Oxygen use, n (%) | 188 (79.7) | 341 (72.2) | 187 (79.9) |
The analysis is restricted to patients admitted to the PICU.
Respiratory support: tracheal intubation, NPPV, or HFNC. HFNC, high‐flow nasal cannula; IQR, interquartile range; NPPV, noninvasive positive‐pressure ventilation; PICU, pediatric intensive care unit.
TABLE 3.
Outcomes during the post‐pandemic period compared with those during the pre‐pandemic period.
| uOR or β | 95% CI | p | |
|---|---|---|---|
| PICU admission | 2.25 | 1.41 to 3.64 | < 0.001 |
| Length of PICU stay a (days) | 1.00 | −3.80 to 5.80 | 0.68 |
| Respiratory support | 1.92 | 1.23 to 3.04 | 0.005 |
| Tracheal intubation | 2.00 | 1.05 to 3.95 | 0.038 |
| NPPV | 0.80 | 0.30 to 2.06 | 0.64 |
| HFNC | 2.24 | 1.14 to 4.59 | 0.022 |
| Oxygen use | 1.02 | 0.65 to 1.60 | 0.95 |
Note: uOR was used for binary outcomes, and β was used for length of PICU stay.
Abbreviations: CI, confidence interval; HFNC, high‐flow nasal cannula; NPPV, noninvasive positive pressure ventilation; PICU, pediatric intensive care unit; uOR, unadjusted odds ratio; β, regression coefficient.
The analysis is restricted to patients admitted to the PICU.
3.3. Respiratory Support
The proportion of patients who received any form of respiratory support (invasive mechanical ventilation, NPPV, or HFNC) was higher during the post‐pandemic period (26.9%, 63/234) than during the pre‐pandemic period (16.1%, 38/236) and pandemic period (12.7%, 60/472; Table 2) and was significantly higher during the post‐pandemic period than during the pre‐pandemic period (p = 0.005; Table 3).
The use of tracheal intubation was more frequent during the post‐pandemic period (12.0%, 28/234) than during the pre‐pandemic (6.4%, 15/236) and pandemic periods (6.8%, 32/472; Table 2). Furthermore, its use was significantly more frequent during the post‐pandemic period than during the pre‐pandemic period (p = 0.038; Table 3). The rate of HFNC use was also significantly higher during the post‐pandemic period (11.5%, 27/234) than during the pre‐pandemic (5.5%, 13/236; p = 0.022); the corresponding rate during the pandemic period was 4.9% (23/472). Conversely, the rate of NPPV use did not differ significantly between the pre‐pandemic period (4.2%, 10/236) and the post‐pandemic period (3.4%, 8/234; p = 0.64; Table 2); the corresponding rate during the pandemic period was 1.1% (5/472).
The proportion of patients requiring oxygen supplementation, which included all forms of respiratory support as well as low‐flow oxygen therapy, was higher during the pre‐pandemic (79.7%, 188/236) and post‐pandemic periods (79.9%, 187/234) than during the pandemic period (72.2%, 341/472), with no significant difference between the pre‐ and post‐pandemic periods (p = 0.95).
3.4. Multivariable Analysis of Factors Associated With PICU Admission
Multivariable logistic regression analysis of factors associated with PICU admission (Table 4) showed that the post‐pandemic period was independently associated with PICU admission compared with the pre‐pandemic period (adjusted odds ratio [aOR]: 2.03, 95% confidence interval [CI]: 1.25–3.34; p = 0.005).
TABLE 4.
Multivariable a logistic regression analysis of factors associated with PICU admission.
| aOR | 95% CI | p | |
|---|---|---|---|
| Period | |||
| Pre‐pandemic | Ref. | ||
| Post‐pandemic | 2.03 | 1.25 to 3.34 | 0.005 |
| Age group | |||
| < 12 months | Ref. | ||
| ≥ 12 months | 0.41 | 0.24 to 0.69 | < 0.001 |
| Underlying disease | |||
| Absent | Ref. | ||
| Present | 2.44 | 1.30 to 4.51 | 0.005 |
| Sex | |||
| Male | Ref. | ||
| Female | 0.98 | 0.61 to 1.57 | 0.93 |
Abbreviations: aOR, adjusted odds ratio; CI, confidence interval; PICU, pediatric intensive care unit.
Each variable is adjusted for the other variables in the model.
4. Discussion
This study demonstrated a marked increase in RSV severity in 2023, with significantly higher PICU admission and respiratory support rates compared with those in 2019. In addition, the use of invasive ventilation and HFNC was higher in the post‐pandemic period. Our 2023 data covered January through July, encompassing the peak RSV activity in our region. Although late‐season cases were not included, we believe these data represent the majority of severe RSV cases in 2023.
During the pandemic period (2020–2022), the median age of hospitalized patients was higher than that in the pre‐ and post‐pandemic periods, likely reflecting delayed primary infection among older children owing to reduced RSV circulation. However, this increase in age was not associated with higher severity, in contrast to the marked increase observed in 2023.
Another notable finding was the higher prevalence of underlying conditions among patients in 2023 compared with 2019 and 2020–2022. This may reflect delayed exposure among high‐risk children who were protected during the pandemic through reduced social contact or prophylaxis. In addition, the shift in RSV seasonality may have disrupted the timing of palivizumab administration, leaving some vulnerable infants unprotected at critical times. However, our multivariable analysis showed that even after adjusting for age and comorbidities, hospitalization in the post‐pandemic period remained an independent risk factor for PICU admission (aOR: 2.03, 95% CI: 1.25–3.34; p = 0.005). These findings suggest that the increased severity may not be fully explained by measured patient characteristics alone and could reflect broader post‐pandemic epidemiological changes.
Several hypotheses may help explain this epidemiological shift. The “immune debt” hypothesis suggests that prolonged lack of exposure to RSV during the pandemic increased the proportion of immunologically susceptible children [10, 11]. An alternative “immunity theft” hypothesis proposes that severe acute respiratory syndrome coronavirus 2 infection may have impaired host immunity to other pathogens [12]. In addition, shifts in RSV seasonality may have reduced the effectiveness of prophylaxis programs, and increased RSV testing or changes in healthcare‐seeking behavior could also have contributed to the observed increase in severe cases [13].
International studies support our findings. Research from the United Kingdom, Canada, the United States, and Denmark reported increased hospitalization and ICU admission rates for pediatric RSV infections after the COVID‐19 pandemic [14, 15, 16, 17]. A multicenter study in Japan by Ozeki et al. similarly reported a shift in RSV seasonality and an increase in the age at infection during the pandemic [18]. Together, these studies suggest that the pandemic had broad and lasting effects on RSV epidemiology and severity worldwide.
Although viral mutations can sometimes contribute to increased severity, as observed with severe acute respiratory syndrome coronavirus 2 variants, a study of RSV strains circulating in the United States during the period 2021–2023 found that they were largely similar to those observed during the period preceding the COVID‐19 pandemic. Therefore, the increased severity of RSV infections might not be attributed to the emergence of new RSV mutations [19].
Taken together, our results suggest that the post‐pandemic increase in RSV severity reflects not only shifts in patient demographics but also broader epidemiological changes. Ongoing monitoring of RSV epidemiological patterns and clinical severity is essential for guiding prophylaxis strategies, optimizing medical resource allocation, and preparing for future epidemics.
4.1. Strengths
Strengths of this study include its two‐center design comprising two hospitals that serve as the main pediatric intensive care centers in the Hanshin area. Another strength is the use of a multivariable analysis that adjusted for age and the presence of underlying diseases when comparing the severity before and after the COVID‐19 pandemic. This study contributes to the understanding of changes in clinical severity of pediatric RSV infections after the COVID‐19 pandemic compared with before the pandemic, potentially aiding in predicting future severity, bed control in each facility, and determining the timing of palivizumab administration.
4.2. Limitations
This study has some limitations. Although the methodology was retrospective, changes in treatment policies and healthcare‐seeking behaviors before and after the COVID‐19 pandemic may have influenced the results. In addition, the potential impact of co‐infections was not assessed, which may have confounded the severity measures.
Furthermore, although this was a multicenter study, both hospitals were located within Hyogo Prefecture, which may have limited the generalizability of the findings to other regions. RSV outbreak patterns and palivizumab administration coverage vary by region. Finally, only partial 2023 data (through July) were available; however, this period included the peak RSV activity in our region.
5. Conclusion
The PICU admission and respiratory support rates were significantly higher during the post‐pandemic period than during the pre‐pandemic period. In addition, the rates of tracheal intubation and HFNC use were significantly higher during the post‐pandemic period than during the pre‐pandemic period. This study highlights the importance of monitoring RSV epidemiological patterns and trends in clinical severity to ensure effective prevention of RSV infection and strategic allocation of medical resources.
Author Contributions
K.F., K.K., T.H. and Y.I. designed the study; K.F. and H.U. collected and analyzed data; K.F., K.K. and Y.I. wrote the manuscript; K.K., Y.I., C.M., and M.K. gave technical support and conceptual advice. All authors read and approved the final manuscript.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgments
The authors would like to thank Dr. Hiroshi Kurosawa of Hyogo Prefectural Kobe Children's Hospital for providing access to the patient data.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.