{'fraction_non_alphanumeric': 0.034650905060953086, 'fraction_numerical': 0.03280384189139269, 'mean_word_length': 4.9867315347191505, 'pattern_counts': {'":': 0, '<': 3, '<?xml version=': 0, '>': 0, 'https://': 1, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Hospitalization rate of respiratory syncytial virus‐associated acute lower respiratory infection among young children in Suzhou, China, 2010–2014

Abstract Background There is a limited amount of data in China on the disease burden of respiratory syncytial virus‐ (RSV) associated acute lower respiratory infection (ALRI) among young children. This study aimed to estimate the hospitalization rate of RSV‐associated ALRI (RSV‐ALRI) among children aged 0–59 months in Suzhou, China. Methods All cases from children hospitalized with ALRI who were aged 0–59 months in Suzhou University Affiliated Children's Hospital during January 2010 to December 2014 were retrospectively identified. Detailed diagnosis and treatment data were collected by reviewing each individual's medical chart. In accordance with the World Health Organization (WHO) influenza disease burden estimation, the hospitalization rate of RSV‐ALRI among children aged 0–59 months in Suzhou, China, was then estimated. Results Out of the 28,209 ALRI cases, 19,317 (68.5%) were tested for RSV, of which the RSV positive proportion was 21.3% (4107/19,317). The average hospitalization rate of RSV‐ALRI for children aged 0–59 months was 14 (95% confidence interval [CI]:14–14)/1000 children years, and that for children aged 0–5, 6–11, 12–23, and 24–59 months were 70 (95% CI: 67–73), 31 (95% CI: 29–33), 11 (95% CI: 10–12), and 3 (95% CI: 3–3)/1000 children years, respectively. Conclusion A considerable degree of RSV‐ALRI hospitalization exists among children aged 0–59 months, particularly in those under 1 year of age. Therefore, an effective monoclonal antibody or vaccine is urgently needed to address the substantial hospitalization burden of RSV infection.


| INTRODUCTION
Acute lower respiratory tract infection (ALRI) remains one of the global leading causes of morbidity and mortality in children under 5 years of age. [1][2][3] Common pathogens that give rise to ALRI in children include Streptococcus pneumoniae, Haemophilus influenzae type b, respiratory syncytial virus (RSV), and influenza virus. RSV is one of the most frequently encountered respiratory viruses that causes childhood ALRI. 2,4,5 It has been estimated that RSV caused 33.1 million new cases of ALRI in children under 5 years of age in 2015, resulting in approximately 3.2 million hospitalizations and 59,600 in-hospital deaths. 6 Although a number of vaccines against RSV are currently under development, with some undergoing advanced stages of clinical trials, a licensed vaccine to prevent RSV infection has yet to be produced.
The only prophylaxis currently approved by the Food and Drug Administration (FDA) is the monoclonal antibody palivizumab. However, palivizumab is only recommended for the prevention of serious disease in high-risk infants, though its high costs hamper its widespread use. [7][8][9] Therefore, estimating the disease burden of RSV infection is of great importance in terms of vaccine development and the prioritization of research funding.
Several studies have reported the prevalence and clinical characteristics of RSV infection among children in China. [10][11][12][13] However, research on the hospitalization burden of RSV-ALRI among this population has not been thoroughly conducted. Hence, accurate estimates of disease burden due to RSV infection are necessary in order to bolster the development of vaccines and serve as guidance for future research priorities. Accordingly, by adopting the World Health Organization (WHO) method of influenza disease burden estimation, 14,15 this study attempts to estimate the hospitalization rate of RSV-ALRI among children aged 0-59 months in Suzhou, China.

| Study site
This retrospective study was conducted at Suzhou University Affiliated Children's Hospital (SCH). Suzhou is located in Jiangsu Province, southeast China, which had a population of 10 million in 2018. It has jurisdiction over five municipal districts (Gusu, Wuzhong, Huqiu, Xiangcheng, and Industrial Park) and five county-level cities. SCH is a unique tertiary hospital for children in Suzhou and is composed of two branches: the Jingde Road Branch in the Gusu district and the Industrial Park Branch in the Industrial Park district. According to a previous study, the catchment area of SCH was defined to be the five municipal districts in Suzhou 16 ( Figure 1).

| Data collection
ALRI was defined according to the International Classification of Disease 10th revision (ICD-10) and discharge diagnosis codes J09-J18 (influenza and pneumonia) and J20-J22 (other ALRIs Trained investigators were then recruited in order to extract the corresponding information from the individual medical chart of the identified ALRI cases. The variables collected in this step covered clinical manifestation, physical signs, biochemical testing results, pathogenic testing results, and therapeutic measures. RSV was detected using a direct immunofluorescence assay (D3 Ultra DFA respiratory virus screening and identification kit, Athens, Ohio, USA). In brief, smears of exfoliated cells were air dried, which was followed by cold acetone fixation. Then, 10 μl of monoclonal fluorescent antibodies against RSV was added to the smears. Specimens were incubated for 30 min in the dark at 37 C and were then subject to a phosphate buffer saline (PBS, pH 7.4) wash. Slides were examined under a fluorescence microscope (excitation wavelength = 488 nm), where a slide with five or more RSV inclusion bodies was considered to be RSV positive. 18 Finally, 28,209 eligible ALRI children were screened out and included in the final analysis ( Figure 2).
Referring to the definition of RSV epidemic period adopted by the U.S. Centers for Disease Control and Prevention, 19,20 the RSV epidemic period was defined as months in which the RSV positive rate exceeded 10% in the seasonal analysis.

| Estimating the catchment population of SCH
According to our Healthcare Admission Survey (HAS) that was conducted in 2011, the hospital admissions for children under 5 years old in SCH accounted for 67.7% of the total hospital admissions in all medical institutions within the catchment area of SCH. 17 Therefore, the annual catchment population of SCH by age group and gender was calculated as Annual catchment population of SCH by age group and gender ¼ 67:7% Â annual population of catchment area by age group and gender: The annual populations of catchment area by age group (0-5, 6-11, 12-23, and 24-59 months) and gender were obtained from the immunization program database of Suzhou Center for Disease Control and Prevention, which covers all residents in the aforementioned age groups. The number of annual RSV-associated hospitalized ALRI cases was calculated as Annual RSV À associated hospitalized ALRI cases by age group and gender Monthly RSV Àassociated hospitalized ALRI cases by age group and gender:

| Estimating the hospitalization rate of RSVassociated ALRI
The annual hospitalization rate of RSV-associated ALRI cases was then calculated as Annual hospitalization rate of RSV À associated ALRI by age group and gender ¼ Annual RSV À associated hospitalized ALRI cases by age group and gender Annual catchment population by age group and gender Â 1000: The confidence intervals (CIs) for the hospitalization rate were calculated according to the standard methods in the WHO guideline. 14,15

| Sensitive analysis
In clinical practice, physicians may likely select suspected RSV infections cases when conducting RSV test. Hence, such a nonrandom test strategy may incur selection bias and affect the accuracy of the estimation. In order to address this, the characteristics between ALRI children who were not tested for RSV and in those who were tested were compared, after which the hospitalization rate of RSV-ALRI was estimated in the following two additional conservative scenarios. In the first scenario, the monthly RSV positive proportion of hospitalized ALRI children who were not tested for RSV was assumed to be half of the children within the same age group and gender stratum who were tested, namely, In the second scenario, it was assumed that no RSV positive cases were present in the hospitalized ALRI cases untested for RSV, namely, α ¼ 0.

| Statistical analysis
Categorical variables were presented as numbers or percentages. Chisquare test was used to compare the RSV positive proportion between groups. A P-value of <.05 was considered to be statistically significant. Data analyses were performed using R version 4.1.0 (R Foundation for Statistical Computing, Vienna, Austria).

| Ethics statement
This study was conducted in accordance with internationally recognized standards for ethnical research and was approved by the Institute Review Board in the School of Public Health at Fudan University.
Because this study was retrospective and utilized medical record data with no patient contact or collection of personal data, taking informed consent was not necessary.

| Hospitalization rate
Compared with the scenario when α ¼ 1, the average hospitalization rate of RSV-ALRI for children aged 0-59 months in the scenario when α ¼ 0.5 dropped 14% to 12 per 1000 children years, and reductions in the percentages of annual age-specific hospitalization rate varied from 8% to 25%. The average hospitalization rate of RSV-ALRI for children aged 0-59 months in scenario when α ¼ 0 dropped 29% to 10 per 1000 children years, and the percentage reduction of annual age-specific hospitalization rate varied from 15% to 55% (Figure 4).

| Discussion
In light of the obtained findings, the average RSV-ALRI hospitalization rate for children aged 0-59 months in Suzhou was found to be 14 (95% CI:  per 1000 children years. Moreover, the hospitalization rate was noted to be highest in children aged 0-5 months, namely, 70 per 1000 children years, which then decreased with rising age to 31 (6-11 months), 11 (12-23 months), and 3 (24-59 months) per 1000 children years. In terms of absolute number, 51% (2099/4107) hospitalized RSV-ALRI cases were observed to be aged <6 months, which was similar to the proportion (45%) reported by Shi et al. 6 Thus, an effective vaccine for use in the pediatric or maternal population is urgently needed. As of September 2021, more than 30 RSV vaccines are under development, of which two maternal vaccines are in phase III trials. 21 If the trials succeed, these vaccines may be able to address the substantial RSV burden present in children. The RSV positive proportion in the present study was found to be consistent with another retrospective study that was conducted in Wenzhou, China, using similar inclusion criteria. 23 However, it was higher than three other studies, in which the RSV positive proportion varied from 8% in 0-5 years to 22% in children <6 months. [24][25][26] Apart from differences in region and time, this study's diverse inclusion criteria may have also contributed to the observed disparity. In contrast to this study, the other three studies used the WHO definition of severe acute respiratory infection, in which fever (≥38 C) was an inclusion criterion. We screened ALRI cases that met the fever requirement and then analyzed the filtered data. In doing so, the RSV positive proportion for children aged 0-5 months was shown to decline significantly from 30.5% to 23.1% (Tables S2 and S3). Notably, as half of the hospitalized ALRI cases aged 0-59 months and four fifths hospitalized ALRI cases aged 0-5 months did not have fever (Table S4), including fever into the inclusion criteria may result in missing a substantial number of ALRI cases without fever. After including fever into the criteria, the hospitalization rate of RSV-ALRI (with fever) for children aged 0-59 months dropped by 57% to 6 per 1000 children years and by 84% to 11 per 1000 children years for children aged 0-5 months ( Figure S1). As confirmed by several studies, case definitions that include fever in RSV surveillance would result in a proportion of missed cases, particularly among young infants. 4,5,27 In this regard, employing broad ALRI inclusion criteria made this study less likely to miss RSV-infected cases and yield more accurate estimates of RSV-ALRI hospitalization rates.
We found few original studies from China can be compared with the present study's estimates on the RSV-ALRI hospitalization rate.
Shi et al estimated that the incidence rate of RSV-ALRI in China for children younger than 5 years was 31.0 (uncertainly range 18.7-50.8) per 1000 children years in 2015. 6 They also estimated that about 10% of RSV-ALRI episodes were severe enough to necessitate hospital admission globally. 2,6 According to this proportion, the hospitaliza- (2-4 years) per 100 children years. 29 Although this study's estimates for RSV-ALRI hospitalization rate in Suzhou were about 2-3 times higher than the above results, they were still comparable. The associated difference may reflect real gaps in disease burden between countries; however, differences in health care policy and health care seeking behavior of the population should not be ignored. In this study, the median length of hospital stay for RSV-ALRI cases was found to be 7 days, which was 2-3 times more than the 2-3 days reported in other studies. 6 supervision.

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1111/irv.12958.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.