Factors associated with severe respiratory syncytial virus infection among hospitalized children in Thammasat University Hospital

Background Respiratory syncytial virus (RSV) is one of the most significant respiratory pathogens that causes acute lower respiratory tract infections (LRTI) early in life. Most children have a history of RSV infection within 24 months of age, and recurrent infections are common throughout life. Methods Children under five years of age were identified through a review of medical records with a diagnosis of RSV-LRTI between 2016 and 2020. Severe RSV-LRTI was defined as a prolonged length of stay (> 7 days), admission to the intensive care unit, need for mechanical ventilation, non-invasive positive pressure ventilation, or in-hospital mortality. Factors associated with severe RSV-LRTI were investigated using univariate and multivariate analyses. Results During the study period, 620 patients were diagnosed with RSV-LRTI and 249 (40.16%) patients had severe RSV-LRTI. In the multivariable logistic regression analysis, the factors for severe RSV-LRTI were being under 3 months (aOR 2.18 CI 1.39-3.43, p0.001), cardiovascular disease (aOR 3.55 CI 1.56-8.06, p0.002), gastrointestinal disease (aOR 5.91 CI 1.90-18.46, p0.002), genetic disease (aOR 7.33 CI 1.43-37.54, p0.017), and pulmonary disease (aOR 9.50, CI 4.56-19.80, p<0.001). Additionally, the presence of ≥ 2 co-morbidities (aOR 6.23 CI 2.81-14.81, p<0.016), experiencing illness for more than 5 days (aOR 3.33 CI 2.19-5.06, p<0.001), co-detection of influenza (aOR 8.62 CI 1.49-38.21, p0.015), and nosocomial RSV infection (aOR 9.13 CI 1.98-41.30, p0.012), markedly increased the risk of severe RSV-LTRI. The severe RSV-LRTI group demonstrated higher hospitalization expenses (median, US $720.77 vs $278.00, respectively; p<0.001), and three infants died in-hospital. Conclusion Children at high risk for RSV-LRTI due to underlying genetic and gastrointestinal diseases are at an increased risk for severe RSV-LRTI. Further studies to determine the cost-effectiveness of RSV immunization in these potential co-morbidities should be initiated to prioritize RSV immunization, especially in resource-constrained regions with limited availability of nirsevimab.


Introduction
Respiratory syncytial virus (RSV) is a viral pathogen with far-reaching consequences in children, and is associated with significant morbidity and mortality.Infants have an increased risk of developing severe RSV infection, often necessitating hospitalization.Hospitalized RSV-associated lower respiratory tract infections (RSV-LRTI) occur globally.In Thailand, the highest peak incidence occurred during the rainy season from July to October.Those aged < 5 years experienced a higher mortality rate due to RSV-LRTI than older children, especially those aged < 1 year. 1 Many recent studies have demonstrated that young age, preterm birth, and pre-existing diseases are significant risk factors for RSV hospitalization.3][4] The RSV season occurs annually in Thailand. 1 However, there are limited available data regarding hospitalization, utilization of medical resources, and risk factors for severe RSV-LRTI.This retrospective study aimed to identify the clinical features and manifestations in hospitalized children with RSV-LRTI, along with the risk factors for severe RSV-LRTI and death.Demographic characteristics and disease severity were considered potential factors influencing the cost of medical treatment and utilization of medical resources.

Ethic statement
The Human Research Ethics Committee of Thammasat University (Medicine) is in full compliance with international guidelines such as Declaration of Helsinki, The Belmont Report, CIOMS Guidelines and the International Conference on Harmonisation-Good Clinical Practice (ICH-GCP), approved our study.The approval number is MTU-EC-PE-0-114/64 and the date of approval is May 20, 2021.Data collection was initiated after requisite approvals were obtained from the Human Research Ethics Committee of Thammasat University (Medicine).
This study received a waiver of informed consent due to its retrospective nature and the absence of direct contact with the study subjects.This study did not involve any intervention or therapy, thereby posing no risks to the subjects.Confidentiality of the present study data was maintained in accordance with the Declaration of Helsinki.

Study design
This retrospective cross-sectional study was initiated at the Thammasat University Hospital (TUH) in Pathum Thani, Thailand, a tertiary care facility with 100 pediatric beds.This study was based on a systematic computer-assisted database search that allowed extraction of retrospective data of the patients aged < 5 years who were discharged with a diagnosis of RSV-LRTI, including clinical bronchitis, bronchiolitis, and pneumonia.The diagnosis of RSV-LRTI was based on medical records approved by the attending physician and ICD-10 coding from hospital discharge summaries.Confirmation of the diagnosis was established either by an RSV antigen immunochromatography assay or a polymerase chain reaction (PCR) test for RSV from specimens taken from nasal or nasopharyngeal swabs.
The severe RSV-LRTI group included children who experienced an unsatisfactory outcome or died.An unsatisfactory outcome was defined as the necessity for non-invasive positive pressure ventilation (NIPPV), or mechanical ventilation, or prolonged hospital stay (over 7 days), in-hospital mortality, or admission to pediatric intensive care unit (PICU).The non-severe group included children with RSV-LRTI who did not experience an unsatisfactory outcome or death.

Data collection
The study population was identified by reviewing inpatient medical records, including patients age 0-5 years old from 2016 to 2020.Factors associated with severe hospitalized RSV-LRTI included baseline characteristics, clinical manifestations, and initial laboratory findings.The baseline characteristics included demographic data and co-morbidities.Clinical manifestations included presenting symptoms, physical examination, and initial laboratory results consisting of electrolytes and complete blood counts.Hospital resource utilization, hospital cost data, and REVISED Amendments from Version 1 In the revised version, several changes have been made.We expanded the discussion to include the effect of children with underlying conditions in a tertiary care academic medical center, the age range, and the severity of the disease.We also discussed the differences in symptoms between the severe and non-severe RSV-LRTI groups, along with the correlation between preterm birth, hematologic disease, and disease severity in both univariable and multivariable analyses.Additionally, we highlighted the strength of the study and the positive and negative impacts on the study population.Minor typographical errors have been corrected, and the specific symbol (*) has been added to indicate significant data.
Any further responses from the reviewers can be found at the end of the article outcomes after hospital stay were collected for both groups.Data on the mode of oxygen supplementation, inotropic drug use, bronchodilator nebulizer, use of montelukast, antibiotic therapy, and blood transfusion were collected to assess hospital resource utilization.The cost data were sourced from the hospital's cost-accounting database.An exchange rate of 35 baht per 1 US dollar was used to convert all expenditures in Thai baht into US dollars.The outcome after the hospital stay was recovery or in-hospital death.The term "nosocomial RSV-LTRI" was defined as signs or symptoms of RSV-LRTI occurring more than 72 h after admission.
The definitions of the variables included cyanotic heart disease or congenital hemodynamic significance, and heart disease was regarded as congenital heart disease (CHD).Cerebral palsy and other central nervous system abnormalities were defined as neurological diseases.Children born before 37 weeks of age were classified as preterm infants.Bronchopulmonary dysplasia (BPD) or asthma is a pulmonary disease.Necrotizing enterocolitis (NEC) with short bowel syndrome, intestinal malformation, esophageal atresia, or biliary atresia was defined as gastrointestinal disease.Hematological diseases included thalassemia and red cell membrane defects.Genetic diseases include Down syndrome, DiGeorge syndrome, Williams syndrome, and Rubinstein-Taybi syndrome.

Data analysis
This retrospective study aimed to identify the factors associated with severe RSV-LRTI, including perinatal history, co-morbidities, clinical manifestations, and laboratory results.In addition, the assessment of hospital resource utilization for RSV-LRTI included the mode of oxygen supplementation, inotropic drug use, bronchodilator nebulizer, use of montelukast, antibiotic therapy, and blood transfusion.
Categorical data were expressed as frequencies and percentages.Continuous data are expressed as medians with interquartile ranges (IQRs).Fisher's exact test was used to compare categorical data.The Wilcoxon rank-sum test was used to compare continuous data.Univariate and multivariate analyses were conducted to ascertain the independent factors associated with severe RSV-LRTI (p<0.05).
Frequencies and percentages were used for categorical data.The median and interquartile range (IQRs) were used for continuous data.Fisher's exact test and Wilcoxon rank-sum test were used to compare the categorical and continuous data, respectively.Univariate and multivariate analyses were conducted to ascertain the independent factors associated with severe RSV-LRTI (p<0.05).

Results
Overall, 1,050 children were admitted for a positive RSV test result.In this study, 620 children diagnosed with RSV-LRTI were included; 10 cases were excluded because of missing values.Baseline characteristics of the patients are shown in Table 1.Of the 620 patients, 249 had severe RSV-LTRI.The mean age of all patients was 16.60 AE 14.56 months old and males accounted for 53.55 percent of all patients.One-third of patients had at least one co-morbidity.Eighteen patients (2.90%) had nosocomial RSV infection, and 11 patients (1.77%) had co-infection with influenza, which occurred specifically in the severe group.The peak of the RSV-LRTI was noted from July to October annually, as demonstrated by the seasonal variation in RSV (Figure 1).Most patients were admitted to the general pediatric ward (96.77%), with an average length of stay of 5.87 AE 2.43 days.A total of 3.23% of patients required PICU admission (Table 2).
Healthcare utilization for RSV disease included hospital and PICU admissions, as well as treatments such as oxygen therapy, mechanical ventilation, inhaled medications, and antibiotics for managing RSV infection.The severe RSV-LTRI group showed significantly increased healthcare utilization and costs, especially in PICU admissions, and increased length of stay.
In cases of severe RSV-LRTI, the prescription rates and the duration usage for salbutamol, adrenaline, and hypertonic saline nebulization were notably higher compared to the non-severe RSV-LRTI (83.53% vs. 59.84% and  4).

Discussion
Evaluating the data collected over five consecutive years, we found that 40 percent of the children demonstrated severe symptoms.6][7][8][9] The predominant occurrence of RSV-LRTI typically manifests in children aged 0-6 months. 10Within our study cohort, infants under 3 months of age exhibited a tendency for severe RSV-induced LRTI.This susceptibility observed in early infancy can be attributed to the immaturity of the lung structure, and the anatomical characteristics of smaller airways, predisposing them to severe RSV-LRTI.
Gastrointestinal diseases, such as NEC with short bowel syndrome, intestinal malformation, or esophageal atresia, were additional significant risk factors for severe RSV-LRTI.Gut microbiome dysbiosis in gastrointestinal anomalies may play a key role in RSV infections.The role of the gut microbiota in regulating the immune system and respiratory infections is increasingly recognized. 11A relationship between gut microbiome dysbiosis and RSV infection was demonstrated in a previous study.Disruptions in microbial abundance and characteristic microbiome shifts are associated with RSV severity. 12wn syndrome, with or without congenital heart defects, has a higher risk of mortality, prolonged length of hospital stay, and more frequent transfer to the PICU. 13,14Our study observed a correlation between genetic disease and RSV-LRTI with 81.81% (9/11) of genetic diseases in the severe RSV-LRTI group with Down syndrome, which demonstrated a 7-fold higher risk for severe RSV-LRTI.Therefore, gastrointestinal anomalies, short bowel syndrome, and Down syndrome should be considered as candidates for RSV immunization.
Other factors related to severe RSV-LRTI were co-morbidities of cardiovascular disease, pulmonary disease, and co-detection of influenza, which is comparable to the findings of previous studies. 4,13,15-18Many studies have indicated that prematurity especially GA <33 weeks, is a risk factor for severe RSV-LRTI; however, this was not statistically significant in this study because the preterm definition in this study was GA < 37 weeks.Hematologic disease was not different in both severe and not severe RSV-LRTI, which is comparable to the finding of the previous study. 15Moreover, the cumulative number of co-morbidities is a potential factor associated with a severe course of hospitalization. 13hildren with two or more co-morbidities were at a significantly higher risk of severe RSV-LRTI.Nevertheless, onefourth of patients with co-morbidities were ineligible for RSV immunization.Further studies are required to determine the cost-effectiveness of immune prophylaxis against RSV for other potential co-morbidities.
Nosocomial RSV infection is identified as one of the factors associated with mortality and PICU admission. 19,20Previous reports have suggested that nosocomial RSV infection is an independent predictor of prolonged hospitalization, higher mortality, and excess hospital charges. 21Our results showed that nosocomial RSV infection was significantly associated with severe RSV-LRTI.Nonetheless, the small number of nosocomial RSV cases limited our ability to detect a correlation between nosocomial RSV infection and mortality.
The comparison between severe and non-severe cases of RSV-LRTI reveals several significant differences in symptoms.
While both groups commonly presented with symptoms such as cough, rhinitis, and feeding difficulties, certain symptoms were more pronounced in the severe RSV-LRTI group.Notably, severe cases exhibited a higher prevalence of tachypnea, apnea, and cyanosis, indicating more severe respiratory distress or profound respiratory compromise.
Furthermore, the severity of respiratory distress manifested in physical examination findings.Chest retractions were more commonly observed in severe cases.Additionally, fine crepitation and wheezing, were more observed in the severe RSV-LRTI group.These findings underscore the importance of recognizing and promptly managing severe respiratory distress in children with RSV-LRTI to optimize clinical outcomes.
Consequently, a tertiary care center tends to attract patients with more severe illness, which reflects the tertiary care setting's patient demographics.The advanced medical resources and specialized care available at tertiary care facilities may influence the management and outcomes of severe RSV-LRTI.Patients with severe illness are more likely to be admitted to the pediatric intensive care unit (PICU), require mechanical ventilation, or experience prolonged hospital stays.Significant therapy costs are associated with managing severe RSV-LRTI in tertiary care settings, where specialized interventions are common.The study's findings contribute to a comprehensive understanding of the clinical and economic implications of RSV-LRTI in children.
The duration of illness prior to admission for more than three days, especially exceeding five days, was considered a risk factor for severe RSV-LRTI, as in a previous study. 22This could be explained by the prolonged duration of illness, which may be associated with complications, notably, atelectasis.Following RSV infection, there is an increase in the quantity and viscosity of the mucous secretions.The loss of ciliated epithelial cells creates widespread mucous plugging across various areas. 23Furthermore, secondary bacterial infections may play a key role in the severity of symptoms, particularly in infants.RSV infection diminishes bacterial clearance, leading to secondary bacterial pneumonia by altering the recruited neutrophils. 24,25Nevertheless, our study did not demonstrate a statistically significant association between secondary bacterial infection and severe RSV-LRTI.This was due to the fact that requests for sputum culture and blood culture in RSV-LRTI are optional and depend on the judgment of the attending physician.
The RSV seasons vary globally and are influenced by climate and geographic location.Several studies have demonstrated a relationship between RSV activity and weather conditions. 26,27Our 2016-2020 study established a correlation between the rainy season (July-October) and RSV-LRTI admission.9][30] However, RSV-LRTI admissions in 2020 predominantly occurred between September and December because of the delayed onset of the rainy season.Furthermore, communities and academic institutions reopened after the relaxation of COVID-19 lockdown measures starting in August 2020, resulting in an upsurge in RSV-LRTI admissions, notably from September.
Management of children hospitalized with RSV infection involves supportive care and should include hydration and, if necessary, supplemental oxygen.In our study, bronchodilators, epinephrine, montelukast, and corticosteroids were used in the treatment of severe RSV-LRTI with statistical significance.However, there is no clinical data to recommend these medications for the treatment of RSV-LRTI. 31Likewise, in previous studies, 15,32 27.9% of our patients were prescribed antibiotics, demonstrating a notably higher frequency of severe RSV-LRTI (59.04% vs. 7.01%).Although antibiotics were prescribed to treat a possible bacterial superinfection in severe RSV-LRTI, 25 the misuse and overuse of antibiotics for RSV infection was established in a previous study. 33Overprescription of antibiotics is the main cause of adverse consequences, not only adverse reactions from the antibiotics but also unnecessary economic burden, financial stress, 34 or antibiotic resistance. 35This result emphasizes the necessity of implementing appropriate antibiotic stewardship programs that have demonstrated effectiveness in reducing antibiotic misuse in RSV-infected children. 36,37erefore, prevention of RSV infection is necessary.However, nirsevimab, palivizumab, and RSV vaccine for pregnancy are not available in Thailand.Currently, there is no approved vaccine for RSV infection in children.Many RSV vaccines targeting infants and young children are undergoing development. 38,39rengths and limitations One major strength of this study is that it included a significant number of patients, which enhanced the reliability of the finding.The use of multivariable logistic regression analysis allowed for the identification of independent factors associated with severe RSV-LRTI while controlling for potential confounders.The criteria for defining severe RSV-LRTI were clearly stated, which provides clarity and consistency in assessing severity.Furthermore, the study provides valuable information for clinicians in identifying high-risk populations and understanding the economic burden associated with managing severe respiratory infections in a tertiary care setting.
This study had some limitations.Despite the relatively high number of patients, the study had a retrospective design and was conducted at a single medical center, which might potentially limit the generalizability of the results.Clinical diagnosis of RSV-associated LRTI was based on medical records approved by the attending physician and ICD-10 from hospital discharge summary.Additionally, the analysis of co-infection was limited because an RT-PCR assay for respiratory viral panels was not feasible in all cases.Evidence of secondary bacterial infection was unavailable in most patients due to the lack of sputum and blood cultures performed in most patients.Furthermore, the study was conducted in a tertiary academic medical center, which may have a population selection bias, including children with chronic conditions.
Overall, while the study provides valuable insights into the risk factors associated with severe RSV-LRTI in children, it is essential to consider these strengths and limitations when interpreting the findings and applying them to clinical practice.Future research could address these limitations by employing prospective designs, multi-center collaborations, and longer follow-up periods.

Conclusion
RSV infection is a major cause of respiratory hospitalization in children.Mortality and morbidity occur frequently in younger infants.Co-morbidities, including gastrointestinal anomaly, short bowel syndrome, Down syndrome, and cardiopulmonary function, are significantly higher risk factors for severe RSV-LRTI.Moreover, the disease severity of RSV-LRTI is correlated with being under 3 months of age, co-infection with influenza, nosocomial RSV infection, and prolonged duration of illness.The primary treatment for RSV infection is supportive care.There are no specific antiviral therapies or vaccines for RSV in children.Effective preventive measures with RSV immune prophylaxis should be prioritized in public health policies and primarily target all infants and children with risk factors to provide coverage throughout the RSV season.The researchers have completed a fairly comprehensive and well written investigation and have managed to cast light on which children may be more vulnerable to severe RSV-associated LRTIthey suggest that this may identify these as being most likely to benefit from targeted protective interventions.

Compliance with journal-specific instructions
Mostly yes-will indicate in the report specific areas where there is deviation.Title Clear, though strictly should indicate that this is a retrospective cross-sectional descriptive study.

Abstract
Provides a good summary of the main findings, although it lacks the aim or purpose of the study.The keywords are adequate.

Methodology
We are told that the 620 patients were recruited from a total of 1 050 children with RSV positive upper respiratory swabs; it is not clear why 420 children were excluded ( a simple flow diagram may clear this).The data collection is well-described-a sentence of explanation will help the reader decide on context and generalisability.The exclusion/inclusion criteria of the sample population are not explicitly included.The study period is defined but the sample size determination is not fully described.
○ Data collected included n, age, clinical characteristics and co-morbidity data , timing-related factors, clinical and operational data.This information was tabulated.I believe that your text notes about the seasonality of RSV-infection is adequate without the need for Figure 1.-just a suggestion.
The statistical analysis section is covered reasonably.

Results
The first sentence in the results section requires some minor editing to indicate the real reason for admission.
The results section has four tables which contain enough information for the reader to interpret without the lengthy repetition in the text paragraphs.Please consider reducing the text.Table 1: summarises the baseline characteristics very well.I wonder somewhat at two of the variables-sore throat-is difficult to understand given that >70% of the study children would not have been able to provide this information due to their young age, making this variable less useful for inclusion.Likewise, cyanosis is quite a subjective observation with much inaccuracy and interobserver variability-most of us cannot detect this until significant desaturation has occurredtherefore, why not use the World Health Organization cut-off for hypoxia-<92%?This goes for Table 2 as well, where desaturation is given at an arbitrary <95%-it would help to understand how this level of desaturation was decided upon.Table 2 is a good table where the severity indicators are depicted and compared, albeit in univariable analysis.The first row of the table is likely redundant seeing as fever is explored more meaningfully in the second row.Table 3 describes the various treatments used on the study children, the most important of which regard the respiratory support required by the children-likely the most appropriate indicators of severity of illness.
Given the current body of evidence and guidelines such as NICE and WHO with respect to the management of bronchiolitis, finding significance in the use of the other treatments listed in those who had severe disease compared to those with non-severe disease is simply a description of measures used in the sicker children at a single tertiary centre.There is no evidence given that the effects of these treatments were evaluated as beneficial in detail in this retrospective observational study.

Major concerns Nil Minor concerns Paragraphs in the Results section which describe what is depicted n Table 4 are unnecessary as
Table 4 illustrates the findings very well.Ensure consistency of terminology: univariable and multivariable regressions are correctly used, compared to univariate and multivariate terms used in the data analysis section of the methods Reference section I would question whether reference 40 is a true reference, even though it refers to a pre-print, it is unconventional to self-reference one's own current paper.

Discussion
The discussion is very long and I would suggest that it should open with a bold appropriate summary of the main findings of the study.

○
The main findings are described, and the relevant published literature is drawn in to ○ compare and contrast cogently.I would suggest that not all findings should be addressedchoose the most impactful.The association of GIT diseases with disease severity made me speculate on the role played by of nutritional status' on these affected children-this was not mentioned in their baseline characteristics-do we have any information on this, i.e., were any of the study cohort malnourished in any way?
○ I would suggest that the tertiary centre's management of children with bronchiolitis with less conventional therapies other those recommended by NICE and WHO Guidelines, has its greatest impact on hospital resources, perhaps this consideration could reduce the paragraph length.

○
The impact of prevention by vaccination is mentioned appropriately but cannot be added to the conclusions as the study did not specifically address this.

Conclusions
The conclusion section is much too long and rehashes some of the background and results, it should be quite clear and concise, one or two sentences and with a sentence on possible future research.I would suggest also shortening the recommendations section to the most important points, e.g., see the abstract.
Given that this is a retrospective study, one should perhaps state that "Co-morbidities, including gastrointestinal anomaly, short bowel syndrome, Down syndrome, and cardiopulmonary function, are…" significant associated factors for severe RSV-LRTI"… rather than 'significantly higher risk factors for severe RSV-LRTI'.
The same comment goes for the use of the phrase 'risk factors for severe RSV-LRTI and death' in the introduction; however, the correct phrase is more correctly stated in the data analysis plan.

Limitations
It is not completely clear in the text what proportion of the co-infections or bacterial coinfections were laboratory proven and what proportion were attending clinician diagnosed; hence the influences of these unidentified potential infections could not be resolved.If the is information is known, clarification is required in the methods section.

Strengths
Despite this, the study population although not a justified sample size, was substantial with adequate available data.The criteria for severity were well described and internationally comparable.At the end of the study the researchers have identified some associated factors for severity of RSV-related LRTI at their tertiary centre.

Ethical considerations
Appropriate attention to ethical considerations.Strengths I wish to acknowledge the huge effort the authors have invested in this study, it is generally well written and presents a significant contribution to the understanding of acute RSV-associated infection in the <5-y-age group at a single centre in Thailand.Whilst the study is overall commendable, I think it would benefit from further revision and shortening of the results section, discussion and a much shorter conclusion which directly relates to the study findings.

Is the work clearly and accurately presented and does it cite the current literature?
Yes  Since this study site is a tertiary care and university hospital, it's probable that most participating children are from high-risk groups with underlying conditions.Hence, it's imperative to approach the assessment of risk factors and establishment of connections with caution. 1.
There is a wealth of intriguing information within this study, prompting consideration of its key message.

2.
RSV infection severity varies across age categories, spanning from 0-3 months, 12-24 months, to over 24 months.It is imperative for the author to focus on analyzing, discussing, and comparing these age-specific trends with previous study findings.Hence, exploring the stratification of RSV infection by age is an intriguing issue.

○
Distinguishing symptoms exist between the severe RSV-LRTI group and the non-severe RSV-LRTI group.It is imperative for the author to discuss these differences in symptoms as they relate to predicting the severity of the condition.

○
The impact of tertiary care on risk factors and severity underscores the significance of ○ discussing the associated therapy costs in this study.It is essential to include additional information to enrich this discussion.The definition of the severe RSV-LRTI group serves as a foundational principle in this study.
For additional clarity and credibility, it is essential to include detailed information regarding this definition along with a proper reference.

○
The type of diagnosis is an intriguing topic for discussion, particularly regarding conditions such as pneumonia, bronchiolitis, and bronchitis.
3. Please, recheck information and add information at -page 5 line 18-24 (below Fig1) and page 8 line 8-15 this content is not match the table.Please that the data is sorted according to the table provided by the author.-In the table, it would be beneficial for the author to add specific symbols (such as *) to indicate significant data, along with footnotes providing explanations below the table.And add "statistically significant".
-in table 1, revise Sever RSV-LRTI -p8 line 5, revise "+" 4. In univariable and multivariable analysis in table 4, There are many characteristics that significant, this reason is hospital type of study site.Preterm and hematologic disease are not significant, this is interesting issue for discussion.Please condense the discussion from page 8, line 20 to page 9, line 5 for a succinct summary. 5. Summary: Page 10 line 7-19, Please request the author to provide a brief summary or modify the information to summarize the results of this study.Exclude any unrelated issues from the discussion.
6.While acknowledging the limitations, this study provides valuable information.The author should consider adding details about how population selection could impact both positive and negative results, as well as strengthening the overall robustness of the study.

Are sufficient details of methods and analysis provided to allow replication by others? Yes
If applicable, is the statistical analysis and its interpretation appropriate?Yes Are all the source data underlying the results available to ensure full reproducibility?Yes Are the conclusions drawn adequately supported by the results?Yes Response: The definition of severe RSV-LRTI adopted in this study diverges from the criteria outlined by the World Health Organization (WHO) and other related investigations.While the WHO guidelines predominantly hinge upon clinical symptoms and specific physiological parameters, such as SpO2 levels and chest wall indrawing, our study delineates severity based on factors associated with adverse outcomes or mortality, which impact hospital resource utilization and costs.
Our definition of severity, although divergent from WHO criteria, aligns with similar approaches seen in studies by Aikphaibul P, et al., Shi Tet al., and Havdal LB et

The type of diagnosis is an intriguing topic for discussion, particularly regarding conditions such as pneumonia, bronchiolitis, and bronchitis.
Response: The diagnosis of RSV-LRTI was based on medical records approved by the attending physician and ICD-10 coding from hospital discharge summaries, as outlined in the study methodology.

Please, recheck information and add information at
3.1 page 5 line 18-24 (below Fig1) and page 8 line 8-15 this content is not match the table.Please ensure that the data is sorted according to the table provided by the author.

Response:
The information has been reviewed and corrected for accuracy.
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Thank you for the opportunity to review " Factors associated with severe respiratory syncytial virus infection among hospitalized children in Thammasat University Hospital [version 2; peer review: 1 approved]" by Bujoungmanee et al.This is a retrospective observational study, carried out at a tertiary academic hospital in Thailand over 2016-2020 conducted in an upper-middle-income-setting, that attempts to understand the challenges and associated factors involved with severity of RSV-associated respiratory illness in children aged <5years.The study was carried out via medical records review.The discussion is quite lengthy.

© 1 Reviewer
2024 Moolasart V.This is an open access peer review report distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Visal Moolasart Department of Disease Control, Bamrasnaradura Infectious Diseases Institute, Ministry of Public Health, Nonthaburi, Thailand After reading the revised version of the manuscript titled "Factors Associated with Severe Respiratory Syncytial Virus Infection Among Hospitalized Children in Thammasat University Hospital," I find the information valuable to the understanding of RSV.I am satisfied with the manuscript.Is the work clearly and accurately presented and does it cite the current literature?Partly Is the study design appropriate and is the work technically sound?Partly Are sufficient details of methods and analysis provided to allow replication by others?Partly If applicable, is the statistical analysis and its interpretation appropriate?Partly Are all the source data underlying the results available to ensure full reproducibility?Partly Are the conclusions drawn adequately supported by the results?Partly Competing Interests: No competing interests were disclosed.Reviewer Expertise: infectious disease I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.Version Report 12 April 2024 https://doi.org/10.5256/f1000research.160633.r260846© 2024 Moolasart V.This is an open access peer review report distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Visal Moolasart Department of Disease Control, Bamrasnaradura Infectious Diseases Institute, Ministry of Public Health, Nonthaburi, Thailand This manuscript delivers a compelling message and provides valuable insights into RSV infection among hospitalized children.However, there are several issues that merit further consideration.
information has been added to the eighth paragraph of the discussion 2.4 The definition of the severe RSV-LRTI group serves as a foundational principle in this study.For additional clarity and credibility, it is essential to include detailed information regarding this definition along with a proper reference.

the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Partly Competing Interests:
No competing interests were disclosed.

have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.
https://doi.org/10.5256/f1000research.165923.r279756 al.This consistency highlights the reliability and applicability of our research within the broader academic conversation, providing a shared basis for assessing severe RSV-LRTI across various clinical and geographical settings.Reference Aikphaibul P, Theerawit T, Sophonphan J, et al.: Risk factors of severe nso respiratory syncytial virus infection in tertiary care center in Thailand.Influenza Other Respir.Viruses.2021;15(1):64-71.32783380 10.1111/irv.12793PMC7767956 Shi T, McAllister DA, O'Brien KL, et al.: Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study.Lancet.2017;390(10098):946-958. Shi T, Vennard S, Mahdy S, et al.Risk Factors for Poor Outcome or Death in Young Children With Respiratory Syncytial Virus-Associated Acute Lower Respiratory Tract Infection: A Systematic Review and Meta-Analysis.J Infect Dis.2022;226(Suppl 1):S10-S16.Havdal LB, Bøås H, Bekkevold T, et al.Risk factors associated with severe disease in respiratory syncytial virus infected children under 5 years of age.Front Pediatr.2022;10:1004739.doi: 10.3389/fped.2022.1004739.eCollection 2022.