Resurgence and Clinical Evolution of Influenza A in Chinese Children: Shifting Epidemiology and Serological Dynamics Across Pre-, Intra-, and Post- Pandemic Eras (2019-2023)

Resurgence and Clinical Evolution of Influenza A in Chinese Children: Shifting Epidemiology and Serological Dynamics Across Pre-, Intra-, and Post- Pandemic Eras (2019-2023) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Resurgence and Clinical Evolution of Influenza A in Chinese Children: Shifting Epidemiology and Serological Dynamics Across Pre-, Intra-, and Post- Pandemic Eras (2019-2023) Guiling Xu, Yu Chen, Yu Zhu, Qing Fang, Xiaotong Xue, Kejun Hu, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7920288/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Jan, 2026 Read the published version in BMC Infectious Diseases → Version 1 posted 12 You are reading this latest preprint version Abstract Objective This study aimed to analyze the epidemiological characteristics and serological profiles of influenza A in children aged 0–18 years before and after the COVID-19 pandemic to inform prevention and control strategies. Methods We conducted a retrospective analysis of 238,494 children tested for influenza A at Shanghai Children's Medical Center (2019.1-2023.12). Positivity rates and serological parameters were evaluated across age groups seasons, and years. Results During the pandemic period, influenza A positivity remained consistently low without seasonal peaks. Conversely, post-pandemic positivity (33.33% in 2023) significantly exceeded pre-pandemic levels (13.66% in 2019), exhibiting winter-spring seasonality with bimodal peaks in February-March and December. School-aged children (≥ 6 years) demonstrated the highest post-pandemic positivity rate (38.86%). Hospitalization rates among influenza A-positive children inversely correlated with age: 16.67% in neonates (≤ 28 days) vs. 1.42% in infants (29d-3y) vs. 0.36% in preschoolers (3-6y) vs. 0.33% in older children (≥ 6y). Children < 6 years predominated in severe diagnoses and comorbid conditions. Conclusions This study delineates the evolving epidemiology of influenza A from 2019 to 2023. Post-pandemic resurgence demonstrated heightened positivity rates and prolonged seasonal activity exceeding pre-pandemic patterns. Young children and those with comorbidities exhibited greater disease severity requiring hospitalization. Enhanced pediatric influenza A prevention is imperative. Covid-19 influenza A pediatric immune debt Figures Figure 1 Figure 2 INTRODUCTION Influenza A virus (Flu A) is a common etiological agent of acute respiratory infections (ARIs) in children, capable of triggering seasonal influenza pandemics exhibiting a spectrum of disease severity. Infected individuals typically present with fever, cough, or myalgia, and recover within one week. However, certain patient populations—particularly young children, older adults, pregnant women, and individuals with specific comorbidities—are at elevated risk for complications leading to medical consultation, hospitalization, and mortality [ 1 ] . The COVID-19 pandemic emerged in China in December 2019. From early 2020 through December 2022, the implementation of nonpharmaceutical interventions (NPIs) effectively curtailed SARS-CoV-2 transmission. Concurrently, these measures impacted the characteristic seasonal epidemiology of FLUA, which shares respiratory transmission routes. Nevertheless, the "immune debt" incurred during the pandemic period poses a significant concern, potentially predisposing children to more severe and extensive future epidemics [ 2 – 4 ] . Existing data indicate that from mid-February to late April 2023, China experienced an influenza epidemic dominated by the influenza A (H1N1) subtype, with its intensity marginally exceeding that of pre-COVID-19 pandemic seasons [ 5 ] . To further investigate the evolving epidemiological characteristics of influenza A and evaluate the clinical utility of serological findings for guiding diagnosis/treatment in the post-pandemic era, we conducted a large-scale, single-center retrospective study at Shanghai Children's Medical Center. This research aims to provide evidence-based, targeted recommendations for influenza A prevention and control in pediatric populations. MATERIALS AND METHODS 1. Study design and approval This study collected data from patients tested for influenza A virus at Shanghai Children's Medical Center between January 2019 and December 2023. For patients undergoing multiple influenza A tests within a single month, only one record was retained when results were consistent, while positive results were prioritized in cases of discordant findings. After applying these deduplication criteria, 238,494 distinct cases were included for analysis. The dataset comprised demographic information (gender, age), influenza A test results, clinical diagnoses, hospitalization status, and complete blood count parameters including white blood cell count (WBC), C-reactive protein (CRP), neutrophil percentage (NEU%), hemoglobin (Hgb), and platelet count (PLT). This retrospective observational study was approved by the Ethics Committee of Shanghai Children's Medical Center with waiver of informed consent. 2. Definitions Based on China's actual COVID-19 pandemic progression, this study defined January 2019-January 23, 2020 as the pre-pandemic period (Phase I), January 24, 2020-December 12, 2022 as the pandemic period (Phase II), and December 13, 2022-December 31, 2023 (Phase III) as the post-pandemic period. The cohort comprised pediatric patients (0-18 years) stratified into four age groups: neonates (≤28 days), infants/toddlers (29 days-3 years), preschoolers (3-6 years), and school-aged/adolescents (≥6 years). Seasons were categorized as spring (March-May), summer (June-August), autumn (September-November), and winter (December-February). Diagnostic classifications encompassed 11 mutually exclusive categories according to standardized diagnostic criteria: upper respiratory tract infection (URTI), bronchitis, pneumonia, severe pneumonia, infectious fever, URTI with non-infectious conditions, bronchitis with non-infectious conditions, pneumonia with non-infectious conditions, severe pneumonia with non-infectious conditions, infectious fever with non-infectious conditions, and non-infectious conditions. Notably, among these patients primarily ‘non-infectious’ conditions include malignancies, congenital heart disease, and immunodeficiency disorders. 3. Data Analysis Based on the results of the Shapiro-Wilk test, continuous variables were expressed as mean and standard deviation or median and interquartile range, and the comparison of the variables of groups were evaluated using Wilcoxon rank-sum test. Categorical variables were displayed as numbers and percentages and were analyzed with the Chi-square test or Fisher’s exact test (when the expected cell number was less than 5). Comparison of the flu-positive rate among multiple groups was performed using the chi-square test or Fisher exact probability method. Post hoc pairwise comparison was further conducted to examine differences between subgroups with Bonferroni correction of P. The receiver operating characteristic (ROC) curve analyses was established to interpret the ability of inflammatory indicators in discriminating flu-positive patients from healthy controls. All statistical analyses were performed with Stata (version 16.0) and Rstudio (version 4.2.2), and P< 0.05 were accepted as significant. RESULTS 1. Characteristics of the study population A total of 238,494 pediatric patients were enrolled between January 2019 and December 2023, with 111,757 (46.86%) girls and 126,737 (53.14%) boys. When stratified by pandemic phases, the pre-pandemic period (January 2019-January 23, 2020) included 111,897 patients (56,158 girls [47.19%], 62,839 boys [52.81%]; median age 5.00 years, IQR 3.00-7.00), while the pandemic period (January 24, 2020-December 12, 2022) comprised 40,473 patients (18,785 girls [46.41%], 21,688 boys [53.59%]; median age 4.00, IQR 2.00-6.00), and the post-pandemic phase (December 13, 2022-2023) contained 79,024 patients (36,814 girls [46.59%], 42,210 boys [53.41%]; median age 6.08, IQR 3.56-8.92). Gender-specific differences in detection rates across all phases reached statistical significance (χ²=41.7, 14.2, and 82.1 for respective periods, all p<0.001; Tables 1.1-1.3), with detailed patient characteristics provided in Table 1 and Supplement Table 1 . 2. Distribution of positive rates in different years and months The overall influenza A positivity rate was 18.36% (43,779/238,494), exhibiting annual fluctuations: 13.66% in 2019, 7.79% in 2020, 1.00% in 2021, 6.79% in 2022, and 33.33% in 2023. During the pandemic period, positivity rates remained consistently low without discernible seasonal peaks, whereas post-pandemic rates significantly exceeded pre-pandemic levels. Both 2019 and 2023 demonstrated bimodal peaks (February - March and December), though the 2023 plateau phase contracted to May-July compared to April-July in 2019 ( Figure 1A ). 3. Distribution of positive rates in various age groups Age-stratified analysis revealed progressively increasing positivity rates with advancing age: 1.12% in neonates (≤28 days), 11.48% in infants (29 days-3 years), 17.31% in preschoolers (3-6 years), and 23.20% in school-aged/adolescents (≥6 years) ( Table 2 ). While all age groups except neonates exhibited concordant epidemiological trends, the pandemic period showed universally low rates without seasonality, contrasting with elevated post-pandemic rates featuring prominent spring and winter peaks ( Figure 1B ), consistent with population-level patterns in Figure 1A. 4. Analysis of hospitalization in various age groups Hospitalization rates demonstrated an inverse relationship with age, declining from 72.16% in neonates to 6.74% in infants, 2.07% in preschoolers, and 2.39% in older children. This gradient persisted among influenza A-positive patients, with corresponding rates of 16.67%, 1.42%, 0.36%, and 0.33%, confirming parallel trends between the overall cohort and infected subpopulation ( Figures 2A and 2B ). 5. Analysis of age in different diagnosis among influenza A-positive children Among 43,779 influenza A-positive children, those diagnosed with URTI included 14,730 (45.36%) aged <6 years, while 48 (50.00%) of URTI-with-comorbidities cases were under six. Similarly, bronchitis diagnoses comprised 2,010 (50.59%) children <6 years versus 5 (62.50%) in the bronchitis-with-comorbidities group. For pneumonia, 490 (54.93%) patients were <6 years compared to 4 (66.67%) with pneumonia-comorbidity complex, and severe pneumonia cases showed 10 (66.67%) and 1 (100.00%) under-six patients respectively. Infectious fever diagnoses included 3,357 (54.40%) children <6 years versus 36 (52.94%) with comorbidities. This progressive increase in younger patients with rising respiratory severity (URTI to severe pneumonia) was paralleled by elevated proportions of under-six children when malignancies, congenital heart disease, or immunodeficiency comorbidities were present ( Figure 2C ). 6. Analysis of serological findings in patients positive and negative for influenza A Serologically, influenza A-positive children demonstrated lower WBC (6.70×10⁹/L vs. 7.88×10⁹/L, P<0.001), CRP (3.30 mg/L vs. 4.20 mg/L, P<0.001), and PLT (200×10⁹/L vs. 201×10⁹/L, P<0.001) but higher NEU% (66.70% vs. 61.80%, P<0.001) and HGB (129 g/L vs. 126 g/L, P<0.001) than negative controls ( Table 3 ). Further stratification showed hospitalized positives had reduced WBC (6.21×10⁹/L vs. 6.70×10⁹/L, P=0.018), NEU% (52.65% vs. 66.70%, P<0.001), and HGB (119 g/L vs. 129 g/L, P<0.001) but elevated CRP (4.50 mg/L vs. 3.30 mg/L, P=0.001) and PLT (240×10⁹/L vs. 200×10⁹/L, P<0.001) versus outpatient positives ( Table 3 ). While neonates (≤28 days) showed no significant serological differences between influenza statuses, all older age groups exhibited marked variations (P<0.001), as did patients with concomitant respiratory infections, bronchitis, or pneumonia (P<0.001). 7. Analysis of inpatients versus outpatients among influenza A-positive children Analysis of 43,779 influenza A-positive cases revealed 220 inpatients versus 43,559 outpatients (hospitalization rate: 5.03%). No significant gender differences existed between groups, but inpatients exhibited significantly younger median age than outpatients (4.00 vs. 6.00 years, P<0.001), aligning with Table 3 findings. DISCUSSION This large-scale retrospective study of 238494 pediatric encounters at Shanghai Children's Medical Center provides critical insights into the profound epidemiological disruption of influenza A (Flu A) by COVID-19 non-pharmaceutical interventions (NPIs) and the subsequent resurgence phase. NPIs did reduce the circulation of COVID-19, as well as other respiratory pathogens during the COVID-19 pandemic period [ 6 ] . Our analysis reveals that COVID-19 NPIs induced a triple evolutionary shift in influenza A dynamics: transmission collapse (2020–2022 positivity ≤ 7.79%), hyperendemic rebound (2023 incidence 2.43 time than pre pandemic levels and 4.27–33 time than pandemic levels), and seasonal distortion (extended spring-summer activity: May–July positivity > 30%). This is in line with other respiratory pathogens in other countries [ 7 – 10 ] . Crucially, we identify asymmetric susceptibility as the core driver of post-NPI severity, where birth cohorts with minimal 2020–2022 viral exposure exhibited profound immunological naïveté, creating a "triple jeopardy" population (children < 6 years with comorbidities) that suffered disproportionate complications [ 2 , 4 , 11 ] . These findings substantiate the immunization debt hypothesis while highlighting emerging vulnerabilities in young children who lack the trained immunity [ 12 , 13 ] . The near-elimination of Flu A during China’s stringent NPIs (2020–2022) demonstrates the effectiveness of measures like school closures and mask mandates against respiratory viruses beyond SARS-CoV-2. However, this suppression incurred an immunological debt through interrupted immune priming in birth cohorts. This suggests that while NPIs broadly suppressed transmission, they created pockets of extreme susceptibility in immunologically naïve children with pre-existing conditions. Our data reveal explosive cross-age transmission in 2023, school-aged children (≥ 6 years) showed the highest absolute positivity, while preschoolers (3–6 years) exhibited the most dramatic relative surge—a 130% increase from 2019 baselines (from 14.03% to 32.23%)—and bore disproportionate severe burden, constituting 66.67% of severe pneumonia cases. This documents a unique age-specific amplification effect, where > 54% of severe diagnoses with comorbidities occurred in children under six—exceeding other global reports of generic post-NPI intensification [ 14 , 15 ] . Our findings refine the traditional high-risk framework by analyzing the hospitalization data, which reveal a steep inverse relationship between age and severity: For neonates (≤ 28 days) suffer the highest hospitalization rate (16.67% of Flu A positive) and for children older than 6 years have lowest severity (0.33% hospitalized). Critically, comorbidities amplified severity across all ages but were most consequential in young children. Among Flu A-positive children with severe pneumonia and comorbidities, 100% were under six years, which in line with other research before COVID-19 pandemics [ 16 , 17 ] . We propose that the seasonal expression of immunological debt is characterized by amplified peak intensity, temporal shift of epidemic peaks, and compressed transmission plateaus - collectively generating a "three-excess" post-NPI phenomenon: higher, earlier, and more concentrated epidemic features. Flu A typically triggers seasonal epidemics, which, in the Shanghai area, are primarily characterized by high incidence during the winter and spring (December to March), with a potential second peak in July to September [ 18 – 20 ] . The restructuring of epidemic windows manifested as a shift from the traditional winter-spring bimodal pattern to a three-phase high-pressure transmission model (winter-early spring-summer) in 2023, accompanied by seasonal compression that shortened the high-prevalence plateau by one month. Concurrently, the monthly average of influenza A-positive cases surged to 2.8 times pre-pandemic (2019) levels. This phenomenon suggests NPIs not merely delayed but fundamentally altered population susceptibility dynamics. Notably, neonates exhibited persistent low susceptibility (positivity rate ≤ 2%) with resilience to seasonal fluctuations. Our analysis of laboratory data further revealed notable mechanistic insights. Key laboratory differences were identified between hospitalized and outpatient influenza A-positive children: hospitalized patients exhibited significantly lower white blood cell counts (WBC: 6.21 vs. 6.70 × 10⁹/L, p = 0.018), neutrophil percentages (NEU%: 52.65% vs. 66.70%, p < 0.001), and hemoglobin levels (Hgb: 119 vs. 129 g/L, p < 0.001), while showing significantly higher C-reactive protein (CRP: 4.50 vs. 3.30 mg/L, p = 0.001) and platelet counts (PLT: 240 vs. 119 × 10⁹/L, p < 0.001). This triad of leukopenia, anemia, and thrombocytosis—accompanied by elevated CRP—suggests dysregulated inflammation and bone marrow suppression in severe pediatric influenza. While previous studies compared Flu A-positive children to healthy controls, our severity-based comparison provides actionable clinical thresholds: WBC < 6.5×10⁹/L, Hgb 200×10⁹/L should raise concern for progression risk in Flu A-positive children. Implementation of these clinical thresholds may reduce severe disease incidence, shorten hospitalization duration, and alleviate disease burden in pediatric influenza cases. The 2023 surge demonstrates that NPIs, while critical for pandemic control, incur immunological costs that manifest asymmetrically across pediatric subpopulations. This necessitates a "catch-up" immunization strategy for cohorts with minimal influenza exposure during 2020–2022 [ 3 , 21 ] . Based on our data landscape, we present evidence-based strategic imperatives for public health intervention. Our data underscores the importance of prioritizing age-targeted campaigns for children under 6 years, particularly those with comorbidities such as congenital heart disease, immunodeficiencies, or tumors. We should intensify comorbidity vigilance by systematically integrating influenza testing into the management of respiratory illnesses in children with underlying conditions. Besides, we propose adapt strategies in bimodal regions like Shanghai by considering staggered vaccination schedules (October for the winter peak and May for the summer resurgence). Furthermore, enhance hospital preparedness to anticipate healthcare system overload from extended surges characterized by disproportionate hospitalizations of young children. According to the clinical evidence mentioned before, leveraging integrated hematological risk thresholds (WBC < 6.5×10⁹/L, Hgb 200×10⁹/L) can facilitate rapid stratification of high-acuity patients, enabling timely intervention. Our study has limitations, including a single-center design that may limit generalizability and a short post-pandemic observation period (only 2023) that warrants longer surveillance; additionally, the neonatal subgroup was under sampled, necessitating multicenter collaboration for this vulnerable population. Consequently, future research should track seroconversion patterns in birth cohorts exposed versus not exposed to influenza during non-pharmaceutical interventions (NPIs), validate hematological severity markers prospectively, and model optimal vaccination timing using regional bimodal incidence data. CONCLUSION This large-scale study delineates the tripartite impact of COVID-19 NPIs on pediatric influenza A epidemiology: transmission collapse, hyperendemic rebound, and seasonal distortion with extended spring-summer activity. Critically, we identify asymmetric susceptibility driven by immunological debt, where children < 6 years with comorbidities bore disproportionate severe burden. The discovery of actionable hematological thresholds enables rapid risk stratification, while the shift to bimodal epidemic peaks necessitates regionally tailored vaccination strategies. These findings compel prioritized protection of young children (< 6 years) through enhanced surveillance, comorbidity-focused testing, and staggered immunization targeting post-NPI vulnerability windows. Declarations CONFLICT OF INTEREST There is no conflict of interest. FUNDING RESOURCE There is no funding. ETHICAL APPROVAL STATEMENT This study was reviewed and approved by the Ethics Committee of Shanghai Children’s Medical Center, under approval number SCMCIRB-K2025192-1. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. AUTHOR CONTRIBUTIONS Yu Zhu & Yu Chen: study design, and data analysis and manuscript preparation. Guiling Xu, Qing Fang, Xiaotong Xue, Kejun Hu, Sha Zhou : study design and data analysis. Li Hong & Ying Xiang: study supervision and manuscript revision. All authors contributed to the article and approved the submitted version. References Uyeki TM, Hui DS, Zambon M, Wentworth DE, Monto AS. Influenza Lancet. 2022;400:693–706. https://doi.org/10.1016/S0140-6736(22)00982-5 . Cohen R, Pettoello-Mantovani M, Somekh E, Levy C. European Pediatric Societies Call for an Implementation of Regular Vaccination Programs to Contrast the Immunity Debt Associated to Coronavirus Disease-2019 Pandemic in Children. J Pediatr 242, 260–261 e263 (2022). https://doi.org/10.1016/j.jpeds.2021.11.061 Nygaard U, Holm M, Rabie H, Rytter M. The pattern of childhood infections during and after the COVID-19 pandemic. Lancet Child Adolesc Health. 2024;8:910–20. https://doi.org/10.1016/S2352-4642(24)00236-0 . Lenglart L, et al. Surge of Pediatric Respiratory Tract Infections after the COVID-19 Pandemic and the Concept of Immune Debt. J Pediatr. 2024;284:114420. https://doi.org/10.1016/j.jpeds.2024.114420 . Li X, et al. Genetic characteristics of H1N1 influenza virus outbreak in China in early 2023. Virol Sin. 2024;39:520–3. https://doi.org/10.1016/j.virs.2024.05.003 . Angoulvant F, et al. Coronavirus Disease 2019 Pandemic: Impact Caused by School Closure and National Lockdown on Pediatric Visits and Admissions for Viral and Nonviral Infections-a Time Series Analysis. Clin Infect Dis. 2021;72:319–22. https://doi.org/10.1093/cid/ciaa710 . Ouldali N, et al. Increase of invasive pneumococcal disease in children temporally associated with RSV outbreak in Quebec: a time-series analysis. Lancet Reg Health Am. 2023;19:100448. https://doi.org/10.1016/j.lana.2023.100448 . Wrenn K, et al. Surge of lower respiratory tract group A streptococcal infections in England in winter 2022: epidemiology and clinical profile. Lancet. 2023;402(Suppl 1). https://doi.org/10.1016/S0140-6736(23)02095-0 . Goldberg-Bockhorn E, Hagemann B, Furitsch M, Hoffmann TK. Invasive Group A Streptococcal Infections in Europe After the COVID-19 Pandemic. Dtsch Arztebl Int. 2024;121:673–80. https://doi.org/10.3238/arztebl.m2024.0127 . Dungu KHS, et al. Mycoplasma pneumoniae incidence, phenotype, and severity in children and adolescents in Denmark before, during, and after the COVID-19 pandemic: a nationwide multicentre population-based cohort study. Lancet Reg Health Eur. 2024;47:101103. https://doi.org/10.1016/j.lanepe.2024.101103 . Rybak A, et al. Association of Nonpharmaceutical Interventions During the COVID-19 Pandemic With Invasive Pneumococcal Disease, Pneumococcal Carriage, and Respiratory Viral Infections Among Children in France. JAMA Netw Open. 2022;5:e2218959. https://doi.org/10.1001/jamanetworkopen.2022.18959 . Schultze JL, Aschenbrenner AC. COVID-19 and the human innate immune system. Cell. 2021;184:1671–92. https://doi.org/10.1016/j.cell.2021.02.029 . Zhang HP, et al. Recent developments in the immunopathology of COVID-19. Allergy. 2023;78:369–88. https://doi.org/10.1111/all.15593 . Pierce CA, et al. COVID-19 and children. Science. 2022;377:1144–9. https://doi.org/10.1126/science.ade1675 . Patel JM. Multisystem Inflammatory Syndrome in Children (MIS-C). Curr Allergy Asthma Rep. 2022;22:53–60. https://doi.org/10.1007/s11882-022-01031-4 . Nayak J, Hoy G, Gordon A. Influenza in Children. Cold Spring Harb Perspect Med. 2021;11. https://doi.org/10.1101/cshperspect.a038430 . Caini S, et al. Distribution of influenza virus types by age using case-based global surveillance data from twenty-nine countries, 1999–2014. BMC Infect Dis. 2018;18:269. https://doi.org/10.1186/s12879-018-3181-y . Liao Y, et al. Characterization of influenza seasonality in China, 2010–2018: Implications for seasonal influenza vaccination timing. Influenza Other Respir Viruses. 2022;16:1161–71. https://doi.org/10.1111/irv.13047 . Si X, Wang L, Mengersen K, Hu W. Epidemiological features of seasonal influenza transmission among 11 climate zones in Chinese Mainland. Infect Dis Poverty. 2024;13:4. https://doi.org/10.1186/s40249-024-01173-9 . Zhu AQ, Li ZJ, Zhang HJ. Spatial timing of circulating seasonal influenza A and B viruses in China from 2014 to 2018. Sci Rep. 2023;13:7149. https://doi.org/10.1038/s41598-023-33726-7 . Zhao P, et al. Epidemiology of respiratory pathogens in patients with acute respiratory infections during the COVID-19 pandemic and after easing of COVID-19 restrictions. Microbiol Spectr. 2024;12:e0116124. https://doi.org/10.1128/spectrum.01161-24 . Tables Tables 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files SupplementaryTables.docx Tables.docx Cite Share Download PDF Status: Published Journal Publication published 17 Jan, 2026 Read the published version in BMC Infectious Diseases → Version 1 posted Editorial decision: Revision requested 12 Nov, 2025 Reviews received at journal 11 Nov, 2025 Reviews received at journal 07 Nov, 2025 Reviews received at journal 05 Nov, 2025 Reviewers agreed at journal 01 Nov, 2025 Reviewers agreed at journal 30 Oct, 2025 Reviewers agreed at journal 30 Oct, 2025 Reviewers invited by journal 30 Oct, 2025 Editor invited by journal 30 Oct, 2025 Editor assigned by journal 29 Oct, 2025 Submission checks completed at journal 29 Oct, 2025 First submitted to journal 22 Oct, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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1","display":"","copyAsset":false,"role":"figure","size":123270,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(A) Distribution of positive rates in different years and months. \u003c/strong\u003eThe horizontal axis shows the months, while the vertical axis displays the positive rate (%). Years (2019–2023) are marked in the figure. \u003cstrong\u003e(B) Seasonal epidemiological trends from 2019 to 2023. \u003c/strong\u003eThe horizontal axis shows the seasons, while the vertical axis displays the positive rate (%). Years (2019–2023) are marked in the figure.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7920288/v1/60e082fb39e2cd1a1442e351.png"},{"id":95567908,"identity":"7e3517c8-2e15-4146-847f-da62ab822e76","added_by":"auto","created_at":"2025-11-10 16:23:39","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":77711,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(A) Hospitalization rates of different age groups in overall cohort.\u003c/strong\u003e The horizontal axis shows the proportion (%), while the vertical axis displays the age. Outpatients are represented by blue, while inpatients are denoted by red. \u003cstrong\u003e(B) Hospitalization rates of different age groups in infected subpopulation. \u003c/strong\u003eThe horizontal axis shows the proportion (%), while the vertical axis displays the age. Outpatients are represented by blue, while inpatients are denoted by red. \u003cstrong\u003e(C) Different diagnosis among influenza A-positive children in different age groups. \u003c/strong\u003eThe horizontal axis shows the proportion (%), while the vertical axis displays different diagnosis.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7920288/v1/43fa6ef4fc761a4a259193a5.png"},{"id":100615751,"identity":"b113f9f0-7f5f-4537-91d8-c8da5367dac4","added_by":"auto","created_at":"2026-01-19 17:36:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":971831,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7920288/v1/c968937f-5b65-4be7-8f04-d80ee64c7b04.pdf"},{"id":95567872,"identity":"f10ab73d-82da-4707-b438-9e1331dc628f","added_by":"auto","created_at":"2025-11-10 16:23:36","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":927582,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTables.docx","url":"https://assets-eu.researchsquare.com/files/rs-7920288/v1/2b854945d9726362a236cdf5.docx"},{"id":95567904,"identity":"6eb6443e-a1e8-4d22-8c6b-c938c5e1cbc0","added_by":"auto","created_at":"2025-11-10 16:23:39","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":497839,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-7920288/v1/089bd53b3a66ff1990f17171.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Resurgence and Clinical Evolution of Influenza A in Chinese Children: Shifting Epidemiology and Serological Dynamics Across Pre-, Intra-, and Post- Pandemic Eras (2019-2023)","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eInfluenza A virus (Flu A) is a common etiological agent of acute respiratory infections (ARIs) in children, capable of triggering seasonal influenza pandemics exhibiting a spectrum of disease severity. Infected individuals typically present with fever, cough, or myalgia, and recover within one week. However, certain patient populations\u0026mdash;particularly young children, older adults, pregnant women, and individuals with specific comorbidities\u0026mdash;are at elevated risk for complications leading to medical consultation, hospitalization, and mortality \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe COVID-19 pandemic emerged in China in December 2019. From early 2020 through December 2022, the implementation of nonpharmaceutical interventions (NPIs) effectively curtailed SARS-CoV-2 transmission. Concurrently, these measures impacted the characteristic seasonal epidemiology of FLUA, which shares respiratory transmission routes. Nevertheless, the \"immune debt\" incurred during the pandemic period poses a significant concern, potentially predisposing children to more severe and extensive future epidemics \u003csup\u003e[\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eExisting data indicate that from mid-February to late April 2023, China experienced an influenza epidemic dominated by the influenza A (H1N1) subtype, with its intensity marginally exceeding that of pre-COVID-19 pandemic seasons \u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. To further investigate the evolving epidemiological characteristics of influenza A and evaluate the clinical utility of serological findings for guiding diagnosis/treatment in the post-pandemic era, we conducted a large-scale, single-center retrospective study at Shanghai Children's Medical Center. This research aims to provide evidence-based, targeted recommendations for influenza A prevention and control in pediatric populations.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003e\u003cstrong\u003e1. Study design and approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study collected data from patients tested for influenza A virus at Shanghai Children\u0026apos;s Medical Center between January 2019 and December 2023. For patients undergoing multiple influenza A tests within a single month, only one record was retained when results were consistent, while positive results were prioritized in cases of discordant findings. After applying these deduplication criteria, 238,494 distinct cases were included for analysis. The dataset comprised demographic information (gender, age), influenza A test results, clinical diagnoses, hospitalization status, and complete blood count parameters including white blood cell count (WBC), C-reactive protein (CRP), neutrophil percentage (NEU%), hemoglobin (Hgb), and platelet count (PLT).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis retrospective observational study was approved by the Ethics Committee of Shanghai Children\u0026apos;s Medical Center with waiver of informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2. Definitions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBased on China\u0026apos;s actual COVID-19 pandemic progression, this study defined January 2019-January 23, 2020 as the pre-pandemic period (Phase I), January 24, 2020-December 12, 2022 as the pandemic period (Phase II), and December 13, 2022-December 31, 2023 (Phase III)\u0026nbsp;as the post-pandemic period. The cohort comprised pediatric patients (0-18 years) stratified into four age groups: neonates (\u0026le;28 days), infants/toddlers (29 days-3 years), preschoolers (3-6 years), and school-aged/adolescents (\u0026ge;6 years). Seasons were categorized as spring (March-May), summer (June-August), autumn (September-November), and winter (December-February). Diagnostic classifications encompassed 11 mutually exclusive categories according to standardized diagnostic criteria: upper respiratory tract infection (URTI), bronchitis, pneumonia, severe pneumonia, infectious fever, URTI with non-infectious conditions, bronchitis with non-infectious conditions, pneumonia with non-infectious conditions, severe pneumonia with non-infectious conditions, infectious fever with non-infectious conditions, and non-infectious conditions. Notably, among these patients primarily \u0026lsquo;non-infectious\u0026rsquo; conditions include malignancies, congenital heart disease, and immunodeficiency disorders.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3. Data Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBased on the results of the Shapiro-Wilk test, continuous variables were expressed as mean and standard deviation or median and interquartile range, and the comparison of the variables of groups were evaluated using Wilcoxon rank-sum test. Categorical variables were displayed as numbers and percentages and were analyzed with the Chi-square test or Fisher\u0026rsquo;s exact test (when the expected cell number was less than 5).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eComparison of the flu-positive rate among multiple groups was performed using the chi-square test or Fisher exact probability method. Post hoc pairwise comparison was further conducted to examine differences between subgroups with Bonferroni correction of P. The receiver operating characteristic (ROC) curve analyses was established to interpret the ability of inflammatory indicators in discriminating flu-positive patients from healthy controls. All statistical analyses were performed with Stata (version 16.0) and Rstudio (version 4.2.2), and P\u0026lt; 0.05 were accepted as significant.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003e1.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCharacteristics of the study population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 238,494 pediatric patients were enrolled between January 2019 and December 2023, with 111,757 (46.86%) girls and 126,737 (53.14%) boys. When stratified by pandemic phases, the pre-pandemic period (January 2019-January 23, 2020) included 111,897 patients (56,158 girls [47.19%], 62,839 boys [52.81%]; median age 5.00 years, IQR 3.00-7.00), while the pandemic period (January 24, 2020-December 12, 2022) comprised 40,473 patients (18,785 girls [46.41%], 21,688 boys [53.59%]; median age 4.00, IQR 2.00-6.00), and the post-pandemic phase (December 13, 2022-2023) contained 79,024 patients (36,814 girls [46.59%], 42,210 boys [53.41%]; median age 6.08, IQR 3.56-8.92). Gender-specific differences in detection rates across all phases reached statistical significance (\u0026chi;\u0026sup2;=41.7, 14.2, and 82.1 for respective periods, all p\u0026lt;0.001; Tables 1.1-1.3), with detailed patient characteristics provided in \u003cstrong\u003eTable 1 and Supplement Table 1\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2. Distribution of positive rates in different years and months\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe overall influenza A positivity rate was 18.36% (43,779/238,494), exhibiting annual fluctuations: 13.66% in 2019, 7.79% in 2020, 1.00% in 2021, 6.79% in 2022, and 33.33% in 2023. During the pandemic period, positivity rates remained consistently low without discernible seasonal peaks, whereas post-pandemic rates significantly exceeded pre-pandemic levels. Both 2019 and 2023 demonstrated bimodal peaks (February - March and December), though the 2023 plateau phase contracted to May-July compared to April-July in 2019 (\u003cstrong\u003eFigure 1A\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3. Distribution of positive rates in various age groups\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAge-stratified analysis revealed progressively increasing positivity rates with advancing age: 1.12% in neonates (\u0026le;28 days), 11.48% in infants (29 days-3 years), 17.31% in preschoolers (3-6 years), and 23.20% in school-aged/adolescents (\u0026ge;6 years) (\u003cstrong\u003eTable 2\u003c/strong\u003e). While all age groups except neonates exhibited concordant epidemiological trends, the pandemic period showed universally low rates without seasonality, contrasting with elevated post-pandemic rates featuring prominent spring and winter peaks (\u003cstrong\u003eFigure 1B\u003c/strong\u003e), consistent with population-level patterns in Figure 1A.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4. Analysis\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;of hospitalization in various age groups\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHospitalization rates demonstrated an inverse relationship with age, declining from 72.16% in neonates to 6.74% in infants, 2.07% in preschoolers, and 2.39% in older children. This gradient persisted among influenza A-positive patients, with corresponding rates of 16.67%, 1.42%, 0.36%, and 0.33%, confirming parallel trends between the overall cohort and infected subpopulation (\u003cstrong\u003eFigures 2A and 2B\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e5. Analysis\u0026nbsp;of\u0026nbsp;age\u0026nbsp;in different diagnosis among influenza A-positive children\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong 43,779 influenza A-positive children, those diagnosed with URTI included 14,730 (45.36%) aged \u0026lt;6 years, while 48 (50.00%) of URTI-with-comorbidities cases were under six. Similarly, bronchitis diagnoses comprised 2,010 (50.59%) children \u0026lt;6 years versus 5 (62.50%) in the bronchitis-with-comorbidities group. For pneumonia, 490 (54.93%) patients were \u0026lt;6 years compared to 4 (66.67%) with pneumonia-comorbidity complex, and severe pneumonia cases showed 10 (66.67%) and 1 (100.00%) under-six patients respectively. Infectious fever diagnoses included 3,357 (54.40%) children \u0026lt;6 years versus 36 (52.94%) with comorbidities. This progressive increase in younger patients with rising respiratory severity (URTI to severe pneumonia) was paralleled by elevated proportions of under-six children when malignancies, congenital heart disease, or immunodeficiency comorbidities were present (\u003cstrong\u003eFigure 2C\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e6. Analysis of serological findings in patients positive and negative for influenza A\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSerologically, influenza A-positive children demonstrated lower WBC (6.70\u0026times;10⁹/L vs. 7.88\u0026times;10⁹/L, P\u0026lt;0.001), CRP (3.30 mg/L vs. 4.20 mg/L, P\u0026lt;0.001), and PLT (200\u0026times;10⁹/L vs. 201\u0026times;10⁹/L, P\u0026lt;0.001) but higher NEU% (66.70% vs. 61.80%, P\u0026lt;0.001) and HGB (129 g/L vs. 126 g/L, P\u0026lt;0.001) than negative controls (\u003cstrong\u003eTable 3\u003c/strong\u003e). Further stratification showed hospitalized positives had reduced WBC (6.21\u0026times;10⁹/L vs. 6.70\u0026times;10⁹/L, P=0.018), NEU% (52.65% vs. 66.70%, P\u0026lt;0.001), and HGB (119 g/L vs. 129 g/L, P\u0026lt;0.001) but elevated CRP (4.50 mg/L vs. 3.30 mg/L, P=0.001) and PLT (240\u0026times;10⁹/L vs. 200\u0026times;10⁹/L, P\u0026lt;0.001) versus outpatient positives (\u003cstrong\u003eTable 3\u003c/strong\u003e). While neonates (\u0026le;28 days) showed no significant serological differences between influenza statuses, all older age groups exhibited marked variations (P\u0026lt;0.001), as did patients with concomitant respiratory infections, bronchitis, or pneumonia (P\u0026lt;0.001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e7. Analysis of inpatients versus outpatients among influenza A-positive children\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnalysis of 43,779 influenza A-positive cases revealed 220 inpatients versus 43,559 outpatients (hospitalization rate: 5.03%). No significant gender differences existed between groups, but inpatients exhibited significantly younger median age than outpatients (4.00 vs. 6.00 years, P\u0026lt;0.001), aligning with \u003cstrong\u003eTable 3\u003c/strong\u003e findings.\u0026nbsp;\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis large-scale retrospective study of 238494 pediatric encounters at Shanghai Children's Medical Center provides critical insights into the profound epidemiological disruption of influenza A (Flu A) by COVID-19 non-pharmaceutical interventions (NPIs) and the subsequent resurgence phase. NPIs did reduce the circulation of COVID-19, as well as other respiratory pathogens during the COVID-19 pandemic period \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Our analysis reveals that COVID-19 NPIs induced a triple evolutionary shift in influenza A dynamics: transmission collapse (2020\u0026ndash;2022 positivity\u0026thinsp;\u0026le;\u0026thinsp;7.79%), hyperendemic rebound (2023 incidence 2.43 time than pre pandemic levels and 4.27\u0026ndash;33 time than pandemic levels), and seasonal distortion (extended spring-summer activity: May\u0026ndash;July positivity\u0026thinsp;\u0026gt;\u0026thinsp;30%). This is in line with other respiratory pathogens in other countries \u003csup\u003e[\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. Crucially, we identify asymmetric susceptibility as the core driver of post-NPI severity, where birth cohorts with minimal 2020\u0026ndash;2022 viral exposure exhibited profound immunological na\u0026iuml;vet\u0026eacute;, creating a \"triple jeopardy\" population (children\u0026thinsp;\u0026lt;\u0026thinsp;6 years with comorbidities) that suffered disproportionate complications \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. These findings substantiate the immunization debt hypothesis while highlighting emerging vulnerabilities in young children who lack the trained immunity \u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe near-elimination of Flu A during China\u0026rsquo;s stringent NPIs (2020\u0026ndash;2022) demonstrates the effectiveness of measures like school closures and mask mandates against respiratory viruses beyond SARS-CoV-2. However, this suppression incurred an immunological debt through interrupted immune priming in birth cohorts. This suggests that while NPIs broadly suppressed transmission, they created pockets of extreme susceptibility in immunologically na\u0026iuml;ve children with pre-existing conditions. Our data reveal explosive cross-age transmission in 2023, school-aged children (\u0026ge;\u0026thinsp;6 years) showed the highest absolute positivity, while preschoolers (3\u0026ndash;6 years) exhibited the most dramatic relative surge\u0026mdash;a 130% increase from 2019 baselines (from 14.03% to 32.23%)\u0026mdash;and bore disproportionate severe burden, constituting 66.67% of severe pneumonia cases. This documents a unique age-specific amplification effect, where \u0026gt;\u0026thinsp;54% of severe diagnoses with comorbidities occurred in children under six\u0026mdash;exceeding other global reports of generic post-NPI intensification \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. Our findings refine the traditional high-risk framework by analyzing the hospitalization data, which reveal a steep inverse relationship between age and severity: For neonates (\u0026le;\u0026thinsp;28 days) suffer the highest hospitalization rate (16.67% of Flu A positive) and for children older than 6 years have lowest severity (0.33% hospitalized). Critically, comorbidities amplified severity across all ages but were most consequential in young children. Among Flu A-positive children with severe pneumonia and comorbidities, 100% were under six years, which in line with other research before COVID-19 pandemics \u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eWe propose that the seasonal expression of immunological debt is characterized by amplified peak intensity, temporal shift of epidemic peaks, and compressed transmission plateaus - collectively generating a \"three-excess\" post-NPI phenomenon: higher, earlier, and more concentrated epidemic features. Flu A typically triggers seasonal epidemics, which, in the Shanghai area, are primarily characterized by high incidence during the winter and spring (December to March), with a potential second peak in July to September \u003csup\u003e[\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. The restructuring of epidemic windows manifested as a shift from the traditional winter-spring bimodal pattern to a three-phase high-pressure transmission model (winter-early spring-summer) in 2023, accompanied by seasonal compression that shortened the high-prevalence plateau by one month. Concurrently, the monthly average of influenza A-positive cases surged to 2.8 times pre-pandemic (2019) levels. This phenomenon suggests NPIs not merely delayed but fundamentally altered population susceptibility dynamics. Notably, neonates exhibited persistent low susceptibility (positivity rate\u0026thinsp;\u0026le;\u0026thinsp;2%) with resilience to seasonal fluctuations.\u003c/p\u003e\u003cp\u003eOur analysis of laboratory data further revealed notable mechanistic insights. Key laboratory differences were identified between hospitalized and outpatient influenza A-positive children: hospitalized patients exhibited significantly lower white blood cell counts (WBC: 6.21 vs. 6.70 \u0026times; 10⁹/L, p\u0026thinsp;=\u0026thinsp;0.018), neutrophil percentages (NEU%: 52.65% vs. 66.70%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and hemoglobin levels (Hgb: 119 vs. 129 g/L, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), while showing significantly higher C-reactive protein (CRP: 4.50 vs. 3.30 mg/L, p\u0026thinsp;=\u0026thinsp;0.001) and platelet counts (PLT: 240 vs. 119 \u0026times; 10⁹/L, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). This triad of leukopenia, anemia, and thrombocytosis\u0026mdash;accompanied by elevated CRP\u0026mdash;suggests dysregulated inflammation and bone marrow suppression in severe pediatric influenza. While previous studies compared Flu A-positive children to healthy controls, our severity-based comparison provides actionable clinical thresholds: WBC\u0026thinsp;\u0026lt;\u0026thinsp;6.5\u0026times;10⁹/L, Hgb\u0026thinsp;\u0026lt;\u0026thinsp;120 g/L, and PLT\u0026thinsp;\u0026gt;\u0026thinsp;200\u0026times;10⁹/L should raise concern for progression risk in Flu A-positive children. Implementation of these clinical thresholds may reduce severe disease incidence, shorten hospitalization duration, and alleviate disease burden in pediatric influenza cases.\u003c/p\u003e\u003cp\u003eThe 2023 surge demonstrates that NPIs, while critical for pandemic control, incur immunological costs that manifest asymmetrically across pediatric subpopulations. This necessitates a \"catch-up\" immunization strategy for cohorts with minimal influenza exposure during 2020\u0026ndash;2022 \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. Based on our data landscape, we present evidence-based strategic imperatives for public health intervention. Our data underscores the importance of prioritizing age-targeted campaigns for children under 6 years, particularly those with comorbidities such as congenital heart disease, immunodeficiencies, or tumors. We should intensify comorbidity vigilance by systematically integrating influenza testing into the management of respiratory illnesses in children with underlying conditions. Besides, we propose adapt strategies in bimodal regions like Shanghai by considering staggered vaccination schedules (October for the winter peak and May for the summer resurgence). Furthermore, enhance hospital preparedness to anticipate healthcare system overload from extended surges characterized by disproportionate hospitalizations of young children. According to the clinical evidence mentioned before, leveraging integrated hematological risk thresholds (WBC\u0026thinsp;\u0026lt;\u0026thinsp;6.5\u0026times;10⁹/L, Hgb\u0026thinsp;\u0026lt;\u0026thinsp;120 g/L, PLT\u0026thinsp;\u0026gt;\u0026thinsp;200\u0026times;10⁹/L) can facilitate rapid stratification of high-acuity patients, enabling timely intervention.\u003c/p\u003e\u003cp\u003eOur study has limitations, including a single-center design that may limit generalizability and a short post-pandemic observation period (only 2023) that warrants longer surveillance; additionally, the neonatal subgroup was under sampled, necessitating multicenter collaboration for this vulnerable population. Consequently, future research should track seroconversion patterns in birth cohorts exposed versus not exposed to influenza during non-pharmaceutical interventions (NPIs), validate hematological severity markers prospectively, and model optimal vaccination timing using regional bimodal incidence data.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eThis large-scale study delineates the tripartite impact of COVID-19 NPIs on pediatric influenza A epidemiology: transmission collapse, hyperendemic rebound, and seasonal distortion with extended spring-summer activity. Critically, we identify asymmetric susceptibility driven by immunological debt, where children\u0026thinsp;\u0026lt;\u0026thinsp;6 years with comorbidities bore disproportionate severe burden. The discovery of actionable hematological thresholds enables rapid risk stratification, while the shift to bimodal epidemic peaks necessitates regionally tailored vaccination strategies. These findings compel prioritized protection of young children (\u0026lt;\u0026thinsp;6 years) through enhanced surveillance, comorbidity-focused testing, and staggered immunization targeting post-NPI vulnerability windows.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCONFLICT OF INTEREST\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere is no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING RESOURCE\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere is no funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eETHICAL APPROVAL STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was reviewed and approved by the Ethics Committee of Shanghai Children\u0026rsquo;s Medical Center, under approval number SCMCIRB-K2025192-1. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYu Zhu \u0026amp; Yu Chen: study design, and data analysis and manuscript preparation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGuiling Xu,\u003cstrong\u003eQing Fang, Xiaotong Xue, Kejun Hu, Sha Zhou\u003c/strong\u003e\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003estudy design and data analysis.\u003c/p\u003e\n\u003cp\u003eLi Hong \u0026amp; Ying Xiang: study supervision and manuscript revision.\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the article and approved the submitted version.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eUyeki TM, Hui DS, Zambon M, Wentworth DE, Monto AS. Influenza Lancet. 2022;400:693\u0026ndash;706. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S0140-6736(22)00982-5\u003c/span\u003e\u003cspan address=\"10.1016/S0140-6736(22)00982-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCohen R, Pettoello-Mantovani M, Somekh E, Levy C. European Pediatric Societies Call for an Implementation of Regular Vaccination Programs to Contrast the Immunity Debt Associated to Coronavirus Disease-2019 Pandemic in Children. \u003cem\u003eJ Pediatr\u003c/em\u003e 242, 260\u0026ndash;261 e263 (2022). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.jpeds.2021.11.061\u003c/span\u003e\u003cspan address=\"10.1016/j.jpeds.2021.11.061\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNygaard U, Holm M, Rabie H, Rytter M. The pattern of childhood infections during and after the COVID-19 pandemic. Lancet Child Adolesc Health. 2024;8:910\u0026ndash;20. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S2352-4642(24)00236-0\u003c/span\u003e\u003cspan address=\"10.1016/S2352-4642(24)00236-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLenglart L, et al. Surge of Pediatric Respiratory Tract Infections after the COVID-19 Pandemic and the Concept of Immune Debt. J Pediatr. 2024;284:114420. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.jpeds.2024.114420\u003c/span\u003e\u003cspan address=\"10.1016/j.jpeds.2024.114420\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLi X, et al. Genetic characteristics of H1N1 influenza virus outbreak in China in early 2023. Virol Sin. 2024;39:520\u0026ndash;3. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.virs.2024.05.003\u003c/span\u003e\u003cspan address=\"10.1016/j.virs.2024.05.003\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAngoulvant F, et al. Coronavirus Disease 2019 Pandemic: Impact Caused by School Closure and National Lockdown on Pediatric Visits and Admissions for Viral and Nonviral Infections-a Time Series Analysis. Clin Infect Dis. 2021;72:319\u0026ndash;22. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/cid/ciaa710\u003c/span\u003e\u003cspan address=\"10.1093/cid/ciaa710\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOuldali N, et al. Increase of invasive pneumococcal disease in children temporally associated with RSV outbreak in Quebec: a time-series analysis. Lancet Reg Health Am. 2023;19:100448. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.lana.2023.100448\u003c/span\u003e\u003cspan address=\"10.1016/j.lana.2023.100448\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWrenn K, et al. Surge of lower respiratory tract group A streptococcal infections in England in winter 2022: epidemiology and clinical profile. Lancet. 2023;402(Suppl 1). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S0140-6736(23)02095-0\u003c/span\u003e\u003cspan address=\"10.1016/S0140-6736(23)02095-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGoldberg-Bockhorn E, Hagemann B, Furitsch M, Hoffmann TK. Invasive Group A Streptococcal Infections in Europe After the COVID-19 Pandemic. Dtsch Arztebl Int. 2024;121:673\u0026ndash;80. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3238/arztebl.m2024.0127\u003c/span\u003e\u003cspan address=\"10.3238/arztebl.m2024.0127\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDungu KHS, et al. Mycoplasma pneumoniae incidence, phenotype, and severity in children and adolescents in Denmark before, during, and after the COVID-19 pandemic: a nationwide multicentre population-based cohort study. Lancet Reg Health Eur. 2024;47:101103. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.lanepe.2024.101103\u003c/span\u003e\u003cspan address=\"10.1016/j.lanepe.2024.101103\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRybak A, et al. Association of Nonpharmaceutical Interventions During the COVID-19 Pandemic With Invasive Pneumococcal Disease, Pneumococcal Carriage, and Respiratory Viral Infections Among Children in France. JAMA Netw Open. 2022;5:e2218959. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1001/jamanetworkopen.2022.18959\u003c/span\u003e\u003cspan address=\"10.1001/jamanetworkopen.2022.18959\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSchultze JL, Aschenbrenner AC. COVID-19 and the human innate immune system. Cell. 2021;184:1671\u0026ndash;92. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.cell.2021.02.029\u003c/span\u003e\u003cspan address=\"10.1016/j.cell.2021.02.029\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhang HP, et al. Recent developments in the immunopathology of COVID-19. Allergy. 2023;78:369\u0026ndash;88. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/all.15593\u003c/span\u003e\u003cspan address=\"10.1111/all.15593\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePierce CA, et al. COVID-19 and children. Science. 2022;377:1144\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1126/science.ade1675\u003c/span\u003e\u003cspan address=\"10.1126/science.ade1675\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePatel JM. Multisystem Inflammatory Syndrome in Children (MIS-C). Curr Allergy Asthma Rep. 2022;22:53\u0026ndash;60. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s11882-022-01031-4\u003c/span\u003e\u003cspan address=\"10.1007/s11882-022-01031-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNayak J, Hoy G, Gordon A. Influenza in Children. Cold Spring Harb Perspect Med. 2021;11. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1101/cshperspect.a038430\u003c/span\u003e\u003cspan address=\"10.1101/cshperspect.a038430\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCaini S, et al. Distribution of influenza virus types by age using case-based global surveillance data from twenty-nine countries, 1999\u0026ndash;2014. BMC Infect Dis. 2018;18:269. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s12879-018-3181-y\u003c/span\u003e\u003cspan address=\"10.1186/s12879-018-3181-y\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLiao Y, et al. Characterization of influenza seasonality in China, 2010\u0026ndash;2018: Implications for seasonal influenza vaccination timing. Influenza Other Respir Viruses. 2022;16:1161\u0026ndash;71. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/irv.13047\u003c/span\u003e\u003cspan address=\"10.1111/irv.13047\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSi X, Wang L, Mengersen K, Hu W. Epidemiological features of seasonal influenza transmission among 11 climate zones in Chinese Mainland. Infect Dis Poverty. 2024;13:4. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s40249-024-01173-9\u003c/span\u003e\u003cspan address=\"10.1186/s40249-024-01173-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhu AQ, Li ZJ, Zhang HJ. Spatial timing of circulating seasonal influenza A and B viruses in China from 2014 to 2018. Sci Rep. 2023;13:7149. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/s41598-023-33726-7\u003c/span\u003e\u003cspan address=\"10.1038/s41598-023-33726-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhao P, et al. Epidemiology of respiratory pathogens in patients with acute respiratory infections during the COVID-19 pandemic and after easing of COVID-19 restrictions. Microbiol Spectr. 2024;12:e0116124. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1128/spectrum.01161-24\u003c/span\u003e\u003cspan address=\"10.1128/spectrum.01161-24\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Covid-19, influenza A, pediatric, immune debt","lastPublishedDoi":"10.21203/rs.3.rs-7920288/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7920288/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e\u003cp\u003eThis study aimed to analyze the epidemiological characteristics and serological profiles of influenza A in children aged 0\u0026ndash;18 years before and after the COVID-19 pandemic to inform prevention and control strategies.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe conducted a retrospective analysis of 238,494 children tested for influenza A at Shanghai Children's Medical Center (2019.1-2023.12). Positivity rates and serological parameters were evaluated across age groups seasons, and years.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eDuring the pandemic period, influenza A positivity remained consistently low without seasonal peaks. Conversely, post-pandemic positivity (33.33% in 2023) significantly exceeded pre-pandemic levels (13.66% in 2019), exhibiting winter-spring seasonality with bimodal peaks in February-March and December. School-aged children (\u0026ge;\u0026thinsp;6 years) demonstrated the highest post-pandemic positivity rate (38.86%). Hospitalization rates among influenza A-positive children inversely correlated with age: 16.67% in neonates (\u0026le;\u0026thinsp;28 days) vs. 1.42% in infants (29d-3y) vs. 0.36% in preschoolers (3-6y) vs. 0.33% in older children (\u0026ge;\u0026thinsp;6y). Children\u0026thinsp;\u0026lt;\u0026thinsp;6 years predominated in severe diagnoses and comorbid conditions.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eThis study delineates the evolving epidemiology of influenza A from 2019 to 2023. Post-pandemic resurgence demonstrated heightened positivity rates and prolonged seasonal activity exceeding pre-pandemic patterns. Young children and those with comorbidities exhibited greater disease severity requiring hospitalization. Enhanced pediatric influenza A prevention is imperative.\u003c/p\u003e","manuscriptTitle":"Resurgence and Clinical Evolution of Influenza A in Chinese Children: Shifting Epidemiology and Serological Dynamics Across Pre-, Intra-, and Post- Pandemic Eras (2019-2023)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-10 16:23:13","doi":"10.21203/rs.3.rs-7920288/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-11-12T06:18:25+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-11T17:48:38+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-07T10:24:07+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-05T11:34:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"97009973340840854696073524927588822506","date":"2025-11-01T12:36:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"204660920603626762602177951746119737674","date":"2025-10-30T15:20:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"238958089190992884033708225606624902283","date":"2025-10-30T13:27:36+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-30T12:30:59+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-10-30T06:00:42+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-30T00:54:47+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-30T00:53:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Infectious Diseases","date":"2025-10-22T07:22:05+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8ce58f14-c54b-44b5-862f-041ac551d185","owner":[],"postedDate":"November 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-19T17:01:58+00:00","versionOfRecord":{"articleIdentity":"rs-7920288","link":"https://doi.org/10.1186/s12879-025-12468-z","journal":{"identity":"bmc-infectious-diseases","isVorOnly":false,"title":"BMC Infectious Diseases"},"publishedOn":"2026-01-17 16:28:32","publishedOnDateReadable":"January 17th, 2026"},"versionCreatedAt":"2025-11-10 16:23:13","video":"","vorDoi":"10.1186/s12879-025-12468-z","vorDoiUrl":"https://doi.org/10.1186/s12879-025-12468-z","workflowStages":[]},"version":"v1","identity":"rs-7920288","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7920288","identity":"rs-7920288","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}