Cytomegalovirus DNAemia in infants with community-acquired pneumonia complicated by respiratory syncytial virus infection: Risk factors and impact on disease severity

Cytomegalovirus DNAemia in infants with community-acquired pneumonia complicated by respiratory syncytial virus infection: Risk factors and impact on disease severity | 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 Cytomegalovirus DNAemia in infants with community-acquired pneumonia complicated by respiratory syncytial virus infection: Risk factors and impact on disease severity Wenxin Li, Zhiao Du, Xinyi Li, Runjia Hua, Feiyang Zhang, Cheng Peng, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7183389/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background This study aims to evaluate the incidence and risk factors for cytomegalovirus (CMV) DNAemia and its association with disease severity in infants with community-acquired pneumonia (CAP) complicated by respiratory syncytial virus (RSV) infection. Methods In this retrospective, cross-sectional study, we investigated the clinical characteristics of consecutive infants diagnosed with CAP complicated with RSV infection and circulatory whole blood CMV DNA on admission. Using binary logistic regression analysis, the clinical data of these infants were analyzed to identify risk factors for disease severity and CMV DNAemia. Results In all, 241 infants with CAP complicated by RSV infection were enrolled in this study. Fifty-five (22.8%) of these infants had CMV DNAemia. Disease severity was greater in infants with CMV DNAemia than in those without. Additionally, CMV DNAemia (odds ratio [OR], 5.517; 95% confidence interval [CI], 1.839–16.553; P = 0.002) was found to be an independent risk factor for pediatric intensive care unit admission. Furthermore, age (+ 1 month; OR, 0.772; 95% CI, 0.617–0.965; P = 0.023), possible bacterial coinfection (OR, 2.392; 95% CI, 1.115–5.121; P = 0.025), and peripheral leukocyte count (+ 1 × 10 9 /L; OR, 1.220; 95% CI, 1.093–1.362; P < 0.001) were independent risk factors for CMV DNAemia. Conclusions Young age, possible bacterial coinfection, and higher peripheral leukocyte count were associated with an increased risk of CMV DNAemia, while infants with CMV DNAemia had greater disease severity than those without. Clinical trial number: Not applicab Cytomegalovirus infection Community-acquired pneumonia Respiratory syncytial virus Risk factors Figures Figure 1 Figure 2 Introduction Human cytomegalovirus (CMV) is a virus belonging to the herpes virus family with a seroprevalence of 10 ~ 80% in children under 1 year of age, varying across country, socioeconomic status, age, and sex [ 1 ]. CMV can establish a lifelong latent infection following primary infection and can give rise to episodes of reactivation. Immunocompetent children with primary CMV infections and reactivations are usually asymptomatic [ 2 ]. However, CMV disease may be symptomatic in those who are immunosuppressed [ 3 ]. CMV infection elicits an immune response characterized by elevated pro-inflammatory serum cytokine levels, thereby affecting the severity of secondary infections [ 4 – 6 ]. Respiratory syncytial virus (RSV) is a leading cause of hospitalization due to community-acquired pneumonia (CAP) among infants worldwide [ 7 , 8 ]. Several risk factors for severe RSV infection have been identified, including immunodeficiencies, prematurity, chronic lung disease, and congenital heart disease [ 9 , 10 ]. However, the impact of CMV infection on the disease severity of RSV infections has not been adequately investigated. A study using induced sputum samples has previously shown that the prevalence of RSV coinfection with CMV was higher in young children with CAP [ 11 ]. Other studies have shown that a higher CMV viral load in blood is associated with the risk of clinical disease [ 12 , 13 ]. The risk factors associated with CMV DNAemia in CAP infants with RSV infection remain elusive as is the impact of CMV DNAemia on disease severity in these patients. The identification of infants at highest risk for CMV DNAemia among those with CAP complicated by RSV infection might allow for the inclusion of more targeted populations in future trials designed for interventions in this clinical group. To this end, this study was aimed at evaluating the incidence and risk factors for CMV DNAemia in infants with CAP complicated with RSV infection and determining whether CMV DNAemia has any effect on disease severity in this population. Materials and methods Patient Population This investigation was designed as a retrospective cross-sectional study. We screened consecutive infants who were hospitalized for CAP at Children’s Hospital of Soochow University, a tertiary teaching hospital in Suzhou city, China, between January 1, 2019 and December 31, 2024. Since CMV is one of the causative pathogens involved in CAP [ 14 ], most of the patients admitted for CAP at our hospital underwent testing for the detection of CMV DNA in whole blood and the CMV antibody test. The criteria for inclusion in this study were as follows: satisfaction of the diagnostic criteria for CAP, positive testing for RSV detection in nasopharyngeal swab samples, and availability of data on CMV serology with CMV whole blood DNA test on admission. The exclusion criteria were as follows: age < 28 days; negative testing for CMV IgG titers; history of receiving antiviral treatment with acyclovir, ganciclovir, or valaciclovir in the past 14 days; and history of acquired or congenital immunodeficiencies and/or receiving blood transfusion within the past 1 month. This study protocol was approved by the Ethics Committee of the Children’s Hospital of Soochow University (2025CS062). Data Collection The medical records of the subjects who met the inclusion criteria were reviewed to collect data on several parameters: (1) demographic data, including age, sex, underlying medical conditions including laryngo/tracheomalacia and congenital heart disease; (2) PCR test results of nasopharyngeal swab samples for the detection of RSV, along with human rhinovirus, human metapneumovirus, human bocavirus, human influenza A virus, human influenza B virus, adenovirus, parainfluenza virus, coronaviruses, Chlamydophila pneumoniae , and Mycoplasma pneumoniae , performed using a commercialized respiratory pathogen detection kit (Health Gen Tech., Ningbo, China) [ 15 ], within 24 hours of admission; (3) laboratory data, including peripheral leukocyte count, platelet count, neutrophil percentage, C-reactive protein level, aspartate aminotransferase, and alanine aminotransferase, performed within 6 hours of admission; (4) presence/absence of CMV DNA in whole blood, as detected using the CMV nucleic acid test kit (Sansure Biotech Co., Ltd. Hunan, China), within 6 hours of admission and with the detection limit being over 400 copies/mL [ 15 ]; (5) serum IgM and IgG anti-CMV levels, as detected using a CMV antibody detection kit (Autobio Diagnostics Co., Ltd. Zhengzhou, China), with CMV IgM titers of ≥ 8 AU/mL and CMV of IgG titers ≥ 10 AU/mL being considered as positive [ 15 ]; and (6) disease severity parameters, including length of hospitalization, admission to and length of stay in the pediatric intensive care unit (PICU), and need for and duration of supplemental oxygen [ 10 ]. CAP was defined by the presence of cough, fever, dyspnea, abnormal breath sounds, and new pulmonary infiltrate on imaging [ 14 ]. CMV DNAemia was defined by the detection of CMV DNA in whole blood. Possible bacterial infection was defined by a semiquantitative culture of nasopharyngeal swab samples with colonization density ranging from 3+ (> 10 colonies in quadrant 3 but 10 colonies in quadrant 4). The anti-CMV therapy administered was determined by the attending physician [ 16 ]. Statistical Analysis Descriptive Analysis: Categorical variables were reported as n (%). The normality of numerical variables was determined by Kolmogorov-Smironov test, and variables not showing normal distribution were presented as median [interquartile range (IQR)]. Bivariate Analysis: Categorical variables were compared using the chi-square test or Fisher’s exact test, as appropriate, whereas numerical variables were compared using the Mann-Whitney U test. Multivariable Analysis: The risk factors associated with PICU requirement, oxygen requirement, and CMV DNAemia were determined using the binary logistic regression model. Age, sex, and variables determined to have a P value of < 0.10 in the univariate analyses were entered into the binary logistic regression model. The variables were selected by using the backward elimination method. The association of predictors with PICU requirement, oxygen requirement, and CMV DNAemia was expressed in terms of odds ratios (ORs) and 95% confidence intervals (95% CIs). P < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS (version 21.0). Results Patient characteristics During the study period, 979 patients with pneumonia underwent RSV serology, CMV serology, and CMV whole blood DNA tests; of these patients, 241 met the diagnostic criteria for CAP complicated by RSV infection. The most common reasons for exclusion were negative test results for RSV detection and age<28 days. These 241 patients were 1 to 11 months old [median: 2.0 months; interquartile range: 1.0–4.0 months]. Fifty-five (22.8%, 55/241) patients tested positive for whole blood CMV DNA, i.e. CMV DNAemia, while the remaining 186 (77.2%, 186/241) were without CMV DNAemia. Ninety (37.3%, 90/241) patients tested positive for CMV IgM, and the rate of CMV IgM positivity was higher among patients with CMV DNAemia than in those without (85.5% vs. 23.1%, P <0.001). Microbiological evaluation In all, 94 (39.0%) of the patients tested positive for the presence of another pathogen detected on admission. Figure 1 shows the distribution of co-infections and their association. Among 241 patients, 73 (30.3%) had a possible bacterial co-infection, 6 (2.5%) had Mycoplasma pneumoniae co-infection, and 36 (14.9%) had viral coinfection. Moreover, 20 (8.3%) patients had at least two co-infections. Clinical characteristics of patients with or without CMV DNAemia The clinical characteristics of patients with and without CMV DNAemia are presented in Table 1 . Compared to those without CMV DNAemia, those with CMV DNAemia had significantly higher peripheral leukocyte count ( P = 0.002), alanine transaminase level ( P = 0.030), aspartate aminotransferase level ( P = 0.045), and percentage of patients with possible bacterial co-infection ( P = 0.014). Table 1 Clinical characteristics of patients with or without CMV DNAemia Characteristic All patients (n = 241) With CMV DNAemia (n = 55) Without CMV DNAemia (n = 186) P Age, months 2.0 (1.0–4.0) 2.0 (2.0–3.0) 2.0 (1.0–4.0) 0.362 Male, n (%) 157 (65.1) 31 (56.4) 126 (67.7) 0.120 Laryngo/tracheomalacia, n (%) 16 (6.6) 5 (9.1) 11 (5.9) 0.372 Congenital heart disease a , n (%) 24 (10.0) 5 (9.1) 19 (10.2) 0.807 Peripheral leukocyte count, 10 9 /L 8.3 (6.5–10.7) 9.1 (7.5–12.2) 7.7 (6.2–10.4) 0.002 Neutrophil count, % 23.7 (17.3–36.0) 22.8 (16.6–38.0) 24.1 (17.3–34.0) 0.925 Platelet count, 10 9 /L 390.0 (313.0-473.0) 368.0 (326.0-453.0) 396.0 (304.0-483.0) 0.356 C-reactive protein, mg/dL 1.8 (0.7-7.0) 1.4 (0.5–6.9) 0.8 (0-3.4) 0.282 Alanine transaminase, U/L 31.2 (22.9–48.7) 38.7 (24.0-79.2) 30.7 (22.1–46.5) 0.030 Aspartate aminotransferase, U/L 47.9 (37.3–63.9) 51.5 (39.1–86.3) 46.8 (37.1–61.6) 0.045 Virus or Mycoplasma pneumoniae co-infection, n (%) 39 (16.2) 9 (16.4) 30 (16.1) 0.967 Possible bacterial co-infection, n (%) 73 (30.3) 24 (43.6) 49 (26.3) 0.014 Data are presented as median (IQR) or n (%), unless otherwise indicated. a Congenital heart disease: atrial septal defect, ventricular septal defect, and patent ductus arteriosus. However, the two groups did not differ significantly with respect to age; percentage of males; percentage of patients with a history of laryngo/tracheomalacia or congenital heart disease; percentage of patients with virus or M. pneumoniae co-infection; neutrophil percentage; platelet count; C-reactive protein level (all P > 0.05). Comparison of disease severity in patients with or without CMV DNAemia To compare the disease severity in patients with or without CMV DNAemia, the parameters used were (1) length of hospitalization, (2) need for and duration of administration of supplemental oxygen, and (3) admission to and length of stay in the PICU. Our analyses revealed that the duration of hospitalization, need for admission to and length of stay in the PICU, and need for and the duration of administration of supplemental oxygen were greater among patients with CMV DNAemia than in those without (all P <0.05) (Table 2 ). Table 2 Disease severity of patients with or without CMV DNAemia Parameters of disease severity All patients (n = 241) With CMV DNAemia (n = 55) Without CMV DNAemia (n = 186) P Length of hospitalization, day 8.0 (7.0–10.0) 9.0 (7.0–11.0) 8.0 (6.0–10.0) 0.001 Need for supplemental oxygen, n (%) 62 (25.7) 20 (36.4) 42 (22.6) 0.040 Duration of supplemental oxygen, day 5.0 (4.0–7.0) 6.0 (5.2-9.0) 5.0 (4.0–6.0) 0.043 Admission to the PICU, n (%) 26 (10.8) 14 (25.5) 12 (6.5) <0.001 Length of stay in the PICU, day 4.0 (3.0-6.2) 5.0 (4.0–8.0) 3.0 (2.2–4.7) 0.035 Data are presented as median (IQR) or n (%), unless otherwise indicated. PICU = pediatric intensive care unit Risk factors for admission to the PICU, need for supplemental oxygen, and CMV DNAemia Using binary logistic regression analysis, we identified several parameters that were independently associated with need for supplemental oxygen, PICU admission, and CMV DNAemia (Fig. 2 ). Among these parameters, age was found to be an independent predictor for the need for supplemental oxygen and CMV DNAemia, while congenital heart disease was an independent predictor for PICU admission and need for supplemental oxygen. Predictors of PICU admission: Patients with congenital heart disease, elevated C-reactive protein, and CMV DNAemia had a higher risk of admission to the PICU. Predictors of need for supplemental oxygen: Younger age, congenital heart disease, laryngo/tracheomalacia, and higher neutrophil percentage were factors associated had an increased risk of need for supplemental oxygen. Predictors of CMV DNAemia: Additionally, infants with younger age, possible bacterial co-infection, and higher peripheral leukocyte count were more likely to have CMV DNAemia than those without. Anti-CMV therapy Among the 55 patients with CMV DNAemia, 5 (9.1%) had received ganciclovir therapy (10 mg/kg/day). Furthermore, among the remaining patients without CMV DNAemia, none received ganciclovir therapy. The rate of ganciclovir treatment was higher among patients with CMV DNAemia than among those without (9.1% VS 0, P = 0.001). Nevertheless, all patients recovered regardless of treatment. Discussion This cross-sectional, retrospective study specifically focuses on the occurrence of CMV DNAemia among infants with CAP complicated by RSV infection. We observed CMV DNAemia in one-fifth of our patients, which suggests a high prevalence of CMV DNAemia in this population. The role of CMV as cause of CAP has been debatable [ 17 – 19 ]. To the best of our knowledge, this is the first comprehensive rigorous clinical study on the prevalence of CMV DNAemia in infants with CAP complicated by RSV infection. We noted that the proportion of patients with possible bacterial co-infection was higher among patients with CMV DNAemia than in those without. CMV can modulate human leukocyte antigen expression, encode IL-10 and alter subsets of memory T cell, that has immunomodulatory effects which might increase the risk for subsequent bacterial infections [ 6 , 20 – 22 ]. The levels of alanine transaminase and aspartate aminotransferase were higher in patients with CMV DNAemia than in patients without, although the elevation itself was not significant. These results are in agreement with those of previous studies, which have shown that hepatic aminotransferases in CMV infection patients are usually mildly elevated, thereby suggesting that cytolytic mechanisms and host adaptive immune response against CMV might be associated with cytopathogenicity of CMV in the liver [ 23 – 25 ]. Similar to previous reports, our study revealed several factors that were independently correlated with the severity of illness, including younger age, history of congenital heart disease or laryngo/tracheomalacia, neutrophil percentage, and C-reactive protein [ 9 , 26 , 27 ]. We found that CMV DNAemia was also an independent predictor for severe CAP complicated by RSV infection, which has not been reported hitherto. In critically ill patients, CMV DNAemia has been associated with worse clinical outcomes, which has been attributed to the amplification of lung and/or systemic inflammation, direct lung injury, and increased risk for secondary nosocomial infections [ 28 , 29 ]. In our study, we also found that the number of patients with possible bacterial co-infection was higher among those with CMV DNAemia than among those without. Multivariate analysis revealed that age was independently associated with CMV DNAemia, with younger infants with immature immunity being more prone to CMV DNAemia than their older counterparts. Additionally, possible bacterial co-infection and peripheral leukocyte count were factors independently associated with CMV DNAemia. Basic research has previously shown that exposure to bacteria prior to RSV infection results in an increase in the expression of TNF-α, which are predominantly produced by neutrophils and monocytes [ 30 ]. TNF-α, in turn, can activate NF-κB, which translocates into the nucleus and promotes CMV replication[ 31 ]. Our study has several limitations. First, since the presence of CMV DNAemia was investigated only on admission, the rate of CMV DNAemia might be underestimated. Second, this study did not include a healthy control group; therefore, this study does not allow for a comparison with the rate of CMV DNAemia among healthy infants. Third, this was a retrospective study with data obtained from a single center, and so, selection bias cannot be ruled out, and multicenter prospective studies are warranted in the future. Fourth, it may be possible that the positive serum CMV IgG titers detected in infants are passive antibodies transmitted from the maternal circulation. Finally, the majority of the patients with CMV DNAemia did not receive anti-CMV therapy, which makes it difficult to determine whether treatment of CMV DNAemia in infants with CAP complicated by RSV infection can indeed improve clinical outcomes. To overcome these shortcomings, multicenter, randomized controlled trials on CMV prevention are warranted. Conclusion We noted that CMV DNAemia was present in 22.8% of our study population of young infants with CAP complicated by RSV infection. We also identified that age, possible bacterial co-infection, and peripheral leukocyte count are independent factors associated with CMV DNAemia. Additionally, CMV DNAemia was found to be independently associated with disease severity in CAP complicated by RSV infection. Abbreviations CMV cytomegalovirus CAP community-acquired pneumonia RSV respiratory syncytial virus CI confidence interval OR odds ratio PICU pediatric intensive care unit Declarations Ethical approval and consent to participate This study performed in accordance with the Declaration of Helsinki. The study was approved by the Ethics Committee of the Children’s Hospital of Soochow University (2025CS062). Because this study presented no more than minimal risk of harm to patient subjects, the Ethics Committee of the Children’s Hospital of Soochow University approved a waiver of patient informed consent. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Funding This work was supported by the Gusu Health Talent Project (grant number GSWS2023047), the 2025 Suiyuan clinical research project of the Children’s Hospital of Soochow University (grant number 2025SYLCYJ09), and the 2025 college students Innovation Training Program of Soochow University (grant number 475). Author Contribution Wenxin Li was responsible for collecting the data and drafting the manuscript. Zhiao Du was responsible for statistical analysis and drafting the manuscript. Xinyi Li was responsible for literature retrieval. Runjia Hua, Feiyang Zhang and Cheng Peng were responsible for collecting the data. Li Huang, Zhengrong Chen, and Huiming Sun were responsible for critical reading of a final version of the manuscript. All authors reviewed the manuscript. Acknowledgement The authors thank all participants involved in this research. 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Docke WD, Prosch S, Fietze E, Kimel V, Zuckermann H, Klug C, et al. Cytomegalovirus reactivation and tumour necrosis factor. Lancet. 1994;343(8892):268–9. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7183389","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":498870122,"identity":"3ac911d3-1f3a-4447-8fd5-092d837b0366","order_by":0,"name":"Wenxin Li","email":"","orcid":"","institution":"Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Wenxin","middleName":"","lastName":"Li","suffix":""},{"id":498870123,"identity":"8099346a-0102-4e32-a4b1-71889a09e00f","order_by":1,"name":"Zhiao Du","email":"","orcid":"","institution":"Children’s Hospital of Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Zhiao","middleName":"","lastName":"Du","suffix":""},{"id":498870124,"identity":"8e0a2da3-c9d5-420d-a77e-171df59a1d81","order_by":2,"name":"Xinyi Li","email":"","orcid":"","institution":"Xian Jiaotong University","correspondingAuthor":false,"prefix":"","firstName":"Xinyi","middleName":"","lastName":"Li","suffix":""},{"id":498870125,"identity":"792f6562-a46f-41bc-8755-f7831d2f8c62","order_by":3,"name":"Runjia Hua","email":"","orcid":"","institution":"Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Runjia","middleName":"","lastName":"Hua","suffix":""},{"id":498870126,"identity":"5dc3418f-1994-431d-bd47-ea1f58ddca20","order_by":4,"name":"Feiyang Zhang","email":"","orcid":"","institution":"Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Feiyang","middleName":"","lastName":"Zhang","suffix":""},{"id":498870127,"identity":"cee98a6e-bce9-45e9-bc41-01437ba679b9","order_by":5,"name":"Cheng Peng","email":"","orcid":"","institution":"Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Cheng","middleName":"","lastName":"Peng","suffix":""},{"id":498870128,"identity":"504c6ad4-9b11-41f9-99c3-37025e053c54","order_by":6,"name":"Li Huang","email":"","orcid":"","institution":"Children’s Hospital of Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Huang","suffix":""},{"id":498870129,"identity":"cab33c83-68c9-476c-964c-3825af4c2bc4","order_by":7,"name":"Zhengrong Chen","email":"","orcid":"","institution":"Children’s Hospital of Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Zhengrong","middleName":"","lastName":"Chen","suffix":""},{"id":498870130,"identity":"3b5bcf19-0c6c-4a7b-b189-d402d47ee8b2","order_by":8,"name":"Huiming Sun","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAw0lEQVRIiWNgGAWjYDACCSBOqLCp52dmPviAeC0PzqQlSLazJRsQrYXxYdvhBIPzPGYCROmQn92dwJDYlpZnfJjBjIGhxiaaoBaDO2c3MCScsyk2O8yQ9oDhWFpuA0EtErlALWVpjNsOMxw3YGw4TFiL/AyQFrbDjJubGdskiNLCcAOkpe1w4gZmZjbitBiAtZxJM5Y4zMZskECMX0AOY/xRYSPH33/+44MPNTZEOIyBgf0HnJlAhPJRMApGwSgYBUQAABz5QQncGk41AAAAAElFTkSuQmCC","orcid":"","institution":"Children’s Hospital of Soochow University","correspondingAuthor":true,"prefix":"","firstName":"Huiming","middleName":"","lastName":"Sun","suffix":""}],"badges":[],"createdAt":"2025-07-22 06:38:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7183389/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7183389/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":89233230,"identity":"3f262d3a-7a68-424b-8106-b638bc52f13f","added_by":"auto","created_at":"2025-08-17 14:32:04","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":235741,"visible":true,"origin":"","legend":"\u003cp\u003eVenn Diagram reporting co-infections in the studied population.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7183389/v1/dc468a676792ff1ae9819a1f.png"},{"id":89232219,"identity":"4da90e29-f03e-4d47-b103-0b634b7719e5","added_by":"auto","created_at":"2025-08-17 14:24:04","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":355593,"visible":true,"origin":"","legend":"\u003cp\u003eRisk factors for PICU requirement, oxygen requirement, and CMV DNAemia.\u003c/p\u003e\n\u003cp\u003eFactors independently associated with PICU requirement, oxygen requirement, and CMV DNAemia using binary logistic regression (reported as odds ratio with their confidence interval) are those with a \u003cem\u003eP \u003c/em\u003eof＜0.05. OR \u0026gt;1 means risk factor, OR＜1 means protective factor. NS indicates non significant. PICU = pediatric intensive care unit.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7183389/v1/df6eefb2f037615ea9113136.png"},{"id":93681140,"identity":"2fb86ed8-3414-426f-99e5-578d1564fb87","added_by":"auto","created_at":"2025-10-16 12:09:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":884941,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7183389/v1/1587e159-e3e4-430d-868d-31f0de6e6e10.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Cytomegalovirus DNAemia in infants with community-acquired pneumonia complicated by respiratory syncytial virus infection: Risk factors and impact on disease severity","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHuman cytomegalovirus (CMV) is a virus belonging to the herpes virus family with a seroprevalence of 10\u0026thinsp;~\u0026thinsp;80% in children under 1 year of age, varying across country, socioeconomic status, age, and sex [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. CMV can establish a lifelong latent infection following primary infection and can give rise to episodes of reactivation. Immunocompetent children with primary CMV infections and reactivations are usually asymptomatic [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. However, CMV disease may be symptomatic in those who are immunosuppressed [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. CMV infection elicits an immune response characterized by elevated pro-inflammatory serum cytokine levels, thereby affecting the severity of secondary infections [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eRespiratory syncytial virus (RSV) is a leading cause of hospitalization due to community-acquired pneumonia (CAP) among infants worldwide [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Several risk factors for severe RSV infection have been identified, including immunodeficiencies, prematurity, chronic lung disease, and congenital heart disease [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, the impact of CMV infection on the disease severity of RSV infections has not been adequately investigated. A study using induced sputum samples has previously shown that the prevalence of RSV coinfection with CMV was higher in young children with CAP [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Other studies have shown that a higher CMV viral load in blood is associated with the risk of clinical disease [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The risk factors associated with CMV DNAemia in CAP infants with RSV infection remain elusive as is the impact of CMV DNAemia on disease severity in these patients.\u003c/p\u003e\u003cp\u003eThe identification of infants at highest risk for CMV DNAemia among those with CAP complicated by RSV infection might allow for the inclusion of more targeted populations in future trials designed for interventions in this clinical group. To this end, this study was aimed at evaluating the incidence and risk factors for CMV DNAemia in infants with CAP complicated with RSV infection and determining whether CMV DNAemia has any effect on disease severity in this population.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003e\u003cb\u003ePatient Population\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThis investigation was designed as a retrospective cross-sectional study. We screened consecutive infants who were hospitalized for CAP at Children\u0026rsquo;s Hospital of Soochow University, a tertiary teaching hospital in Suzhou city, China, between January 1, 2019 and December 31, 2024. Since CMV is one of the causative pathogens involved in CAP [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], most of the patients admitted for CAP at our hospital underwent testing for the detection of CMV DNA in whole blood and the CMV antibody test.\u003c/p\u003e\u003cp\u003eThe criteria for inclusion in this study were as follows: satisfaction of the diagnostic criteria for CAP, positive testing for RSV detection in nasopharyngeal swab samples, and availability of data on CMV serology with CMV whole blood DNA test on admission. The exclusion criteria were as follows: age\u0026thinsp;\u0026lt;\u0026thinsp;28 days; negative testing for CMV IgG titers; history of receiving antiviral treatment with acyclovir, ganciclovir, or valaciclovir in the past 14 days; and history of acquired or congenital immunodeficiencies and/or receiving blood transfusion within the past 1 month.\u003c/p\u003e\u003cp\u003e This study protocol was approved by the Ethics Committee of the Children\u0026rsquo;s Hospital of Soochow University (2025CS062).\u003c/p\u003e\u003cp\u003e\u003cb\u003eData Collection\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe medical records of the subjects who met the inclusion criteria were reviewed to collect data on several parameters: (1) demographic data, including age, sex, underlying medical conditions including laryngo/tracheomalacia and congenital heart disease; (2) PCR test results of nasopharyngeal swab samples for the detection of RSV, along with human rhinovirus, human metapneumovirus, human bocavirus, human influenza A virus, human influenza B virus, adenovirus, parainfluenza virus, coronaviruses, \u003cem\u003eChlamydophila pneumoniae\u003c/em\u003e, and \u003cem\u003eMycoplasma pneumoniae\u003c/em\u003e, performed using a commercialized respiratory pathogen detection kit (Health Gen Tech., Ningbo, China) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], within 24 hours of admission; (3) laboratory data, including peripheral leukocyte count, platelet count, neutrophil percentage, C-reactive protein level, aspartate aminotransferase, and alanine aminotransferase, performed within 6 hours of admission; (4) presence/absence of CMV DNA in whole blood, as detected using the CMV nucleic acid test kit (Sansure Biotech Co., Ltd. Hunan, China), within 6 hours of admission and with the detection limit being over 400 copies/mL [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]; (5) serum IgM and IgG anti-CMV levels, as detected using a CMV antibody detection kit (Autobio Diagnostics Co., Ltd. Zhengzhou, China), with CMV IgM titers of \u0026ge;\u0026thinsp;8 AU/mL and CMV of IgG titers\u0026thinsp;\u0026ge;\u0026thinsp;10 AU/mL being considered as positive [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]; and (6) disease severity parameters, including length of hospitalization, admission to and length of stay in the pediatric intensive care unit (PICU), and need for and duration of supplemental oxygen [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eCAP was defined by the presence of cough, fever, dyspnea, abnormal breath sounds, and new pulmonary infiltrate on imaging [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. CMV DNAemia was defined by the detection of CMV DNA in whole blood. Possible bacterial infection was defined by a semiquantitative culture of nasopharyngeal swab samples with colonization density ranging from 3+ (\u0026gt;\u0026thinsp;10 colonies in quadrant 3 but \u0026lt;\u0026thinsp;10 colonies in quadrant 4) to 4+ (\u0026gt;\u0026thinsp;10 colonies in quadrant 4). The anti-CMV therapy administered was determined by the attending physician [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eDescriptive Analysis: Categorical variables were reported as n (%). The normality of numerical variables was determined by Kolmogorov-Smironov test, and variables not showing normal distribution were presented as median [interquartile range (IQR)].\u003c/p\u003e\u003cp\u003eBivariate Analysis: Categorical variables were compared using the chi-square test or Fisher\u0026rsquo;s exact test, as appropriate, whereas numerical variables were compared using the Mann-Whitney \u003cem\u003eU\u003c/em\u003e test.\u003c/p\u003e\u003cp\u003eMultivariable Analysis: The risk factors associated with PICU requirement, oxygen requirement, and CMV DNAemia were determined using the binary logistic regression model. Age, sex, and variables determined to have a \u003cem\u003eP\u003c/em\u003e value of \u0026lt;\u0026thinsp;0.10 in the univariate analyses were entered into the binary logistic regression model. The variables were selected by using the backward elimination method. The association of predictors with PICU requirement, oxygen requirement, and CMV DNAemia was expressed in terms of odds ratios (ORs) and 95% confidence intervals (95% CIs). \u003cem\u003eP\u0026thinsp;\u0026lt;\u003c/em\u003e\u0026thinsp;0.05 was considered statistically significant. All statistical analyses were performed using SPSS (version 21.0).\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cb\u003ePatient characteristics\u003c/b\u003e\u003c/p\u003e\u003cp\u003eDuring the study period, 979 patients with pneumonia underwent RSV serology, CMV serology, and CMV whole blood DNA tests; of these patients, 241 met the diagnostic criteria for CAP complicated by RSV infection. The most common reasons for exclusion were negative test results for RSV detection and age\u0026lt;28 days. These 241 patients were 1 to 11 months old [median: 2.0 months; interquartile range: 1.0\u0026ndash;4.0 months]. Fifty-five (22.8%, 55/241) patients tested positive for whole blood CMV DNA, i.e. CMV DNAemia, while the remaining 186 (77.2%, 186/241) were without CMV DNAemia. Ninety (37.3%, 90/241) patients tested positive for CMV IgM, and the rate of CMV IgM positivity was higher among patients with CMV DNAemia than in those without (85.5% vs. 23.1%, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001).\u003c/p\u003e\u003cp\u003e\u003cb\u003eMicrobiological evaluation\u003c/b\u003e\u003c/p\u003e\u003cp\u003eIn all, 94 (39.0%) of the patients tested positive for the presence of another pathogen detected on admission. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the distribution of co-infections and their association. Among 241 patients, 73 (30.3%) had a possible bacterial co-infection, 6 (2.5%) had \u003cem\u003eMycoplasma pneumoniae\u003c/em\u003e co-infection, and 36 (14.9%) had viral coinfection. Moreover, 20 (8.3%) patients had at least two co-infections.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eClinical characteristics of patients with or without CMV DNAemia\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe clinical characteristics of patients with and without CMV DNAemia are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Compared to those without CMV DNAemia, those with CMV DNAemia had significantly higher peripheral leukocyte count (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002), alanine transaminase level (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.030), aspartate aminotransferase level (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.045), and percentage of patients with possible bacterial co-infection (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.014).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eClinical characteristics of patients with or without CMV DNAemia\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharacteristic\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAll patients (n\u0026thinsp;=\u0026thinsp;241)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eWith CMV DNAemia (n\u0026thinsp;=\u0026thinsp;55)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eWithout CMV DNAemia (n\u0026thinsp;=\u0026thinsp;186)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge, months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2.0 (1.0\u0026ndash;4.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.0 (2.0\u0026ndash;3.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.0 (1.0\u0026ndash;4.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.362\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e157 (65.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e31 (56.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e126 (67.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.120\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLaryngo/tracheomalacia, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e16 (6.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5 (9.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e11 (5.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.372\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCongenital heart disease\u003csup\u003ea\u003c/sup\u003e, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e24 (10.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5 (9.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e19 (10.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.807\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePeripheral leukocyte\u003c/p\u003e\u003cp\u003ecount, 10\u003csup\u003e9\u003c/sup\u003e/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8.3 (6.5\u0026ndash;10.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e9.1 (7.5\u0026ndash;12.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e7.7 (6.2\u0026ndash;10.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNeutrophil count, %\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e23.7 (17.3\u0026ndash;36.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e22.8 (16.6\u0026ndash;38.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e24.1 (17.3\u0026ndash;34.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.925\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePlatelet count, 10\u003csup\u003e9\u003c/sup\u003e\u003c/p\u003e\u003cp\u003e/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e390.0\u003c/p\u003e\u003cp\u003e(313.0-473.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e368.0\u003c/p\u003e\u003cp\u003e(326.0-453.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e396.0\u003c/p\u003e\u003cp\u003e(304.0-483.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.356\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eC-reactive protein, mg/dL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.8 (0.7-7.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.4 (0.5\u0026ndash;6.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.8 (0-3.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.282\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlanine transaminase, U/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e31.2 (22.9\u0026ndash;48.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e38.7 (24.0-79.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e30.7 (22.1\u0026ndash;46.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.030\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAspartate aminotransferase, U/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e47.9 (37.3\u0026ndash;63.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e51.5 (39.1\u0026ndash;86.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e46.8 (37.1\u0026ndash;61.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.045\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVirus or \u003cem\u003eMycoplasma pneumoniae\u003c/em\u003e co-infection, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e39 (16.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e9 (16.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e30 (16.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.967\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePossible bacterial co-infection, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e73 (30.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e24 (43.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e49 (26.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.014\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eData are presented as median (IQR) or n (%), unless otherwise indicated.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003ea\u003c/sup\u003e Congenital heart disease: atrial septal defect, ventricular septal defect, and patent ductus arteriosus.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eHowever, the two groups did not differ significantly with respect to age; percentage of males; percentage of patients with a history of laryngo/tracheomalacia or congenital heart disease; percentage of patients with virus or \u003cem\u003eM. pneumoniae\u003c/em\u003e co-infection; neutrophil percentage; platelet count; C-reactive protein level (all \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\u003cp\u003e\u003cb\u003eComparison of disease severity in patients with or without CMV DNAemia\u003c/b\u003e\u003c/p\u003e\u003cp\u003eTo compare the disease severity in patients with or without CMV DNAemia, the parameters used were (1) length of hospitalization, (2) need for and duration of administration of supplemental oxygen, and (3) admission to and length of stay in the PICU. Our analyses revealed that the duration of hospitalization, need for admission to and length of stay in the PICU, and need for and the duration of administration of supplemental oxygen were greater among patients with CMV DNAemia than in those without (all \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDisease severity of patients with or without CMV DNAemia\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eParameters of disease severity\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAll patients (n\u0026thinsp;=\u0026thinsp;241)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eWith CMV DNAemia (n\u0026thinsp;=\u0026thinsp;55)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eWithout CMV DNAemia (n\u0026thinsp;=\u0026thinsp;186)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLength of hospitalization, day\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8.0\u003c/p\u003e\u003cp\u003e(7.0\u0026ndash;10.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9.0\u003c/p\u003e\u003cp\u003e(7.0\u0026ndash;11.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e8.0\u003c/p\u003e\u003cp\u003e(6.0\u0026ndash;10.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNeed for supplemental oxygen, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e62 (25.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20 (36.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e42 (22.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.040\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDuration of supplemental oxygen, day\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.0\u003c/p\u003e\u003cp\u003e(4.0\u0026ndash;7.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6.0\u003c/p\u003e\u003cp\u003e(5.2-9.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5.0\u003c/p\u003e\u003cp\u003e(4.0\u0026ndash;6.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.043\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdmission to the PICU, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e26 (10.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14 (25.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12 (6.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLength of stay in the PICU, day\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.0\u003c/p\u003e\u003cp\u003e(3.0-6.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.0\u003c/p\u003e\u003cp\u003e(4.0\u0026ndash;8.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.0\u003c/p\u003e\u003cp\u003e(2.2\u0026ndash;4.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.035\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eData are presented as median (IQR) or n (%), unless otherwise indicated.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003ePICU\u0026thinsp;=\u0026thinsp;pediatric intensive care unit\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eRisk factors for admission to the PICU, need for supplemental oxygen, and CMV DNAemia\u003c/b\u003e\u003c/p\u003e\u003cp\u003eUsing binary logistic regression analysis, we identified several parameters that were independently associated with need for supplemental oxygen, PICU admission, and CMV DNAemia (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Among these parameters, age was found to be an independent predictor for the need for supplemental oxygen and CMV DNAemia, while congenital heart disease was an independent predictor for PICU admission and need for supplemental oxygen.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003ePredictors of PICU admission:\u003c/p\u003e\u003cp\u003ePatients with congenital heart disease, elevated C-reactive protein, and CMV DNAemia had a higher risk of admission to the PICU.\u003c/p\u003e\u003cp\u003ePredictors of need for supplemental oxygen:\u003c/p\u003e\u003cp\u003eYounger age, congenital heart disease, laryngo/tracheomalacia, and higher neutrophil percentage were factors associated had an increased risk of need for supplemental oxygen.\u003c/p\u003e\u003cp\u003ePredictors of CMV DNAemia:\u003c/p\u003e\u003cp\u003eAdditionally, infants with younger age, possible bacterial co-infection, and higher peripheral leukocyte count were more likely to have CMV DNAemia than those without.\u003c/p\u003e\u003cp\u003e\u003cb\u003eAnti-CMV therapy\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAmong the 55 patients with CMV DNAemia, 5 (9.1%) had received ganciclovir therapy (10 mg/kg/day). Furthermore, among the remaining patients without CMV DNAemia, none received ganciclovir therapy. The rate of ganciclovir treatment was higher among patients with CMV DNAemia than among those without (9.1% VS 0, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001). Nevertheless, all patients recovered regardless of treatment.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis cross-sectional, retrospective study specifically focuses on the occurrence of CMV DNAemia among infants with CAP complicated by RSV infection. We observed CMV DNAemia in one-fifth of our patients, which suggests a high prevalence of CMV DNAemia in this population. The role of CMV as cause of CAP has been debatable [\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. To the best of our knowledge, this is the first comprehensive rigorous clinical study on the prevalence of CMV DNAemia in infants with CAP complicated by RSV infection.\u003c/p\u003e\u003cp\u003eWe noted that the proportion of patients with possible bacterial co-infection was higher among patients with CMV DNAemia than in those without. CMV can modulate human leukocyte antigen expression, encode IL-10 and alter subsets of memory T cell, that has immunomodulatory effects which might increase the risk for subsequent bacterial infections [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe levels of alanine transaminase and aspartate aminotransferase were higher in patients with CMV DNAemia than in patients without, although the elevation itself was not significant. These results are in agreement with those of previous studies, which have shown that hepatic aminotransferases in CMV infection patients are usually mildly elevated, thereby suggesting that cytolytic mechanisms and host adaptive immune response against CMV might be associated with cytopathogenicity of CMV in the liver [\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eSimilar to previous reports, our study revealed several factors that were independently correlated with the severity of illness, including younger age, history of congenital heart disease or laryngo/tracheomalacia, neutrophil percentage, and C-reactive protein [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. We found that CMV DNAemia was also an independent predictor for severe CAP complicated by RSV infection, which has not been reported hitherto. In critically ill patients, CMV DNAemia has been associated with worse clinical outcomes, which has been attributed to the amplification of lung and/or systemic inflammation, direct lung injury, and increased risk for secondary nosocomial infections [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. In our study, we also found that the number of patients with possible bacterial co-infection was higher among those with CMV DNAemia than among those without.\u003c/p\u003e\u003cp\u003eMultivariate analysis revealed that age was independently associated with CMV DNAemia, with younger infants with immature immunity being more prone to CMV DNAemia than their older counterparts. Additionally, possible bacterial co-infection and peripheral leukocyte count were factors independently associated with CMV DNAemia. Basic research has previously shown that exposure to bacteria prior to RSV infection results in an increase in the expression of TNF-α, which are predominantly produced by neutrophils and monocytes [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. TNF-α, in turn, can activate NF-κB, which translocates into the nucleus and promotes CMV replication[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eOur study has several limitations. First, since the presence of CMV DNAemia was investigated only on admission, the rate of CMV DNAemia might be underestimated. Second, this study did not include a healthy control group; therefore, this study does not allow for a comparison with the rate of CMV DNAemia among healthy infants. Third, this was a retrospective study with data obtained from a single center, and so, selection bias cannot be ruled out, and multicenter prospective studies are warranted in the future. Fourth, it may be possible that the positive serum CMV IgG titers detected in infants are passive antibodies transmitted from the maternal circulation. Finally, the majority of the patients with CMV DNAemia did not receive anti-CMV therapy, which makes it difficult to determine whether treatment of CMV DNAemia in infants with CAP complicated by RSV infection can indeed improve clinical outcomes. To overcome these shortcomings, multicenter, randomized controlled trials on CMV prevention are warranted.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWe noted that CMV DNAemia was present in 22.8% of our study population of young infants with CAP complicated by RSV infection. We also identified that age, possible bacterial co-infection, and peripheral leukocyte count are independent factors associated with CMV DNAemia. Additionally, CMV DNAemia was found to be independently associated with disease severity in CAP complicated by RSV infection.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCMV cytomegalovirus\u003c/p\u003e\u003cp\u003eCAP community-acquired pneumonia\u003c/p\u003e\u003cp\u003eRSV respiratory syncytial virus\u003c/p\u003e\u003cp\u003eCI confidence interval\u003c/p\u003e\u003cp\u003eOR odds ratio\u003c/p\u003e\u003cp\u003ePICU pediatric intensive care unit\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\u003cp\u003e This study performed in accordance with the Declaration of Helsinki. The study was approved by the Ethics Committee of the Children’s Hospital of Soochow University (2025CS062). Because this study presented no more than minimal risk of harm to patient subjects, the Ethics Committee of the Children’s Hospital of Soochow University approved a waiver of patient informed consent.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eThis work was supported by the Gusu Health Talent Project (grant number GSWS2023047), the 2025 Suiyuan clinical research project of the Children’s Hospital of Soochow University (grant number 2025SYLCYJ09), and the 2025 college students Innovation Training Program of Soochow University (grant number 475).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eWenxin Li was responsible for collecting the data and drafting the manuscript. Zhiao Du was responsible for statistical analysis and drafting the manuscript. Xinyi Li was responsible for literature retrieval. Runjia Hua, Feiyang Zhang and Cheng Peng were responsible for collecting the data. Li Huang, Zhengrong Chen, and Huiming Sun were responsible for critical reading of a final version of the manuscript. All authors reviewed the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe authors thank all participants involved in this research.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCannon MJ, Schmid DS, Hyde TB. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol. 2010;20(4):202\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSouquette A, Frere J, Smithey M, Sauce D, Thomas PG. A constant companion: immune recognition and response to cytomegalovirus with aging and implications for immune fitness. Geroscience. 2017;39(3):293\u0026ndash;303.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJackson SE, Mason GM, Wills MR. Human cytomegalovirus immunity and immune evasion. Virus Res. 2011;157(2):151\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eForte E, Zhang Z, Thorp EB, Hummel M. Cytomegalovirus Latency and Reactivation: An Intricate Interplay With the Host Immune Response. Front Cell Infect Microbiol. 2020;10:130.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBarton ES, White DW, Cathelyn JS, Brett-McClellan KA, Engle M, Diamond MS, et al. Herpesvirus latency confers symbiotic protection from bacterial infection. 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Severe respiratory syncytial virus infection in children: burden, management, and emerging therapies. Lancet. 2024;404(10458):1143\u0026ndash;56.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGarcia CG, Bhore R, Soriano-Fallas A, Trost M, Chason R, Ramilo O, et al. Risk factors in children hospitalized with RSV bronchiolitis versus non-RSV bronchiolitis. Pediatrics. 2010;126(6):e1453\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhou W, Lin F, Teng L, Li H, Hou J, Tong R, et al. Prevalence of herpes and respiratory viruses in induced sputum among hospitalized children with non typical bacterial community-acquired pneumonia. PLoS ONE. 2013;8(11):e79477.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLanari M, Lazzarotto T, Venturi V, Papa I, Gabrielli L, Guerra B, et al. Neonatal cytomegalovirus blood load and risk of sequelae in symptomatic and asymptomatic congenitally infected newborns. Pediatrics. 2006;117(1):e76\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEmery VC, Sabin CA, Cope AV, Gor D, Hassan-Walker AF, Griffiths PD. Application of viral-load kinetics to identify patients who develop cytomegalovirus disease after transplantation. Lancet. 2000;355(9220):2032\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSubspecialty Group of Respiratory Diseases TSoPCMA. Editorial Board CJoP. [Guidelines for management of community acquired pneumonia in children (the revised edition of 2013) (I)]. Zhonghua Er Ke Za Zhi. 2013;51(10):745\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWang X, Lu Y, Chen F, Ruan L, Gu L, Wang T, et al. Clinical characteristics of pediatric patients hospitalized with community-acquired pneumonia and cytomegalovirus DNA detected in bronchoalveolar lavage fluid. Front Pediatr. 2024;12:1407174.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSubspecialty Group of Infectious Diseases TSoPCMA, National Pediatric Clinical Virology Cooperative. Editorial Board CJoP. [A proposal for the diagnosis, treatment and prophylaxis of cytomegalovirus diseases in children]. Zhonghua Er Ke Za Zhi. 2012;50(4):290\u0026ndash;2.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLahti E, Peltola V, Waris M, Virkki R, Rantakokko-Jalava K, Jalava J, et al. Induced sputum in the diagnosis of childhood community-acquired pneumonia. Thorax. 2009;64(3):252\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCevey-Macherel M, Galetto-Lacour A, Gervaix A, Siegrist CA, Bille J, Bescher-Ninet B, et al. Etiology of community-acquired pneumonia in hospitalized children based on WHO clinical guidelines. Eur J Pediatr. 2009;168(12):1429\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRuuskanen O, Lahti E, Jennings LC, Murdoch DR. Viral pneumonia. Lancet. 2011;377(9773):1264\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBoeckh M, Nichols WG. Immunosuppressive effects of beta-herpesviruses. Herpes. 2003;10(1):12\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNichols WG, Corey L, Gooley T, Davis C, Boeckh M. High risk of death due to bacterial and fungal infection among cytomegalovirus (CMV)-seronegative recipients of stem cell transplants from seropositive donors: evidence for indirect effects of primary CMV infection. J Infect Dis. 2002;185(3):273\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePourgheysari B, Khan N, Best D, Bruton R, Nayak L, Moss PA. The cytomegalovirus-specific CD4\u0026thinsp;+\u0026thinsp;T-cell response expands with age and markedly alters the CD4\u0026thinsp;+\u0026thinsp;T-cell repertoire. J Virol. 2007;81(14):7759\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTezer H, Kanik Yuksek S, Gulhan B, Ozkaya Parlakay AN, Tuna Kirsaclioglu C. Cytomegalovirus hepatitis in 49 pediatric patients with normal immunity. Turk J Med Sci. 2016;46(6):1629\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSinzger C, Plachter B, Grefte A, The TH, Jahn G. Tissue macrophages are infected by human cytomegalovirus in vivo. J Infect Dis. 1996;173(1):240\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLivingston-Rosanoff D, Daley-Bauer LP, Garcia A, McCormick AL, Huang J, Mocarski ES. Antiviral T cell response triggers cytomegalovirus hepatitis in mice. J Virol. 2012;86(23):12879\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eO'Donnell DR, Carrington D. Peripheral blood lymphopenia and neutrophilia in children with severe respiratory syncytial virus disease. Pediatr Pulmonol. 2002;34(2):128\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDo Q, Dao TM, Nguyen TNT, Tran QA, Nguyen HT, Ngo TT. Procalcitonin Identifies Bacterial Coinfections in Vietnamese Children with Severe Respiratory Syncytial Virus Pneumonia. Biomed Res Int. 2020;2020:7915158.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eImlay H, Limaye AP. Current Understanding of Cytomegalovirus Reactivation in Critical Illness. J Infect Dis. 2020;221(Suppl 1):S94\u0026ndash;102.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLimaye AP, Boeckh M. CMV in critically ill patients: pathogen or bystander? Rev Med Virol. 2010;20(6):372\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOwen AR, Farias A, Levins AM, Wang Z, Higham SL, Mack M, et al. Exposure to bacterial PAMPs before RSV infection exacerbates innate inflammation and disease via IL-1alpha and TNF-alpha. Mucosal Immunol. 2024;17(6):1184\u0026ndash;98.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDocke WD, Prosch S, Fietze E, Kimel V, Zuckermann H, Klug C, et al. Cytomegalovirus reactivation and tumour necrosis factor. Lancet. 1994;343(8892):268\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Cytomegalovirus infection, Community-acquired pneumonia, Respiratory syncytial virus, Risk factors","lastPublishedDoi":"10.21203/rs.3.rs-7183389/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7183389/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study aims to evaluate the incidence and risk factors for cytomegalovirus (CMV) DNAemia and its association with disease severity in infants with community-acquired pneumonia (CAP) complicated by respiratory syncytial virus (RSV) infection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this retrospective, cross-sectional study, we investigated the clinical characteristics of consecutive infants diagnosed with CAP complicated with RSV infection and circulatory whole blood CMV DNA on admission. Using binary logistic regression analysis, the clinical data of these infants were analyzed to identify risk factors for disease severity and CMV DNAemia.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn all, 241 infants with CAP complicated by RSV infection were enrolled in this study. Fifty-five (22.8%) of these infants had CMV DNAemia. Disease severity was greater in infants with CMV DNAemia than in those without. Additionally, CMV DNAemia (odds ratio [OR], 5.517; 95% confidence interval [CI], 1.839–16.553; \u003cem\u003eP\u003c/em\u003e = 0.002) was found to be an independent risk factor for pediatric intensive care unit admission. Furthermore, age (+ 1 month; OR, 0.772; 95% CI, 0.617–0.965; \u003cem\u003eP\u003c/em\u003e = 0.023), possible bacterial coinfection (OR, 2.392; 95% CI, 1.115–5.121; \u003cem\u003eP\u003c/em\u003e = 0.025), and peripheral leukocyte count (+ 1 × 10\u003csup\u003e9\u003c/sup\u003e/L; OR, 1.220; 95% CI, 1.093–1.362; \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001) were independent risk factors for CMV DNAemia.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYoung age, possible bacterial coinfection, and higher peripheral leukocyte count were associated with an increased risk of CMV DNAemia, while infants with CMV DNAemia had greater disease severity than those without.\u003c/p\u003e\n\u003cp\u003eClinical trial number: Not applicab\u003c/p\u003e","manuscriptTitle":"Cytomegalovirus DNAemia in infants with community-acquired pneumonia complicated by respiratory syncytial virus infection: Risk factors and impact on disease severity","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-17 14:24:00","doi":"10.21203/rs.3.rs-7183389/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d38b4bd8-59cc-459a-857d-4c043f058c0a","owner":[],"postedDate":"August 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-16T12:08:46+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-17 14:24:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7183389","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7183389","identity":"rs-7183389","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}