Evaluation of a targeted congenital cytomegalovirus testing strategy: utilizing cytomegalovirus IgM antibody screening followed by DNA diagnosis

Evaluation of a targeted congenital cytomegalovirus testing strategy: utilizing cytomegalovirus IgM antibody screening followed by DNA diagnosis | 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 Evaluation of a targeted congenital cytomegalovirus testing strategy: utilizing cytomegalovirus IgM antibody screening followed by DNA diagnosis Dongming Li, Weiyuan Zhuo, Zhikun Liang, Yuanyuan Feng, Minzhu Pan, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4240543/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: Congenital cytomegalovirus (cCMV) infection is a prominent global public health concern due to its association with enduring neurological sequelae and sensorineural hearing impairments. Despite the recommendation for universal cCMV screening, its implementation remains limited. Consequently, alternative targeted testing strategies have been explored to augment detection rates. This study aimed to assess the efficacy of a targeted strategy for screening for cCMV utilizing CMV-IgM antibody screening followed by DNA diagnosis. Methods: A retrospective analysis was conducted, utilizing data collected between January 2013 and December 2022, encompassing all infants who underwent early cCMV testing. The testing protocol entailed an initial screening of CMV-IgM antibodies, subsequently confirmed through the detection of CMV-DNA in urine, blood, or both, to ascertain cCMV infection. Comprehensive data pertaining to infant presentation, test modalities, and outcomes were recorded for subsequent analysis. Results: Of the total 60,950 infants subjected to CMV-IgM testing, 816 progressed to CMV-DNA diagnostic testing. Indications for CMV-DNA testing encompassed clinical symptoms (84.31%), maternal HIV infection (8.09%), maternal CMV infection (7.23%), and fetal CMV infection (0.37%). Among the tested population, 95 infants received a diagnosis of cCMV infection, accounting for 0.16% of all screened infants, 11.64% of those who underwent CMV-DNA testing, and 94.74% of symptomatic infants. Fifteen different symptoms were identified, with the highest detection rates for cCMV being hepatitis (38.46%, 5/13), intestinal intussusception (33.33%, 2/6), abnormal CNS imaging (25%, 3/12), jaundice (16.24%, 57/351), sepsis (16.13%, 15/95), and pneumonitis (14.29%, 37/259). The sensitivity and specificity of CMV-IgM screening for cCMV, based on CMV-DNA diagnosis, were determined to be 69.47% and 94.59%, respectively. Conclusions: The targeted testing strategy utilizing CMV-IgM antibody screening followed by DNA diagnosis exhibits promising potential in substantially enhancing the detection rate of infants affected by cCMV who might otherwise remain undiagnosed. Further investigation is warranted to validate and optimize this approach, as well as assess its feasibility, implementation, and cost-effectiveness in diverse clinical settings. Cytomegalovirus Congenital infection Screening Immunoglobulin M Polymerase chain reaction Introduction Congenital cytomegalovirus (cCMV) is a prevalent congenital infection, affecting approximately 0.67% of live births globally ( 1 , 2 ). While most infants with cCMV are asymptomatic at birth, around 10% exhibit symptoms, and these symptomatic cases are often associated with long-term neurological complications ( 3 – 5 ). Moreover, even asymptomatic infants are at risk of developing sensorineural hearing loss (SNHL) ( 5 , 6 ). Compared to other congenital diseases identified through newborn screening, cCMV infection poses a significant burden, underscoring its importance in global public health ( 1 , 7 ). Timely diagnosis of cCMV within the first 21 days after birth is crucial to differentiate it from acquired CMV infection ( 8 ). However, due to the lack of universal CMV screening for infants, a substantial number of infected infants, particularly those with symptoms, go undetected ( 9 ). Studies have shown that early treatment with antiviral agents, such as valganciclovir or ganciclovir, can improve long-term hearing and developmental outcomes in symptomatic cCMV infants ( 10 , 11 ). Additionally, comprehensive follow-up and developmental interventions, including physical therapy, audiology, and occupational therapy, are recommended ( 12 ). Unfortunately, the detection rate of symptomatic cCMV infants has been relatively low in multiple studies ( 11 – 14 ). In the Chinese population, CMV seroprevalence is notably high, exceeding 95%. For asymptomatic neonates who do not pass the hearing screening, a comprehensive physical assessment and continuous auditory monitoring are advised. The target population for cCMV screening primarily includes newborns born to mothers with CMV infection during pregnancy, newborns exposed to HIV, and newborns presenting clinical symptoms. To enhance cCMV detection, our center has implemented a hospital-based screening approach since 2013. This study aims to evaluate the effectiveness of a targeted testing strategy utilizing CMV-IgM antibody screening followed by DNA diagnosis for cCMV. The study also aims to identify screening indicators associated with cCMV infection. Materials and methods Study design This retrospective study encompassed all infants receiving outpatient or inpatient care at the maternal and children health hospital of the Guangxi Zhuang Autonomous Region, China, from January 1, 2013, to December 31, 2022. Being a tertiary-level hospital, it functions as a referral center for neonatal intensive care and high-risk pregnancies. In our targeted testing strategy, CMV-IgM testing was conducted on blood samples from all infants. Confirmation of CMV-IgM positivity relied on positive results from real-time fluorescent quantitative PCR (RT-PCR) analysis of urine or blood. Infants suspected of cCMV infection underwent further CMV-DNA testing in urine or blood. A diagnosis of cCMV infection was established if PCR yielded positive results in either urine or blood; in case of a negative blood PCR, a supplementary urine sample was required for confirmation. The indications for CMV-DNA testing included maternal CMV infection, maternal HIV infection, clinical symptoms, and fetal CMV infection. Data collection Data were collected on infants testing positive for CMV based on RT-PCR results for urine or blood within 21 days after birth. Collected information included reasons for CMV testing, type of CMV test conducted, newborn hearing screen (NBHS) status, and diagnosis based on clinical, physical, laboratory, and imaging examinations ( 15 ). Various clinical symptoms and signs were documented, including intrauterine growth restriction (IUGR), small for gestational age (SGA), jaundice, neonatal asphyxia, pneumonitis, splenomegaly, hepatomegaly, sepsis, chorioretinitis, necrotizing enterocolitis, microcephaly or macrocephaly, thrombocytopenia, petechiae, abnormal central nervous system (CNS) imaging (including hydrocephalus, ventriculomegaly, leukomalacia), intestinal intussusception, and hepatitis. Symptoms or signs with clear etiology were excluded from consideration related to cCMV infection. Infants might present with one or more symptoms or signs. Statistical methods SPSS version 26 was used for statistical analyses. Chi-squared tests compared serologic and PCR results, with significance set at p < 0.05. Sensitivity, specificity, positive predictive values (PPV), and negative predictive values (NPV) were calculated using PCR methods as the reference standard. Results From January 1, 2013, to December 31, 2022, a total of 60,950 infants underwent CMV-IgM screening, resulting in 105 (0.17%) positive cases. Among them, 816 infants (1.34%) proceeded to CMV-DNA testing, leading to the diagnosis of cCMV in 95 cases. This accounts for 0.16% of all screened infants and 11.64% of those who underwent CMV-DNA testing. Out of the 105 CMV-IgM positive cases, 66 were confirmed as cCMV, while 29 out of the 719 CMV-IgM negative cases were confirmed as cCMV. The sensitivity and specificity of CMV-IgM screening for cCMV were determined to be 69.47% and 94.59%, respectively. Additionally, compared to PCR, the PPV and NPV for IgM were found to be 62.86% and 95.92%, respectively (Table 1 ). Table 1 Results of CMV DNA and IgM for testing congenital CMV in infants No of infants CMV DNA Positive Negative CMV IgM antibody positive 105 66 39 CMV IgM antibody negative 711 29 682 Total 816 95 721 Abbreviations: CMV: cytomegalovirus, IgM: immunoglobulin M. Among the CMV-NDA tests performed, urine PCR was the most commonly used method (64.46%), followed by urine and blood PCR (34.31%), and blood PCR (1.23%) (Table 2 ). Among the 280 infants who underwent blood and urine CMV-DNA detection, 76 (27.14%) tested positive in urine, while only 49 (17.50%) tested positive in blood. Table 2 Summary of types of samples from 816 cases undergoing CMV-DNA detection Type of test Tested number (%) Positive (n) Positive percentage(%) Urine (total) 806 (98.77) 85 10.55 Urine only 526 (64.46) 9 1.71 Urine and blood 280 (34.31) 76 27.14 Blood (total) 290 (35.59) 59 20.34 Blood only 10 (1.23) 10 100.00 CMV-DNA testing was conducted based on various indications, including clinical symptoms (n = 688; 84.31%), maternal CMV infection (n = 59; 7.23%), HIV exposure (n = 66; 8.09%), and fetal CMV infection (n = 3; 0.37%). The prevalence of cCMV in these respective groups was 11.6% (80/688), 6.1% (4/66), 14.3% (8/59), and 100% (3/3). Among all infants tested, regardless of the indication, 90.69% (740/816) exhibited one or more clinical symptoms. cCMV was confirmed in 90 out of 740 cases (12.16%) (Table 3 ). A total of fifteen different symptoms or signs were identified, with the highest detection rates for cCMV being hepatitis (38.46%, 5/13), intestinal intussusception (33.33%, 2/6), abnormal CNS imaging (25%, 3/12), jaundice (16.24%, 57/351), sepsis (16.13%, 15/95), and pneumonitis (14.29%, 37/259) (Table 4 ). Table 3 Summary of reasons for CMV-DNA testing Reasons for testing Tested (n) Positive (n) Percentage(%) Maternal CMV infection (total) 59 8 14.3 Maternal CMV infection only 22 2 9.1 Maternal CMV infection + Clinical symptoms 37 6 16.7 HIV exposed (total) 66 4 6.1 HIV exposed only 49 1 2.0 HIV exposed + Maternal CMV infection 4 1 25.0 HIV exposed + Clinical symptoms 13 2 15.4 Fetal CMV infection (total) 3 3 100.0 Fetal CMV infection only 1 1 100.0 Fetal CMV infection + Clinical symptoms 2 2 100.0 Clinical symptoms (total) 688 80 11.6 Clinical symptoms only 740 90 12.2 Abbreviations: CMV: cytomegalovirus, HIV: human immunodeficiency virus Table 4 Clinical symptoms exhibiting the highest diagnostic yield for cCMV infection Indication for testing Symtpoms alone(n = 688) Clinical symptoms total (n = 740) Symptom Infants tested cCMV Infants tested cCMV N N % N N % IUGR 443 34 7.67 468 37 7.91 SGA 439 35 7.97 452 37 8.19 Jaundice 323 48 14.86 351 57 16.24 Neonatal asphyxia 252 18 7.14 266 21 7.89 Pneumonitis 244 34 13.93 259 37 14.29 Splenomegaly or/and Hepatomegaly 199 15 7.54 203 16 7.88 Sepsis 91 14 15.38 93 15 16.13 Eye complications 97 13 13.40 99 14 14.14 Necrotizing enterocolitis 53 7 13.21 55 7 12.73 Microcephaly or macrocephaly 33 2 6.06 36 3 8.33 Thrombocytopenia 25 2 8.00 26 2 7.69 Petechia 12 1 8.33 15 2 13.33 Abnormal CNS imaging 9 2 22.22 12 3 25.00 Intestinal intussusception 4 1 25.00 6 2 33.33 Hepatitis 11 4 36.36 13 5 38.46 Abbreviations: IUGR: intrauterine growth restriction, SGA: small for gestational age, CNS: central nervous system Among the 688 infants tested based on clinical symptoms, the highest detection rates for cCMV included hepatitis (38.46%, 5/13), intestinal intussusception (33.33%, 2/6), abnormal CNS imaging (25%, 3/12), jaundice (16.24%, 57/351), sepsis (16.13%, 15/95), and pneumonitis (14.29%, 37/259) (Table 4 ). The majority of infants (72.97%, 502/688) had two or more symptoms or signs, and cCMV was confirmed in 68 out of 502 cases (13.55%). Among 186 infants tested due to an isolated symptom, 12 (6.45%) were confirmed to have cCMV, including 9 cases of isolated Jaundice and 3 cases of pneumonia. Among the 816 infants who underwent CMV-DNA testing, 771 (94.49%) had results of NBHS. Out of these, 86 infants were diagnosed with cCMV, while 685 had negative results. The prevalence of NBHS failure was 37.21% (32/86) in the cCMV group and 19.12% (131/685) in the negative-CMV group. Discussion In this study, we employed a CMV targeted testing strategy involving IgM antibody screening followed by DNA diagnosis for cCMV in a large population. Compared to an expanded targeted CMV testing approach, We observed a higher number of cases( 15 – 17 ). Our study, conducted in a tertiary care health center in Guangxi, southern China, identified common testing criteria and more symptoms associated with cCMV infection in infants. The prevalence of cCMV was highest among infants underwent CMV-DNA tested due to fetal CMV infection, followed by maternal CMV infection, clinical symptoms, and HIV exposure. Notably, hearing screening failure is not considered an indicator for cCMV screening in China, especially in infants without clinical symptoms. However, our finding suggest an association between hearing screening failure and cCMV, highlighting the importance of considering it as indicator for screening. Due to the lack of universal CMV testing in most countries, solely relying on clinician judgment may lead to missed cases of cCMV infection ( 17 ). Therefore, identifying clinical symptoms associated with cCMV infection in infants is crucial. Our study found a higher proportion and greater variety of symptoms compared to a study by Akiva et al., who reported symptoms in 71.8% of infants with only eight types of symptoms ( 16 ). It can be attributed to the fact that all infants underwent CMV-IgM testing, and a larger number of infants presented clinical symptoms, making our results more representative. The Six main types of symptoms were IUGR, SGA, jaundice, RDS, pneumonitis, and splenomegaly or/and Hepatomegaly, However, we observed a higher prevalence of cCMV in cases of hepatitis, intestinal intussusception, and abnormal CNS imaging, despite a smaller numbers of tests conducted for these specific symptoms. These findings emphasize the importance of considering a wide range of symptoms in the diagnosis and management of cCMV infection. It's noteworthy that some cCMV-infected infants, including two HIV-exposed infants, one with fetal CMV infection, and two with maternal CMV infection, did not exhibit any clinical symptoms, potentially evading symptom-based testing. The high number of suspected cases in our study can be attributed to the fact that our centers serve as the largest referral center for high-risk pregnancies in the province, with a dedicated prenatal diagnosis clinic for congenital diseases, including CMV, during pregnancy ( 19 ). Prenatal screening of mothers for CMV lacks effectiveness. Therefore, implementing supplementary postnatal cCMV screening programs remains crucial to ensure early detection and appropriate management of affected infants. The Guangxi Zhuang Autonomous Region ranks third in terms of HIV infections in China, with an annual incidence of over 500 HIV-exposed newborns ( 20 ). Routine CMV screening should be conducted among HIV-exposed infants, as they have shown an elevated risk of speech and language delay and adverse neurodevelopmental outcomes ( 21 ). This testing approach was developed as a modest endeavor to enhance the detection of cCMV infants and identify more severely affected cases. Therefore, we did not abandon CMV-IgM testing for cCMV screening, despite the possibility of false-positive and false-negative results ( 6 ). In our study, the sensitivity and specificity of CMV-IgM screening for cCMV were 69.47% and 94.59%, respectively. This is somewhat lower than the value reported by Ohyama et al. (84.4% and 99.3%) ( 22 ). This variance may be attributed to the superior diagnostic accuracy of PCR methods and the substantial number of controls included in our study. As the sensitivity is not optimal, our next course of action involves investigating the sensitivity of various CMV-IgM testing reagents and selecting a more sensitive reagent for CMV screening, until universal DNA testing becomes a viable option In terms of testing methods, the diagnosis of cCMV infection should include RT-PCR of urine, saliva, or both, with saliva being the preferred sample ( 23 ). However, implementing a screening program that includes saliva testing faces challenges in China due to the lack of diagnostic kits and logistical complexities in collecting urine from all infants. To mitigate this, we conducted concurrent blood and urine PCR tests in certain cases, particularly among children approaching the age of 21 days ( 24 ). Interestingly, we found that urine PCR was more sensitive than blood PCR in detecting CMV, consistent with findings reported by Choudhary et al. ( 25 ). Therefore, conducting urine tests for children with negative blood test results is advisable to improve the accuracy of cCMV diagnosis. Limitations Despite the insights gained from our study, there were several limitations. The evaluation of indications for testing was based on chart reviews of infants in outpatient or inpatient settings, which may not have comprehensively captured all reasons for cCMV detection. Additionally, long-term follow-up data were not collected, and the sensitivity of CMV-IgM testing was found to be suboptimal. These limitations should be considered when interpreting the results of our study. Conclusion This study highlights the potential of a targeted testing strategy utilizing CMV-IgM antibody screening followed by DNA diagnosis in improving the detection rate of cCMV-infected infants. While this screening strategy is not perfect, it offers a reasonable compromise given the current constraints. Further research is needed to validate and optimize this strategy and assess its feasibility, implementation, and cost-effectiveness in various clinical settings. Such information will be valuable in guiding clinical practice and optimizing the detection and management of cCMV infection. Declarations Acknowledgments Not applicable . Author contributions DL, WZ, CF and XH conceived the idea for this study; DL WZ performed data analyzed, summarized results; ZL, YF and PM collected the data and performed part of genetic tests; DL, WZ, CF and XH drafted, revised and reviewed the manuscript; All authors have read and approved the manuscript. Funding This work was supportead by the Health Department of Guangxi Province (Z20161a08), and construction project for clinical key specialties in the Guangxi Zhuang Autonomous Region. Data availability statement All data generated or analyzed during the course of this study are documented in this article. Please refer to the corresponding author for additional information. Ethics approval and consent to participate This study was approved by the Medical Ethics Committee of Guangxi Maternal and Child Health Hospital. The legal guardians of all patients have provided written informed consent. Consent for publication Not applicable . Competing interests The authors declare no competing interests. Author details a Department of Laboratory Medicine, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530012, China. References Manicklal S, Emery VC, Lazzarotto T, Boppana SB, Gupta RK. The "silent" global burden of congenital cytomegalovirus. Clin Microbiol Rev. 2013; 26:86-102. Ssentongo P, et al. Congenital Cytomegalovirus Infection Burden and Epidemiologic Risk Factors in Countries With Universal Screening: A Systematic Review and Meta-analysis. JAMA Netw Open. 2021; 4: e2120736. Fowler KB, et al. A Targeted Approach for Congenital Cytomegalovirus Screening Within Newborn Hearing Screening. Pediatrics. 2017; 139:e20162128. Cherry J, Demmler-Harrison GJ, Kaplan SL, Steinbach WJ, Hotez PJ. Feigin and Cherry’s Textbook of Pediatric Infectious Diseases, 8th ed. Philadelphia, PA: Elsevier; 2019. Ross SA, Kimberlin D. Clinical outcome and the role of antivirals in congenital cytomegalovirus infection. Antiviral Res. 2021; 191: 105083. Vos B, Noll D, Whittingham J, Pigeon M, Bagatto M, Fitzpatrick EM. Cytomegalovirus-A Risk Factor for Childhood Hearing Loss: A Systematic Review. Ear Hear. 2021; 42: 1447-61. Gievers LL, Holmes AV, Loyal J, Larson IA, Oliveira CR, Waldman EH, Khaki S. Ethical and Public Health Implications of Targeted Screening for Congenital Cytomegalovirus. Pediatrics. 2020; 146: e20200617. Jenks CM, Hoff SR, Mithal LB. Congenital Cytomegalovirus Infection: Epidemiology, Timely Diagnosis, and Management. Neoreviews. 2021; 22:e606-e613. Sorichetti B, et al. Symptomatic Congenital Cytomegalovirus Infection Is Underdiagnosed in British Columbia. J Pediatr. 2016; 169:316-7. Kimberlin DW, et al. Valganciclovir for symptomatic congenital cytomegalovirus disease. N Engl J Med. 2015; 372:933-43. Hilary McCrary, et al. Outcomes from an Expanded Targeted Early Cytomegalovirus Testing Program. J Pediatr Infect Dis. 2020; 15: 189-94. Suarez D, et al. Analysis of an Expanded Targeted Early Cytomegalovirus Testing Program. Otolaryngol Head Neck Surg. 2023; 169: 679-86. Vande Walle C, et al. Implications of isolated white matter abnormalities on neonatal MRI in congenital CMV infection: a prospective single-centre study. BMJ Paediatr Open. 2023; 7:e002097. Masarweh K, et al. The Yield of Targeted Examination for the Detection of Symptomatic Congenital Cytomegalovirus Infection. Isr Med Assoc J. 2021; 23:318-22. Kliegman RM. Nelson's Textbook of Pediatric. 20th ed. Philadelphia: ELSEVIER, 2015. Akiva MH, et al. Identifying Clinical Criteria for an Expanded Targeted Approach to Screening for Congenital Cytomegalovirus Infection-A Retrospective Study. Int J Neonatal Screen. 2023; 9:40. Jenks CM, Mithal LB, Hoff SR. Early Identification and Management of Congenital Cytomegalovirus. Otolaryngol Clin North Am. 2021; 54:1117-127. Fang BX, et al. Etiology of newborn hearing impairment in Guangdong province: 10-year experience with screening, diagnosis, and follow-up. World J Pediatr. 2020; 16: 305-13. He S, et al. Etiology and Perinatal Outcome of Nonimmune Hydrops Fetalis in Southern China. AJP Rep. 2017; 7:e111-15. Zhao J, et al. Rate of HIV Transmission and Associated Factors Among HIV-Exposed Infants in Guangxi, China: 2014-2019. AIDS Res Hum Retroviruses. 2020; 36:647-55. Barton M, Forrester AM, McDonald J. Update on congenital cytomegalovirus infection: Prenatal prevention, newborn diagnosis, and management. Paediatr Child Health. 2020; 25:395-96. Ohyama S, et al. Diagnostic Value of Cytomegalovirus IgM Antibodies at Birth in PCR-Confirmed Congenital Cytomegalovirus Infection. Int J Mol Sci. 2019; 20:3239. Eventov-Friedman S, et al. Saliva Real-Time Polymerase Chain Reaction for Targeted Screening of Congenital Cytomegalovirus Infection. J Infect Dis. 2019; 220:1790-96. Huang Y, et al. Comparison of detection strategies for screening and confirming congenital cytomegalovirus infection in newborns in a highly seroprevalent population: a mother-child cohort study. Lancet Reg Health West Pac. 2021;12:100182. Choudhary A, Pati SK, Patro RK, Deorari AK, Dar L. Comparison of conventional, immunological and molecular techniques for the diagnosis of symptomatic congenital human cytomegalovirus infection in neonates and infants. Indian J Med Microbiol. 2015;33:15-9. Additional Declarations No competing interests reported. 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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-4240543","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":291170160,"identity":"e1a6b62c-fc10-4088-b638-a3408bc071f8","order_by":0,"name":"Dongming Li","email":"","orcid":"","institution":"Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region","correspondingAuthor":false,"prefix":"","firstName":"Dongming","middleName":"","lastName":"Li","suffix":""},{"id":291170163,"identity":"9d59c1e1-7b02-4e7b-b33e-9ad9a6285740","order_by":1,"name":"Weiyuan Zhuo","email":"","orcid":"","institution":"Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region","correspondingAuthor":false,"prefix":"","firstName":"Weiyuan","middleName":"","lastName":"Zhuo","suffix":""},{"id":291170165,"identity":"c5ff83d7-968b-4931-81c0-ff63e0e6c50c","order_by":2,"name":"Zhikun Liang","email":"","orcid":"","institution":"Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region","correspondingAuthor":false,"prefix":"","firstName":"Zhikun","middleName":"","lastName":"Liang","suffix":""},{"id":291170169,"identity":"586c9a05-272e-4dee-b19d-f9c543b30a97","order_by":3,"name":"Yuanyuan Feng","email":"","orcid":"","institution":"Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region","correspondingAuthor":false,"prefix":"","firstName":"Yuanyuan","middleName":"","lastName":"Feng","suffix":""},{"id":291170173,"identity":"408cac42-6851-4779-92d1-6ad898f6d94e","order_by":4,"name":"Minzhu Pan","email":"","orcid":"","institution":"Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region","correspondingAuthor":false,"prefix":"","firstName":"Minzhu","middleName":"","lastName":"Pan","suffix":""},{"id":291170175,"identity":"1af0c98b-55f6-4a31-b959-981e1ab0e7ab","order_by":5,"name":"Chunyun Fu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6klEQVRIiWNgGAWjYBAC9gYGNiirseHAhwoGHoJaeA7AtPAcPvhwxhmStEikJRvzthHhMB6J5GePeXccTtzOkGMmOXNenYw5+wHGDx9z8GlJMzfmPXM4cWfDGTOJj9sO81j2JDBLztyGW4u9RA6bNG/b4cQNB3uAtmw7wGNwIIGNmRePFh64lsM8ZtK8c+p4DM4/IFbLMTag9xuYeQxuELKF55mZ5Ny2dOMNZ5iBgXzsMFDLw2a8fuFhT34m8bbNWnbD/YfAqKypszc4n3zww0c8WqCgGZnD2EBQPRDUEaNoFIyCUTAKRioAAO5GVAZrRtjCAAAAAElFTkSuQmCC","orcid":"","institution":"Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region","correspondingAuthor":true,"prefix":"","firstName":"Chunyun","middleName":"","lastName":"Fu","suffix":""},{"id":291170177,"identity":"74ad2859-da94-4577-8467-c9aded3ecce3","order_by":6,"name":"Xuehua Hu","email":"","orcid":"","institution":"Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region","correspondingAuthor":false,"prefix":"","firstName":"Xuehua","middleName":"","lastName":"Hu","suffix":""}],"badges":[],"createdAt":"2024-04-09 08:09:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4240543/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4240543/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":62087633,"identity":"b15c80dd-87d9-442a-8333-8eca472910d5","added_by":"auto","created_at":"2024-08-09 07:05:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":492839,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4240543/v1/bf8bb3e1-08b0-47ba-9e80-86454d41eb0a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Evaluation of a targeted congenital cytomegalovirus testing strategy: utilizing cytomegalovirus IgM antibody screening followed by DNA diagnosis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCongenital cytomegalovirus (cCMV) is a prevalent congenital infection, affecting approximately 0.67% of live births globally (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). While most infants with cCMV are asymptomatic at birth, around 10% exhibit symptoms, and these symptomatic cases are often associated with long-term neurological complications (\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Moreover, even asymptomatic infants are at risk of developing sensorineural hearing loss (SNHL) (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Compared to other congenital diseases identified through newborn screening, cCMV infection poses a significant burden, underscoring its importance in global public health (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTimely diagnosis of cCMV within the first 21 days after birth is crucial to differentiate it from acquired CMV infection (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). However, due to the lack of universal CMV screening for infants, a substantial number of infected infants, particularly those with symptoms, go undetected (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Studies have shown that early treatment with antiviral agents, such as valganciclovir or ganciclovir, can improve long-term hearing and developmental outcomes in symptomatic cCMV infants (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Additionally, comprehensive follow-up and developmental interventions, including physical therapy, audiology, and occupational therapy, are recommended (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Unfortunately, the detection rate of symptomatic cCMV infants has been relatively low in multiple studies (\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn the Chinese population, CMV seroprevalence is notably high, exceeding 95%. For asymptomatic neonates who do not pass the hearing screening, a comprehensive physical assessment and continuous auditory monitoring are advised. The target population for cCMV screening primarily includes newborns born to mothers with CMV infection during pregnancy, newborns exposed to HIV, and newborns presenting clinical symptoms. To enhance cCMV detection, our center has implemented a hospital-based screening approach since 2013. This study aims to evaluate the effectiveness of a targeted testing strategy utilizing CMV-IgM antibody screening followed by DNA diagnosis for cCMV. The study also aims to identify screening indicators associated with cCMV infection.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003e This retrospective study encompassed all infants receiving outpatient or inpatient care at the maternal and children health hospital of the Guangxi Zhuang Autonomous Region, China, from January 1, 2013, to December 31, 2022. Being a tertiary-level hospital, it functions as a referral center for neonatal intensive care and high-risk pregnancies.\u003c/p\u003e \u003cp\u003eIn our targeted testing strategy, CMV-IgM testing was conducted on blood samples from all infants. Confirmation of CMV-IgM positivity relied on positive results from real-time fluorescent quantitative PCR (RT-PCR) analysis of urine or blood. Infants suspected of cCMV infection underwent further CMV-DNA testing in urine or blood. A diagnosis of cCMV infection was established if PCR yielded positive results in either urine or blood; in case of a negative blood PCR, a supplementary urine sample was required for confirmation. The indications for CMV-DNA testing included maternal CMV infection, maternal HIV infection, clinical symptoms, and fetal CMV infection.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eData collection\u003c/h2\u003e \u003cp\u003eData were collected on infants testing positive for CMV based on RT-PCR results for urine or blood within 21 days after birth. Collected information included reasons for CMV testing, type of CMV test conducted, newborn hearing screen (NBHS) status, and diagnosis based on clinical, physical, laboratory, and imaging examinations (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Various clinical symptoms and signs were documented, including intrauterine growth restriction (IUGR), small for gestational age (SGA), jaundice, neonatal asphyxia, pneumonitis, splenomegaly, hepatomegaly, sepsis, chorioretinitis, necrotizing enterocolitis, microcephaly or macrocephaly, thrombocytopenia, petechiae, abnormal central nervous system (CNS) imaging (including hydrocephalus, ventriculomegaly, leukomalacia), intestinal intussusception, and hepatitis. Symptoms or signs with clear etiology were excluded from consideration related to cCMV infection. Infants might present with one or more symptoms or signs.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStatistical methods\u003c/h3\u003e\n\u003cp\u003eSPSS version 26 was used for statistical analyses. Chi-squared tests compared serologic and PCR results, with significance set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Sensitivity, specificity, positive predictive values (PPV), and negative predictive values (NPV) were calculated using PCR methods as the reference standard.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eFrom January 1, 2013, to December 31, 2022, a total of 60,950 infants underwent CMV-IgM screening, resulting in 105 (0.17%) positive cases. Among them, 816 infants (1.34%) proceeded to CMV-DNA testing, leading to the diagnosis of cCMV in 95 cases. This accounts for 0.16% of all screened infants and 11.64% of those who underwent CMV-DNA testing.\u003c/p\u003e \u003cp\u003eOut of the 105 CMV-IgM positive cases, 66 were confirmed as cCMV, while 29 out of the 719 CMV-IgM negative cases were confirmed as cCMV. The sensitivity and specificity of CMV-IgM screening for cCMV were determined to be 69.47% and 94.59%, respectively. Additionally, compared to PCR, the PPV and NPV for IgM were found to be 62.86% and 95.92%, respectively (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\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\u003eResults of CMV DNA and IgM for testing congenital CMV in infants\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNo of infants\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eCMV DNA\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCMV IgM antibody positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e105\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCMV IgM antibody negative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e711\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e682\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e816\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e721\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eAbbreviations: CMV: cytomegalovirus, IgM: immunoglobulin M.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAmong the CMV-NDA tests performed, urine PCR was the most commonly used method (64.46%), followed by urine and blood PCR (34.31%), and blood PCR (1.23%) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Among the 280 infants who underwent blood and urine CMV-DNA detection, 76 (27.14%) tested positive in urine, while only 49 (17.50%) tested positive in blood.\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\u003eSummary of types of samples from 816 cases undergoing CMV-DNA detection\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType of test\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTested number (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePositive (n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePositive percentage(%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrine (total)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e806 (98.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrine only\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e526 (64.46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.71\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrine and blood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e280 (34.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e27.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood (total)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e290 (35.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20.34\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood only\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10 (1.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e100.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eCMV-DNA testing was conducted based on various indications, including clinical symptoms (n\u0026thinsp;=\u0026thinsp;688; 84.31%), maternal CMV infection (n\u0026thinsp;=\u0026thinsp;59; 7.23%), HIV exposure (n\u0026thinsp;=\u0026thinsp;66; 8.09%), and fetal CMV infection (n\u0026thinsp;=\u0026thinsp;3; 0.37%). The prevalence of cCMV in these respective groups was 11.6% (80/688), 6.1% (4/66), 14.3% (8/59), and 100% (3/3). Among all infants tested, regardless of the indication, 90.69% (740/816) exhibited one or more clinical symptoms. cCMV was confirmed in 90 out of 740 cases (12.16%) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). A total of fifteen different symptoms or signs were identified, with the highest detection rates for cCMV being hepatitis (38.46%, 5/13), intestinal intussusception (33.33%, 2/6), abnormal CNS imaging (25%, 3/12), jaundice (16.24%, 57/351), sepsis (16.13%, 15/95), and pneumonitis (14.29%, 37/259) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of reasons for CMV-DNA testing\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReasons for testing\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTested (n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePositive (n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePercentage(%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal CMV infection (total)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal CMV infection only\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal CMV infection\u0026thinsp;+\u0026thinsp;Clinical symptoms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHIV exposed (total)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHIV exposed only\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHIV exposed\u0026thinsp;+\u0026thinsp;Maternal CMV infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e25.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHIV exposed\u0026thinsp;+\u0026thinsp;Clinical symptoms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e15.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFetal CMV infection (total)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e100.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFetal CMV infection only\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e100.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFetal CMV infection\u0026thinsp;+\u0026thinsp;Clinical symptoms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e100.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical symptoms (total)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e688\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical symptoms only\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e740\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eAbbreviations: CMV: cytomegalovirus, HIV: human immunodeficiency virus\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical symptoms exhibiting the highest diagnostic yield for cCMV infection\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\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=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIndication for testing\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eSymtpoms alone(n\u0026thinsp;=\u0026thinsp;688)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eClinical symptoms total (n\u0026thinsp;=\u0026thinsp;740)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSymptom\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInfants tested\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003ecCMV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eInfants tested\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003ecCMV\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIUGR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e443\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e468\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7.91\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSGA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e439\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e452\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e8.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJaundice\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e323\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e351\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e16.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeonatal asphyxia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e252\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e266\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7.89\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumonitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e244\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e259\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e14.29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSplenomegaly or/and Hepatomegaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e199\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e203\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7.88\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSepsis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e16.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEye complications\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e14.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNecrotizing enterocolitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e12.73\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMicrocephaly or macrocephaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e8.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7.69\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePetechia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e13.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbnormal CNS imaging\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e25.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntestinal intussusception\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e33.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e38.46\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eAbbreviations: IUGR: intrauterine growth restriction, SGA: small for gestational age, CNS: central nervous system\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAmong the 688 infants tested based on clinical symptoms, the highest detection rates for cCMV included hepatitis (38.46%, 5/13), intestinal intussusception (33.33%, 2/6), abnormal CNS imaging (25%, 3/12), jaundice (16.24%, 57/351), sepsis (16.13%, 15/95), and pneumonitis (14.29%, 37/259) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The majority of infants (72.97%, 502/688) had two or more symptoms or signs, and cCMV was confirmed in 68 out of 502 cases (13.55%). Among 186 infants tested due to an isolated symptom, 12 (6.45%) were confirmed to have cCMV, including 9 cases of isolated Jaundice and 3 cases of pneumonia.\u003c/p\u003e \u003cp\u003eAmong the 816 infants who underwent CMV-DNA testing, 771 (94.49%) had results of NBHS. Out of these, 86 infants were diagnosed with cCMV, while 685 had negative results. The prevalence of NBHS failure was 37.21% (32/86) in the cCMV group and 19.12% (131/685) in the negative-CMV group.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e In this study, we employed a CMV targeted testing strategy involving IgM antibody screening followed by DNA diagnosis for cCMV in a large population. Compared to an expanded targeted CMV testing approach, We observed a higher number of cases(\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Our study, conducted in a tertiary care health center in Guangxi, southern China, identified common testing criteria and more symptoms associated with cCMV infection in infants.\u003c/p\u003e \u003cp\u003eThe prevalence of cCMV was highest among infants underwent CMV-DNA tested due to fetal CMV infection, followed by maternal CMV infection, clinical symptoms, and HIV exposure. Notably, hearing screening failure is not considered an indicator for cCMV screening in China, especially in infants without clinical symptoms. However, our finding suggest an association between hearing screening failure and cCMV, highlighting the importance of considering it as indicator for screening.\u003c/p\u003e \u003cp\u003eDue to the lack of universal CMV testing in most countries, solely relying on clinician judgment may lead to missed cases of cCMV infection (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Therefore, identifying clinical symptoms associated with cCMV infection in infants is crucial. Our study found a higher proportion and greater variety of symptoms compared to a study by Akiva et al., who reported symptoms in 71.8% of infants with only eight types of symptoms (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). It can be attributed to the fact that all infants underwent CMV-IgM testing, and a larger number of infants presented clinical symptoms, making our results more representative. The Six main types of symptoms were IUGR, SGA, jaundice, RDS, pneumonitis, and splenomegaly or/and Hepatomegaly, However, we observed a higher prevalence of cCMV in cases of hepatitis, intestinal intussusception, and abnormal CNS imaging, despite a smaller numbers of tests conducted for these specific symptoms. These findings emphasize the importance of considering a wide range of symptoms in the diagnosis and management of cCMV infection.\u003c/p\u003e \u003cp\u003eIt's noteworthy that some cCMV-infected infants, including two HIV-exposed infants, one with fetal CMV infection, and two with maternal CMV infection, did not exhibit any clinical symptoms, potentially evading symptom-based testing. The high number of suspected cases in our study can be attributed to the fact that our centers serve as the largest referral center for high-risk pregnancies in the province, with a dedicated prenatal diagnosis clinic for congenital diseases, including CMV, during pregnancy (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Prenatal screening of mothers for CMV lacks effectiveness. Therefore, implementing supplementary postnatal cCMV screening programs remains crucial to ensure early detection and appropriate management of affected infants. The Guangxi Zhuang Autonomous Region ranks third in terms of HIV infections in China, with an annual incidence of over 500 HIV-exposed newborns (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Routine CMV screening should be conducted among HIV-exposed infants, as they have shown an elevated risk of speech and language delay and adverse neurodevelopmental outcomes (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis testing approach was developed as a modest endeavor to enhance the detection of cCMV infants and identify more severely affected cases. Therefore, we did not abandon CMV-IgM testing for cCMV screening, despite the possibility of false-positive and false-negative results (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). In our study, the sensitivity and specificity of CMV-IgM screening for cCMV were 69.47% and 94.59%, respectively. This is somewhat lower than the value reported by Ohyama et al. (84.4% and 99.3%) (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). This variance may be attributed to the superior diagnostic accuracy of PCR methods and the substantial number of controls included in our study. As the sensitivity is not optimal, our next course of action involves investigating the sensitivity of various CMV-IgM testing reagents and selecting a more sensitive reagent for CMV screening, until universal DNA testing becomes a viable option\u003c/p\u003e \u003cp\u003eIn terms of testing methods, the diagnosis of cCMV infection should include RT-PCR of urine, saliva, or both, with saliva being the preferred sample (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). However, implementing a screening program that includes saliva testing faces challenges in China due to the lack of diagnostic kits and logistical complexities in collecting urine from all infants. To mitigate this, we conducted concurrent blood and urine PCR tests in certain cases, particularly among children approaching the age of 21 days (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Interestingly, we found that urine PCR was more sensitive than blood PCR in detecting CMV, consistent with findings reported by Choudhary et al. (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Therefore, conducting urine tests for children with negative blood test results is advisable to improve the accuracy of cCMV diagnosis.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eDespite the insights gained from our study, there were several limitations. The evaluation of indications for testing was based on chart reviews of infants in outpatient or inpatient settings, which may not have comprehensively captured all reasons for cCMV detection. Additionally, long-term follow-up data were not collected, and the sensitivity of CMV-IgM testing was found to be suboptimal. These limitations should be considered when interpreting the results of our study.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study highlights the potential of a targeted testing strategy utilizing CMV-IgM antibody screening followed by DNA diagnosis in improving the detection rate of cCMV-infected infants. While this screening strategy is not perfect, it offers a reasonable compromise given the current constraints. Further research is needed to validate and optimize this strategy and assess its feasibility, implementation, and cost-effectiveness in various clinical settings. Such information will be valuable in guiding clinical practice and optimizing the detection and management of cCMV infection.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDL, WZ, CF and XH conceived the idea for this study; DL WZ performed data analyzed, summarized results; ZL, YF and PM collected the data and performed part of genetic tests; DL, WZ, CF and XH drafted, revised and reviewed the manuscript; All authors have read and approved the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supportead by\u0026nbsp;the Health Department of Guangxi Province (Z20161a08), and construction project for clinical key specialties in the Guangxi Zhuang Autonomous Region.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during the course of this study are documented in this article. Please refer to the corresponding author for additional information.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by\u0026nbsp;the Medical Ethics Committee of Guangxi Maternal and Child Health Hospital. The legal guardians of all patients have provided written informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare \u0026nbsp;no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Department of Laboratory Medicine, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530012, China.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eManicklal S, Emery VC, Lazzarotto T, Boppana SB, Gupta RK. The \u0026quot;silent\u0026quot; global burden of congenital cytomegalovirus. Clin Microbiol Rev. 2013; 26:86-102.\u003c/li\u003e\n\u003cli\u003eSsentongo P, et al. Congenital Cytomegalovirus Infection Burden and Epidemiologic Risk Factors in Countries With Universal Screening: A Systematic Review and Meta-analysis. JAMA Netw Open. 2021; 4: e2120736.\u003c/li\u003e\n\u003cli\u003eFowler KB, et al. A Targeted Approach for Congenital Cytomegalovirus Screening Within Newborn Hearing Screening. Pediatrics. 2017; 139:e20162128.\u003c/li\u003e\n\u003cli\u003eCherry J, Demmler-Harrison GJ, Kaplan SL, Steinbach WJ, Hotez PJ. Feigin and Cherry\u0026rsquo;s Textbook of Pediatric Infectious Diseases, 8th ed. Philadelphia, PA: Elsevier; 2019.\u003c/li\u003e\n\u003cli\u003eRoss SA, Kimberlin D. Clinical outcome and the role of antivirals in congenital cytomegalovirus infection. Antiviral Res. 2021; 191: 105083.\u003c/li\u003e\n\u003cli\u003eVos B, Noll D, Whittingham J, Pigeon M, Bagatto M, Fitzpatrick EM. Cytomegalovirus-A Risk Factor for Childhood Hearing Loss: A Systematic Review. Ear Hear. 2021; 42: 1447-61. \u003c/li\u003e\n\u003cli\u003eGievers LL, Holmes AV, Loyal J, Larson IA, Oliveira CR, Waldman EH, Khaki S. Ethical and Public Health Implications of Targeted Screening for Congenital Cytomegalovirus. Pediatrics. 2020; 146: e20200617.\u003c/li\u003e\n\u003cli\u003eJenks CM, Hoff SR, Mithal LB. Congenital Cytomegalovirus Infection: Epidemiology, Timely Diagnosis, and Management. Neoreviews. 2021; 22:e606-e613.\u003c/li\u003e\n\u003cli\u003eSorichetti B, et al. Symptomatic Congenital Cytomegalovirus Infection Is Underdiagnosed in British Columbia. J Pediatr. 2016; 169:316-7.\u003c/li\u003e\n\u003cli\u003eKimberlin DW, et al. Valganciclovir for symptomatic congenital cytomegalovirus disease. N Engl J Med. 2015; 372:933-43.\u003c/li\u003e\n\u003cli\u003eHilary McCrary, et al. Outcomes from an Expanded Targeted Early Cytomegalovirus Testing Program. J Pediatr Infect Dis. 2020; 15: 189-94.\u003c/li\u003e\n\u003cli\u003eSuarez D, et al. Analysis of an Expanded Targeted Early Cytomegalovirus Testing Program. Otolaryngol Head Neck Surg. 2023; 169: 679-86.\u003c/li\u003e\n\u003cli\u003eVande Walle C, et al. Implications of isolated white matter abnormalities on neonatal MRI in congenital CMV infection: a prospective single-centre study. BMJ Paediatr Open. 2023; 7:e002097.\u003c/li\u003e\n\u003cli\u003eMasarweh K, et al. The Yield of Targeted Examination for the Detection of Symptomatic Congenital Cytomegalovirus Infection. Isr Med Assoc J. 2021; 23:318-22.\u003c/li\u003e\n\u003cli\u003eKliegman RM. Nelson\u0026apos;s Textbook of Pediatric. 20th ed. Philadelphia: ELSEVIER, 2015.\u003c/li\u003e\n\u003cli\u003eAkiva MH, et al. Identifying Clinical Criteria for an Expanded Targeted Approach to Screening for Congenital Cytomegalovirus Infection-A Retrospective Study. Int J Neonatal Screen. 2023; 9:40.\u003c/li\u003e\n\u003cli\u003eJenks CM, Mithal LB, Hoff SR. Early Identification and Management of Congenital Cytomegalovirus. Otolaryngol Clin North Am. 2021; 54:1117-127.\u003c/li\u003e\n\u003cli\u003eFang BX, et al. Etiology of newborn hearing impairment in Guangdong province: 10-year experience with screening, diagnosis, and follow-up. World J Pediatr. 2020; 16: 305-13.\u003c/li\u003e\n\u003cli\u003eHe S, et al. Etiology and Perinatal Outcome of Nonimmune Hydrops Fetalis in Southern China. AJP Rep. 2017; 7:e111-15.\u003c/li\u003e\n\u003cli\u003eZhao J, et al. Rate of HIV Transmission and Associated Factors Among HIV-Exposed Infants in Guangxi, China: 2014-2019. AIDS Res Hum Retroviruses. 2020; 36:647-55. \u003c/li\u003e\n\u003cli\u003eBarton M, Forrester AM, McDonald J. Update on congenital cytomegalovirus infection: Prenatal prevention, newborn diagnosis, and management. Paediatr Child Health. 2020; 25:395-96. \u003c/li\u003e\n\u003cli\u003eOhyama S, et al. Diagnostic Value of Cytomegalovirus IgM Antibodies at Birth in PCR-Confirmed Congenital Cytomegalovirus Infection. Int J Mol Sci. 2019; 20:3239.\u003c/li\u003e\n\u003cli\u003eEventov-Friedman S, et al. Saliva Real-Time Polymerase Chain Reaction for Targeted Screening of Congenital Cytomegalovirus Infection. J Infect Dis. 2019; 220:1790-96. \u003c/li\u003e\n\u003cli\u003eHuang Y, et al. Comparison of detection strategies for screening and confirming congenital cytomegalovirus infection in newborns in a highly seroprevalent population: a mother-child cohort study. Lancet Reg Health West Pac. 2021;12:100182. \u003c/li\u003e\n\u003cli\u003eChoudhary A, Pati SK, Patro RK, Deorari AK, Dar L. Comparison of conventional, immunological and molecular techniques for the diagnosis of symptomatic congenital human cytomegalovirus infection in neonates and infants. Indian J Med Microbiol. 2015;33:15-9. \u003c/li\u003e\n\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, Congenital infection, Screening, Immunoglobulin M, Polymerase chain reaction","lastPublishedDoi":"10.21203/rs.3.rs-4240543/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4240543/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Congenital cytomegalovirus (cCMV) infection is a prominent global public health concern due to its association with enduring neurological sequelae and sensorineural hearing impairments. Despite the recommendation for universal cCMV screening, its implementation remains limited. Consequently, alternative targeted testing strategies have been explored to augment detection rates. This study aimed to assess the efficacy of a targeted strategy for screening for cCMV utilizing CMV-IgM antibody screening followed by DNA diagnosis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e A retrospective analysis was conducted, utilizing data collected between January 2013 and December 2022, encompassing all infants who underwent early cCMV testing. The testing protocol entailed an initial screening of CMV-IgM antibodies, subsequently confirmed through the detection of CMV-DNA in urine, blood, or both, to ascertain cCMV infection. Comprehensive data pertaining to infant presentation, test modalities, and outcomes were recorded for subsequent analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Of the total 60,950 infants subjected to CMV-IgM testing, 816 progressed to CMV-DNA diagnostic testing. Indications for CMV-DNA testing encompassed clinical symptoms (84.31%), maternal HIV infection (8.09%), maternal CMV infection (7.23%), and fetal CMV infection (0.37%). Among the tested population, 95 infants received a diagnosis of cCMV infection, accounting for 0.16% of all screened infants, 11.64% of those who underwent CMV-DNA testing, and 94.74% of symptomatic infants. Fifteen different symptoms were identified, with the highest detection rates for cCMV being hepatitis (38.46%, 5/13), intestinal intussusception (33.33%, 2/6), abnormal CNS imaging (25%, 3/12), jaundice (16.24%, 57/351), sepsis (16.13%, 15/95), and pneumonitis (14.29%, 37/259). The sensitivity and specificity of CMV-IgM screening for cCMV, based on CMV-DNA diagnosis, were determined to be 69.47% and 94.59%, respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e The targeted testing strategy utilizing CMV-IgM antibody screening followed by DNA diagnosis exhibits promising potential in substantially enhancing the detection rate of infants affected by cCMV who might otherwise remain undiagnosed. Further investigation is warranted to validate and optimize this approach, as well as assess its feasibility, implementation, and cost-effectiveness in diverse clinical settings.\u003c/p\u003e","manuscriptTitle":"Evaluation of a targeted congenital cytomegalovirus testing strategy: utilizing cytomegalovirus IgM antibody screening followed by DNA diagnosis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-18 19:34:13","doi":"10.21203/rs.3.rs-4240543/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":"31afe068-c3ad-4f52-b6b5-8b7032f7de9d","owner":[],"postedDate":"April 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-08-09T06:57:40+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-18 19:34:13","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4240543","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4240543","identity":"rs-4240543","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}