CC BY-NC-ND 4.0 · Avicenna J Med 2022; 12(01): 003-009
DOI: 10.1055/s-0041-1739236
Review Article

Detection of Cytomegalovirus Infection in Infants with Biliary Atresia: A Meta-analysis

1   Department of Surgery, Faculty of Medicine, University of Khartoum, Khartoum, Sudan
Almutasim B. E. Elhassan
1   Department of Surgery, Faculty of Medicine, University of Khartoum, Khartoum, Sudan
1   Department of Surgery, Faculty of Medicine, University of Khartoum, Khartoum, Sudan
Almigdad H.M. Ali
1   Department of Surgery, Faculty of Medicine, University of Khartoum, Khartoum, Sudan
Mohamed Elata Hassan Elbathani
1   Department of Surgery, Faculty of Medicine, University of Khartoum, Khartoum, Sudan
Osman Omer Ali Abdallah
1   Department of Surgery, Faculty of Medicine, University of Khartoum, Khartoum, Sudan
Asaad Ahmed Mohamed Ahmed
1   Department of Surgery, Faculty of Medicine, University of Khartoum, Khartoum, Sudan
Abazr A. H. Ibrahim
1   Department of Surgery, Faculty of Medicine, University of Khartoum, Khartoum, Sudan
Mohammed Suliman Tawer Salman
1   Department of Surgery, Faculty of Medicine, University of Khartoum, Khartoum, Sudan
Mahmoud Elnil
1   Department of Surgery, Faculty of Medicine, University of Khartoum, Khartoum, Sudan
Mazin A.M. Elhassan
1   Department of Surgery, Faculty of Medicine, University of Khartoum, Khartoum, Sudan
Abdelhamid Ibrahim Hassan Abuzied
1   Department of Surgery, Faculty of Medicine, University of Khartoum, Khartoum, Sudan
› Author Affiliations
Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.


Objectives Biliary atresia (BA) is the most common indication of liver transplantation in children. Several reports attributed BA to both prenatal and perinatal etiologies, including a viral infection-induced autoimmune response that targets the bile ducts. Cytomegalovirus (CMV) remains the most common virus being linked to BA. This meta-analysis aimed to estimate to what extent CMV infection is detected in patients with BA.

Methods This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The databases of MEDLINE, Embase, Scopus, WHO-Virtual Health Library (VHL), ScienceDirect, and Google Scholar were used for the systematic search. The risk of bias was assessed using the Newcastle–Ottawa scale. Random effects model was used to estimate the pooled prevalence estimate with the corresponding 95% confidence interval (CI) using Comprehensive Meta-Analysis Software version 3.3.

Results A total of 19 studies that fulfilled the eligibility criteria were included in the meta-analysis. The total number of infants with BA was 630 patients, and the pooled overall prevalence of CMV infection among them was 25.4% (95% CI: 15.9%–38.0%). There was high heterogeneity among studies (I2 = 85.1%, p < .001), and subgroup analyses showed significant regional differences (X2 = 48.9, p <.001). Data on the prognosis of CMV-associated BA were scarce and obtainable from few studies that suggested an association between detection of CMV infection and poor prognosis of BA.

Conclusions The limited available data demonstrates that the rate of detection of CMV infection is high in infants with BA. There is still a need for large studies with appropriate controls for obtaining more reliable results about the various aspects of the association between CMV infection and BA.

Authors Contribution

S.M. conceptualized the research idea and designed the study; S.M., A.A., M.E. and A.I. undertook articles searching, articles assessment, and review; S.M., M.E., and A.E. undertook data extraction and analysis; All authors interpreted the results and drafted the manuscript. All authors revised and approved the final manuscript.

Publication History

Article published online:
14 December 2021

© 2021. Syrian American Medical Society. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (

Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India

  • References

  • 1 Asai A, Miethke A, Bezerra JA. Pathogenesis of biliary atresia: defining biology to understand clinical phenotypes. Nat Rev Gastroenterol Hepatol 2015; 12 (06) 342-352
  • 2 Sokol RJ, Mack C, Narkewicz MR, Karrer FM. Pathogenesis and outcome of biliary atresia: current concepts. J Pediatr Gastroenterol Nutr 2003; 37 (01) 4-21
  • 3 Kodoa K, Sakamotoa K, Imaib T. et al. Cytomegalovirus-associated biliary atresia. J Pediatr Surg Case Rep 2018; 35: 17-20
  • 4 Zagory JA, Nguyen MV, Wang KS. Recent advances in the pathogenesis and management of biliary atresia. Curr Opin Pediatr 2015; 27 (03) 389-394
  • 5 Feng J, Huang L. The virus infection and biliary atresia. Curr Pediatr Rev 2008; 4: 164-168
  • 6 Bezerra JA. Potential etiologies of biliary atresia. Pediatr Transplant 2005; 9 (05) 646-651
  • 7 Feldman AG, Mack CL. Biliary atresia: cellular dynamics and immune dysregulation. Semin Pediatr Surg 2012; 21 (03) 192-200
  • 8 Zhao D, Long XD, Xia Q. Recent advances in etiology of biliary atresia. Clin Pediatr (Phila) 2015; 54 (08) 723-731
  • 9 Hill R, Hussain M, Quaglia A. et al. TH-17 cells infiltrate the liver in biliary atresia and are related to prognosis. Paper presented at: Proceedings of the 3rd EUPSA/BAPS Combined Congress; 13 - 16 June 2012; Rome, Italy
  • 10 Fischler B, Woxenius S, Nemeth A, Papadogiannakis N. Immunoglobulin deposits in liver tissue from infants with biliary atresia and the correlation to cytomegalovirus infection. J Pediatr Surg 2005; 40 (03) 541-546
  • 11 Brindley SM, Lanham AM, Karrer FM, Tucker RM, Fontenot AP, Mack CL. Cytomegalovirus-specific T-cell reactivity in biliary atresia at the time of diagnosis is associated with deficits in regulatory T cells. Hepatology 2012; 55 (04) 1130-1138
  • 12 Liberati A, Altman DG, Tetzlaff J. et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 2009; 62 (10) e1-e34
  • 13 Ross SA, Novak Z, Pati S, Boppana SB. Overview of the diagnosis of cytomegalovirus infection. Infect Disord Drug Targets 2011; 11 (05) 466-474
  • 14 Stagno S, Tinker MK, Elrod C, Fuccillo DA, Cloud G, O'Beirne AJ. Immunoglobulin M antibodies detected by enzyme-linked immunosorbent assay and radioimmunoassay in the diagnosis of cytomegalovirus infections in pregnant women and newborn infants. J Clin Microbiol 1985; 21 (06) 930-935
  • 15 Centers for Disease Control and Prevention. Cytomegalovirus and congenital Infection—Interpretation of laboratory tests. Accessed September 2019 at:
  • 16 Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994; 50 (04) 1088-1101
  • 17 Numazaki Y, Oshima T, Tanaka A. et al. Demonstration of IgG EA (early antigen) and IgM MA (membrane antigen) antibodies in CMV infection of healthy infants and in those with liver disease. J Pediatr 1980; 97 (04) 545-549
  • 18 Tarr PI, Haas JE, Christie DL. Biliary atresia, cytomegalovirus, and age at referral. Pediatrics 1996; 97 (6 Pt 1): 828-831
  • 19 Fischler B, Ehrnst A, Forsgren M, Örvell C, Nemeth A. The viral association of neonatal cholestasis in Sweden: a possible link between cytomegalovirus infection and extrahepatic biliary atresia. J Pediatr Gastroenterol Nutr 1998; 27 (01) 57-64
  • 20 Domiati-Saad R, Dawson DB, Margraf LR, Finegold MJ, Weinberg AG, Rogers BB. Cytomegalovirus and human herpesvirus 6, but not human papillomavirus, are present in neonatal giant cell hepatitis and extrahepatic biliary atresia. Pediatr Dev Pathol 2000; 3 (04) 367-373
  • 21 Jevon GP, Dimmick JE. Biliary atresia and cytomegalovirus infection: a DNA study. Pediatr Dev Pathol 1999; 2 (01) 11-14
  • 22 Rauschenfels S, Krassmann M, Al-Masri AN. et al. Incidence of hepatotropic viruses in biliary atresia. Eur J Pediatr 2009; 168 (04) 469-476
  • 23 Shen C, Zheng S, Wang W, Xiao XM. Relationship between prognosis of biliary atresia and infection of cytomegalovirus. World J Pediatr 2008; 4 (02) 123-126
  • 24 Fjaer RB, Bruu AL, Nordbø SA. Extrahepatic bile duct atresia and viral involvement. Pediatr Transplant 2005; 9 (01) 68-73
  • 25 De Tommaso AM, Andrade PD, Costa SC, Escanhoela CA, Hessel G. High frequency of human cytomegalovirus DNA in the liver of infants with extrahepatic neonatal cholestasis. BMC Infect Dis 2005; 5 (01) 108
  • 26 Goedhals D, Kriel J, Hertzog ML, Janse van Rensburg MN. Human cytomegalovirus infection in infants with prolonged neonatal jaundice. J Clin Virol 2008; 43 (02) 216-218
  • 27 Yaghobi R, Didari M, Gramizadeh B. et al. Study of viral infections in infants with biliary atresia. Indian J Pediatr 2011; 78 (04) 478-481
  • 28 Xu Y, Yu J, Zhang R. et al. The perinatal infection of cytomegalovirus is an important etiology for biliary atresia in China. Clin Pediatr (Phila) 2012; 51 (02) 109-113
  • 29 Soomro GB, Abbas Z, Hassan M, Luck N, Memon Y, Khan AW. Is there any association of extra hepatic biliary atresia with cytomegalovirus or other infections?. J Pak Med Assoc 2011; 61 (03) 281-283
  • 30 Schukfeh N, Al-Gamrah A, Petersen C, Kuebler JF. Detection of hepatotropic viruses has no impact on the prognosis after Kasai procedure. J Pediatr Surg 2012; 47 (10) 1828-1832
  • 31 Goel A, Chaudhari S, Sutar J. et al. Detection of Cytomegalovirus in liver tissue by polymerase chain reaction in infants with neonatal cholestasis. Pediatr Infect Dis J 2018; 37 (07) 632-636
  • 32 Gou Q, Chen Y, Yu C. et al. Biliary atresia in twins'population: a retrospective multicenter study in mainland China. Pediatr Surg Int 2020; 36 (06) 711-718
  • 33 Situmorang L, Setyoboedi B, Arief S, Mastutik G. Infection of Cytomegalovirus (CMV) in cholestasis infant with biliary atresia. Indonesian Journal of Clinical Pathology and Medical Laboratory 2019; 26 (02) 175-181
  • 34 Meshram H, Velhal S, Padwal V. et al. Hepatic interferon γ and tumor necrosis factor a expression in infants with neonatal cholestasis and cytomegalovirus infection. Clin Exp Hepatol 2020; 6 (04) 367-373
  • 35 Smith M, Zuckerman M, Kandanearatchi A, Thompson R, Davenport M. Using next-generation sequencing of microRNAs to identify host and/or pathogen nucleic acid signatures in samples from children with biliary atresia - a pilot study. Access Microbiol 2020; 2 (07) acmi000127
  • 36 Kenneson A, Cannon MJ. Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev Med Virol 2007; 17 (04) 253-276
  • 37 Zuhair M, Smit GSA, Wallis G. et al. Estimation of the worldwide seroprevalence of cytomegalovirus: A systematic review and meta-analysis. Rev Med Virol 2019; (e-pub ahead of print). DOI: 10.1002/rmv.2034.
  • 38 Davenport M. Biliary atresia: clinical aspects. Semin Pediatr Surg 2012; 21 (03) 175-184
  • 39 Song Z, Dong R, Shen Z, Chen G, Zheng Y. Surgical outcome and etiologic heterogeneity of infants with biliary atresia who received Kasai operation less than 60 days after birth. Medicine (Baltimore) 2017; 96 (26) e7267
  • 40 Fischler B, Svensson JF, Nemeth A. Early cytomegalovirus infection and the long-term outcome of biliary atresia. Acta Paediatr 2009; 98 (10) 1600-1602
  • 41 Zani A, Quaglia A, Hadzić N, Zuckerman M, Davenport M. Cytomegalovirus-associated biliary atresia: an aetiological and prognostic subgroup. J Pediatr Surg 2015; 50 (10) 1739-1745
  • 42 Parolini F, Hadzic N, Davenport M. Adjuvant therapy of cytomegalovirus IgM + ve associated biliary atresia: prima facie evidence of effect. J Pediatr Surg 2019; 54 (09) 1941-1945
  • 43 Shah I, Bhatnagar S. Biliary atresia and cytomegalovirus and response to valganciclovir. Indian Pediatr 2012; 49 (06) 484-486