Human cytomegalovirus and Epstein-Barr virus infection in inflammatory bowel disease: Need for mucosal viral load measurement

doi:10.3748/wjg.v21.i6.1915

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World Journal of Gastroenterology

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World J Gastroenterol. Feb 14, 2015; 21(6): 1915-1926
Published online Feb 14, 2015. doi: 10.3748/wjg.v21.i6.1915

Human cytomegalovirus and Epstein-Barr virus infection in inflammatory bowel disease: Need for mucosal viral load measurement

Rachele Ciccocioppo, Francesca Racca, Stefania Paolucci, Giulia Campanini, Lodovica Pozzi, Elena Betti, Roberta Riboni, Alessandro Vanoli, Fausto Baldanti, Gino Roberto Corazza

Rachele Ciccocioppo, Francesca Racca, Elena Betti, Gino Roberto Corazza, Centre for the Study and Cure of Inflammatory Bowel Disease, Clinica Medica I, IRCCS San Matteo Hospital Foundation, University of Pavia, 27100 Pavia, Italy

Stefania Paolucci, Giulia Campanini, Fausto Baldanti, SS Virologia Molecolare - SC Virologia e Microbiologia, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy

Lodovica Pozzi, Servizio di Endoscopia Digestiva, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy

Roberta Riboni, Alessandro Vanoli, Servizio di Anatomia Patologica; Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy

Author contributions: Ciccocioppo R designed the study, was in charge of the diagnostic and therapeutic management of the patients, analyzed and interpreted the data, wrote the manuscript, and obtained funding. She has approved the final draft submitted; Racca F collected and analyzed the data. She has approved the final draft submitted; Paolucci S and Campanini G performed the quantitative real-time PCR analysis; They have approved the final draft submitted; Pozzi L carried out the endoscopic examinations with appropriate biopsy sampling. She has approved the final draft submitted; Betti E was involved in collecting patients’ clinical data and technical support. She has approved the final draft submitted; Riboni R performed the immunohistochemistry analysis. She has approved the final draft submitted; Vanoli A analyzed the immunohistochemistry results. He has approved the final draft submitted; Baldanti F participated in the management of patients and in drafting the manuscript. He has approved the final draft submitted; Corazza GR was in charge of the management of the patients and critically revised the article for important intellectual content, he has approved the final draft submitted.

Supported by (in part) Fondazione IRCCS Policlinico San Matteo (Progetto di Ricerca Corrente) entitled: “Studio della espressione del recettore per i prodotti finali della glicosilazione avanzata (RAGE) nelle Malattie Infiammatorie Croniche Intestinali”, No. 08064409.

Correspondence to: Rachele Ciccocioppo, MD, Centre for the Study and Cure of Inflammatory Bowel Disease, Clinica Medica I, IRCCS San Matteo Hospital Foundation, University of Pavia, Piazzale Golgi 19, 27100 Pavia, Italy. rachele.ciccocioppo@unipv.it

Telephone: +39-382-502786 Fax: +39-382-502618

Received: August 6, 2014
Peer-review started: August 6, 2014
First decision: September 15, 2014
Revised: October 3, 2014
Accepted: November 18, 2014
Article in press: November 19, 2014
Published online: February 14, 2015
Processing time: 189 Days and 12.2 Hours

Abstract

AIM: To evaluate the best diagnostic technique and risk factors of the human Cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) infection in inflammatory bowel disease (IBD).

METHODS: A cohort of 40 IBD patients (17 refractory) and 40 controls underwent peripheral blood and endoscopic colonic mucosal sample harvest. Viral infection was assessed by quantitative real-time polymerase chain reaction and immunohistochemistry, and correlations with clinical and endoscopic indexes of activity, and risk factors were investigated.

RESULTS: All refractory patients carried detectable levels of HCMV and/or EBV mucosal load as compared to 13/23 (56.5%) non-refractory and 13/40 (32.5%) controls. The median DNA value was significantly higher in refractory (HCMV 286 and EBV 5.440 copies/10⁵ cells) than in non-refractory (HCMV 0 and EBV 6 copies/10⁵ cells; P < 0.05 and < 0.001) IBD patients and controls (HCMV and EBV 0 copies/10⁵ cells; P < 0.001 for both). Refractory patients showed DNA peak values ≥ 10³ copies/10⁵ cells in diseased mucosa in comparison to non-diseased mucosa (P < 0.0121 for HCMV and < 0.0004 for EBV), while non-refractory patients and controls invariably displayed levels below this threshold, thus allowing us to differentiate viral colitis from mucosal infection. Moreover, the mucosal load positively correlated with the values found in the peripheral blood, whilst no correlation with the number of positive cells at immunohistochemistry was found. Steroid use was identified as a significant risk factor for both HCMV (P = 0.018) and EBV (P = 0.002) colitis. Finally, a course of specific antiviral therapy with ganciclovir was successful in all refractory patients with HCMV colitis, whilst refractory patients with EBV colitis did not show any improvement despite steroid tapering and discontinuation of the other medications.

CONCLUSION: Viral colitis appeared to contribute to mucosal lesions in refractory IBD, and its correct diagnosis and management require quantitative real-time polymerase chain reaction assay of mucosal specimens.

Keywords: Inflammatory bowel disease; Quantitative real-time polymerase chain reaction; Steroid therapy; Refractory; Viral infection

Core tip: This study investigated the presence of human Cytomegalovirus and Epstein-Barr virus (EBV) infection in patients with refractory and non-refractory inflammatory bowel disease (IBD). We identified quantitative real-time polymerase chain reaction assay of mucosal specimens as the best diagnostic technique. This allowed us to distinguish between viral colitis and infection through the identification of a cutoff value. All refractory IBD patients carried the highest mucosal viral loads, which correlated with the severity of mucosal damage and endoscopic activity. EBV infection was the most prevalent. Finally, steroid therapy was identified as a significant risk factor for viral colitis.