Table 1.
Main studies recording the impact of cytomegalovirus on inflammatory bowel diseases course
| Studies by chronological order | No. of studied patients by type of IBD | Method used for CMV detection | Main results of the study | Impact of CMV |
| Vega et al[51], 1999 | 7 UC and 2 CD | Histology and IHC | Ganciclovir allowed clinical remission in 5/7 patients, with absence of CMV markers after antiviral therapy | Unfavorable |
| Cottone et al[52], 2001 | 55 UC and 7 CD | Histology and IHC | Antiviral treatment (3 with ganciclovir and 2 with foscarnet) allowed clinical remission in 5/7 patients | Unfavorable |
| PCR in PBMC | ||||
| Papadakis et al[53], 2001 | 5 UC, 3 CD, 2 indeterminate colitis; all medically refractory | Heterogeneous (serology, histology, IHC, ISH, PCR, cell culture) | Ganciclovir improved clinical outcome in 8/9 patients | Unfavorable |
| Wada et al[54], 2003 | 47 moderate to severe UC | pp65 antigenemia and IHC | Association of CMV infection with steroid resistance [13/16 (81.3%) vs 9/31 (29%), P = 0.001] and severe endoscopic score (P < 0.05); ganciclovir effective in 8/12 patients (66.7%) | Unfavorable |
| Criscuoli et al[55], 2004 | 38 UC and 4 CD with severe disease | pp65 antigenemia, qualitative PCR in leucocytes, histology and IHC | No clear association with steroid resistance, no need for antiviral therapy | None |
| Kambham et al[56], 2004 | 80 UC | IHC | CMV detected in 10 of 40 (25%) patients with refractory UC vs 1 of 40 (2.5%) patients with nonrefractory UC | Unfavorable |
| Kishore et al[57], 2004 | 61 UC and 2 CD | Serology (IgM), qualitative PCR in biopsy | CMV infection associated with poor outcome, with surgical treatment (4/10 vs 4/53, P < 0.05) and death (3/10 vs 0/53, P < 0.005) | Unfavorable |
| Alain et al[58], 2005 | 63 CD and 28 UC | Serology (IgM), viruria, pp65 antigenemia, detection of mRNA in blood, tissue cell culture of blood and tissue, histology and IHC | 8/14 patients with CMV infection experienced high dose steroid or azathioprine; ganciclovir improved 4/4 treated patients | Unfavorable |
| Maconi et al[59], 2005 | 77 UC with colectomy | Histology and IHC | Trend for an association between CMV reactivation and corticoresistance (15/55, 27.3% vs 2/22, 9.1%, P = 0.123) | Unfavorable |
| Dimitroulia et al[12], 2006 | 58 UC and 27 CD | PCR in blood and IHC | No association with disease severity | None |
| Kojima et al[60], 2006 | 126 UC with colectomy | Histology and IHC | CMV markers in surgical specimens more frequently detected in patients with severe or refractory disease | Unfavorable |
| Lavagna et al[61], 2006 | 24 refractory UC leading to colectomy | IHC and PCR in tissue | No pouchitis in CMV positive patients (compared to 3/21 of CMV negative ones) | None |
| Kuwabara et al[13], 2007 | 34 UC and 16 CD | IHC | CMV positive cell density associated with steroid resistance and colectomy rate | Unfavorable |
| Minami et al[62], 2007 | 23 severe UC | Heterogeneous (serology or histology or IHC or PCR in blood) | 18 out 23 patients receiving CyA exhibited CMV infection; 15/18 (83.3%) CMV positive required colectomy; colectomy could be avoided in the 3 remaining patients by administration of ganciclovir | Unfavorable |
| Matsuoka et al[63], 2007 | 69 moderate to severe UC | pp65 antigenemia and qPCR in plasma, histology | Low peripheral viral load observed in 25/48 patients; none exhibited CMV markers in tissue. No impact on clinical outcome and spontaneous clearance of CMV markers in blood without ganciclovir | None |
| Yoshino et al[14], 2007 | 30 UC refractory to immunosuppressive therapies | qPCR in tissue | Clinical remission after ganciclovir alone in 4/12 treated, the remaining 8 required additional anti-inflammatory treatment | Unfavorable |
| Domènech et al[64], 2008 | 114 active UC | pp65 antigenemia tissue: histology, IHC and detection of pp67 mRNA | Steroid and CyA treatment predisposes to CMV reactivation in colon (6/19); ganciclovir associated to remission in 3/6 patients; CMV markers detected in 2 surgical specimens | Unfavorable |
| Maher et al[65], 2009 | 49 UC and 23 CD with active disease | Serology, histology and IHC | CMV infection more frequent in steroid resistant patients (8/23, 34.8% vs 1/31, 3.2%) | Unfavorable |
| Kim et al[17], 2010 | 122 UC | IHC | CMV-positive patients required hospitalization (OR = 4.9; 95%CI: 1.2-19.0) and were hospitalized ≥ 7 d (OR = 5.0; 95%CI: 1.6-21.3) | Unfavorable |
| Lévêque et al[16], 2010 | 33 CD and 20 UC | qPCR in tissue | CMV infection more frequent after corticoid or azathioprine therapy; no relation with disease severity; no need of antiviral therapy | None |
| Omiya et al[42], 2010 | 20 UC | PCR in tissue | Absence of large ulcer in case of CMV infection | None |
| Suzuki et al[66], 2010 | 73 UC | pp65 antigenemia | Irregular ulceration associated to 100% of CMV infection | Unfavorable |
| Criscuoli et al[67], 2011 | 28 UC with CMV reactivation | Histology, IHC and nested PCR in tissue | Persistence of CMV markers in colon after acute colitis flare-up despite remission | None |
| Nguyen et al[22], 2011 | 26 UC and 17 CD | Histology and IHC | Higher colectomy rate in patients exhibiting high grade infection; decreased colectomy rate with ganciclovir use | Unfavorable |
| Roblin et al[10], 2011 | 42 moderate to severe UC | qPCR in tissue | The tissue CMV DNA load is predictive of resistance to immunosuppressive therapy; ganciclovir treatment cleared CMV DNA in tissue and improved outcome in 7/8 patients | Unfavorable |
| Al-Zafiri et al[20], 2012 | 13 CD and 18 UC with CMV reactivation | IHC | Colectomy rate higher (9/31, 29%) in CMV positive than in CMV negative (65/581, 11.2%) IBD patients | Unfavorable |
| Kim et al[68], 2012 | 72 moderate to severe UC treated with IV steroids | PCR in tissue | Association of CMV infection with steroid resistance; clinical improvement after ganciclovir (11/14) | Unfavorable |
| Yoshino et al[69], 2012 | 17 UC refractory to tacrolimus | qPCR in tissue | Colectomy-free time lower in CMV positive patients than in CMV-negative ones (35.7% at 17.7 mo vs 88.9% at 45.9 mo respectively, log-rank test P < 0.005) | Unfavorable |
| Fukuchi et al[70], 2013 | 51 active UC | IHC or qPCR in tissue | CMV DNA became negative after GMAA in patients with clinical remission | Unfavorable |
| IIda et al[71], 2013 | 187 active UC | pp65 antigenemia | CMV infection more frequent in steroid refractory patients (27/82, 32.9% vs 6/105, 5.7%) | Unfavorable |
| Kopylov et al[72], 2013 | 13 UC with CMV reactivation | IHC | The disease was more severe in the 7 patients requiring ganciclovir therapy, including 1 death and 3 colectomies | Unfavorable |
| Delvincourt et al[73], 2014 | 26 UC and 110 IBD hospitalized | qPCR in blood or tissue | No alteration of the course of IBD flare | None |
| Do Carmo et al[74], 2014 | 249 CD+151 UC | Qualitative PCR in stools | CMV infection is rare (only 9 patients) and is not associated with IBD disease activity | None |
| Inokuchi et al[75], 2014 | 118 UC | pp65 antigenemia | Delay to clinical remission higher in CMV positive patients (21 d vs 16 d, P < 0.01); ganciclovir decreased the rate of colectomy in multivariate analysis | Unfavorable |
| Kim et al[76], 2014 | 72 moderate to severe UC | Heterogeneous (serology or histology or IHC or PCR) | Cumulative colectomy (log rank, P = 0.025) and disease flare-up rates (log-rank, P = 0.048) higher in CMV positive patients | Unfavorable |
| Kim et al[77], 2014 | 229 moderate to severe UC | IHC and pp65 antigenemia | Association between positive pp65 antigenemia and rate of colectomy (13/39, 33.3% vs 5/44, 11.4%, P < 0.05) | Unfavorable |
| Maconi et al[78], 2014 | 30 UC and 8 CD with active colitis and CMV infection | Histology/IHC | Antiviral therapy associated with a higher clinical remission rate at 12 mo (77.8% vs 45%, P < 0.05, and 77.8% vs 19.4%, P < 0.05) in UC patients and patients with steroid-dependent/refractory disease, respectively | Unfavorable |
| Matsumoto et al[79], 2014 | 222 UC | Antigenemia, histology, PCR | CMV infection as a risk factor for hospitalization because of UC aggravation (OR = 8.2, 95%CI: 1.91-35.33, P < 0.005) | Unfavorable |
| Olaisen et al[80], 2014 | 77 patients undergoing colectomy | IHC | CMV positive patients received higher doses of corticoids and were at higher risk of postoperative complications | Unfavorable |
| Yamada et al[81], 2014 | 33 refractory UC | qPCR in tissue | Induction remission rate by infliximab lower (54.5%) in CMV-positive patients than in CMV-negative ones (81.8%) although not statistically significant | Unfavorable |
| Chun et al[82], 2015 | 43 moderate to severe UC | pp65 antigenemia | Positive antigenemia associated with steroid refractoriness (11/12, 91.7% vs 12/31, 38.7%, P < 0.005); ganciclovir improved outcome: colectomy in 2/8 (25%) vs 2/4 (50%) | Unfavorable |
| Ciccocioppo et al[32], 2015 | 24 UC and 16 CD | qPCR in tissue | In refractory patients, more frequent CMV infection and higher viral load; efficacy of ganciclovir in all refractory patients | Unfavorable |
| Jones et al[83], 2015 | 1111 IBD patients | Histology, IHC, ISH | Antiviral therapy improved surgery-free survival outcome | Unfavorable |
| Gauss et al[84], 2015 | 166 UC and 131 CD | IHC and PCR in tissue | CMV reactivation associated to longer hospital stay (P < 0.001) | Unfavorable |
| McCurdy et al[41], 2015 | 45 UC, 21 CD and 2 indeterminate IBD colitis | Histology, ISH, IHC | CMV reactivation associated to medically refractory disease (OR = 3.69, P < 0.001) and endoscopic ulcers (OR = 2.95, P < 0.001) | Unfavorable |
| Minami et al[85], 2015 | 29 severe UC treated either with tacrolimus or infliximab | qPCR in tissue | Colectomy rate higher in patients with CMV infection (5/6, 83.3% vs 8/23, 34.8%, P < 0.05) | Unfavorable |
GMAA: Granulocyte/monocyte adsorptive apheresis; IHC: Immunohistochemistry; ISH: In situ hybridization; NAAT: Nucleic acid amplification test; PBMC: Peripheral blood monocular cells; PCR: Polymerase chain reaction; qPCR: Quantitative real-time PCR; IBD: Inflammatory bowel diseases; CD: Crohn’s disease; UC: Ulcerative colitis; CMV: Cytomegalovirus.