Cytomegalovirus and ulcerative colitis: Place of antiviral therapy

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.