Is cytomegalovirus infection related to inflammatory bowel disease, especially steroid-resistant inflammatory bowel disease? A meta-analysis

Figures & data

Figure 1 Flow diagram of selected studies.

Table 1 Main characteristics of the studies included in the meta-analysis

Study	Source of cases	Study design type	Disease type	Definition of disease	Detection of HCMV	Case		Control
						HCMV+	Total	HCMV+	Total
Rahbar et al,^Citation8 2003	Sweden	Case–control	UC and CD (IBD)	WHO	DNA	22	23	0	10
Wakefiels et al,^Citation10 1992	United Kingdom	Case–control	IBD	WHO	DNA	36	50	6	21
Verdonk et al,^Citation9 2006	The Netherlands	Case–control	IBD	WHO	pp65	12	31	17	53
Marszatek et al,^Citation11 2011	Poland	Case–control	IBD	WHO	DNA IgG IgM	13 9 0	32	8 5 0	15
Nahar et al,^Citation12 2015	Japan	Case–control	UC	WHO	DNA	26	71	6	188
Domenech et al,^Citation13 2008	Spain	Case–control	UC	WHO	IgG	66	94	19	25
Sipponen et al,^Citation14 2011	Finland	Case–control	IBD	WHO	pp65	64	79	6	15
Knosel et al,^Citation15 2009	Germany	Case–control	CD	WHO	DNA	2	56	0	10
Lavagna et al,^Citation16 2006	Italy	Case–control	UC	WHO	IE DNA	1 3	24	0	20
Dimitroulia et al,^Citation17 2006	Greece	Case–control	IBD	WHO	pp65 DNA	10 23	85	0 5	42
Van Kruiningen et al,^Citation18 2007	USA	Case–control	CD	WHO	DNA	1	70	1	41
Kuwabara et al,^Citation19 2007	Japan	Case–control	IBD	WHO	IE	18	34	3	31
Yi et al,^Citation1 2013	People’s Republic of China	Case–control	IBD	WHO	DNA IgG IgM	190 172 4	226	173 147 1	290
Ciccocioppo et al,^Citation20 2015	Italy	Case–control	IBD	WHO	IE	9	40	2	40
Ciccocioppo et al,^Citation34 2016	Italy	Case–control	IBD	WHO	IE	51	64	7	25
Criscuoli et al,^Citation21 2015	Italy	Case–control	UC	WHO	DNA Pp65	11 8	24	2 2	24
Taherkhani et al,^Citation22 2015	Iran	Case–control	UC	WHO	DNA	12	98	0	67
Thörn et al,^Citation23 2016	Sweden	Case–control	IBD	WHO	IgM DNA	14 12	67	1 0	34

Abbreviations: CD, Crohn’s disease; HCMV, human cytomegalovirus; IBD, inflammatory bowel disease; IE, immediate-early; UC, ulcerative colitis; WHO, World Health Organization.

Table 2 Main characteristics of the relationship between CMV infection and steroid-resistant IBD

Study	Source of cases	Study design type	Disease type	Definition of disease	Detection of HCMV	HCMV+		HCMV−
						Steroid resistant/refractory	Total	Steroid resistant/refractory	Total
Lévêque et al,^Citation24 2010	France	Case	IBD	WHO	DNA	0	5	8	29
Domènech et al,^Citation13 2008	Spain	Case	UC	WHO	IgG	13	29	6	14
Iida et al,^Citation3 2013	Japan	Case	UC	WHO	IgG IgM	62	141	20	46
Wada et al,^Citation25 2003	Japan	Case	UC	WHO	pp65	13	16	9	31
Kambham et al,^Citation26 2004	USA	Case	UC	WHO	CMV inclusions IE	12	13	28	67
Maconi et al,^Citation27 2005	Italy	Case	UC	WHO	IE	15	17	40	60
Kuwabara et al,^Citation19 2007	Japan	Case	IBD	WHO	IE	13	14	2	8
Maher et al,^Citation28 2009	Egypt	Case	IBD	WHO	IgM IE	8	9	15	63
Criscuoli et al,^Citation29 2011	Italy	Case	UC	WHO	CMV inclusions IE DNA Pp65	6	28	11	57
Mccurdy et al,^Citation30 2015	USA	Case	IBD	WHO	CMV inclusions IE	40	68	61	202
Ciccocioppo et al,^Citation20 2015	Italy	Case	IBD	WHO	IE	4	9	13	31
Ciccocioppo et al,^Citation34 2016	Italy	Case	IBD	WHO	IE	25	51	0	13
Cottone et al,^Citation31 2001	Italy	Case	IBD	WHO	DNA	7	7	12	55
Criscuoli et al,^Citation31 2004	Italy	Case	IBD	WHO	pp65 DNA	4	9	8	33
Criscuoli et al,^Citation21 2015	Italy	Case	UC	WHO	CMV inclusions IE DNA pp65	5	11	7	13
Kim et al,^Citation35 2012	Korea	Case	UC	WHO	DNA	14	31	7	41
Ormeci et al,^Citation33 2016	Turkey	Case	IBD	WHO	DNA	8	13	5	72

Abbreviations: HCMV, human cytomegalovirus; IBD, inflammatory bowel disease; IE, immediate-early; CMV, cytomegalovirus; UC, ulcerative colitis; WHO, World Health Organization.

Figure 2 Forest plot (random-effect model) of the association between HCMV infection and IBD stratified by the study design based on HCMV IgG tests.

Abbreviations: CI, confidence interval; HCMV, human cytomegalovirus; IBD, inflammatory bowel disease; MH, Mantel–Haenszel; OR, odds ratio.

Figure 3 Forest plot (random-effect model) of the association between HCMV infection and IBD stratified by the study design based on HCMV IgM tests.

Abbreviations: CI, confidence interval; HCMV, human cytomegalovirus; IBD, inflammatory bowel disease; MH, Mantel–Haenszel; OR, odds ratio.

Figure 4 Forest plot (random-effect model) of the association between HCMV infection and IBD stratified by the study design based on HCMV DNA tests.

Abbreviations: CI, confidence interval; HCMV, human cytomegalovirus; IBD, inflammatory bowel disease; MH, Mantel–Haenszel; OR, odds ratio.

Figure 5 Forest plot (random-effect model) of the association between HCMV infection and IBD stratified by the study design based on HCMV IE tests.

Abbreviations: CI, confidence interval; HCMV, human cytomegalovirus; IBD, inflammatory bowel disease; IE, immediate-early; MH, Mantel–Haenszel; OR, odds ratio.

Figure 6 Forest plot (random-effect model) of the association between HCMV infection and IBD stratified by the study design based on HCMV pp65 tests.

Abbreviations: CI, confidence interval; HCMV, human cytomegalovirus; IBD, inflammatory bowel disease; MH, Mantel–Haenszel; OR, odds ratio.

Table 3 Main characteristics of the studies included in the meta-analysis

Characteristics	Subgroup	N (Study)	N (Subject)	OR	95% CI	I2 (%)
All ethnicity		17	1,306	3.84	2.12–6.97	67
	Caucasian	11	220	3.47	1.43–8.41	65
	Asian	4	140	4.75	1.16–19.52	80
	Other	2	141	5.43	1.22–24.17	55
CMV detection	IgG	1	43	1.08	0.30–3.92	Not applicable
	DNA	4	253	6.40	1.13–36.33	71
	IE	4	203	5.86	1.17–29.37	61
	pp65	1	47	10.59	2.42–46.33	Not applicable
	CMV inclusion + IE	2	350	5.43	1.22–24.17	55
	IgG + IgM	1	187	1.02	0.52–2.00	Not applicable
	IgM + IE	1	72	25.60	2.96–221.58	Not applicable
	pp65 + DNA	1	42	2.50	0.54–11.63	Not applicable
	CMV inclusion + IE + DNA + pp65	2	109	0.98	0.39–2.45	0

Abbreviations: CI, confidence interval; CMV, cytomegalovirus; IE, immediate-early; OR, odds ratio.

Figure 7 Begg’s funnel plot of the association between HCMV infection and IBD based on HCMV DNA tests.

Abbreviations: HCMV, human cytomegalovirus; IBD, inflammatory bowel disease; OR, odds ratio; SE, standard error of the mean.

Figure 8 Begg’s funnel plot of the association between HCMV infection and steroid-resistant IBD.

Abbreviations: HCMV, human cytomegalovirus; IBD, inflammatory bowel disease; OR, odds ratio; SE, standard error of the mean.

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