Cytomegalovirus is a Risk Factor for VTE in ANCA Vasculitis

Table 1. UHBFT patient demographics in relation to CMV serostatus
Characteristic	All patients n = 259	CMV status
Characteristic	All patients n = 259	CMV+ve patients n = 157	CMV−ve patients n = 102	p value*
Median age at diagnosis in years (IQR)	58 (46–68)	62 (50–70)	50 (36–64)	< 0.001
Male gender	139 (54%)	85 (55%)	53 (52%)	0.657
GPA	160 (62%)	91 (58%)	69 (68%)	0.279
MPA	94 (36%)	63 (40%)	31 (30%)
CSS	5 (2%)	3 (2%)	2 (2%)
PR3 +ve	151 (58%)	90 (57%)	61 (60%)	0.693
MPO +ve	108 (42%)	67 (43%)	41 (40%)	0.693
Ethnicity:				0.304
White British	229 (88%)	134 (85%)	95 (93%)
Asian or Asian British-Pakistani	10 (4%)	7 (5%)	3 (3%)
Asian or Asian British-Indian	7 (3%)	5 (3%)	2 (2%)
Black or Black British-Caribbean	4 (2%)	4 (3%)	0
Any other	9 (3%)	7 (4%)	2 (2%)
Induction treatment:
Cyclophosphamide	199 (78%)	119 (77%)	80 (79%)	0.718
Rituximab	8 (3%)	3 (2%)	5 (5%)	0.174
Cyclophosphamide and rituximab	4 (2%)	3 (2%)	1 (1%)	0.553
Azathioprine	18 (7%)	10 (6%)	8 (8%)	0.648
Mycophenolate mofetil	15 (6%)	15 (10%)	0	0.001
Methotrexate	7 (3%)	4 (3%)	3 (3%)	0.848
Organ involvement:
Renal	179 (69%)	115 (73%)	64 (63%)	0.074
ENT	62 (24%)	33 (21%)	29 (28%)	0.172
Pulmonary haemorrhage	24 (9%)	17 (11%)	7 (7%)	0.282
Lung	68 (26%)	42 (27%)	26 (25%)	0.822
Nervous system	22 (8%)	16 (10%)	6 (6%)	0.224
Eye	22 (8%)	13 (8%)	9 (9%)	0.878
Median creatinine at diagnosis μmol/L (IQR)	173 (92–407)	212 (100–422)	142 (87–374)	0.107
Dialysis requirement at diagnosis or during follow-up	45 (17%)	32 (20%)	13 (13%)	0.113
Median duration of follow-up in years (IQR)	8.5 (4.6–12.4)	8.3 (4.2–12.2)	8.9 (5.5–12.7)	0.136
Median CRP at diagnosis mg/L (IQR)	58 (16–139)	65 (20–152)	42 (12–112)	0.052
Median urine ACR at diagnosis mg/mmol (IQR)	36 (2–132)	47 (3–185)	23 (1–93)	0.069
Median serum albumin at diagnosis g/L (IQR)	35 (30–40)	35 (29–39)	36 (30–42)	0.085

Table 2. Comparison between UHBFT patients that experienced a VTE episode during follow-up versus those that did not
Characteristic	VTE status
Characteristic	Patients with no VTE n = 229	Patients with VTE n = 30	p value
Median age at diagnosis in years (IQR)	57 (45–68)	61 (52–69)	0.235
Male gender	120 (52%)	19 (63%)	0.259
GPA	142 (62%)	18 (60%)	0.670
MPA	82 (36%)	12 (40%)
CSS	5 (2%)	0
PR3 +ve	131 (57%)	20 (67%)	0.323
MPO +ve	98 (43%)	10 (33%)	0.323
Caucasian ethnicity	207 (90%)	27 (90%)	0.945
CMV seropositive	132 (58%)	25 (83%)	0.007
Induction treatment:
Cyclophosphamide	176 (78%)	23 (85%)	0.343
Rituximab	8 (4%)	0	0.322
Cyclophosphamide and rituximab	4 (2%)	0	0.487
Azathioprine	17 (7%)	1 (4%)	0.469
Mycophenolate mofetil	12 (5%)	3 (11%)	0.225
Methotrexate	7 (3%)	0	0.355
Organ involvement
Renal	154 (67%)	25 (83%)	0.073
ENT	58 (25%)	4 (13%)	0.148
Pulmonary haemorrhage	23 (10%)	1 (3%)	0.233
Lung	64 (28%)	4 (13%)	0.087
Nervous system	20 (9%)	2 (7%)	0.703
Eye	21 (9%)	1 (3%)	0.281
Dialysis requirement at diagnosis or during follow-up	35 (13%)	10 (33%)	0.014
Median creatinine at diagnosis μmol/L (IQR)	164 (91–389)	241 (163–593)	0.062
Median CRP at diagnosis mg/L (IQR)	44 (14–132)	139 (63–244)	< 0.001
Median urine ACR at diagnosis mg/mmol (IQR)	31 (2–120)	90 (16–314)	0.112
Median serum albumin at diagnosis g/L (IQR)	35 (30–40)	33 (29–37)	0.107
Median Hb at diagnosis g/L (IQR)	100 (88–122)	96 (88–118)	0.313
VTE event pre-AAV diagnosis	5 (2%)	2 (7%)	0.154
Malignancy at diagnosis of AAV	3 (1%)	1 (3%)	0.398
Malignancy at diagnosis of VTE or end of f/u	24 (11%)	2 (7%)	0.513
Warfarin at diagnosis of AAV	3 (1%)	1 (3%)	0.392

Table 3. Factors associated with VTE by univariable and multivariable analysis in UHBFT patients
Variable	Univariable analysis*		Multivariable analysis
Variable	HR (confidence interval)	p value	HR (confidence interval)	p value
Age at diagnosis in years	1.026 (1.005–1.049)	0.016	1.009 (0.984–1.034)	0.479
CMV seropositive	3.485 (1.449–8.386)	0.005	2.960 (1.094–8.011)	0.033
Dialysis requirement at diagnosis or during follow-up	2.586 (1.267–5.276)	0.009	2.081 (0.962–4.499)	0.063
CRP at diagnosis mg/L	1.005 (1.003–1.008)	< 0.001	1.005 (1.002–1.008)	0.001
ENT organ involvement	0.377 (0.118–0.960)	0.042	0.686 (0.201–2.334)	0.546

Cox regression analysis used
*Only those variables with a p value < 0.05 after univariable analysis are included in this table. All other variables are included in the supplemental material

Table 4. Patients with a VTE episode > 12 months after initial diagnosis of AAV
Characteristic	All episodes n = 14
CMV seropositive	14 (100%)
Clinical relapse at time of VTE	5 (36%)
Infection requiring hospitalisation at time of VTE	4 (29%)
Malignancy at time of VTE	3 (21%)
Median creatinine at time of VTE in μmol/L (IQR)	143 (110–188)
Median CRP at time of VTE in mg/L	42 (27–122)
Median urine ACR at time of VTE mg/mmol (IQR)	5 (1–8)
Median serum albumin at time of VTE g/L (IQR)	38 (33–46)
Median serum Hb at time of VTE g/L (IQR)	119 (93–126)
Median time to VTE event in years (IQR)	6.5 (3.4–13.0)

Authors and Disclosures

C. King^1,2*, R. Patel¹, C. Mendoza³, J. K. Walker¹, E. Y. Wu⁴, P. Moss², M. D. Morgan⁵, D. O'Dell Bunch⁶, L. Harper^1,7 and D. Chanouzas^1,8

¹Department of Renal Medicine, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham, UK. ²Institute of Immunology and Immunotherapy, University of Birmingham, Cancer Sciences Building, Edgbaston, Birmingham B15 2TT, UK. ³University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC, USA. ⁴University of North Carolina Pediatric Allergy, Immunology, and Rheumatology, Chapel Hill, USA. ⁵Hull York Medical School, University of Hull, Hull, UK. ⁶University of North Carolina Department of Medicine, Kidney Centre, Chapel Hill, NC, USA. ⁷Institute of Applied Health Research, University of Birmingham, Birmingham, UK. ⁸Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.

*Correspondence
catherine.king4@nhs.net

Authors' contributions
CK was involved in the acquisition, analysis and interpretation of the data as well as drafting and revising of the manuscript. RP was involved in the acquisition and analysis of the data. CM was involved in the acquisition and analysis of the data and revision of the manuscript. JKW was involved in the acquisition and analysis of the data. EW was involved in the acquisition of the data. PM was involved in the conceptualisation and design of the study as well as revising the manuscript. MDM was involved in the conceptualisation and design of the study as well as revising the manuscript. DB was involved in the design of the study, acquisition and analysis of the data as well as revising the manuscript. LH was involved in the conceptualisation and design of the study as well as revising the manuscript. DC was involved in the conceptualisation and design of the study and interpretation of the data as well as drafting and revising the manuscript. All authors read and approved the final manuscript.

Competing interests
The authors declare that they have no competing interests.