Long-Term Survival, Morbidity, Social Functioning and Risk of Disability in Patients with a Herpes Simplex Virus Type 1 or Type 2 Central Nervous System Infection, Denmark, 2000–2016

Figures & data

Table 1 Characteristics of Patients with HSV-1 and HSV-2 in Cerebrospinal Fluid, and Their Corresponding Comparison Cohorts, Denmark, 2000–2016

Characteristics	HSV-1 Cohort	Population Comparison Cohort HSV-1	HSV-2 Cohort	Population Comparison Cohort HSV-2
Total	208	2080	283	2830
Female sex – no. (%)	112 (54)	1120 (54)	201 (71)	2010 (71)
Median age at study inclusion – years (interquartile range)	60 (41–70)	60 (41–70)	38 (28–48)	38 (28–48)
Age below 16 years at study inclusion (%)	16 (8)	160 (8)	7 (2)	70 (2)
Age between 20–60 years at study inclusion (%)	90 (43)	900 (43)	247 (87)	2470 (87)
Born in Denmark – no. (%)	197 (95)	1922 (92)	266 (94)	2486 (88)
High school education (%)	111 (53)	1116 (54)	188 (66)	1893 (67)
Charlson Comorbidity Index score >0 – no. (%)^¶,$	73 (35)	547 (26)	57 (20)	366 (13)
Cancer, total – no. (%)^$	29 (14)	192 (9)	21 (7)	108 (4)
Median observation time – years (interquartile range)	3.7 (0.7–9.1)	6.2 (2.5–10.1)	5.2 (2.2–9.9)	5.5 (2.7–10.5)
Total observation time, years	1071	13,431	1671	18,114
Died – no. (%)^#	69 (33)	288 (14)	21 (7)	77 (3)
Diagnosed with cancer – no. (%)^#	12 (6)	161 (8)	7 (2)	83 (3)
Diagnosed with dementia – no. (%)^#	7 (3)	21 (1)	0 (0)	7 (0)
Emigrated – no. (%)^#	3 (1)	26 (1)	11 (4)	43 (2)
Lost to follow up – no. (%)^#	0 (0)	1 (0)	0 (0)	5 (1)

Notes: ^¶The Charlson Comorbidity Index (CCI) score derived from diagnoses recorded in the Danish National Patient Registry at study inclusion. For simplicity, we dichotomized scores (CCI score=0 and CCI score >0). ^$Diagnosed before study inclusion, ^#After study inclusion.

Abbreviations: HSV-1, herpes simplex virus type 1; HSV-2, herpes simplex virus type 2.

Figure 1 Survival in persons with herpes simplex virus (HSV) type 1 and type 2 central nervous system (CNS) infection (full lines) and in members of the comparison cohorts (broken lines). (A) Survival after HSV-1 CNS infection. (B) Survival after HSV-2 CNS infection. (C) Survival after HSV-2 CNS infection in persons without a prior diagnosis of cancer.

Table 2 Mortality Rate Ratios (MRRs) and Incidence Rate Ratios (IRRs) for Cancer and Dementia Diagnoses in Patients with HSV-1 and HSV-2 in Cerebrospinal Fluid Compared with Members of the Matched Comparison Cohorts

	HSV-1 Patients versus Comparison Cohort Members		HSV-2 Patients versus Comparison Cohort Members
Mortality	MRR	95% CI	MRR	95% CI
Mortality in first year of follow-up	10.9	7.3, 16.4	8.4	4.4, 16.0
Mortality from the second year and onwards	1.3	0.8, 1.9	0.8	0.3, 2.2
Morbidity	IRR	95% CI	IRR	95% CI
Cancer	0.9	0.5, 1.7	0.9	0.4, 2.0

Abbreviations: HSV-1, herpes simplex virus type 1; HSV-2, herpes simplex virus type 2; CI, confidence interval.

Table 3 Hospitalization Inpatient Days, Number of Outpatient Visits, Proportion Visiting a Department of Neurology, Proportion with a Hospital Visit Associated with Epilepsy, Employment Status, Sick Leave, Proportion Receiving Disability Pension, and Marital Status Among Patients with HSV-1 or HSV-2 in Cerebrospinal Fluid and Members of the Comparison Cohorts

Years from Study Inclusion	Patients with HSV-1	Comparison Cohort	Difference	95% CI of Difference	Patients with HSV-2	Comparison Cohort	Difference	95% CI of Difference
Hospitalization (mean inpatient days/year)
−2	1.5	1.0	0.5	−0.6, 1.6	1.3	0.5	0.9	−0.3, 2.0
0	55.6	1.6	54.1	47.3, 60.9	16.2	0.8	15.4	11.9, 19.0
1	2.5	1.5	1.1	−0.3, 2.5	1.5	0.7	0.8	0.1, 1.5
2	3.2	1.3	1.9	0.1, 3.6	1.6	0.6	1.0	−0.1, 2.1
5	1.7	1.4	0.3	−1.5, 2.0	2.1	0.6	1.5	−0.2, 3.2
Outpatient visits (mean visits/year)
−2	2.5	1.8	0.6	−0.3, 1.5	2.5	1.4	1.2	−0.1, 2.4
0	11.7	2.1	9.6	4.2, 14.9	5.0	1.5	3.5	2.4, 4.6
1	3.2	2.2	1.0	−0.1, 2.1	3.0	1.7	1.4	0.1, 2.6
2	2.1	2.4	−0.3	−1.2, 0.5	3.2	1.7	1.5	−0.2, 3.2
5	2.3	2.4	−0.1	−1.1, 0.8	3.2	1.9	1.3	0.3, 3.2
Proportion visiting a department of neurology (%)
−2	3.0	2.3	0.7	−1.7, 3.1	1.8	1.5	0.3	−1.4, 1.9
0	33.2	1.9	31.3	24.9, 37.7	15.2	2.1	13.1	8.9, 17.3
1	34.8	2.0	32.8	25.3, 40.4	10.3	2.2	8.1	4.3, 11.9
2	23.6	2.3	21.3	14.2, 28.4	6.3	2.1	4.2	1.1, 7.4
5	20.2	2.0	18.3	9.9, 26.6	7.5	2.2	5.5	1.2, 9.8
Proportion with a hospital visit associated with a diagnosis of epilepsy
−2	0.5	0.2	0.2	−0.7,1.2	0.0	0.3	−0.3	−0.5, −0.1
0	17.8	0.1	17.6	12.4, 22.8	2.8	0.2	2.6	0.7, 4.6
1	17.4	0.1	17.3	11.3, 23.3	0.8	0.3	0.5	−0.7, 1.6
2	10.0	0.2	9.8	4.8, 14.7	0.9	0.3	0.6	−0.6, 1.9
5	7.9	0.3	7.5	1.9, 13.1	0.7	0.1	0.6	−0.8, 1.9
Proportion employed (%)^#
−2	77.0	85.1	−8.0	−17.2, 1.1	85.9	82.3	3.6	−1.1, 8.3
0	72.5	82.4	−9.9	−20.0, 0.3	78.7	79.7	−1.0	−6.8, 4.9
1	54.4	74.9	−20.5	−32.7, −8.2	79.3	80.7	−1.4	−7.6, 4.9
2	59.4	77.0	−17.6	−30.0, −5.2	75.8	77.5	−1.8	−8.8, 5.2
5	52.2	72.0	−19.8	−34.7, −4.8	80.6	77.0	3.6	−4.6, 11.9
Days of sick leave/year^$
−2	10.6	17.5	−6.9	−7.7, −6.0	23.5	23.0	0.5	−0.2, 1.2
0	134.4	20.2	114.2	111.0, 117.4	49.9	24.3	25.7	24.5, 26.8
1	97.1	14.9	82.2	78.9, 85.4	39.3	24.5	14.8	13.7, 15.9
2	25.0	14.2	10.9	9.1, 12.6	21.7	24.4	−2.7	−3.6, −1.8
5	6.9	11.2	−4.3	−5.5, −3.1	28.6	19.5	9.1	7.9, 10.4
Proportion on disability pension (%)^#
−2	12.6	7.6	5.1	−2.1, 12.3	5.1	3.7	1.4	−1.5, 4.3
0	15.0	9.3	5.8	−2.3, 13.8	6.8	4.6	2.2	−1.4, 5.7
1	19.1	10.4	8.7	−0.9, 18.3	6.3	5.0	1.3	−2.5, 5.0
2	28.1	11.4	16.7	5.4, 28.0	9.6	6.0	3.6	−1.2, 8.3
5	32.6	10.4	22.2	8.4, 36.0	7.1	8.3	−1.1	−6.5, 4.2
Proportion married (%)*
−2	73.0	70.1	2.9	−3.7, 9.6	41.1	47.2	−6.2	−12.4, 0.1
0	73.0	70.7	2.3	−4.3, 9.0	42.3	50.7	−8.4	−14.6, −2.1
1	75.2	70.3	4.9	−2.6, 12.3	38.9	53.1	−14.2	−20.7, −7.7
2	75.0	70.5	4.5	−3.3, 12.3	38.9	54.4	−15.5	−22,4, −8.6
5	69.2	70.7	−1.4	−12.0, 9.2	42.6	57.7	−15.2	−23.7, −6.7
Proportion divorced (%)*
−2	7.9	11.4	−3.4	−7.6, 0.7	14.1	8.0	6.1	1.7, 10.4
0	9.5	11.9	−2.3	−6.8, 2.1	16.1	8.7	7.4	2.8, 11.9
1	10.6	12.6	−1.9	−7.2, 3.4	19.2	9.3	10.0	4.8, 15.1
2	12.5	13.3	−0.8	−6.8, 5.2	19.0	9.4	9.6	4.1. 15.0
5	14.1	13.6	0.5	−7.5, 8.5	23.4	11.2	12.2	5.0, 19.4

Notes: ^#Includes only individuals aged 20–60 years at study inclusion. *Includes only individuals aged >20 years at study inclusion. ^$Includes only individuals aged 20–60 years at study inclusion and registered as employed.

Abbreviations: HSV-1, herpes simplex virus type 1; HSV-2, herpes simplex virus type 2; CI, confidence interval.

Figure 2 Proportion on disability pension* among patients with herpes simplex virus (HSV) type 1 and type 2 central nervous system infections (black) and members of the comparison cohorts (white) by years before and after study inclusion. (A) HSV-1 CNS infection. (B) HSV-2 CNS infection.

Note: *Among individuals aged 20–60 years at study inclusion.

Figure 3 Cumulative incidence of an unfavorable outcome (death, dementia, receipt of a disability pension, and nursing home residency) in patients with herpes simplex virus (HSV) type 1 and type 2 central nervous system (CNS) infections (full lines) and members of the comparison cohorts (broken lines). (A) Unfavorable outcome after HSV-1 CNS infection. (B) Unfavorable outcome after HSV-2 CNS infection. (C) Unfavorable outcome after HSV-2 CNS infection in persons without a prior diagnosis of cancer.