Several diseases are associated with herpes zoster (HZ). However, whether sciatica is a stressor leading to HZ development remains unclear. Here, we evaluated the occurrence of HZ in patients with sciatica.
Methods
The sciatica cohort consisted of patients first diagnosed as having sciatica between 2000 and 2012. All patients with sciatica were randomly age, sex and index year matched with control individuals without sciatica. The primary outcome was diagnosis of HZ. All individuals were followed until HZ diagnosis, withdrawal from the insurance, death, or December 31, 2013, whichever occurred first. HZ risk in the two cohorts was further analyzed with age, sex and comorbidity stratification.
Results
In total, 49,023 patients with sciatica and 49,023 matched controls were included. Female patients were more likely to have HZ development than were male patients [adjusted hazard ratio (HR) = 1.07, 95% confidence interval (CI) = 1.02–1.12]. After adjustments for all the covariates, HZ risk was significantly higher in the sciatica cohort than in the control cohort (adjusted HR = 1.19; 95% CI = 1.12–1.25).
Conclusion
Sciatica increased HZ risk. Thus, HZ risk should be addressed whenever physicians encounter patients with sciatica, HZ vaccination should be considered especially those aged over 50.
Hinweise
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Abkürzungen
HZ
Herpes zoster
HR
Hazard ratio
CI
Confidence interval
VZV
Varicella-zoster virus
LHID2000
Longitudinal Health Insurance Database 2000
NHIRD
National Health Insurance Research Database
ICD-9-CM
International Classification of Diseases, Ninth Revision, Clinical Modification
BDI
Beck Depression Inventory
Background
Sciatica is characterized by a burning sensation or shooting pain caused by irritation or compression of the sciatic nerve, and the most common cause of sciatica is spinal disc herniation. Sciatica prevalence and incidence rates have been reported to be 1.2–43% and 1–37%, respectively; the large variations may be due to the differences in definitions or study population in the concerned studies [1, 2]. Sciatica treatment intensity is dependent on disease severity, and the treatment can include exercise, manual therapy, medication, spinal injection and surgery [3].
Herpes zoster (HZ), a painful vesicular eruption, occurs due to varicella-zoster virus (VZV) reactivation. HZ incidence was 9.92 per 1000 person-years in immunocompetent, unvaccinated adults aged ≥50 years, with a case-fatality rate of 0.04% [4]. HZ incidence can be high after transplantation. Kim et al. reported that HZ incidence after liver transplantation in adults was 16.3 per 1000 person-years. HZ incidence was 9.1, 10.0, and 11.9% at 3, 5, and 10 years after transplantation, respectively [5]. Postherpetic neuralgia is a painful complication; Salvetti et al. found that one-tenth of HZ patients suffered from this, with the highest proportion of 15.56% being found in patients aged 75–79 years [6].
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Diseases with chronic pain such as adhesive capsulitis of the shoulder [7], chronic interstitial cystitis [8], and lateral epicondylitis [9] are associated with HZ occurrence. Sciatica is one of the diseases with chronic pain, the association between sciatica and HZ development might be existed. In this paper, we evaluated HZ occurrence in patients with sciatica to understand whether sciatica is a stressor leading to HZ development.
Methods
Study design and research database
We designed a population-based retrospective cohort study. Here, the study data were extracted from the claims data in the Longitudinal Health Insurance Database 2000 (LHID2000); which includes systemically collected claims data of 1 million National Health Insurance (NHI) as well as the random samples in Taiwan NHI Research Database (NHIRD). NHIRD, managed by the National Health Research Institutes, contains data of beneficiaries of the NHI program established in 1995 to provide comprehensive and universal health care coverage to approximately 99% Taiwan residents. NHIRD include data on enrollment files, claims data, disease diagnose, prescriptions, outpatient visits, and hospital admissions. All diagnoses are coded using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic codes. To ensure data privacy, patient data are released to researchers in an electronically encrypted form and thus, the requirement to obtain informed consent was waived. This study has been approved by the Research Ethics Committee at China Medical University Hospital (CMUH104-REC2–115-CR-4).
Data availability statement
The dataset used in this study is held by the Taiwan Ministry of Health and Welfare (MOHW). The MOHW must approve our application to access this data. Any researcher interested in accessing this dataset can submit an application form to the Ministry of Health and Welfare requesting access. Please contact the staff of MOHW (Email: stcarolwu@mohw.gov.tw) for further assistance. Taiwan Ministry of Health and Welfare Address: No.488, Sec. 6, Zhongxiao E. Rd., Nangang Dist., Taipei City 115, Taiwan (R.O.C.). Phone: + 886–2–8590-6848. All relevant data are within the paper.
Study population
We identified patients first diagnosed as having sciatica (ICD-9-CM 724.3) between January 1, 2000 and December 31, 2012, and included them in the sciatica cohort. The index date was defined as the date of sciatica diagnosis. We excluded patients aged < 20 years, and with a HZ history before the index date. Every patient with sciatica was randomly age (every 5-year interval), sex and index date matched with a control individual without sciatica from the same database and then this individual was assigned to the control cohort under the same criteria.
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Outcome and covariate assessment
The outcome of interest was a new diagnosis of HZ (ICD-9-CM 053) between January 1, 2000 and December 31, 2013. All individuals were followed until HZ occurrence, withdrawal from NHI, death, or December 31, 2013, whichever occurred first. We considered several covariates as potential confounders including sex, age, and baseline comorbidities. Inpatient and outpatient data were used to define the status of comorbidities including chronic kidney disease (ICD-9-CM 585and 586), obesity (ICD-9-CM 278), diabetes (ICD-9-CM 250), coronary artery disease (ICD-9-CM 410–414), depression (ICD-9-CM 296.2, 296.3, 300.4 and 311), and lumbar disc herniation (ICD-9-CM 722.10).
Statistical analysis
Characteristics of all included individuals were first analyzed descriptively. The differences of categorical and continuous variables between the sciatica and control cohorts were tested using the t and chi-square tests. The incidence rate was defined as the number of events per 1000 person-years. Cox proportional hazards regression model adjusted for age, sex and comorbidity was used to determine the association between sciatica and HZ risk. The results were presented as a hazard ratio (HR) with accompanying 95% confidence interval (CI). We estimated the cumulative incidence of HZ in the sciatica and control cohorts by using the Kaplan–Meier method, and the differences were examined using the log-rank test. HZ risk in the two cohorts was further analyzed after age, sex and comorbidity stratification. A two-sided p of < 0.05 was considered statistically significant. All data processing and statistical analyses were performed using SAS (version 9.4; SAS Institute Inc., Cary, NC, USA).
Results
In total, 49,023 patients with sciatica and 49,023 matched controls were included. Table 1 presents the demographic characteristics and comorbidities in the two cohorts. The age and sex distribution was similar between the sciatica and control cohorts after matching. Compared with the control cohort, the sciatica cohort had significantly higher diabetes, coronary artery disease, depression, obesity, cancer and lumbar disc herniation prevalence (p < 0.001). The mean follow-up duration was 7.44 (±3.82) and 7.42 (±3.83) years in sciatica and control cohorts, respectively.
Table 1
Demographic characteristics and comorbidities in cohorts with and without Sciatica
Variable
Sciatica
p-value
No
Yes
N = 49,023
N = 49,023
Age, year
0.99
≤ 49
18,729 (38.2)
18,729 (38.2)
50–64
16,682 (34.0)
16,682 (34.0)
65+
13,612 (27.8)
13,612 (27.8)
Mean ± SDa
54.1 ± 15.4
54.8 ± 15.1
< 0.001
Sex
0.99
Female
27,378 (55.9)
27,378 (55.9)
Male
21,645 (44.2)
21,645 (45.2)
Comorbidity
Diabetes
3849 (7.85)
4592 (9.37)
< 0.001
CAD
7491 (15.3)
11,260 (23.0)
< 0.001
Depression
2016 (4.11)
3356 (6.85)
< 0.001
Chronic kidney disease
859 (1.75)
926 (1.89)
0.11
Obesity
544 (1.11)
932 (1.90)
< 0.001
Cancer
1376 (2.81)
1178 (2.40)
< 0.001
Lumbar disc herniation
16,769 (34.2)
38,692 (78.9)
< 0.001
Chi-Square Test; a: T-Test
CAD denotes coronary artery disease
Cox proportional hazards regression models for analyzing the risk of variables contributing to HZ are presented in Table 2. After adjustment for all the covariates, the sciatica cohort had a significantly higher HZ risk than did the control cohort (adjusted HR = 1.19; 95% CI = 1.12–1.25). Moreover, HZ risk was significantly higher in patients aged 50–64 years (adjusted HR = 2.10; 95% CI = 1.97–2.23) and those aged > 65 years (adjusted HR = 2.48; 95% CI = 2.32–2.66) than in those aged < 49 years. Female patients were more likely to have HZ than were male patients (adjusted HR = 1.07, 95% CI = 1.02–1.12). Moreover, patients with diabetes, coronary artery disease, depression, chronic kidney disease, cancer and lumbar disc herniation had a significantly higher HZ risk than did those without any comorbidity.
Table 2
The incidence and risk factors for herpes zoster
Variable
Event
PY
Ratea
Crude HR(95% CI)
Adjusted HRb
(95% CI)
Sciatica
No
2899
368,778
7.86
1.00
1.00
Yes
3981
375,977
10.6
1.35 (1.28, 1.41)***
1.19 (1.12, 1.25)***
Age, year
≤ 49
1551
310,651
4.99
1.00
1.00
50–64
2839
254,722
11.2
2.25 (2.11, 2.39)***
2.10 (1.97, 2.23)***
65+
2490
179,382
13.9
2.84 (2.67, 3.03)***
2.48 (2.32, 2.66)***
Sex
Female
4192
426,137
9.84
1.16 (1.11, 1.22)***
1.07 (1.02, 1.12)*
Male
2688
318,618
8.44
1.00
1.00
Comorbidity
Diabetes
No
6113
690,290
8.86
1.00
1.00
Yes
767
54,465
14.1
1.61 (1.50, 1.74)***
1.14 (1.05, 1.12)**
CAD
No
5039
615,072
8.19
1.00
1.00
Yes
1841
129,683
14.2
1.75 (1.66, 1.85)***
1.18 (1.12, 1.25)***
Depression
No
6455
709,775
9.09
1.00
1.00
Yes
425
34,980
12.2
1.36 (1.23, 1.50)***
1.11 (1.01, 1.23)*
Chronic kidney disease
No
6727
735,561
9.15
1.00
1.00
Yes
153
9193
16.6
1.88 (1.60, 2.20)***
1.28 (1.09, 1.50)**
Obesity
No
6788
735,209
9.23
1.00
1.00
Yes
92
9546
9.64
1.06 (0.87, 1.31)
Cancer
No
6691
730,816
9.16
1.00
1.00
Yes
189
13,939
13.6
1.51 (1.31, 1.75)***
1.21 (1.05, 1.40)*
Lumbar disc herniation
No
2538
348,796
7.28
1.00
1.00
Yes
4342
395,959
11.0
1.53 (1.46, 1.61)***
1.24 (1.17, 1.31)***
Ratea, incidence rate, per 1000 person-years; Crude HR, relative hazard ratio; Adjusted HRb: multivariable analysis including age, sex, and comorbidities of diabetes, and CAD;
*p < 0.05, **p < 0.01, ***p < 0.001
Table 3 presents the stratification analysis results. After age, sex and comorbidity stratification, HZ incidence was significantly higher in the sciatica cohort than in the control cohort (p < 0.001). Similarly, the Kaplan-Meier analysis results revealed that the cumulative incidence of HZ was significantly different between the sciatica and control cohorts (log-rank test, p < 0.001; Fig. 1).
Table 3
Incidence of herpes zoster by age, sex and comorbidity and Cox model measured hazards ratio for patients with Sciatica compared those without Sciatica
Variables
Sciatica
Crude HR (95% CI)
Adjusted HRb (95% CI)
No
Yes
Event
PY
Ratea
Event
PY
Ratea
Age, years
≤ 49
662
154,980
4.27
889
155,671
5.71
1.34 (1.21, 1.48)***
1.17 (1.04, 1.31)***
50–64
1174
127,099
9.24
1665
127,623
13.1
1.41 (1.31, 1.52)***
1.30 (1.19, 1.41)***
65+
1063
86,700
12.3
1427
92,682
15.4
1.25 (1.16, 1.36)***
1.11 (1.02, 1.21)***
Sex
Female
1758
211,353
8.32
2434
214,784
11.3
1.36 (1.28, 1.45)***
1.21 (1.14, 1.30)***
Male
1141
157,426
7.25
1547
161,192
9.60
1.32 (1.23, 1.43)***
1.14 (1.04, 1.24)***
Comorbidity c
No
1242
213,614
5.81
586
73,197
8.01
1.35 (1.22, 1.49)***
1.37 (1.24, 1.51)***
Yes
1657
155,164
10.7
3395
302,780
11.2
1.04 (0.98, 1.11)
1.14 (1.08, 1.21)***
Ratea, incidence rate, per 1000 person-years; Crude HR, relative hazard ratio; Adjusted HRb: multivariable analysis including age, sex, and comorbidities of diabetes, CAD, and lumbar disc herniation;
cIndividuals with any comorbidity of diabetes, CAD, depression, and chronic kidney disease, obesity, cancer, and lumbar disc herniation were classified into the comorbidity group
***p < 0.001
Fig. 1
Cummulative incidence comparison of herpes zoster for patients with (dashed line) or without (solid line) sciatica
×
Similar results were observed for HZ by propensity score methods as sensitivity analysis. We recreated a non-sciatica cohort well matched for age, sex, index year and comorbidities including diabetes, CAD, depression, chronic kidney disease, obesity, cancer, lumbar disc herniation (Table 4). With this newly selected non-sciatica cohort, the associations between sciatica and HZ (adjusted HR = 1.19, 95% CI = 1.12–1.27) remained strongly (Table 5).
Table 4
Demographic characteristics and comorbidities in cohorts with and without sciatica by propensity score matching
Variable
Sciatica
p-value
No
Yes
N = 27,097
N = 27,097
Age, year
0.74
≤ 49
9228 (34.1)
9262 (34.2)
50–64
9400 (34.7)
9378 (34.6)
65+
8469 (31.3)
8457 (31.2)
Mean ± SDa
55.8 ± 15.1
55.8 ± 15.2
0.99
Sex
0.99
Female
15,740 (58.1)
15,778 (58.2)
Male
11,357 (41.9)
11,319 (41.8)
Comorbidity
Diabetes
2488 (9.18)
2488 (9.03)
0.55
CAD
5517 (20.4)
5528 (20.4)
0.91
Depression
1438 (5.31)
1457 (5.38)
0.72
Chronic kidney disease
508 (1.87)
458 (1.69)
0.10
Obesity
384 (1.42)
379 (1.40)
0.86
Cancer
772 (2.85)
719 (2.65)
0.16
Lumbar disc herniation
16,769 (61.9)
16,766 (61.9)
0.98
Chi-Square Test; a: T-Test
CAD denotes coronary artery disease
Table 5
Overall Incidence of herpes zoster (per 1000 person-years) and estimated hazard ratios according to sciatica status using Cox method by propensity score matching
Sciatica
No
Yes
Variable
(N = 27,097)
(N = 27,097)
Herpes zoster.
Person-years
203,946
208,742
Follow-up time (y), Mean ± SD
7.53 ± 3.87
7.70 ± 3.84
Event, n
1813
2239
Ratea
8.89
10.7
Crude HR (95% CI)
1(Reference)
1.21 (1.13, 1.28)***
Adjusted HRb (95% CI)
1(Reference)
1.19 (1.12, 1.27)***
Ratea, incidence rate, per 1000 person-years; Crude HR, relative hazard ratio; Adjusted HRb: multivariable analysis including age, sex, and comorbidities of diabetes, and CAD;
***p < 0.001
Discussion
This is the first population-based study to assess HZ risk in patients with sciatica; patients with sciatica were 1.19 times more likely to develop HZ than were those without.
About 90% of sciatica is caused by spinal disc herniation [10]. Because an inflammatory response in the lumbosacral nerve roots due to herniated nucleus pulposus and mechanical deformation on the nerve, sensation of pain occurs [11]. However, Stafford et al. emphasized that herniation of nucleus pulposus is not the only cause of sciatica, and we should not forget other causes [11].
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Diseases with chronic pain such as adhesive capsulitis of the shoulder [7], chronic interstitial cystitis [8], and lateral epicondylitis [9] are associated with risk of HZ. Sciatica is one of common chronic pain syndrome which is a stressor for affected individual. Stress can activate neural or hormonal activity in order to restore homeostasis [12]. It is believed that stress and pain will produce changes in the perceptual and stress system, resulting in abnormal output patterns of the body’s own neuromatrix [12]. These mechanisms are strongly associated with decreasing the VZV-specific cellular immunity; thus, increasing risk of HZ in patients with sciatica should be considered.
In a comprehensive review of the evidence from systematic reviews, Parreira et al. identified risk factors for sciatica from 54 items, with depression being an adverse risk factor [13]. Oosterhuis et al. investigated prognostic factors for work participation in patients with sciatica through systemic reviews and found a similar result: less depression was a favourable factor for return to work [14]. Lower back pain is a discomfort experienced by patients with sciatica. Tutoglu et al. assessed depression severity in patients with sciatica and neuropathic pain, sciatica without neuropathic pain, and healthy participants by using Beck Depression Inventory (BDI) and found mean BDI scores of 5.89 (±5.37), 20.88 (±12.39) and 4.21 (±5.95). BDI was significantly higher in patients with sciatica and neuropathic pain [15]. Max et al. examined depression symptoms by using the 36-items short form of Mental Health Scale for patients with sciatica after surgery and found that depression symptoms were significantly alleviated after surgery if the pain was reduced by > 25%. And, the mean score remained unchanged if there was no or only slight pain relief [16]. The patients with chronic pain may experience depression [17]. Narita et al. reported that chronic pain had an anxiogenic effect in mice and that this phenomenon may be associated with changes in opioidergic function in the amygdala [17]. The mechanisms of pain leading to depression were identified by Max et al. through pain-gene interaction by using a clinical genetic method, they considered that the short-term and 1-year effect on mood after surgery for sciatica was on the mu opioid receptor and galanin-2 receptor [16].
Irwin et al. found that depression is associated with decreasing VZV-specific cellular immunity [18]. Thus, the risk of HZ is increased in patients with depression. Choi et al. found that HZ prevalence was 6.8% in patients with depression and 6.3% in controls and that patients with depression had a 1.09 times higher HZ risk than did those without depression [19]. In a similar population-based study of Liao et al., HZ incidence was 4.58 and 3.54 per 1000 person-years in patients with depression and controls. In addition, their case cohort was 1.11 times more likely to develop HZ than was their control cohort [20]. Because sciatica and sciatica-related conditions such as pain and depression are stressful, there is a strong possibility for sciatica patients to develop HZ.
HZ prevalence typically increases with age as corroborated by our results (Table 1); among our patients with sciatica, HZ incidence was higher in patients aged < 65 years (Table 3). Furthermore, regardless of whether the patients had comorbilities, HZ incidence remained high. These results confirmed that the presence of sciatica might be a stressor leading to HZ development.
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Limitations
This was a retrospective study and thus there were several limitations. First, sciatica severity and HZ severity and location which may affect the treatment decision and prognosis, are unavailable in NHIRD. Second, lifestyles information such as smoking, is also unavailable in the NHIRD. A strongly association between smoking and sciatica was confirmed by several studies [13, 21]. This could also influence the outcome of this study. Third, influence of medication was not analyzed in the present study. Drugs may influence the immune system which resulted to HZ occurrence. However, medication will be given immediately after diagnosis of diseases in both groups due to the unique insurance system with high accessibility, thus the medication bias can be ignored. Fourth, diagnostic bias between different specialists may occur. Nevertheless, all insurance claims are sent to the NHI Administration and reviewed by experts through a strict system of audit and penalty. Therefore, the diagnostic codes are reliable. Despite these limitations, the population-based study provided sufficient evidence for persuasive research through inclusion a large number of patients. Thus, we confirm that HZ risk is higher in patients with sciatica than in those without.
Conclusion
The presence of sciatica increased HZ risk. Thus, HZ risk should be noted when physicians encounters patients with sciatica, and HZ vaccination should be considered especially those aged over 50.
Acknowledgements
Not Applicable.
Ethics approval and consent to participate
The NHIRD encrypts patient personal information to protect privacy and provides researchers with anonymous identification numbers associated with relevant claims information, including sex, date of birth, medical services received, and prescriptions. Therefore, patient consent is not required to access the NHIRD. This study was approved to fulfill the condition for exemption by the Institutional Review Board (IRB) of China Medical University (CMUH104-REC2–115-AR4). The IRB also specifically waived the consent requirement.
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Consent for publication
Not applicable.
Competing interests
The authors declare no financial or other conflicts of interest.
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Update Orthopädie und Unfallchirurgie
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