Association between ischemic stroke and pyogenic spondylitis in Korea: Nationwide longitudinal cohort study

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J Cerebrovasc Endovasc Neurosurg. 2023;25(2):143-149

Publication date (electronic) : 2023 January 17

doi : https://doi.org/10.7461/jcen.2023.E2022.09.001

Soo Hyun Lee¹, Hakyung Kim², In-bo Han¹, Seung Hun Sheen¹, Je Beom Hong³, Seil Sohn^,1

¹Department of Neurosurgery, CHA University, CHA Bundang Medical Center, Seongnam, Korea

²Genome & Health Big Data Branch, Department of Public Health, Graduate School of Public Health, Seoul National University, Seoul, Korea

³Department of Neurosurgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea

Correspondence to Seil Sohn Department of Neurosurgery, CHA University, CHA Bundang Medical Center, 59 Yatap-ro, Bundang-gu, Seongnam 13496, Korea Tel +82-31-780-1924 Fax +82-2-780-5269 E-mail seilsohn@gmail.com

Received 2022 September 6; Revised 2022 December 31; Accepted 2022 December 31.

Abstract

INTRODUCTION

Pyogenic spondylitis (PS) is rare disease that covers a broad range of clinical area including pyogenic spondylodiscitis, septic discitis, vertebral osteomyelitis, and epidural abscess [3,13,15,16,26]. However, the incidence of PS is increasing due to the increase in the elderly and immunocompromised patients [3,13,26]. Several studies have been conducted on the relationship between PS and infection [3,15,16,26]. It is usually caused by hematogenous spread of bacteria [3,14,26]. However, there were no studies and information on the direct relationship between the increase in ischemic stroke (IS) by PS. This nationwide longitudinal study was conducted to clarify whether the infectious disease, PS, increases the incidence of IS. This study did not exclude PS as a result of postoperative complications.

MATERIALS AND METHODS

Establishment of the study cohort

The group diagnosed with PS according to the ICD-10 code (M46.2-M46.8, M49.2-M49.3) was included in the PS group. Only 10,890 PS subjects were selected out of a total of 15,547 patients in the NHISS database. By excluding those diagnosed with PS before Jan. 1, 2004 and 10,237 patients who had never been hospitalized, a group of 628 patients newly diagnosed with PS after Jan. 1, 2004 could be derived and were monitored until Dec. 31, 2015. By using the greedy matching algorithm of the ‘Match IT’ R package, 3,140 people were selected as a control group in 1:5 age- and sex- stratified matching (without replacement) [18,19]. The patient groups included in this study were followed from the first diagnosis of IS until death or the end of the study (Fig. 1). Among the PS and control group, IS patients were selected by using the following criteria: ICD-10 codes (I63 or I64), IS confirmed by brain CT or MRI scan and hospitalization ≥1 day [17,18]. The risk of IS was evaluated by adjusting for other factors such as age, sex and comorbidities (hypertension, diabetes mellitus, and dyslipidemia), and values could be derived accordingly.

Fig. 1.

Flow of cohort formation process. This study was a 12-year longitudinal cohort study completed on the basis of the NHIS-HEALS cohort. NHISS, National Health Insurance Service-Health Screening; NHIS, National Health Insurance Service

RESULTS

Characteristics of the PS and control group

For the PS group, 628 patients newly diagnosed with PS were selected and 3140 patients were selected for the control group. Of these, 323 patients (51.43%) were male and 199 patients (48.57%) were female. The mean age of the patients was 59.09±9.35 years. In the presence of diabetes, there was difference in prevalence between the two groups (P<0.01) (Table 1).

Table 1.

Characteristics in the PS and control group

IS in the PS and control group

The likelihood of the occurrence of IS was higher in the PS group than that of IS in the control group. Through the Kaplan-Meier curves, the cumulative incidence of IS was higher in the PS group (Fig. 2). Multivariate analysis of Cox proportional hazards regression Model 1 showed that the IS hazard ratio for the PS group was 3.518 compared to the control group (95% CI: 2.546-4.801, Table 2). In the Model 2, the IS hazard ratio was 3.419 compared to the control group (95% CI: 2.473-4.729, Table 2).

Fig. 2.

The Kaplan-Meier curves with cumulative incidence of ischemic stroke in the pyogenic spondylitis and control groups.

Table 2.

Adjusted hazard ratio for IS in the PS and control group

Subgroup analysis of IS incidence rate

The IS incidence rate was different between PS and control group in both of male (95% CI: 1.953-4.935, Table 3) and female subgroup (95% CI: 2.517-6.207, Table 3). The incidence of IS was significantly different between PS and control group in both of age <65 (95% CI: 3.173-7.731, Table 3) and age >65 subgroup (95% CI: 1.473-3.852, Table 3). The IS incidence rate was different in both of non-hypertensive (95% CI: 2.045-5.183, Table 3) and hypertensive subgroup (95% CI: 2.373-5.826, Table 3). Furthermore, the incidence of IS was significantly different in non-dyslipidemic (95% CI: 2.509-4.960, Table 3), dyslipidemic (95% CI: 1.165-8.768, Table 3) and non-diabetic subgroup (95% CI: 2.652-5.414, Table 3). However, there was no significant difference between PS and control group in diabetic subgroup (95% CI: 0.953-4.360, Table 3).

Table 3.

IS incidence rate in subgroup analyses between PS and control group

DISCUSSION

According to our study, there was 3.518 fold increased incidence of IS after adjusting sex and age and 3.419 fold increased incidence of IS after adjusting sex, age, and underlying disease (diabetic, dyslipidemia, hypertension). The study results showed that the incidence of IS was higher in the PS group in male, female, under 65 years of age, over 65 years of age, non-diabetic, non-dyslipidemic, dyslipidemic, non-hypertensive and hypertensive.

PS is an uncommon spinal infection that can give patients a serious and life-threatening condition [3,15,16,26]. The most common organism of PS is S. aureus [3,13,15,16,26]. Research on PS reports diabetes mellitus (DM), long-term steroid therapy, substance abuse, malnutrition, malignancy, liver cirrhosis and HIV as risk factors [4,12,14,15,26]. Currently, there is a lack of research and information on the direct relationship between PS and IS. However, several studies have been conducted on the link between infection and IS. Acute and chronic infections have been reported to accelerate the progression of atherosclerosis, leading to acute ischemic stroke [7,11,12,17,18,29]. Grau et al. [10] reported bacterial infections significantly increased the risk for cerebrovascular ischemia (95% CI, 2.0 to 16.9; P<.002). In addition, it has been reported that C-reactive protein (CRP) can be used as a strong indicator in relation to vascular disease [5,9]. Increased lipoprotein and plasminogen activator inhibitor-1 can be used as biomarkers for the progression of intracranial atherosclerotic disease [1,2,6,10,12,17,20,22,25,29,30]. Ross et al. [25] reported that inflammation is associated with an increase in fibrinogen and CRP, both of which are associated with an early sign of atherosclerosis. In addition to that, interleukin-6 (IL-6) was reported as a major inflammatory cytokine associated with a predictive marker of stroke risk [8,9,20,21,24]. Although infection increases the risk of IS, it has been reported that IS increases the risk of infection by inducing immunosuppression [7,12,27,28]. Several studies have shown that infection and IS are closely related [4,7,8,10,12,21,24,27-29].

Interpretation of the graph (Fig. 2) becomes possible through these inflammatory factors. It can be seen that the slope of the graph is steep in the early stage of diagnosis, because IS occurred in many patients due to atherosclerotic changes caused by inflammatory factors. A delayed onset of IS was seen in the remaining patients with intracranial atherosclerotic changes. Therefore, it can be seen that the slope of the graph becomes smoother over time. Near the end of the follow-up period, it shows a flat slope which indicates no accumulation of IS after a long period of time. This is because the IS had already occurred at the beginning and middle of the follow-up period.

Since PS is a disease caused by infection of the spine, it can be expected that the risk of IS may be increased. However, further studies are needed to elucidate the direct causes and mechanisms.

There are several limitations in our study. First, this study was conducted by classifying gender, age, and underlying disease in the NHIS database, and did not include individual lifestyles (Alcohol, tobacco, regular diet and exercise, etc.) [18,19] and biomarkers (CRP, IL-6, fibrinogen, lipoprotein, and plasminogen activator inhibitor-1 etc.) [1,2,6,8,10,12,17,20-22,24,25,29,30]. Second, information on the clinical severity of individual PS patients was not included in the data. Further studies may be required due to the difficulties in randomization to various factors not included in the data.

While there may be shortcomings in several areas, this is the largest nationwide longitudinal study showing an increased risk of IS in patients with PS.

CONCLUSIONS

Through this nationwide longitudinal study, it was found that the risk of IS was increased in PS patients.

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