Background Studies investigating the epidemiological relationship between scrub typhus and the subsequent development of acute coronary syndrome (ACS) are lacking. Therefore, we conducted a nationwide longitudinal cohort study in Taiwan to explore whether patients with scrub typhus are at an increased risk of developing ACS.
Methods This study investigated the incidence and risk factors for ACS in 5215 patients newly diagnosed with scrub typhus from the Taiwan National Health Insurance Research Database between 2000 and 2011. The comparison cohort contained 20 860 persons from the general population without scrub typhus. The follow-up period ran from the time of the initial diagnosis for scrub typhus to the date of an ACS event, censoring, or 31 December 2011. We used Cox proportional hazard regression models to analyse the risk of ACS by including the variables of sex, age and comorbidities.
Results The incidence of ACS was higher in patients with scrub typhus than in the comparison cohort (3.10 vs 1.92 per 1000 person-years). The HR of developing ACS increased by 37% in patients with scrub typhus after adjusting for age, sex and comorbidities. Men, increased age, hypertension, diabetes, hyperlipidaemia, chronic obstructive pulmonary disease and coronary artery disease were identified as independent risk factors of developing ACS after controlling for covariates. The prominent effect of scrub typhus on subsequent ACS development appeared within 1 year after infection.
Conclusions This nationwide study determined that patients with scrub typhus exhibited a 37% increase in the risk of subsequently developing ACS compared with that of the general population.
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Acute coronary syndrome (ACS), characterised by a sudden reduction of blood flow in the coronary arteries, comprises non-ST-segment elevation (unstable angina and non-Q wave myocardial infarction) and ST-segment elevation myocardial infarction. This syndrome is a life-threatening disorder that leads to high morbidity and mortality despite advances in treatment.1 ,2 Hypertension, diabetes and hyperlipidaemia are well-established traditional cardiovascular risk factors of atherosclerotic progression, which contributes to the development of ACS.3 ,4 Cerebrovascular accidents (CVAs) and cardiovascular diseases share similar risk factors in circulatory system disorders. Numerous studies have reported that chronic obstructive pulmonary disease (COPD) associated with reduced lung function is a strong risk factor for cardiovascular events, independent of smoking.5 ,6 Interest in the relationship between infection and atherosclerosis-induced coronary heart disease has recently increased.7–9
Scrub typhus is a mite-borne acute febrile infectious disease in humans caused by Orientia tsutsugamushi (previously called Rickettsia tsutsugamushi), and typically causes those infected by it to present with high fever, myalgia, headache, and a maculopapular rash with eschar formation. Additionally, renal failure, pneumonitis, acute respiratory distress syndrome, myocarditis and meningoencephalitis have been reported as complications of scrub typhus.10 ,11 Taiwan is an endemic area for scrub typhus.12 Increased incidences and a high standardised incidence rate of scrub typhus are clustered in the less developed, mountainous areas of Central and Eastern Taiwan.12 The epidemiological relationship between scrub typhus and the subsequent development of ACS remains unclear. Therefore, we conducted a longitudinal nationwide cohort study to explore whether patients with scrub typhus are at an increased risk of subsequently developing ACS.
The National Health Insurance (NHI) is a nationwide insurance programme that covered ambulatory care, hospital admissions, dental care, prescription drugs, intervention procedures and disease profiles for over 99% of the 23.74 million Taiwanese residents in 2009.13 The National Health Research Institutes was commissioned by the Bureau of National Health Insurance (BNHI) to create the National Health Insurance Research Database (NHIRD) for medical research, which comprises administrative and health claims data generated by the NHI programme. The database information has been described in detail in previous studies.14 ,15 We analysed deidentified secondary data; therefore, no informed consent was required. This study was approved by the Ethics Review Board of China Medical University (CMU-REC-101-012). A diagnostic code was used based on the format of the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). The high accuracy and validity of ICD-9-CM diagnoses in the NHIRD have been described in previous studies.16 ,17
Figure 1 shows the flow diagram of sampling scheme in this study. In this population-based retrospective cohort study, we identified patients aged over 20 years with newly diagnosed scrub typhus (ICD-9-CM codes 081.0, 081.2, and 081.9) from hospitalisation records from 2000 to 2011 as the scrub typhus cohort. The index date for the patients with scrub typhus was the date of their first admission visit. We excluded patients with a diagnosis of ACS (ICD-9-CM codes 410, 411.1, and 411.8) before the index date and participants with missing information on age or sex. For each patient with scrub typhus, four comparisons were randomly selected from the pool of participants without scrub typhus and ACS at the baseline, frequency matched by the year of index date, age (every 5-year span) and sex.
In endemic areas, a scrub typhus diagnosis can be made based on clinical presentations. When in doubt, diagnosis may be confirmed by conducting a laboratory test, such as a serological test, the Weil–Felix test, indirect immunofluorescence, and PCR.
Identifying the Outcome Variable
All the participants were followed-up to evaluate the occurrence of ACS until 31 December 2011, or they were censored because of death, withdrew from the NHI programme, or were lost to follow-up. The confirmation of ACS events was based on ICD-9-CM discharge codes 410, 411.1 and 411.8 in the NHIRD.
The following comorbidities associated with an increased risk of ACS development were also included: hypertension (ICD-9-CM codes 401–405), diabetes (ICD-9-CM codes 250), hyperlipidaemia (ICD-9-CM codes 272), CVA (ICD-9-CM codes 430–438), COPD (ICD-9-CM codes 490–492, 494, 496), congestive heart failure (CHF; ICD-9-CM codes 428), asthma (ICD-9-CM codes 493) and coronary artery disease (CAD; ICD-9-CM codes 413–414 not including ICD-9-CM codes 410–412) which were identified based on diagnoses made upon hospital admission before the index date to manage the potential confounding effect of the ACS risk factor.
Discrete variables are presented as counts or percentages. Continuous variables are described as mean±SD. SAS V.9.2 software (SAS Institute, Cary, North Carolina, USA) was used for data analysis. A 2-sided p value of <0.05 was considered statistically significant. The incidence rate was calculated as the number of incident ACS cases identified during the follow-up, divided by the total person-years of follow-up for each cohort according to sex, age and comorbidities. Poisson regression models were used to evaluate the scrub typhus cohort to compare the cohort incidence rate ratios (IRR) and 95% CI. The multivariable Cox proportional hazards model was used to investigate the association between scrub typhus and the risk of developing ACS over time, and was also adjusted for age, sex and comorbidities of hypertension, diabetes, hyperlipidaemia, CVA, COPD, CHF, asthma and CAD. Additionally, data analysis was conducted to evaluate the interaction among scrub typhus, COPD, hypertension, diabetes and CAD. The cumulative incidence of ACS for both the scrub typhus and comparison cohorts was calculated using the Kaplan–Meier method, and the difference was tested using the log-rank test.
Demographic characteristics and comorbidities of patients with scrub typhus and the comparison cohort
The eligible study participants included 5215 patients in the scrub typhus cohort and 20 860 individuals in the comparison cohort. Most of the participants in this study were men (64.9%), and nearly seven-tenths were aged <50 years (mean age approximately 46 years). Most of the patients with scrub typhus tended to have hypertension, diabetes, hyperlipidaemia, CVA, COPD, CHF, asthma and CAD compared with the comparison cohort (table 1). The mean follow-up time is 5.13 years (SD=3.34) and 5.21 (SD=3.30) for the scrub typhus cohort and the non-scrub typhus cohort, respectively.
Comparison of the incidence and HR of ACS stratified by sex and age between patients with scrub typhus and the comparison cohort
Compared with the comparison cohort, the scrub typhus cohort exhibited greater incidence rates of ACS (3.10 vs 1.92 per 1000 person-years), with an adjusted HR of 1.37 (95% CI 1.05 to 1.77) after controlling for demographic factors and comorbidities (table 2). For women, the incidence densities were 3.15 and 1.45 per 1000 person-years between patients with scrub typhus and the comparison cohort, with a 2.17-fold relative IRR of ACS (95% CI 1.90 to 2.50). Men had a significantly higher rate of developing ACS compared with that of women (adjusted HR=2.03, 95% CI 1.57 to 2.62). When stratified by age, the incidence density rates of ACS increased with age, and those who were 35–49 years of age had a 2.50-fold higher relative IRR of ACS (95% CI 2.15 to 2.91). After adjusting for covariates, the risk of ACS increased with age (patients ≤34 years of age as the reference group), with an adjusted HR of 17.7 among those aged 65 years and older (95% CI 10.5 to 29.8).
Comparison of the incidence and HR of ACS stratified by comorbidities between people with and without scrub typhus
The incidence of ACS was 17.3 and 14.5 per 1000 person-years in patients presenting with CHF in the patients with scrub typhus and the comparison cohort, respectively (table 3). Among the comorbidities, the risk of ACS was associated with diabetes (adjusted HR =2.77, 95% CI 2.04 to 3.76), hypertension (adjusted HR 1.88, 95% CI 1.38 to 2.76), hyperlipidaemia (adjusted HR=1.67, 95% CI 1.08 to 2.56), COPD (adjusted HR=1.63, 95% CI 1.07 to 2.49) and CAD (adjusted HR=1.53, 95% CI 1.03 to 2.27).
The risk of ACS in patients with scrub typhus associated with COPD, hypertension and diabetes
Table 4 lists the ACS incidence associated with the interaction of scrub typhus, COPD, hypertension, diabetes and CAD. Compared with those without scrub typhus, COPD and hypertension, patients with scrub typhus presenting with COPD and hypertension exhibited an adjusted HR of 6.82 (95% CI 3.17 to 14.7). The ACS incidence was much higher in patients with scrub typhus, COPD and diabetes. Scrub typhus patients coexisting with COPD and diabetes had an adjusted HR of 8.64 (95% CI 3.19 to 23.4), compared with those without scrub typhus, COPD and diabetes. Compared with those without scrub typhus, COPD and CAD, patients with scrub typhus presenting with COPD and CAD exhibited an adjusted HR of 5.27 (95% CI 1.67 to 16.6).
ACS event risk according to follow-up years
Table 5 shows the adjusted HR for developing ACS, stratified by follow-up time. The incidence density rates of ACS were the highest and significant in the first 6 months, 4.82 and 1.18 per 1000 person-years in patients with scrub typhus and the comparison cohort, respectively. We observed a 3.34-fold significant increase in the risk of developing ACS within the 6-month follow-up period (95% CI 1.47 to 7.70).
Figure 2 illustrates that the cumulative incidence of ACS was higher in the scrub typhus cohort than in the comparison cohort (p<0.001).
Scrub typhus is highly prevalent in Eastern and Southeast Asia, and Northern Australia.18 This is the first study to determine that patients with scrub typhus exhibited a 1.33-fold greater risk of subsequently developing ACS than did the general population, by using a nationwide population-based cohort study. Although patients with scrub typhus exhibited a significantly higher proportion of comorbid diseases compared with those of the comparison cohort, scrub typhus remained an independent risk factor of developing ACS after adjusting for sex, age and comorbidities.
The pathogenesis of ACS involves a complex interplay among the endothelium, inflammatory cells and blood thrombogenicity.19 ,20 Atherosclerosis is the ongoing process of plaque formation that involves the intima of arteries; the condition progresses throughout a person’s life before finally manifesting as an acute ischaemic event.21 When the endothelium has been damaged, the inflammatory cells migrate into the subendothelium by binding to endothelial adhesion molecules and undergo differentiation to release chemoattractants and cytokines at the plaque site, eventually leading to plaque disruption.22
The underlying mechanism of scrub typhus with an increased risk of developing ACS is unclear. Scrub typhus activates human immune and inflammatory mediators that generalise systemic inflammatory responses.23 Inflammation may activate clotting, thereby decreasing the activity of natural anticoagulant mechanisms and impairing the fibrinolytic system.22–25 Additionally, inflammatory processes involved in the pathogenesis of arteriosclerosis enhance vascular O2 formation, leading to endothelial dysfunction.26 When the interactions between inflammation-coagulation and inflammation-endothelial dysfunction overwhelm the natural defence systems, catastrophic events may occur, such as those manifested in ACS. Recent epidemiological studies have also indicated the relationship with infection and subsequent cardiac events.27–30
Compared with women, men presented with a 2.03-fold increased risk of developing ACS. This finding is consistent with a previous report.31 The incidence of ACS increased as age increased in both cohorts. The age-specific crude relative risk indicated that ACS risk was significantly higher in the cohort with scrub typhus than in the comparison cohort. Moreover, older adults also exhibited a greater risk of developing ACS than did younger adults after controlling for sex and comorbidities. As people age, the risk for atherosclerosis increases, and lifestyle factors cause plaque to gradually build in the arteries.32
Hypertension, diabetes, hyperlipidaemia, CVA, COPD and CHF are related to an increased risk of ACS. These findings are consistent with previous reports.20 ,33 However, hypertension, diabetes, hyperlipidaemia and COPD remain independent risk factors of ACS after adjusting for covariates. Furthermore, patients with scrub typhus presenting with COPD and hypertension, or COPD and diabetes, exhibited multiplicative risks of developing ACS compared with the general population.
The prominent risk of developing ACS appeared in the first year of scrub typhus infection. This phenomenon may be associated with infection that triggered inflammation and coagulation. Therefore, providing holistic care for comorbidities is critical to preventing ACS development in addition to treating scrub typhus.
The strength of this population-based longitudinal cohort study is that it indicates the association of scrub typhus with an increased risk of subsequently developing ACS through the use of a nationwide epidemiologic method. We enrolled a large sample of participants. Additionally, because NHI is universal and mandatory in Taiwan, NHI beneficiaries have been assigned unique personal identification numbers that enabled us to trace the participants throughout the study follow-up period. The results are robust because several multivariable analyses were used for assessing the increased risk of developing ACS.
However, several limitations must be considered when interpreting these findings. First, the NHIRD does not provide daily life information such as smoking habits, Body Mass Index, physical activity levels, socioeconomic status and family history, all of which are potential confounding factors in this study. COPD, CVA and CAD are well-known comorbidities strongly correlated with smoking. We used these comorbidities for adjustment to minimise the influence of smoking. Second, the study cases were selected according to ICD-9 codes, which may potentially have caused a misclassification bias despite that the BNHI uses an auditing mechanism to minimise diagnostic uncertainty and misclassification. Third, the scrub typhus cohort is more prevalent with a history of comorbidities. They were more likely to visit a doctor and this might cause detection bias because of frequent examinations. Additionally, the lack of drug-treatment data, such as those on hormone replacement therapy and the use of anticoagulants and antiplatelet drugs, may have influenced the primary outcomes of this study.
In conclusion, this nationwide longitudinal cohort study determined that patients with scrub typhus are at a 1.33-fold greater risk of developing ACS compared with that of the general population. The peak risk of developing ACS appeared within 6 months and persisted for 12 months after scrub typhus infection was contracted. Additionally, the multiplicative risks of ACS were significant among patients with scrub typhus combined with comorbid diseases. Clinicians should be aware of the increased ACS risk in patients with scrub typhus and provide appropriate cardiovascular management in addition to treating scrub typhus. However, because the study findings are based on an observational study, additional studies should be conducted to confirm this epiphenomenon in the future.
What is already known on this subject?
Studies investigating the epidemiological relationship between scrub typhus and the subsequent development of acute coronary syndrome (ACS) are lacking.
What might this study add?
The incidence of ACS was higher in patients with scrub typhus than in the comparison cohort.
Men, increased age, hypertension, diabetes, hyperlipidaemia, and chronic obstructive pulmonary disease were identified as independent risk factors of developing ACS after controlling for covariates.
The prominent effect of scrub typhus on subsequent ACS development appeared within 1 year after infection.
How might this impact on clinical practice?
Clinicians should be aware of the increased ACS risk in patients with scrub typhus and provide appropriate cardiovascular management in addition to treating scrub typhus.
Contributors All authors have contributed significantly, and all authors are in agreement with the content of the manuscript. Conception/design: W-SC, C-HK. Provision of study materials: C-HK. Collection and/or assembly of data: all authors. Data analysis and interpretation: W-SC, C-LL, C-HK. Manuscript writing: all authors. Final approval of manuscript: all authors.
Funding This work was supported by grants from China Medical University (CMU102-BC-2); Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW103-TDU-B-212-113002); Health and welfare surcharge of tobacco products, China Medical University Hospital Cancer Research Center of Excellence (MOHW103-TD-B-111-03, Taiwan); and International Research-Intensive Centers of Excellence in Taiwan (I-RiCE) (NSC101-2911-I-002-303).
Competing interests None.
Ethics approval This study was approved by the Ethics Review Board of China Medical University (CMU-REC-101-012).
Provenance and peer review Not commissioned; externally peer reviewed.
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