Scrub typhus increases the risk of developing acute coronary syndrome: a nationwide cohort study

Scrub typhus increases the risk of developing acute

coronary syndrome: a nationwide cohort study

Wei-Sheng Chung, ^1,2 Cheng-Li Lin, ^3,4 Wu-Huei Hsu, ^5,6 Chia-Hung Kao ^6,7

INTRODUCTION

Acute coronary syndrome (ACS), characterised by a sudden reduction of blood fow 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.

Hypertension, diabetes and hyperlipidaemia are well-established traditional cardiovascular risk factors of atherosclerotic progression, which contributes to the

development of ACS.

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.

Interest in the relationship between infection and atherosclerosis-induced coronary heart disease has recently increased.

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.

Taiwan is an endemic

area for scrub typhus.

Increased incidences and a high standardised incidence rate of scrub typhus are clustered in the less developed, mountainous

areas of Central and Eastern Taiwan.

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.

METHODS Data source

The National Health Insurance (NHI) is a nationwide insurance programme that covered ambulatory care, hospital admissions, dental care,

prescription drugs, intervention procedures and disease profles for over 99% of the 23.74 million Taiwanese residents in 2009.

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.

We analysed deidentifed 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

Classifcation of Diseases, 9th Revision, Clinical

Modifcation (ICD-9-CM). The high accuracy and validity of ICD-9-CM diagnoses in the NHIRD

have been described in previous studies.

Study participants Figure 1 shows the fow diagram of sampling scheme in this study. In this population-based retrospective cohort study, we identifed 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 frst 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.

Exposure variable

In endemic areas, a scrub typhus diagnosis can be made based on clinical presentations. When in doubt, diagnosis may be confrmed by conducting a laboratory test, such as a serological test,

the Weil–Felix test, indirect immunofuorescence, 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 confrmation of ACS events was based on ICD-9-CM discharge codes 410, 411.1 and 411.8 in the NHIRD.

Comorbidities

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

identifed based on diagnoses made upon hospital admission before the index date to manage the potential confounding effect of the ACS risk factor.

Statistical analysis

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 signifcant. The incidence rate was calculated as the

number of incident ACS cases identifed 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.

RESULTS

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 stratifed 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 signifcantly higher rate of developing ACS compared with that of women (adjusted HR=2.03, 95% CI 1.57 to 2.62). When stratifed 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 stratifed 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, stratifed by follow-up time. The incidence density rates of ACS were the highest and signifcant in the frst 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 signifcant

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).

DISCUSSION

Scrub typhus is highly prevalent in Eastern and Southeast Asia, and Northern Australia.

This is the frst 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 signifcantly 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, infammatory 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 fnally manifesting as an acute ischaemic event.

When the endothelium has been damaged, the infammatory 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.

The underlying mechanism of scrub typhus with an increased risk of developing ACS is unclear. Scrub typhus activates human immune and infammatory mediators that generalise systemic infammatory responses.

Infammation may activate clotting, thereby decreasing the activity of natural anticoagulant mechanisms and impairing the fbrinolytic system.

Additionally,

infammatory processes involved in the pathogenesis of arteriosclerosis enhance vascular O

formation, leading to endothelial

dysfunction.

When the interactions between infammationcoagulation

and infammation-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.

Compared with women, men presented with a 2.03-fold

increased risk of developing ACS. This fnding is consistent with a previous report.

The incidence of ACS increased as age increased in both cohorts. The age-specifc crude relative risk indicated that ACS risk was signifcantly 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.

Hypertension, diabetes, hyperlipidaemia, CVA, COPD and CHF are related to an increased risk of ACS. These fndings are consistent with previous reports.

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 frst

year of scrub typhus infection. This phenomenon may be associated with infection that triggered infammation 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 benefciaries have been assigned unique personal identifcation 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 fndings. 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 infuence of smoking. Second, the study cases were selected according to ICD-9 codes, which may potentially have caused a misclassifcation bias despite that the BNHI uses an

auditing mechanism to minimise diagnostic uncertainty and misclassifcation.

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 infuenced 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 signifcant 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 fndings are based on

an observational study, additional studies should be conducted

to confrm this epiphenomenon in the future.