Mycoplasma pneumonia increases the risk of acute coronary syndrome: a nationwide population-based cohort study.

Mycoplasma pneumonia increases the risk of

acute coronary

syndrome: a nationwide population-based

cohort study

W.-S. CHUNG

, W.-H. HSU

, C.-L. LIN

and C.-H. KAO

Introduction

Acute coronary syndrome (ACS), which results from a sudden reduction of blood flow in the coronary arteries, comprises unstable angina and myocardial infarction with or without ST-segment elevation. This syndrome is a life-threatening disorder that leads to high morbidity and mortality despite advances in

treatment.1,2 Hypertension, diabetes and hyperlipidemia

are well-known major cardiovascular risk factors for atherosclerosis progression, which contributes to the development of ACS.3,4 Stroke and cardiovascular

diseases share similar risk factors in the disorders

of the circulatory system. Interest in the relationship between infection and atherosclerosisinduced

coronary heart disease has increased;5–9

for example, Iriz et al.10 showed that the direct

vessel wall colonization of chlamydia pneumoniae infection resulted in the progression of atheromatous plaques. Recent studies have also demonstrated that respiratory tract infection may trigger the development of acute myocardial infarction.11–13

Mycoplasma pneumonia (MP) is a common respiratory pathogen that produces diseases of varied

severity, ranging from mild upper respiratory tract infections to severe atypical pneumonia. Most studies have reported that approximately 10–30% of

are due to MP.14–16 Moreover, Mycoplasma pneumoniae

is the second most common causative pathogen of CAP for adults in Taiwan.16

MP is typically characterized by a benign outcome, even in cases without adequate antimicrobial

therapy. The beneficial effect of adequate treatment in shortening the course of the illness has been

demonstrated.17 In addition to respiratory tract infection,

MP also produces extrapulmonary manifestations including neurological, hepatic and cardiac

diseases, and hemolytic anemia, polyarthritis and erythema multiforme. However, the epidemiological relationships of MP and the subsequent development of ACS remain undetermined. Thus, we

conducted a longitudinal nationwide cohort study in Taiwan to explore whether patients with MP have an increased risk of subsequent ACS development.

Methods

Data source and study participants

Taiwan launched a single-payer compulsory National Health Insurance (NHI) program in 1995 that covers over 99% of the country’s population (23.74 million people).18 The insurance programs

were conducted after scrambling the identification details of residents to find data suitable for public use. The National Health Insurance Research Database (NHIRD) has been described in detail in our previous studies.19,20 The current retrospective

cohort study included data from the NHIRD for the entire population of Taiwan containing healthcare claims between 1996 and 2011. The NHIRD consists of registration files and claims data for reimbursement. All insurance claims should be

scrutinized by medical reimbursement specialists and peer review. Diagnoses were based on the International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM).

Several Taiwan studies had demonstrated the high accuracy and validity of ICD-9-CM diagnosis in NHIRD.21,22 This study was approved by the

Ethics Review Committee at China Medical University and Hospital (CMU-REC-101-012).

Figure 1 shows the selection process of the participants in the two study cohorts. We identified

adults newly diagnosed with MP (the first hospitalization for MP) (ICD-9-CM 483.0) from inpatient

claims during the period from 2004 to 2011. The date of the first hospitalization for MP was identified as the index date. Patients with a history of coronary artery disease (ICD-9-CM 410-414) before the index date with incomplete age or sex information were excluded. For each participant, hospitalization records of comorbidities were obtained before the

index date. Covariates included sex, age, hypertension (ICD-9 codes 401-405), diabetes (ICD-9 code

250), hyperlipidemia 9 code 272), stroke (ICD-9 codes 430-438) and heart failure (ICD-(ICD-9 code 428). All participants without a history of coronary artery disease and MP were randomly selected from all NHI beneficiaries.

For each MP patient, four comparisons were randomly selected from the pool of participants without

MP and coronary artery disease at the baseline, frequency matched by the year of index date, age

(every 5-year span), sex and comorbidities of hypertension, diabetes, hyperlipidemia, stroke and heart

failure. The index date in comparisons controls was randomly assigned the date as cases.

Main outcome

The main outcome was hospitalization with a new diagnosis of ACS (ICD-9-CM 410, 411.1, 411.8) during the follow-up period. The person-years of

the follow-up period were estimated for the participants beginning from the index date until the ACS

follow up, withdrawal from the insurance system, or 31 December 2011.

Statistical analysis

We used the _2 test to determine the differences in

categorical demographic variables and comorbidities between the MP and non-MP cohorts, and employed the Student’s t test to examine the mean ages between both cohorts. The overall- and sex-, age-, comorbidity-, and follow-up time-specific incidence rates (per 1000 person-years) were calculated for

each group. Univariable and multivariable Cox proportional hazard regression analyses were performed

to estimate the hazard ratios (HRs) and

95% confidence intervals (CIs) of ACS development

in the MP group compared with the comparison group. Multivariable models were simultaneously

adjusted for sex, age and the comorbidities of hypertension, diabetes, hyperlipidemia, stroke and heart

failure. We assessed the cumulative incidence of ACS by using the Kaplan–Meier method to compare the MP patients with the comparison cohort. We estimated their differences by conducting a logrank test and used SAS software (version 9.2 for

Windows; SAS Institute Inc., Cary, NC, USA) for all data analyses. The Kaplan–Meier curves were plotted using R software (version 2.14.1; R Development Core Team, Vienna, Austria). P<0.05 was considered statistically significant.

Results

Demographic characteristics and

comorbidities in MP and comparison

cohorts

In this study, we identified 12 152 patients newly diagnosed with MP during 2004–2011 as the exposure cohort and 48 600 participants without an MP

diagnosis as the comparison group. The MP and non-MP cohorts showed no significant differences based on distributions of sex, age and comorbidities

(Table 1); there were more women than men in both cohorts (53.2 vs. 46.8%), and _40% of the participants were younger than 34 years of age.

Incidence and HRs of ACS stratified by sex,

age, comorbidity and follow-up: comparison

between MP and comparison cohorts

During the 34 450 and 144 490 person-years of follow-up, the overall incidence density of ACS was significantly higher in MP patients than in the comparison group (3.08 vs. 2.42, respectively, per 1000 person-years) with the adjusted HR= 1.37 (95% CI = 1.10–1.70) (Table 2). Figure 2 shows the Kaplan–Meier curves of ACS cumulative incidence in the MP and non-MP cohorts. A higher risk of ACS occurrence was noted in patients with MP than in the non-MP cohort, indicating a statistically significant difference (log-rank test, P<0.0001). Although

the ACS incidence rate was greater in men than in women in both cohorts, the relative risks of ACS in the sex-specific MP patients and comparison cohort were significant for women (adjusted HR= 1.49; 95% CI = 1.06–2.08). The ACS incidence increased with age in both cohorts; however, the relative risk of ACS in the age-specific MP cohort and comparison cohort was greater for both the younger group (adjusted HR= 1.48; 95% CI = 1.01–2.16) and the older group (adjusted HR= 1.34; 95% CI = 1.02– 1.74). The ACS incidence increased in participants presenting with any comorbidity in both cohorts, although the relative risks of ACS in the comorbidity-specific MP cohort and comparison cohort were also significant for participants without (adjusted

HR= 2.24; 95% CI = 1.45–3.46). Sub-group analysis in follow-up time revealed the higher risk occurred

during the more than a 12-month follow-up (adjusted HR= 1.36, 95% CI = 1.03–1.79).

Cox model analysis of risk factors affecting

ACS development

The results of univariable and multivariable Cox

proportional hazard analyses for the association between ACS and MP are listed in Table 3. The adjusted

HR of ACS development was a 1.06-fold

increase (95% CI = 1.05–1.06) with age (every 1 year) and a 1.47-fold increase for men as opposed to for women (adjusted HR= 1.47, 95% CI = 1.21– 1.78). The risk of developing ACS was greater for patients with the comorbidities of hypertension

(adjusted HR= 2.38, 95% CI = 1.90–2.98), hyperlipidemia (adjusted HR= 1.76, 95% CI = 1.36–2.29),

diabetes (adjusted HR= 1.73, 95% CI =), and heart failure (adjusted HR= 1.56, 95% CI = 1.41–2.11).

Discussion

Studies investigating the relationship between MP and ACS are rare; thus, this is the first populationbased longitudinal cohort study to determine that,

compared with the general population, patients with MP exhibited a 1.37-fold risk of subsequently developing ACS. Pourahmad et al.23 indicated a

2.7-fold relative risk of MP on myocardial infarction through a case–control study; however, they did not control for major traditional risk factors to estimate the contribution of MP to the development of ACS. Chlamydia pneumonia and MP are reportedly associated with atherosclerosis and the progression of atheromatous plaques, which are related

ACS.9,24,25 Van Eeden et al.26 also proposed plausible

mechanistic pathways through which lung inflammation, systemic inflammatory response and

endothelial dysfunction lead to atherosclerosis and plaque disruption that progress to ACS. In addition, infection and inflammation may modulate thrombotic responses by upregulating the activation of

procoagulants, downregulating that of anticoagulants, and suppressing fibrinolysis, all of which

result in a hypercoagulable status and progression to vascular obstruction.27

The ACS incidence rate was greater in men than in women in both cohorts, which is consistent with results from previous studies.13,28 The ACS incidence

also increased with age in both cohorts; however, the adjusted HRs of ACS development for the age-specific MP patients and the comparison cohort were greater for the younger group than for the older group, indicating that the health effect of MP on the development of ACS was greater in younger adults than in older adults.

The effect of MP on subsequent ACS development appeared to 12 months after infection. Mycoplasma pneumoniae infection may disseminate systemically from the lungs to the peripheral blood mononuclear cells and localize in arteries where it may infect endothelial cells, vascular smooth muscle cells and monocytes/macrophages, as well as promote an inflammatory atherogenic process and further vascular obstruction.29,30

The strength of this nationwide population-based longitudinal cohort study is that it demonstrates the association of MP with an increased risk of subsequent ACS development by using an epidemiologic

method. We enrolled a large sample of participants, and because NHI is universal and mandatory in Taiwan, NHI beneficiaries have been assigned unique personal identification numbers that allow them to be traced in the NHIRD records throughout the study follow-up period. The results are robust because several multivariable analyses were used for assessing the increased risk of ACS development. However, several limitations must be considered when interpreting these findings. First, the NHIRD does not provide detailed 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. Second, the study cases were selected according

to ICD-9-CM codes, which may potentially

cause a misclassification bias despite the ability of the auditing mechanism used by the Bureau of National Health Insurance to minimize diagnostic uncertainty and misclassification. Third, the

NHIRD did not provide the results of laboratory examination such as MP antibody titers, culture report

and chest X-ray, which may be related disease severity. In addition, the lack of drug-treatment data, such as those on hormone-replacement therapy and the use of contraceptives, anticoagulants and antiplatelet drugs, may have influenced the primary outcomes

of this study.

In conclusion, this nationwide study of 12 152 MP patients with a follow-up of 34 450 personyears determined that compared with the general

population, MP patients exhibit a 37% increase in the risk of subsequent ACS development. The ACS risk appeared 12 months after developing MP. Clinicians should be aware of the increased ACS risk in patients with MP and provide appropriate cardiovascular management in addition to MP treatment.