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Increased Risk of Dementia Among Patients With Pulmonary Tuberculosis: A Retrospective Population-Based Cohort Study

American Journal of Alzheimer’s Disease & Other Dementias® 1-6 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1533317515577186 aja.sagepub.com

Yi-Hao Peng, MSc1,2, Chih-Yu Chen, MD3, Ching-Hua Su, BS4, Chih-Hsin Muo, MSc5, Kuan-Fei Chen, MD6,7, Wei-Chih Liao, MD2,3, and Chia-Hung Kao, MD8,9

Abstract Objective: We investigated and compared the risk of dementia development in a cohort of patients with tuberculosis (TB). Methods: The study involved 6473 patient with newly diagnosed TB, and each patient was randomly frequency matched with 4 people without TB based on age, sex, and index year. The risk of dementia development was analyzed using Cox proportional hazards regression. Results: Among the patients with TB, the overall risk of developing dementia was 1.21-fold significantly higher than the non-TB cohort. In the stratified analysis of dementia risks, only the patients with TB who were male or 50 to 64 years of age exhibited a significantly higher risk of dementia development compared with those without TB. An analysis of the follow-up duration revealed that patients with TB had a 1.78-fold increased risk within 1 year of follow-up. Conclusion: Patients with TB have a significantly higher risk of developing dementia than that of the general population. Keywords tuberculosis, dementia, cohort study, comorbidity

Introduction Dementia is a prevalent neurodegenerative disorder affecting elderly people, characterized by considerable impairment of intellect, memory, and personality without impairment of consciousness beyond what might be expected from natural aging. Because of its major medical, social, and economic impacts, dementia is an increasing burden worldwide.1 Previous studies have associated several risk factors with dementia, including socioeconomic status, hypertension, hypercholesterolemia, diabetes, head injury, and depression.2,3 Pulmonary tuberculosis (TB) is a critical global public health concern. One third of the world’s population is believed to have latent TB infection, which carries a risk of subsequent progression to an active state at any time. Moreover, TB is second only to HIV/AIDS as the major cause of death from a single infectious agent, primarily caused by the species Mycobacterium tuberculosis. In 2012, the World Health Organization reported that 8.6 million people were affected by TB worldwide, and 1.3 million people died of TB. In Taiwan, the estimated incidence of TB in 2011 was approximately 54.5 per 100 000 person-years, with pulmonary TB accounting for approximately 94% of all cases with TB.4 Although the etiology of dementia is heterogeneous, a growing number of studies have provided evidence indicating the

critical role of inflammation in the pathogenesis of dementia.5-7 In addition, inflammation is crucial for pathogenesis of TB.8

1

Department of Respiratory Therapy, China Medical University Hospital, Taichung, Taiwan 2 Department of Respiratory Therapy, China Medical University, Taichung, Taiwan 3 Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, China Medical University Hospital, Taichung, Taiwan 4 Section of Respiratory Therapy, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan 5 Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan 6 Department of Neurology, China Medical University Hospital, Taichung, Taiwan 7 Department of Neurology, China Medical University Beigang Hospital, Yunlin, Taiwan 8 Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan 9 Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan Corresponding Author: Chia-Hung Kao, MD, Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung 40447, Taiwan. Email: [email protected]

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American Journal of Alzheimer’s Disease & Other Dementias®

2 A previous epidemiologic study suggested that inflammation triggered by an infectious agent may play a role in the pathogenesis of dementia.9 However, pulmonary TB is not generally considered a risk factor for development of dementia. Therefore, we conducted a longitudinal nationwide populationbased cohort study to test the hypothesis of whether pulmonary TB increases the subsequent risk of dementia.

hypertension (401.XX-405.XX), hyperlipidemia (272.XX), diabetes (250.XX), heart failure (428.XX), head injury (850.XX-854.XX and 959.01), stroke (430.XX-438.XX), and depression (296.2X, 396.3X, 300.4X, and 311.XX). The comorbidities were considered only if they were diagnosed before the index date.

Statistical Analysis Methods Data Source This retrospective cohort study was conducted using data obtained from the Longitudinal Health Insurance Database (LHID), which is a subset of the National Health Insurance Research Databases (NHIRD) maintained by the Bureau of National Health Insurance, Taiwan. The National Health Insurance (NHI) program was established in March 1995, providing insurance coverage for more 99% the population in Taiwan (http://www.nhi.gov.tw/). Taiwan launched the NHI program in 1995, providing insurance coverage for more than 99% of the population in Taiwan (http://www.nhi.gov.tw/), operated by the single payer, the government. Medical reimbursement specialists and peer review should scrutinize all insurance claims. The identification of diseases in the NHIRD was based on the International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM), which were judged and determined by related specialists and physicians according to the standard clinical criteria. The LHID contains the medical records (from 1996 to 2011) of 1 million insurant who were randomly selected from the original 2000 Beneficiary Registry. In accordance with the Personal Information Protection Act, the insurant data were electronically depersonalized before being released for research purposes.

Study Participants From the LHID, we collected data on 6904 patients whose pulmonary TB (ICD-9-CM 011.XX) was newly diagnosed between 2000 and 2010. The index date was defined as the date of TB diagnosis. Patients younger than 20 years or with a history of dementia before the index date were excluded. Subsequently, the TB cohort in this study comprised 6473 patients with TB. For the comparison cohort, people without TB or dementia before the index date were selected from the LHID and frequency matched by age, sex, and index year as the TB cohort at a ratio of 4:1.

A chi-square test was performed to determine the difference in demographic characteristics between the TB and the comparison cohorts. The incidence of dementia per 1000 person-years was calculated for the 2 cohorts. Cox proportional hazard regression was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) of dementia and dementia-associated risk factors. A multivariable Cox proportional hazard model was adjusted to account for the effects of age, sex, and comorbidity, differing significantly from the unadjusted model. Age-, sex-, and comorbidity-specific risks were assessed in multivariable model. For the future analysis, we assessed the risk of dementia development stratified by study duration. Cumulative incidence curves for dementia in the 2 cohorts were plotted based on Kaplan-Meier analysis, and the difference between the 2 cohorts was tested by performing a log-rank test. SAS Version 9.3 for Windows (SAS Institute, Cary, North Carolina) was employed for all statistical analyses, and the level of significance was set at .05 in a 2-tailed test.

Data Availability Statement All data and related metadata were deposited in an appropriate public repository. The data on the study population that were obtained from the NHIRD (http://w3.nhri.org.tw/nhird//date_ 01.html) are maintained in the NHIRD (http://nhird.nhri. org.tw/). The NHRI is a nonprofit foundation established by the government.

Ethics Statement 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. Patient consent is not required to access the NHIRD. This study was approved by the Institutional Review Board (IRB) of China Medical University (CMU-REC-101-012). The IRB specifically waived the consent requirement.

End Point and Comorbidity

Results

All study participants were followed up from the index date until the onset of dementia (ICD-9-CM 290.XX, 294.1X and 331.0X), withdrawal from the NHI program, or the end of 2011. The diagnoses of dementia were based on the ICD-9-CM codes which were judged and determined by related specialists and physicians. The comorbidities (ICD-9-CM) considered in this study were atrial fibrillation (AF; 427.31),

Among 32 363 study participants selected for this retrospective cohort study, 6473 were assigned the TB cohort, and the remaining 25 890 were assigned to the comparison cohort. The mean age of the TB cohort was 59.7 (standard deviation ¼ 18.2), and most of them were men (69.0%). Compared with the comparison cohorts, the patients with TB were more likely to have comorbidities, except for hyperlipidemia (Table 1).

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Peng et al

3

Table 1. Demographic Characteristics Between the TB and the Comparison Cohorts. TB (N ¼ 6473) Variable Age, year 20-34 34-49 50-64 65-79 80þ Mean (SD) Gender Women Men Comorbidity AF Hypertension Hyperlipidemia Diabetes Heart failure Stroke Depression Head injury

n

%

Comparison (N ¼ 25 890) n

%

P Value .99

810 12.5 1169 18.1 1529 23.6 2159 33.3 809 12.5 59.7 (18.2)

3240 12.5 4676 18.1 6116 23.6 8624 33.3 3234 12.5 59.0 (18.2) .99

2004 4469

31.0 69.0

8016 17 874

1.0 69.0

121 2726 1274 1366 454 569 294 302

1.87 42.1 19.7 21.1 7.01 8.79 4.54 4.67

367 10457 5405 3599 1181 1495 978 675

1.42 40.3 20.9 13.9 4.56 5.77 3.78 2.61

.008 .01 .03

Increased risk of dementia among patients with pulmonary tuberculosis: a retrospective population-based cohort study.

We investigated and compared the risk of dementia development in a cohort of patients with tuberculosis (TB)...
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