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The association between influenza infection, vaccination, and atrial fibrillation: A nationwide case-control study

  • Ting-Yung Chang
    Affiliations
    Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    Institute of Clinical Medicine, Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
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  • Tze-Fan Chao
    Affiliations
    Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    Institute of Clinical Medicine, Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
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  • Chia-Jen Liu
    Affiliations
    Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    Institute of Public Health and School of Medicine, National Yang-Ming University, Taipei, Taiwan
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  • Su-Jung Chen
    Correspondence
    Address reprint requests and correspondence: Dr Su-Jung Chen, Division of Infectious Diseases, Department of Medicine, Taipei Veterans General Hospital, No 201, Sec 2, Shih-Pai Rd, Taipei, Taiwan
    Affiliations
    Institute of Public Health and School of Medicine, National Yang-Ming University, Taipei, Taiwan

    Division of Infectious Diseases, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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  • Fa-Po Chung
    Affiliations
    Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    Institute of Clinical Medicine, Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
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  • Jo-Nan Liao
    Affiliations
    Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    Institute of Clinical Medicine, Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
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  • Ta-Chuan Tuan
    Affiliations
    Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    Institute of Clinical Medicine, Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan

    Division of Cardiology, Taipei Municipal Gan-Dau Hospital, Taipei, Taiwan
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  • Tzeng-Ji Chen
    Affiliations
    Department of Family Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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  • Shih-Ann Chen
    Affiliations
    Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    Institute of Clinical Medicine, Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
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Published:February 01, 2016DOI:https://doi.org/10.1016/j.hrthm.2016.01.026

      Background

      Influenza infection could activate systemic inflammatory responses and increase the sympathetic tone that plays an important role in the pathogenesis of atrial fibrillation (AF).

      Objectives

      The goal of the present study was to investigate whether influenza infection was a risk factor for AF. We also aimed to study whether influenza vaccination could decrease the risk of AF.

      Methods

      From 2000 to 2010, a total of 11,374 patients with newly diagnosed AF were identified from the Taiwan National Health Insurance Research Database. On the same date of enrollment, 4 control patients (without AF) with matched age and sex were selected to be the control group for each study patient. The relationship between AF and influenza infection or vaccination 1 year before the enrollment was analyzed.

      Results

      Compared with patients without influenza infection or vaccination (reference group; n = 38,353), patients with influenza infection without vaccination (n = 1369) were associated with a significantly higher risk of AF with an odds ratio of 1.182 (P = .032) after adjustment for baseline differences. The risk of AF was lower in patients receiving influenza vaccination without influenza infection (n = 16,452) with an odds ratio of 0.881 (P < .001). In patients who have received influenza vaccination and experienced influenza infection (n = 696), the risk of AF was similar to that in the reference group (odds ratio 1.136; P = .214). The lower risk of AF with vaccination was consistently observed in subgroup analyses.

      Conclusion

      Influenza infection was significantly associated with the development of AF, with an 18% increase in the risk, which could be reduced through influenza vaccination.

      Keywords

      Background

      Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice, accounting for frequent hospitalizations, hemodynamic abnormalities, and thromboembolic events.
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      • et al.
      2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
      The prevalence of AF is about 0.4%–1% in the general population, increasing with age.
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      • Hylek E.M.
      • Phillips K.A.
      • Chang Y.
      • Henault L.E.
      • Selby J.V.
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      Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study.
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      • Hart R.G.
      Prevalence, age distribution, and gender of patients with atrial fibrillation: analysis and implications.
      It is associated with a 5-fold increased risk of ischemic stroke, 3-fold increased risk of heart failure, and 2-fold increased risk of both dementia and mortality.
      • January C.T.
      • Wann L.S.
      • Alpert J.S.
      • et al.
      2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
      Although the precise mechanisms of AF are not well understood, accumulating evidence indicated that inflammation and autonomic nervous system were involved in the pathogenesis of AF.
      • Boos C.J.
      • Anderson R.A.
      • Lip G.Y.
      Is atrial fibrillation an inflammatory disorder?.
      • Guo Y.
      • Lip G.Y.
      • Apostolakis S.
      Inflammation in atrial fibrillation.
      • Issac T.T.
      • Dokainish H.
      • Lakkis N.M.
      Role of inflammation in initiation and perpetuation of atrial fibrillation: a systematic review of the published data.
      Many inflammatory biomarkers and mediators, such as C-reactive protein (CRP), tumor necrosis factor α (TNF-α), interleukin 2 (IL-2), IL-6, and IL-8, were reported to be higher in patients with AF.
      • Guo Y.
      • Lip G.Y.
      • Apostolakis S.
      Inflammation in atrial fibrillation.
      • Issac T.T.
      • Dokainish H.
      • Lakkis N.M.
      Role of inflammation in initiation and perpetuation of atrial fibrillation: a systematic review of the published data.
      In addition, sympathetic and parasympathetic nervous systems also play an important role in the initiation and perpetuation of AF.
      • Chen P.S.
      • Chen L.S.
      • Fishbein M.C.
      • Lin S.F.
      • Nattel S.
      Role of the autonomic nervous system in atrial fibrillation: pathophysiology and therapy.
      • Park H.W.
      • Shen M.J.
      • Lin S.F.
      • Fishbein M.C.
      • Chen L.S.
      • Chen P.S.
      Neural mechanisms of atrial fibrillation.
      • Shen M.J.
      • Choi E.K.
      • Tan A.Y.
      • Lin S.F.
      • Fishbein M.C.
      • Chen L.S.
      • Chen P.S.
      Neural mechanisms of atrial arrhythmias.
      Influenza infection could cause significant morbidity and mortality, and it is a serious human health concern worldwide. Influenza infection not only results in the production of proinflammatory cytokines, such as IL-1β, IL-6, IL-18, and TNF-α,
      • Julkunen I.
      • Sareneva T.
      • Pirhonen J.
      • Ronni T.
      • Melen K.
      • Matikainen S.
      Molecular pathogenesis of influenza a virus infection and virus-induced regulation of cytokine gene expression.
      but also activates the sympathetic nervous system,
      • Grebe K.M.
      • Takeda K.
      • Hickman H.D.
      • Bailey A.L.
      • Embry A.C.
      • Bennink J.R.
      • Yewdell J.W.
      Cutting edge: sympathetic nervous system increases proinflammatory cytokines and exacerbates influenza a virus pathogenesis.
      • Dunn A.J.
      • Powell M.L.
      • Meitin C.
      • Small Jr, P.A.
      Virus infection as a stressor: influenza virus elevates plasma concentrations of corticosterone, and brain concentrations of MHPG and tryptophan.
      which are all related to the occurrence of AF. Although influenza infection has been reported to be associated with an increased risk of myocardial infarction and stroke,
      • Warren-Gash C.
      • Hayward A.C.
      • Hemingway H.
      • Denaxas S.
      • Thomas S.L.
      • Timmis A.D.
      • Whitaker H.
      • Smeeth L.
      Influenza infection and risk of acute myocardial infarction in England and Wales: a caliber self-controlled case series study.
      • Grau A.J.
      • Urbanek C.
      • Palm F.
      Common infections and the risk of stroke.
      the relationship between influenza infection and AF has not been well studied previously. The goal of the present study was to investigate whether influenza infection was a risk factor for AF. We also aimed to study whether influenza vaccination, a useful way to reduce the risk of influenza infection, could decrease the risk of AF.

      Methods

      Database

      This study used the National Health Insurance Research Database (NHIRD) released by the Taiwan National Health Research Institutes. The National Health Insurance (NHI) system is a mandatory universal health insurance program that offers comprehensive medical care coverage to all Taiwanese residents. The NHIRD was a cohort data set that contained all the medical claims data for 1,000,000 beneficiaries (mean age 34.8 ± 20.9 years; n = 513,876, 51.4% men), who were randomly sampled from the 25.68 million enrollees under the NHI program. These random samples have been confirmed by the National Health Research Institutes to be representative of the Taiwanese population. In this cohort data set, the patients’ original identification numbers have been encrypted to protect their privacy, but the encrypting procedure was consistent, so that a linkage of the claims belonging to the same patient was feasible within the NHI database and can be followed continuously. The database with a large sample size provided an excellent opportunity to study the association between influenza infection, vaccination, and the risk of AF. The study was approved by the Institutional Review Board of Taipei Veterans General Hospital, Taipei, Taiwan.

      Study population and control group

      From January 1, 2000, to December 31, 2010, a total of 11,374 patients 20 years or older with the newly diagnosed AF were identified from the NHIRD using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes (427.31).
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      • Liu C.J.
      • Chen S.J.
      • et al.
      The association between the use of non-steroidal anti-inflammatory drugs and atrial fibrillation: a nationwide case-control study.
      • Chao T.F.
      • Huang Y.C.
      • Liu C.J.
      • et al.
      Acute myocardial infarction in patients with atrial fibrillation with a CHA2DS2-VASc score of 0 or 1: a nationwide cohort study.
      • Chao T.F.
      • Liu C.J.
      • Wang K.L.
      • Lin Y.J.
      • Chang S.L.
      • Lo L.W.
      • Hu Y.F.
      • Tuan T.C.
      • Chen T.J.
      • Lip G.Y.
      • Chen S.A.
      Should atrial fibrillation patients with 1 additional risk factor of the CHA2DS2-VASc score (beyond sex) receive oral anticoagulation?.
      The diagnostic accuracy of AF using ICD-9-CM codes in the NHIRD has been validated previously.
      • Levy M.Z.
      • Quispe-Machaca V.R.
      • Ylla-Velasquez J.L.
      • et al.
      Impregnated netting slows infestation by Triatoma infestans.
      • Chang C.H.
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      • Lai M.S.
      Continuation of statin therapy and a decreased risk of atrial fibrillation/flutter in patients with and without chronic kidney disease.
      We defined the date of the first diagnosis of AF when each patient was enrolled to be the index date. On the same index date, 4 control patients (without AF) with matched age and sex were selected to be the control group (n = 45,496) for each study patient. We selected controls using risk set sampling,
      • Wacholder S.
      • McLaughlin J.K.
      • Silverman D.T.
      • Mandel J.S.
      Selection of controls in case-control studies. I. Principles.
      which means that when a patient with AF was identified, 4 persons without AF who were still at risk at that point in time were selected from the data set. Thereafter, histories of influenza infection and vaccination 1 year before the enrollment were analyzed and compared between the study and control groups. The flowchart of the enrollment of study patients is given in Figure 1.
      Figure thumbnail gr1
      Figure 1Flowchart of the enrollment of study patients. A total of 11,374 patients with AF were enrolled as the study group. The exposure to influenza infection and vaccination 1 year before the enrollment was analyzed and compared with that of patients without AF (control group; n = 45,496).
      Information on important comorbid conditions of each individual was retrieved from the medical claims based on the ICD-9-CM codes. We defined patients with a certain disease only when it was a discharge diagnosis or repeatedly confirmed more than twice in outpatient department. The diagnostic accuracies of important comorbidities in the NHIRD, such as hypertension, diabetes mellitus, heart failure, myocardial infarction, hyperlipidemia, and chronic obstructive pulmonary disease, have been validated before.
      • Lin C.C.
      • Lai M.S.
      • Syu C.Y.
      • Chang S.C.
      • Tseng F.Y.
      Accuracy of diabetes diagnosis in health insurance claims data in Taiwan.
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      • Kao Y.H.
      • Lin S.J.
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      • Lai M.L.
      Validation of the National Health Insurance Research Database with ischemic stroke cases in Taiwan.

      Statistical analysis

      The data are presented as mean ± SD for normally distributed continuous variables and n(%) for categorical variables. The differences between continuous values were assessed using an unpaired 2-tailed t test for normally distributed continuous variables and Mann-Whitney rank-sum test for skewed variables. The χ2 test was used for the comparisons of nominal variables. The risk of patients in developing AF was expressed as the odds ratio, which was analyzed using the logistic regression analysis. All statistical significances were set at P < .05, and all statistical analyses were performed using SPSS 17.0 (SPSS Inc., IBM, Chicago).

      Results

      Patients’ characteristics

      The baseline characteristics of the patients with and without AF are summarized in Table 1. The mean age of the study population was 70.9 ± 13.4 years, and 55.7% of the patients were men. The age and sex were matched between the study and control groups. In regard to the comorbidities and frequencies of medical utilizations, patients with AF had more comorbidities and received imaging studies and visited outpatient department for upper respiratory tract and influenza infections more frequently than did patients without AF.
      Table 1Baseline characteristics of the patients with and without atrial fibrillation
      VariablesStudy group (with AF) (n = 11,374)Control group (without AF) (n = 45,496)P value
      Age, years70.9 ± 13.470.9 ± 13.40.955
      Age ≥65 years old8,305 (73.0)33,206 (73.0)0.947
      Gender (male)6,338 (55.7)25,352 (55.7)1.0
      Medical history
       Hypertension7,834 (68.9)22,979 (50.5)<0.001
       Diabetes mellitus3,325 (29.2)10,155 (22.3)<0.001
       Congestive heart failure3,802 (33.4)4,142 (9.1)<0.001
       Myocardial infarction639 (5.6)823 (1.8)<0.001
       Peripheral vascular diseases876 (7.7)2,278 (5.0)<0.001
       COPD3,923 (34.5)9,974 (21.9)<0.001
       ESRD922 (8.1)1,722 (3.8)<0.001
       Ischemic stroke/TIA2,432 (21.4)5,871 (12.9)<0.001
       Hemorrhagic stroke314 (2.8)777 (1.7)<0.001
       GERD548 (4.8)1,609 (3.5)<0.001
       Sleep apnea17 (0.1)36 (0.1)0.028
       Cancer2,432 (21.4)8,082 (17.8)<0.001
       Dyslipidemia2,766 (24.3)9,509 (20.9)<0.001
      Dementia850 (7.5)2,548 (5.6)<0.001
      Major depression787 (6.9)2,370 (5.2)<0.001
       Autoimmune diseases568 (5.0)1,955 (4.3)0.001
       Liver cirrhosis287 (2.5)798 (1.8)<0.001
       Statin use1,212 (10.7)3,960 (8.7)<0.001
      Medical utilization (mean times 1 year before the enrollment)
       Computed tomography/MRI0.36 ± 0.760.16 ± 0.51<0.001
       OPD visit for URTI2.16 ± 4.331.70 ± 3.84<0.001
       Visit of influenza clinic0.17 ± 1.170.14 ± 1.020.006
       All-cause admission0.80 ± 1.520.31 ± 0.96<0.001

      Influenza infection, vaccination, and risk of AF

      Patients were divided into 4 groups on the basis of the status of influenza infection and vaccination. Patients who did not experience influenza infection nor receive vaccination 1 year before the index date were defined as the reference group. The risk of AF occurrence related to influenza infection and vaccination represented by odds ratios is shown in Table 2. After adjustment for age, sex, comorbidities, and medical utilizations, patients with influenza infection without vaccination were associated with a significantly higher risk of AF development with an adjusted odds ratio of 1.182 (95% confidence interval [CI] 1.014–1.378; P = .032) as compared with the reference group. The risk of AF was lower in patients receiving influenza vaccination without influenza infection (odds ratio 0.881; 95% CI 0.836–0.928; P < .001). In patients who have received influenza vaccination and experienced influenza infection, the risk of AF was similar to that in the reference group (odds ratio 1.136; 95% CI 0.929–1.389; P = .214).
      Table 2Associations between influenza infection, vaccination, and atrial fibrillation
      Influenza infection and vaccinationNo. of patientsMultivariate regression model
      Adjusted for age, sex, medical history, and medical utilization listed in Table 1.
      Odds ratio95% CIP
      Neither (reference group)38,3531
      Influenza infection only1,3691.1821.014–1.378.032
      Vaccination only16,4520.8810.836–0.928<.001
      Influenza infection and vaccination6961.1360.929–1.389.214
      CI = confidence interval.
      low asterisk Adjusted for age, sex, medical history, and medical utilization listed in Table 1.
      A matching of Charlson Comorbidity Index
      • Deyo R.A.
      • Cherkin D.C.
      • Ciol M.A.
      Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases.
      in addition to age and sex among patients with and without AF was performed, and the baseline characteristics of these 2 groups are summarized in Online Supplemental Table 1. The associations between influenza infection, vaccination, and AF were similar to the results of analyses performed in patients who were not matched for Charlson Comorbidity Index (Online Supplemental Table 2).
      In patients receiving influenza vaccination and without influenza infection (n = 16,452), influenza vaccination was consistently associated with a lower risk of AF as compared with patients without influenza infection and vaccination (reference group) in different groups of patients stratified by age, sex, and important comorbidities (Figure 2).
      Figure thumbnail gr2
      Figure 2Forest plot describing subgroup analysis of the association between vaccination and AF. For patients receiving influenza vaccination and without influenza infection (n = 16,452), influenza vaccination was consistently associated with a lower risk of AF as compared with patients without influenza infection and vaccination (reference group) in different groups of patients stratified by age, sex, and important comorbidities. AF = atrial fibrillation; CI = confidence interval; COPD = chronic obstructive pulmonary disease; ESRD = end-stage renal disease; OR = odds ratio. *Adjusted for age, sex, medical history, and medical utilization listed in . +Cardiovascular diseases included peripheral vascular diseases, myocardial infarction, and ischemic stroke/transient ischemic attack.

      Discussion

      Main findings

      In this nationwide case-control study that enrolled a total of 56,870 patients, we investigated the association between influenza infection, vaccination, and the risk of AF. The main findings were as follows: (1) influenza infection may increase the risk of AF, and the risk could be reduced through vaccination; And (2) influenza vaccination was consistently associated with a lower risk of AF in different groups of patients.

      Influenza infection and risk of AF

      What is the possible mechanism behind the association between influenza infection and AF we observed in the present study? Several studies
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      Is atrial fibrillation an inflammatory disorder?.
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      Inflammation in atrial fibrillation.
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      • Lakkis N.M.
      Role of inflammation in initiation and perpetuation of atrial fibrillation: a systematic review of the published data.
      have supported a close link between AF and inflammatory processes. An elevated serum CRP level was reported to be related to AF development, increased AF burden, and higher recurrence rate after catheter ablation and electrical cardioversion for AF.
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      Both TNF-α and IL-6 levels were significantly correlated with the left atrial diameter and duration of AF.
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      have demonstrated that a higher IL-6 level was associated with a higher risk of AF after coronary artery bypass graft surgery and a higher AF recurrence rate after cardioversion and radiofrequency catheter ablation. Furthermore, the autonomic nervous system played a vital role in the initiation and perpetuation of AF, and sympathovagal discharges could be a trigger for paroxysmal AF.
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      During influenza infection, epithelial cells and leukocytes infected by influenza produced several proinflammatory cytokines, including IL-6 and TNF-α.
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      Serum CRP levels were also elevated in many inflammatory diseases including bacterial and, to a lesser degree, viral infections, such as influenza.
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      In response to influenza infection, the sympathetic nervous system was activated and modulated the immune system to increase proinflammatory cytokines, which further exacerbated influenza virus pathogenesis.
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      Taken together, influenza infection might increase the risk of AF through the activation of systemic inflammatory responses and increase of sympathetic tone. However, the precise mechanisms responsible for the link between influenza infection and AF remain unclear, and further studies are necessary to investigate this issue.

      Clinical applications

      The occurrence of cardiac arrhythmias after influenza infection, including atrioventricular block,
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      cardiac conduction system affection,
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      atrial arrhythmia,
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      and ventricular arrhythmia,
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      was reported in previous case reports. The present study represents the first population-based study investigating the association between influenza infection, vaccination, and occurrence of AF. According to the findings presented here, the possibility of AF should be kept in mind when patients with influenza infection complained of palpitation or experienced ischemic stroke. In addition, influenza vaccination may be a useful way to reduce the AF burden associated with influenza infection, and high-risk patients should be encouraged to receive influenza vaccination annually.

      Study limitations

      There are several limitations of the present study. First, personal information such as smoking habit, physical activity, and body mass index were not available from this registry database. In addition, echocardiographic parameters, such as left atrial dimension and left ventricular ejection fraction, were absent. Therefore, we were not able to control well for all potential confounders, although we have tried to adjust for important comorbidities in the Cox regression model. Second, the diagnosis of AF was based on the diagnostic code registered by the physicians responsible for the treatments of patients and was not further checked externally. However, the diagnostic accuracy of AF in the NHIRD has been validated before.
      • Levy M.Z.
      • Quispe-Machaca V.R.
      • Ylla-Velasquez J.L.
      • et al.
      Impregnated netting slows infestation by Triatoma infestans.
      • Chang C.H.
      • Lee Y.C.
      • Tsai C.T.
      • Chang S.N.
      • Chung Y.H.
      • Lin M.S.
      • Lin J.W.
      • Lai M.S.
      Continuation of statin therapy and a decreased risk of atrial fibrillation/flutter in patients with and without chronic kidney disease.
      Third, influenza infection was diagnosed using ICD-9 codes with concomitant use of antiviral agents and was not further confirmed on the basis of the results of viral culture with throat swab. The diagnostic accuracy of influenza infection cannot be fully ascertained. Lastly, while we reported the significant association between AF and influenza infection, these results were derived from an observational database. Therefore, we were not able to conclude whether influenza infection was the direct cause of the increased risk of AF, and only a prospective and randomized trial can answer the question. However, the observed lower risk of AF in patients receiving influenza vaccination may partly support the hypothesis that influenza infection was an important risk factor for AF.

      Conclusion

      In this observational study, influenza infection was significantly associated with the development of AF, with an 18% increase in the risk, which could be reduced through influenza vaccination. A further prospective and large-scale trial is necessary to confirm the findings of the present study.

      Appendix. Supplementary materials

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