Annual influenza vaccination reduces total hospitalization in patients
with chronic hepatitis B virus infection: A population-based analysis
Fu-Hsiung Su a,b,c,d, Ya-Li Huang e, Fung-Chang Sung f,g, Chien-Tien Su a,h, Wen-Hsin Hsu i,Shih-Ni Chang f,g, Chih-Ching Yeh h,j,*
a Department of Family Medicine, Taipei Medical University Hospital, Taipei, Taiwan b Department of Family Medicine, School of Medicine, Taipei Medical University, Taipei,
Taiwan
c Master Program in Long-Term Care, College of Nursing, Taipei medical University, Taipei,
Taiwan
d School of Medicine, Flinders University, Bedford Park, South Australia, Australia
e Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
f Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan g Graduate Institute of Clinical Medical Science, School of Medicine, College of Medicine,
China Medical University, Taichung, Taiwan
h School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan
i Department of Gastroenterology and Hepatology, Yuan’s General Hospital, Kaoshiung,
Taiwan
jDepartment of Public Health, China Medical University, Taichung, Taiwan
Address correspondence to:
Chih-Ching Yeh, PhD Professor
School of Public Health, College of Public Health and Nutrition, Taipei Medical University 250 Wu-Hsing Street, Taipei, Taiwan 11031
TEL: 886-2-2736-1661ext 6534 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
EMAIL: ccyeh@tmu.edu.tw 31
ABSTRACT
Background:
This study evaluated hospitalization and mortality in patients with chronic hepatitis B virus infection (HBV (+)) and matched comparison patients after stratifying the patients according to annual influenza vaccination (Vaccine (+)).Methods: Data from Taiwan’s National Health Insurance program from 2000 to 2009 were
used to identify HBV(+)/vaccine(+) (n = 4,434), HBV(+)/Vaccine(–) (n = 3,646), HBV(–)/Vaccine(+) (n = 8,868), and HBV(–)/Vaccine(–) (n = 8,868) cohorts. The risk of pneumonia/influenza, respiratory failure, intensive care, hospitalization, and mortality in the four cohorts was evaluated.Results: The total hospitalization rate was significantly lower in patients with chronic HBV
infection who received an annual influenza vaccination than in chronic HBV-infected patients who did not receive an influenza vaccination (16.29 vs. 24.02 per 100 person-years), contributing to an adjusted hazard ratio (HR) of 0.56 (95% confidence interval (CI) = 0.50– 0.62). The HBV(+)/Vaccine(+) cohort also had lower risks than the HBV(+)/Vaccine(–) cohort for pneumonia and influenza (adjusted HR = 0.79, 95% CI = 0.67–0.92), intensive care unit admission (adjusted HR = 0.33, 95% CI = 0.25–0.43), and mortality (adjusted HR = 0.19, 95% CI = 0.15–0.24).Conclusions:
Our results suggest that annual influenza vaccination can reduce the risk ofhospitalization and mortality in patients with chronic HBV infection. 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51
Keywords: hepatitis B virus; influenza; vaccination; population-based study
52 53
1. Introduction
Influenza is an acute febrile illness that is predominantly caused by infection with influenza virus types A and B, leading to outbreaks of variable severity from late autumn to early spring in the northern hemisphere. The two principal features of influenza are epidemics and high mortality. Primary complications include viral pneumonitis, bacterial pneumonia, and acute respiratory distress syndrome [1]. Influenza-related morbidity and mortality are markedly increased in elderly people, pregnant women, the immunocompromized, and patients with underlying chronic diseases such as diabetes mellitus (DM), coronaropathy,
chronic obstructive pulmonary disease, chronic liver disease and chronic renal disease [2]. Annual influenza vaccination is the primary strategy for preventing influenza and its complications. In 2010, the Disease Control Center (CDC) and the CDC Advisory Committee on Immunization Practices (ACIP) recommended that all people aged ≥ 6 months with no contraindications receive routine annual influenza vaccinations [3]. When the vaccine supply is limited, high-risk groups, including people with medical conditions such as heart problems, renal and lung diseases, metabolic disorders, haematological disorders, and chronic liver disease, should receive priority (CDC 2013). Since 2007, the USA ACIP has recommended that patients with chronic liver disease receive routine annual influenza vaccinations [4]. Similarly, the World Health Organization recommends that annual influenza vaccination should be considered for pregnant women at all stages of pregnancy, children aged 6 months 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72
to 5 years, elderly individuals (≥65 years of age), individuals with chronic medical conditions, and health-care workers [5].
Previous research on influenza vaccination and chronic liver disease has predominantly focused on patients with cirrhosis of the liver. These studies have suggested that patients with cirrhosis benefit from influenza vaccination and can be safely immunized [1, 6-9]. However, few studies have focused on the clinical benefits of influenza vaccination in chronic liver disease patients, particularly patients with chronic hepatitis B virus (HBV) infection [1, 10]. Recently, one review concluded that there is an insufficient level of evidence regarding the effectiveness of influenza vaccination among patients with chronic liver disease [11].
Taiwan is a hyperendemic region of chronic HBV infection [12] and thus provides a unique setting in which to evaluate the benefits of influenza vaccination among patients with chronic HBV infection. Influenza-related morbidity and mortality are markedly increased in patients with underlying chronic diseases. Therefore, in this study, we used a nationwide population-based insurance data set to investigate the influence of influenza vaccination on
influenza-related morbidity and mortality in patients with chronic HBV infection.
2. Material and Methods
2.1. Data source
Data were retrieved from Taiwan’s National Health Insurance Research Database (NHIRD), which is maintained by the Taiwan National Health Research Institutes (NHRI), 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92
Department of Health. Taiwan initiated its state-run National Health Insurance (NHI) program in 1995 to provide affordable health care to all Taiwanese citizens [13]. By the end of 1996, the NHI program covered approximately 99% of Taiwan’s population and was contracted with 97% of all hospitals and clinics [14]. Taiwan’s NHIRD contains claims data on 1,000,000 patients randomly selected from all insured enrollees to represent the health profiles of all citizens. The sample contains the original medical claims of all citizens covered by the NHI program, and these claims are distributed according to sex, age, and average payroll-related insurance payment. With approval from the NHRI, data on ambulatory care claims, inpatient claims, and updated registries for beneficiaries from 2000 to 2010 were used in this study. Diagnoses are coded according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). The NHRI safeguards the privacy and confidentiality of all beneficiaries and transfers the health insurance data to researchers only after ethical approval has been obtained. For this study, access to the NHIRD was approved
by the NHRI Ethics Review Committee.
In Taiwan, the annual campaign for publicly funded influenza vaccination begins in early October. The primary targets are people aged ≥ 65 years, children aged > 6 months and < 12 years, people living in nursing care facilities, people categorized as having “catastrophic illness” or “rare disease”, health workers, people whose occupations involve livestock
breeding, and people aged 60–64 years with chronic medical conditions. 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111
2.2. Study sample
The study data, which were recorded between 2000 and 2010, were obtained from the NHIRD. In this study, we identified 35,063 patients with diagnoses of HBV (ICD-9-CM Codes 070.2, 070.3, V02.61) infection during the period of 2000-2009. We excluded those 81 participants with only one diagnosis of acute or unspecified HBV infection (ICD-9-CM Codes 070.20, 070.21, 0.70.30, 070.31) concurrent with a diagnosis of impairment of liver function (ICD-9-CM Codes 794.8). Patients who received a second diagnosis of hepatitis virus infection six months after being diagnosed with acute or unspecified HBV infection were classified as chronic cases. The index date for patients with chronic HBV infection was the first instance of having chronic HBV infection identified. To limit the study sample to the adult population, 1,938 individuals aged < 20 years were excluded. 33 participants diagnosed with human immunodeficiency virus (ICD-9-CM Codes 042, 043,044, V08, and 795·8) and 3,448 individuals with HBV/HCV dual infection were also excluded. After excluding 1,653 patients diagnosed with influenza (ICD-9-CM Code 487) 1 year before the index date, 27,910 individuals with chronic HBV infection were enrolled in this study. Amongst the eligible chronic HBV infected patients (HBV (+)), 4,434 patients who had received the annual seasonal influenza vaccine (Vaccine (+)) (ICD-9-CM Codes V04·7 and V04·8) were identified and included in the HBV(+)/Vaccine(+) cohort, and the vaccination date was used as the index date. The HBV(+)/Vaccine(–) cohort was randomly selected from the remaining 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131
HBV(+) patients who received no influenza vaccination. For each patient in the HBV(+)/Vaccine(+) cohort, two comparison HBV(–) patients were selected and frequency matched according to age, sex, and index date. The HBV(+)/Vaccine(–) cohort comprised only 3,646 patients because HBV(+) patients are more likely to receive the influenza vaccine than to remain unimmunised.
In the two comparison HBV(–) groups, patients with any type of hepatitis, including chronic hepatitis (ICD-9-CM Codes 070.9, 571.4, 571.8, 571.9, and 573.3), HBV, HCV, or HBV/HCV dual infection, were excluded. Patients in the HBV(–) group were divided into HBV(–)/Vaccine(+) and HBV(–)/Vaccine(–) cohorts. Patients in these two cohorts were excluded and matched according to the criteria used for the HBV(+)/Vaccine(+) cohort. Initially, 939,052 patients were retrieved from the NHIRD after excluding patients with any type of chronic hepatitis, including 130,215 patients who received an influenza vaccination and 808,837 patients who received no influenza vaccination. After the exclusion criteria were applied to the HBV(+)/Vaccine(+) cohort, 8,868 matched patients were included in the
HBV(–)/Vaccine(+) and HBV(–)/Vaccine(–) cohorts (Fig. 1).
2.3. Outcome measures
Follow-up person-years were measured for each patient from the index date for 1 year or until selected events, death, or withdrawal from the NHI database. The outcomes of interest were total hospitalization, pneumonia or influenza (ICD-9-CM Codes 480–487), 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150
hospitalization for heart disease (ICD-9-CM Codes 401–429), respiratory failure (ICD-9-CM Codes 518.81–518.84, 799.1), intensive care unit (ICU) admission, and death. We were also interested in exploring possible secondary outcomes to influenza infection including the hospitalization rates for unspecified septicemia, bacteremia, or viremia (ICD-9-CM Codes 038.x, 790.7, and 790.8). Potential baseline comorbidities, including diabetes mellitus (ICD-9-CM Code 250), coronary artery disease (ICD-(ICD-9-CM Codes 410–413, 414.01–414.05, 414.8, 414.9), congestive heart failure (ICD-9-CM Codes 428, 398.91, 402.x1), hypertension 9-CM Codes 401–405), hyperlipidemia 9-CM Code 272), atrial fibrillation (ICD-9-CM Code 427.31), chronic obstructive pulmonary disease (ICD-(ICD-9-CM Codes 490–496), renal disease (ICD-9-CM Codes 580–589), cancer (ICD-9-CM Codes 140–165, 170–175, 179–189, 190–199, 200, 202, 203, 210–213, 215–229, 235–239, 654.1, 654.10, 654.11, 654.12, 654.13, 654.14), stroke (ICD-9-CM Codes 430–438), dementia (ICD-9-CM Codes 290, 291.2, 292.82, 331), and cirrhosis of the liver (ICD-9-CM Codes 571.2, 571.5, 571.6,),
were identified by searching for the diagnostic codes at any time after 2000.
2.4. Statistical analysis
The distributions of sociodemographic factors (sex and age), previous history of pneumococcal vaccination, and comorbidities were compared amongst the four cohorts, and the incidence rates for hospitalization, infection (pneumonia or influenza, septicemia, bacteremia, and viraemia), heart disease, respiratory failure, ICU admission, and mortality 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170
were estimated. The incidence rate ratio of the comparison between two cohorts, with a 95% confidence interval (CI), was estimated using a Poisson regression. Univariate analysis of Kaplan-Meier estimates and a log-rank test were used to evaluate the probability of hospitalization free events and surviving between the HBV(+)/Vaccine(+) and HBV(+)/Vaccine(–) cohorts. Crude and adjusted hazard ratios (HRs) and 95% CIs for the outcomes of interest were estimated using univariate and multivariate Cox proportional hazard regression models. To evaluate the associations between HBV status and influenza vaccination and the risk of selected events and influenza-related hospitalization were performed using the Cox models. All analyses were performed using SAS statistical software for Windows (Version 9.3; SAS Institute, Inc, Cary, NC, USA), and the significance level was set at 0.05.
3. Results
3.1. Baseline characteristics and comorbidities of the study patients
The patients in the HBV(+)/Vaccine(‒) cohort were more likely to be men and to be younger than the patients in the other three cohorts (Table 1). The patients in the HBV(+)/Vaccine(+) cohort tended to present with the highest number of comorbidities, followed by the patients in the HBV(‒)/Vaccine(+) cohort. Of the four cohorts, the
HBV(‒)/Vaccine(‒) cohort presented with the lowest number of comorbidities. 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190
3.2. Risk of hospitalization and various medical outcomes occurring between 2000 and 2009 among influenza-vaccinated and non-vaccinated HBV-infected patients.
As shown in Table 2, among our patients with chronic hepatitis B infection, the incidence of total hospitalization was lower in the influenza- vaccinated cohort than in the non-vaccinated cohort (16.29 vs. 24.02 per 100 person-years). An adjusted HR of 0.56 (95% CI = 0.50–0.62) indicated the protective effects of the influenza vaccination against hospitalization in the HBV carriers. Compared with the non-influenza vaccinated patients with chronic hepatitis B, the patients with chronic hepatitis B infection in the vaccinated cohort were less likely to be hospitalized for sepsis (1.07 vs. 2.74 per 100 person-years; adjusted HR 0.31 [95% CI = 0.22–0.45]) and heart diseases (0.11 vs. 0.32 per 100 person-years; adjusted HR 0.22 [95% CI = 0.08–0.66]), less likely to be admitted to the ICU (2.09 vs. 4.75 per 100 person-years; adjusted HR 0.33 [95% CI = 0.25–0.43]), and were associated with a lower risk of pneumonia/influenza (8.81 vs. 9.91 per 100 person-years; adjusted HR 0.79 [95% CI = 0.67–0.92]), respiratory failure (0.61 vs. 1.92 per 100 person-years; adjusted HR 0.27 [95% CI = 0.17–0.43]) and mortality (1.89 vs. 8.65 per 100 person-years; adjusted HR 0.19 [95% CI = 0.15–0.24]). Fig. 2 A–G showed that the HBV(+)/Vaccine(+) cohort had a significantly lower cumulative proportion of total hospitalization (P < 0.0001) (Fig. 2A), hospitalization for septicemia, bacteremia, or viraemia (P < 0.0001) (Fig. 2C), hospitalization for heart disease (P = 0.044) (Fig. 2D), respiratory failure (P < 0.0001) (Fig. 2E), ICU 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209
admission (P < 0.0001) (Fig. 2F), and mortality (P < 0.0001) (Fig. 2G) compared with the HBV(+)/Vaccine(‒) cohort.
3.3. Risk of hospitalization and various medical outcomes occurring between 2000 and 2009 among HBV-positive and HBV-negative patients who received their annual influenza vaccination.
As shown in Table 3, among our subjects who received influenza vaccination, the adjusted HRs of the total hospitalization rates were 0.94 (95% CI = 0.85–1.04) in the HBV(+) cohort compared with the HBV(‒) cohort. Compared with the HBV(‒) cohort, the HBV(+) cohort was less likely to experience respiratory failure (adjusted HR 0.57 [95% CI = 0.36– 0.89]). The adjusted HRs of 0.69 (95% CI = 0.53–0.90) and 0.59 (95% CI = 0.45–0.78) indicated the protective effects of influenza vaccination against ICU admission and mortality in the HBV carriers in comparison with the non-HBV subjects. The risk of developing pneumonia and influenza was lower in the HBV(+) cohort than in the HBV(‒) cohort (adjusted HR 0.87 [95% CI = 0.77–0.99]).
3.4. Risk of hospitalization and various medical outcomes occurring between 2000 and 2009 among influenza-vaccinated and non-vaccinated HBV-negative patients.
As shown in Table 4, the adjusted HRs of the total hospitalization rates were 1.13 (95% CI = 1.04–1.24) in the HBV(‒)/Vaccine(+) cohort, compared with the 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229
HBV(‒)/Vaccine(‒) cohort after we controlled for sex, age, pneumococcal vaccine, and related comorbidities showing significance in Table 1. The risk of developing pneumonia and influenza was also higher in the HBV(‒)/Vaccine(+) cohort than in the HBV(‒)/Vaccine(‒) cohort (adjusted HR 1.17 [95% CI = 1.05–1.30]).
4. Discussion
Our study results suggest that influenza vaccination is associated with a reduced risk of severe outcomes requiring hospitalization in patients with chronic HBV infection. Our study is one of the first population-based studies that may suggest the utility of an influenza vaccination campaign targeting patients with chronic HBV infection to reduce their risk of hospitalization and mortality.
Seasonal influenza and its secondary bacterial infections represent a serious threat to patients with chronic liver disease, particularly patients with cirrhosis [8]. Influenza can cause hepatitis [15] by inducing the production of toxic metabolites and proinflammatory cytokines, such as tumor necrosis factor alpha, interleukin (IL)-1, and IL-6, which contribute to liver damage [16-18]. In addition, influenza predisposes patients to bacterial lung infections and increases the risk of pneumococcal infection [19]. Influenza infection occasionally causes hepatic decompensation without typical influenza symptoms in patients with chronic liver disease [9, 18], potentially delaying antiviral therapy and increasing influenza-related
mortality. 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249
Studies have indicated that the anti-influenza vaccine is well tolerated by patients with chronic liver diseases, including patients with liver cirrhosis [1, 6, 7, 9, 10, 20-22], among whom the influenza vaccine is sufficiently immunogenic [7, 20, 23, 24]. Song et al. reported that vaccinating cirrhotic patients reduced the incidence of laboratory-confirmed influenza and atypical influenza symptoms, such as myalgia, hepatic decompensation oliguria, and uncontrolled ascites, during the influenza season [9]. Sayyad et al. recently enrolled 93 patients and divided them into cirrhotic patients (n = 28), inactive HBV carriers (n = 31), and healthy participants (n = 34) [1]. Four weeks after vaccination, the seroconversion rates of the vaccine strains ranged from 71.4% to 100% in the cirrhotic patients, from 70.6% to 94.1% in the inactive HBV carriers, and from 58.1% to 80.7% in the healthy participants. The seroconversion rates and antibody GMTs against the H3N2 and H1N1 strains of the cirrhotic patients and inactive carriers of HBV exhibited nonsignificant differences from those of the healthy participants. Therefore, influenza vaccination can be implemented in cirrhotic patients and inactive HBV carriers as well as in healthy people, and should be considered in such patients to reduce influenza-associated morbidity and mortality.
In addition, some studies suggested that the prevention of influenza through annual influenza vaccination represents a cost-effective means of reducing influenza-related complications and mortality in vulnerable patients with chronic liver disease and cirrhosis [1, 7, 9, 10, 21, 22, 25]. However, a review concluded that there is an insufficient level of 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268
evidence regarding the effectiveness of influenza vaccination among patients with chronic liver disease [11]. Indeed there are conflicting results, as some studies showed an impaired
immunization response [20].
Our study results indicated that immunization reduces total hospitalization and related hospitalization events in patients with chronic HBV infection when compared with HBV carriers who received no influenza vaccination (Table 2). We also observed that the incidence rates of pneumonia/influenza, respiratory failure, ICU admission, and mortality were significantly lower for patients in the HBV(+)/Vaccine(+) cohort than those in the
HBV(–)/Vaccine(+) cohort (Table 3).
However, the HBV(–)/Vaccine(+) patients were more likely than the HBV(–)/Vaccine(–) patients to be hospitalized because the majority of vaccinated individuals in Taiwan are at high risk for poor health, hence their priority for the annual influenza vaccination. The primary targets of the influenza vaccination program are elderly people, people living in nursing care facilities, people categorised as having catastrophic illness or rare disease, and people aged 60–64 years with chronic medical conditions. The fact that HBV(+)/Vaccine(+) patients were at a lower risk for hospitalization and mortality than HBV(–)/Vaccine(+) patients might further suggest that immunized chronic HBV infected patients responded better than patients with other chronic conditions in terms of risk of
hospitalization and mortality. 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287
In addition, all the patients with chronic HBV infection have been considered for inclusion in this study. Hence, our population was very heterogeneous, featuring patients without hepatitis, with hepatitis, and with cirrhosis. However, even after adjusting for cirrhosis of the liver as a possible confounding factor (Table 1), the results of this study suggest that there are protective benefits of vaccination in terms of a lower risk of hospitalization and other selected medical outcomes. Therefore, even HBV positive patients without terminal liver disease may stand to benefit from influenza vaccination. However, on account of the conflicting evidence presented in the literature [11], further studies are
warranted to bolster the validity of these observations.
The strengths of our study include the large national representative dataset, the cohort design, and the one-year follow-up for each cohort. The one-year follow-up can determine the
possibility of delayed complications of influenza.
This study had several limitations. First, patients with chronic HBV infection do not exhibit clinical symptoms and might not seek medical attention. Claims for medical services are not available for such patients. Therefore, we likely included some patients with asymptomatic hepatitis infection in our non-HBV cohorts. However, if viral hepatitis infection is associated causally with hospitalization, then this misclassification might have caused the risk of hospitalization to be underestimated, strengthening our study results. Second, the diagnoses of influenza, HBV infection, HCV infection, and other comorbid 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306
medical conditions such as septicemia, bacteremia, and viremia were dependent on ICD-9-CM coding. As we do not have access to any laboratory data, we cannot further comment on the identity of the causative pathogens of these conditions. However, the NHI Bureau of Taiwan randomly samples a fixed percentage of claims from every hospital, randomly interviews patients, and reviews charts annually to verify the validity of diagnoses and quality of care. Clinical laboratory evidence is required by the NHI Bureau of Taiwan, the sole health insurance payer in Taiwan, in order to prescribe antiinfluenza agents. Therefore, the
diagnoses of influenza can be considered accurate.
Our study results revealed that influenza vaccination significantly reduces influenza-related total hospitalization and mortality in patients with chronic HBV infection, In consideration of the increased risk of influenza in HBV carriers, all patients with chronic HBV infection should be considered as an appropriate target group for annual influenza vaccination.
Contributors
FHS and YLH designed, analyzed, and interpreted the data and drafted the manuscript. FCS, CTS, WHH, and SNC performed statistical analyses and interpreted the data. CCY conceived the study, participated in study design, analysis, and interpretation, and critically revised the manuscript. All authors read and approved the final manuscript.
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Declaration of interests
The authors have no competing interests to declare.
Acknowledgements
This work was funded by Taipei Medical University Hospital (101TMU-TMUH-13) and Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence
(MOHW103-TDU-B-212-113002). 327 328 329 330 331 332 333
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Table 1
Demographic characteristics of patients stratified according to the status of chronic hepatitis B virus infection and influenza vaccination from 2000 to 2009.
HBV(‒) HBV(+) Vaccine(‒) Vaccine(+ ) Vaccine(‒ ) Vaccine(+) P value n = 8868 n = 8868 n = 3646 n = 4434 Age, years <0.00 1 20‒39 17 30 (19. 5) 17 30 (19. 5) 86 5 (23. 7) 865 (19 .5) 40‒59 32 46 (36. 6) 32 46 (36. 6) 16 23 (44. 5) 162 3 (36 .6) ≥60 38 92 (43. 9) 38 92 (43. 9) 11 58 (31. 8) 194 6 (43 .9) Sex 0.147 Women 39 06 (44. 1) 39 06 (44. 1) 15 31 (42. 0) 195 3 (44 .1) Men 49 62 (56. 0) 49 62 (56. 0) 21 15 (58. 0) 248 1 (56 .0) Pneumococcal vaccine <0.00 1 No 88 58 (99. 9) 83 83 (94. 5) 36 42 (99. 9) 427 3 (96 .4) Yes 18 (0.2) 53 2 (6.0 ) 4 (0.1 ) 161 (3. 6) Comorbidity Diabetes mellitus 12 17 (13. 7) 18 40 (20. 8) 68 9 (18. 9) 114 9 (25 .9) <0.00 1 CAD 13 58 (15. 3) 20 81 (23. 5) 58 1 (15. 9) 117 9 (26 .6) <0.00 1 CHF 37 8 (4.3) 56 7 (6.4 ) 12 8 (3.5 ) 297 (6. 7) <0.00 1 Hypertension 27 38 (30. 9) 37 50 (42. 3) 11 15 (30. 6) 191 9 (43 .3) <0.00 1 Hyperlipidemia 17 89 (20. 2) 24 70 (27. 9) 95 2 (26. 1) 175 7 (39 .6) <0.00 1 Atrial fibrillation 91 (1.0) 14 (1.6 34 (0.9 71 (1. <0.00 400 401 402
5 ) ) 6) 1 COPD 24 40 (27. 5) 36 93 (41. 6) 12 02 (33. 0) 204 7 (46 .2) <0.00 1 Renal disease 71 9 (8.1) 10 85 (12. 2) 42 6 (11. 7) 734 (16 .6) <0.00 1 Cancer 23 6 (2.7) 26 7 (3.0 ) 18 1 (5.0 ) 257 (5. 8) <0.00 1 Stroke 94 4 (10. 7) 14 26 (16. 1) 34 4 (9.4 ) 651 (14 .7) <0.00 1 Dementia 14 2 (1.6) 20 8 (2.4 ) 33 (0.9 ) 74 (1. 7) <0.00 1 Cirrhosis of the liver 83 (0.9) 10
2 (1.2 ) 40 6 (11. 1) 404 (9. 1) <0.00 1 Hospitalization during the
preceding year 81 7 (9.2) 11 90 (13. 4) 56 0 (15. 4) 665 (15 .0) <0.00 1 CAD: coronary artery disease; CHF: congestive heart failure; COPD: chronic obstructive
pulmonary disease; HBV (-): participants without chronic hepatitis B virus infection; HBV (+): participants with chronic hepatitis B virus infection; Vaccine (-): participants didn’t receive annual seasonal influenza vaccine; Vaccine (+): participants received annual seasonal influenza
vaccine. 403 404 405 406 407 408
Table 2
Risk of hospitalization and various medical outcomes occurring between 2000 and 2009 among influenza-vaccinated and non-vaccinated HBV-infected patients.
Vaccine(‒) Vaccine(+) Crude HR Adjusted HR
Outcome Even PY Ratea Even PY Ratea IRR (95% CI) (95% CI)b
Total hospitalization 748 3114 24.02 661 4057 16.29 0.68 0.68 (0.62-0.76)* 0.56 (0.50-0.62)*
Pneumonia/influenza 329 3321 9.91 370 4198 8.81 0.89 0.89 (0.77-1.04) 0.79 (0.67-0.92)*
Hospitalization for septicemia, bacteremia, or viremiac 94 3430 2.74 47 4381 1.07 0.39 0.39 (0.28-0.56)* 0.31 (0.22-0.45)* Hospitalization for heart disease 11 3435 0.32 5 4397 0.11 0.36 0.35 (0.12-1.02) 0.22 (0.08-0.66)*
Respiratory failure 66 3440 1.92 27 4392 0.61 0.32 0.32 (0.21-0.51)* 0.27 (0.17-0.43)*
Intensive care unit 161 3392 4.75 91 4363 2.09 0.44 0.44 (0.34-0.57)* 0.33 (0.25-0.43)*
Mortality 297 3434 8.65 83 4397 1.89 0.22 0.22 (0.17-0.28)* 0.19 (0.15-0.24)*
a Rate, incidence rate, per 100 person-years.
b Adjusted for age, sex, pneumococcal vaccine, diabetes mellitus, CAD, CHF, hypertension, hyperlipidemia, atrial fibrillation, COPD, renal disease, cancer, stroke, dementia, cirrhosis of the liver, and hospitalization during the preceding year.
c Unspecified septicemia, bacteremia, or viremia secondary to influenza infection. * P < 0.05
Even: numbers of events; HR: hazard ratio; IRR: incidence rate ratio; PY: person-years; Vaccine (-): participants didn’t receive annual seasonal influenza vaccine; Vaccine (+): participants received annual seasonal influenza vaccine.
409 410 411 412 413 414 415 416 417 418 419
Table 3
Risk of hospitalization and various medical outcomes occurring between 2000 and 2009 among HBV-positive and HBV-negative patients who received their annual influenza vaccination.
HBV(‒) HBV(+) Crude HR Adjusted HR
Outcome Even PY Ratea Even PY Ratea IRR (95% CI) (95% CI)b
Total hospitalization 1241 8020 15.47 661 4057 16.29 1.05 1.06 (0.96-1.16) 0.94 (0.85-1.04) Pneumonia/influenza 850 8269 10.28 370 4198 8.81 0.86 0.86 (0.76-0.97)* 0.87 (0.77-0.99)* Hospitalization for septicemia, bacteremia, or viremiac 79 8627 0.92 47 4381 1.07 1.16 1.17 (0.82-1.68) 1.03 (0.69-1.54) Hospitalization for heart disease 25 8630 0.29 5 4397 0.11 0.38 0.39 (0.15-1.02) 0.47 (0.17-1.28)
Respiratory failure 101 8616 1.17 27 4392 0.61 0.52 0.53 (0.34-0.80)* 0.57 (0.36-0.89)*
Intensive care unit 224 8562 2.62 91 4363 2.09 0.80 0.80 (0.62-1.02) 0.69 (0.53-0.90)*
Mortality 218 8637 2.52 83 4397 1.89 0.75 0.75 (0.58-0.96)* 0.59 (0.45-0.78)*
a Rate, incidence rate, per 100 person-years.
b Adjusted for age, sex, pneumococcal vaccine, and comorbidities (significant in Table 1). c Unspecified septicemia, bacteremia, or viremia secondary to influenza infection.
* P < 0.05.
Even: numbers of events; HR: hazard ratio; IRR: incidence rate ratio; PY: person-years; HBV (-): participants without chronic hepatitis B virus infection; HBV (+): participants with chronic hepatitis B virus infection.
420 421 422 423 424 425 426 427 428 429
Table 4
Risk of hospitalization and various medical outcomes occurring between 2000 and 2009 among influenza-vaccinated and non-vaccinated HBV-negative patients.
Vaccine(‒) Vaccine(+) Crude HR Adjusted HR
Outcome Eve n PY Rate a Ev en PY Rat ea IR R (95% CI) (95% CI)b Total hospitalization 922 83 47 11.0 5 124 1 802 0 15. 47 1.4 0 1.40 (1.28-1.52)* 1.13 (1.04-1.24)* Pneumonia/influenza 621 84 44 7.35 850 826 9 10. 28 1.4 0 1.39 (0.26-1.55)* 1.17 (1.05-1.30)* Hospitalization for septicemia, bacteremia, or
viremiac 85 87 28 0.97 79 862 7 0.9 2 0.9 5 0.94 (0.69-1.28) 0.77 (0.56-1.06)
Hospitalization for heart disease 19 87
38 0.22 25 863 0 0.2 9 1.3 2 1.33 (0.73-2.42) 0.88 (0.46-1.65) Respiratory failure 87 87 30 1.00 101 861 6 1.1 7 1.1 7 1.17 (0.88-1.56) 0.90 (0.67-1.21)
Intensive care unit 187 86
88 2.15 224 856 2 2.6 2 1.2 2 1.21 (1.00-1.48)* 0.93 (0.76-1.13) Mortality 238 87 42 2.72 218 863 7 2.5 2 0.9 3 0.93 (0.77-1.12) 0.84 (0.70-1.02) a Rate, incidence rate, per 100 person-years.
b Adjusted for age, sex, pneumococcal vaccine, and comorbidities (significant in Table 1). C Unspecified septicemia, bacteremia, or viremia secondary to influenza infection.
* P < 0.05. 430 431 432 433 434 435 436
Even: numbers of events; HR: hazard ratio; IRR: incidence rate ratio; PY: person-years; Vaccine (-): participants didn’t receive annual seasonal influenza vaccine; Vaccine (+): participants received annual seasonal influenza vaccine.
437 438 439
Figure Legends
Figure 1. Selection of the study sample.
Figure 2. Probability free of total hospitalization (A), pneumonia or influenza (B),
hospitalization for septicemia, bacteremia, or viremia (C), hospitalization for heart disease (D), respiratory failure (E), intensive care unit admission (F), and mortality (G) for patients with chronic hepatitis B infection with (black line) or without (gray line) influenza vaccination.
440 441 442 443 444 445 446 447 448 449
