Effect of influenza vaccination on the outcomes of hospitalization for kidney disease in a geriatric population: A propensity-score matched study

Background and aims The effects of influenza vaccination (IV) on the outcomes of patients with kidney disease (KD) are not completely understood. We aimed to evaluate and compare the outcomes during admission of KD between elderly patients who did or did not receive an IV within the previous 12 months. Methods We used health insurance research data in Taiwan and conducted a population-based cohort study that included 22,590 older people aged ≥ 65 years who were hospitalized for KD in 2008–2013. We performed propensity score matching (case-control ratio 1:1) to select 4386 eligible IV recipients and 4386 nonrecipient controls for comparison. The adjusted odds ratios (ORs) with 95% confidence intervals (CIs) of IV associated with complications and mortality during KD admission were calculated using multivariable logistic regression analyses. Results During hospitalization for KD, IV was significantly associated with lower risks of 30-day in-hospital mortality (OR 0.56, 95% CI 0.39–0.82), septicemia (OR 0.77, 95% CI 0.68–0.87), and intensive care (OR 0.85, 95% CI 0.75–0.96). Additionally, IV recipients had a shorter length of hospital stay and lower medical expenditure than nonrecipients. Subgroup analyses further showed that the association of IV with reduced adverse events was confined to patients aged ≥ 75 years. Conclusions Previous IV was associated with reduced risks of complications and mortality and in elderly patients hospitalized for KD. We raised the possibility and suggested the need to promote IV for this susceptible population of patients with KD.


Introduction
Kidney disease (KD) is a leading cause of premature mortality and disability, affecting approximately 700 million people and leading to 1.2 million deaths annually worldwide [1,2]. Patients with KD are susceptible to infection and related complications due to their compromised immune function and exaggerated inflammatory response to pathogens [3,4]. A graded association between a reduced glomerular filtration rate and mortality risk has been observed in patients with chronic renal insufficiency [5]. Among people with KD, older patients are at a higher risk of mortality than younger patients [6]. However, few therapeutic strategies have been proven shown to be effective in improving clinical outcomes for patients with KD [7,8].
Influenza is a common respiratory infection and is considered an important burden on health and society worldwide [9]. It has a substantial impact on the general population and may cause serious complications, particularly in the elderly and patients with chronic diseases [10,11]. Influenza causes higher rates of mortality and morbidity in patients with KD than in individuals without KD [11,12].
Influenza vaccination (IV) has been shown to be effective in reducing hospitalizations for influenza, pneumonia, cardiovascular events, and all-cause mortality among the elderly population [13][14][15][16] or patients with stroke [17] and pulmonary diseases [18,19]. Several studies have investigated the beneficial effects of IV on reducing infection and other complications in patients with KD [20][21][22][23][24]. However, the relationship between IV and outcomes of KD has not yet been completely clarified due to some limitations of previous studies, including the inconsistent definition of old age [22,23], inadequate control for confounding factors [22,23], the lack of a comprehensive evaluation of critical outcomes [22,23], and a focus on specific kidney diseases [20,21,24]. In addition, most previous studies evaluated the long-term outcomes (one year after vaccination) of patients with KD [20][21][22][23][24]. Therefore, researchers have not clearly determined whether IV is associated with short-term mortality and morbidity during hospitalization for KD. Accordingly, we conducted a population-based cohort study to evaluate the association of IV with subsequent mortality and morbidity among elderly people hospitalized for KD.

Data source
In this study, we analyzed the research database of health insurance in Taiwan. Insurance programs have been implemented since 1995 and cover more than 99% of the Taiwanese population. The available information of this research database includes age, sex, birth date, diagnoses, examinations, prescriptions, treatments, and medical expenditures for outpatient and inpatient medical services. The reliability of this database has been well accepted by important international scientific journals [14,[17][18][19][21][22][23][24]. Information on beneficiaries was scrambled to protect personal privacy and all data were fully anonymized before we accessed them. Our research team accessed the research database to obtain the retrospective data used in this study in December 5, 2017. This study was approved by the institutional review board of Taipei Medical University that also waived the need for informed consent of this study (TMU-JIRB-201509050; TMU-JIRB-201505055; TMU-JIRB-2022).

Study design
In a nested retrospective cohort study, we initially included 22,590 patients aged more than 65 years who were hospitalized for KD during 2008-2013. We selected 5,200 patients who had received IV within 12 months before the index KD admission. Each patient with KD who received IV was matched with an unvaccinated patient with KD using the propensity score matching procedure to balance sociodemographic characteristics (age, sex, and low income), types of kidney disease, and coexisting medical conditions. The selection process of study participants was shown in Fig 1. In this study, the inclusion criteria of KD patients are based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes (included 580-588, 590, and 591) and physicians' primary diagnosis of hospitalization.

Measures and definitions
In this study, we defined the short-term outcomes as identifying complications and mortality during the index hospitalization. The low-income status of patients was defined as qualifying . We also considered admission to the intensive care unit, the length of the hospital stay, and medical expenditures during KD admission as study outcomes. We compared the outcomes between patients with or without prior IV.

Statistical analysis
The frequency matching and propensity-score matching were used to conduct the current matching procedure. We performed the propensity score matching analysis to balance the distribution of baseline demographic and clinical characteristics between patients with and without IV. A nonparsimonious multivariable logistic regression model was used to estimate a propensity score for patients with KD who received IV. Based on previous related studies [14,17], the covariates included in this model were chosen based on clinical significance, including age, sex, low income, type of KD, hypertension, mental disorders, diabetes, chronic obstructive pulmonary disease, ischemic heart disease, heart failure, hyperlipidemia, liver cirrhosis, Parkinson's disease, and renal dialysis. We matched patients with KD who received IV to non-IV patients using a greedy matching algorithm (without replacement) with a caliper width of 0.2 SD of the log odds of the estimated propensity score. We used Statistical Analysis System software version 9.1 (SAS Institute Inc, Cary, NC) to perform data analyses. We used frequencies (percentages) and chi-square tests to analyze and compare baseline categorical variables between patients with KD with and without IV. We analyzed continuous variables using t tests and by calculating the means ± standard deviations. The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of IV associated with mortality and morbidity during KD admission were analyzed with multivariable logistic regression analyses. Additional analyses stratified by age, sex, and number of medical conditions were performed to examine KD outcomes in patients with and without IV within these strata.

Results
The unmatched baseline characteristics of patients with KD who did or did not receive IV are shown in Table 1 (N = 22,590). After matching (Table 2), no differences in the baseline characteristics were observed between patients with KD who did or did not receive without IV (N = 8772).

Discussion
As shown in the present study, elderly patients receiving IV within the previous 12 months had reduced risks of septicemia, intensive care, and mortality during hospitalizations for KD. A shorter length of hospital stay and lower medical expenditures were also noted in IV users compared to non-IV patients during KD admission. The beneficial effect of IV was especially significant in patients with KD aged � 75 years. To our knowledge, this study is the first to focus on the short-term outcomes during KD admission, which provides an important clinical implication in the context of kidney failure. Few studies have investigated the relationship between IV and KD outcomes [20][21][22][23][24]. Compared with previous studies [20][21][22][23][24], we included a variety of kidney diseases and performed a comprehensive evaluation of critical outcomes in patients with KD to increase the generalizability of our results. A prior IV was associated with lower risks of all-cause mortality, septicemia, and need for intensive care, consistent with previous studies [20][21][22][23][24]. Although the rates of pneumonia and stroke were lower in the vaccine cohort than in the control cohort, the association did not reach statistical significance, in contrast to some studies [13,16,17,21]. This discrepancy is possibly attributable to our relatively shorter follow-up period compared with previous studies [13,16,21]. IV prior to hospitalization reduces the risks of mortality and readmission among geriatric populations admitted with pneumonia [25,26]. Based on our results, the protective effect of IV may be generalizable to hospitalized patients with KD, irrespective of the types of kidney disease and different medical conditions. Notably, our stratified analyses showed that the association between IV and a reduced number of adverse events was stronger in the subgroup of age � 75 years, consistent with some other studies [22,23]. We proposed the following explanations for the observed phenomena in this study. First, patients with influenza virus infection are susceptible to a secondary bacterial infection, which contributes to serious complications, such as mortality and the need for intensive care [27]. IV may protect against secondary bacterial infections by preventing influenza infection and improving the in-hospital outcome during KD admission. Second, previous studies suggested that IV reduces the risk of hospitalizations for influenza, pneumonia, cardiovascular diseases, and all-cause mortality [13-19, 22, 23, 25, 26]. Influenza infection might exacerbate coexisting diseases, especially in fragile patients with KD. The health condition of vaccine recipients may have been better than nonrecipients and hence improved in-hospital outcomes of KD hospitalization. Third, hospitalized patients are susceptible to nosocomial influenza and pneumonia [16,28]. A prior IV might protect against possible nosocomial infections and thereby reduce overall mortality. Fourth, we found that IV was associated with fewer adverse events in patients aged � 75 years but not < 75 years. Based on this finding, older people are more vulnerable to influenza infection and associated complications than younger people [29]. Therefore, older patients might have benefitted more from IV than their younger counterparts in this study. Finally, patients receiving IV annually might have higher levels of health consciousness, Table 3. Adverse outcomes of kidney disease admissions for patients with and without influenza vaccination (after propensity-score matching). ambulatory independence, and support from family members and social networks than nonrecipients. Patients' knowledge, attitudes, and practice of health behaviors and socioeconomic factors may influence the outcomes of patients with KD [30,31].

No IV (N = 4,386) IV (N = 4,386) Risk of outcomes
Our results indicate an urgent need to promote IV for elderly patients with KD. However, the administration of vaccines to this vulnerable population is challenging. Antibody responses to IV, measured as seroconversion and seroprotection, decrease with increasing age [32]. The immunogenicity of the influenza vaccine is also attenuated in patients with kidney failure [33]. Current guidelines highly recommend the annual administration of seasonal inactivated influenza vaccines to adults with KD [34]. Among geriatric patients with KD, a high-dose trivalent influenza vaccine may be safe and immunogenic [35,36]. In addition, an MF59-adjuvanted influenza vaccine exhibited better immunogenicity in patients with end-stage renal disease in a previous study [37]. Regarding the optimal influenza vaccine schedules for patients with KD, sufficient scientific evidence from large-scale randomized trials is unavailable [35,38].
Our study has some limitations. First, distinct serotypes of seasonal influenza vaccines and vaccine adjuvants may activate different levels of immunogenic reactions [37,39]. Although the present study was unable to standardize types of vaccines, we used the stated serotypes of vaccines used each year. Second, our database did not contain information on host-related factors that may affect influenza vaccine responsiveness, such as preexisting immunity and genetic polymorphisms [40]. Third, baseline kidney function and the duration of KD for each subject was unknown due to data unavailability. Fourth, the cause of death was unclear, and a causal relationship between vaccination and a reduced mortality rate is difficult to infer. Fifth, we did not measure markers of inflammatory and immune responses and therefore were unable to elucidate the biological mechanism underlying the results of our statistical analyses. Finally, we admitted that residual confounding possibly existed in this study since we were unable to control all potential confounding factors in the current analysis.
In conclusion, prior receipt of IV was significantly associated with reduced mortality, septicemia, and need for intensive care in geriatric patients hospitalized for KD. Additionally, vaccine recipients had a shorter length of hospitalization and lower medical expenditures than nonrecipients. The protective effect of IV was especially significant in patients aged � 75 years. These results provide evidence to promote the delivery of influenza vaccines to patients with KD as a prophylactic measure to protect against adverse events.
Supporting information S1 Table. Adverse outcomes of kidney disease admissions for patients with and without influenza vaccination (before matching). (DOCX)