Pneumococcal and Influenza Vaccination Coverage in Patients with Heart Failure: A Systematic Review

Background/Objectives: As heart failure (HF) patients face increased vulnerability to respiratory infections, optimizing pneumococcal and influenza vaccination coverage becomes pivotal for mitigating additional health risks and reducing hospitalizations, morbidity, and mortality rates within this population. In this specific subpopulation of patients, vaccination coverage for pneumococcal and influenza holds heightened significance compared to other vaccines due to their susceptibility to respiratory infections, which can exacerbate existing cardiovascular conditions and lead to severe complications or even death. However, despite the recognized benefits, vaccination coverage among HF patients remains below expectations. The aim of the present systematic review was to assess the vaccination coverage for influenza and pneumococcus in HF patients from 2005 to 2023 and the vaccination’s effects on survival and hospitalizations. Methods: The authors developed the protocol of the review in accordance with the PRISMA guidelines, and the search was performed in databases including PubMed and Scopus. After the initial search, 851 studies were found in PubMed Library and 1961 in Scopus (total of 2812 studies). Results: After the initial evaluation, 23 publications were finally included in the analysis. The total study population consisted of 6,093,497 participants. Regarding the influenza vaccine, vaccination coverage ranged from low rates of 2.5% to very high rates of 97%, while the respective pneumococcal vaccination coverage ranged from 20% to 84.6%. Most studies demonstrated a beneficial effect of vaccination on survival and hospitalizations. Conclusions: The present systematic review study showed a wide variety of vaccination coverage among patients with heart failure.


Introduction
Heart failure (HF) affects more than 6.5 million individuals in the United States, and this number is expected to increase significantly by 2030 [1,2].HF is the major cause of hospitalization in the elderly and has a significant economic impact on patients, their families, and healthcare systems worldwide [3].HF is a clinical syndrome frequently characterized by acute exacerbations and onset of symptoms, and vaccination against influenza and pneumococcus in these patients could be offered as a cost-effective intervention to improve quality of life and reduce hospitalizations [4].The benefits of influenza vaccination coverage as a measure of secondary prevention in ischemic heart disease have been already reported in previous studies [5].However, evidence for influenza and pneumococcal vaccination coverage, specifically in HF patients, still remains limited.
Influenza infection is a major trigger of cardiac decompensation in patients with HF [6].Knowledge regarding the impact of influenza vaccination on cardiovascular mortality in these patients is still under investigation.Influenza vaccination is recommended by most National Immunizations Programs and cardiac societies for patients with HF [5,7,8].People over the age of 65 are at increased risk of getting ill and developing more severe symptoms of pneumococcal disease or influenza, including several complications [9,10].While studies have shown the benefit of these vaccines in the general public [11,12], research is still ongoing on their usefulness in HF patients.The primary indicator of successful vaccination programs is high vaccination coverage rates among frail patients.The World Health Organization suggests routine annual influenza vaccinations for everyone aged 6 months and older who do not have contraindications to vaccination, and especially for population subgroups who are the most vulnerable to developing serious complications from airborne transmitted infections, including the elderly, people with chronic health problems, pregnant women, and young children.
In HF patients, vaccination coverage for pneumococcal and influenza holds heightened significance compared to other vaccines due to their susceptibility to respiratory infections, which can exacerbate existing cardiovascular conditions and lead to severe complications or even death [9,10].Pneumococcal and influenza vaccines specifically target pathogens known to cause respiratory illnesses prevalent in this population, thereby reducing the risk of pneumonia, exacerbations of heart failure, and cardiovascular events [4,5].Ensuring high vaccination rates for these diseases not only safeguards individual health but also helps alleviate the strain on healthcare systems by minimizing hospitalizations and associated costs [11,12].Thus, prioritizing pneumococcal and influenza vaccination in heart failure patients constitutes a critical preventive measure for preserving both cardiac and overall well-being.However, despite the current recommendations, vaccination coverage for pneumococcal and influenza in patients with HF still remains limited.
The aim of this systematic review was to investigate the existing knowledge regarding influenza and pneumococcal vaccination coverage in patients with HF within the last 18 years and analyze the effect of vaccination on HF outcomes including survival and hospitalization rates.

Search Strategy
The initial search was conducted on the PubMed and Scopus databases by 2 independent reviewers, and included published studies from 2005 to 2023 on influenza and pneumococcal vaccination coverage in patients with HF.This systematic review was conducted in accordance with the proposed reporting items for systematic reviews and meta-analyses (PRISMA) search checklist [13].We also used the PICOS criteria for the eligibility of articles (Table 1).Search terms that were used included the words "vaccination in heart failure patients", "vaccination coverage in heart failure patients", or "heart failure and vaccination".The total process of articles' exclusion included three rounds.The first exclusion round was performed by reviewing the title, the second exclusion round by reading the abstract, and the third was based on a reading of the full paper.

Selection Criteria
Seroprevalence studies, experimental studies, descriptive studies, observational studies, or studies that included the health benefits of adult influenza and pneumococcal vaccination in patients with HF were included in our review.We excluded case reports or articles that did not include humans, articles where the intervention was only mentioned in the authors' recommendations, and articles where the impact of the intervention was not sufficiently described.

Data Extraction
For this evaluation, a specific data extraction form was created.To evaluate the caliber and consistency of data gathering, two reviewers (D.P. and A.X.) independently piloted the extraction procedure.Data regarding vaccination coverage, population characteristics, HF patients, interventions, vaccine type, outcome definition, and vaccination status were extracted.

Results
The study's flow chart is demonstrated in Figure 1.In the present systematic review, after the initial screening and the final evaluation of the full texts, we finally included 23 studies.The clinical characteristics of HF patients are demonstrated in Table 2.The results showed variety in the percentages of the vaccination coverage (Table 3).Our results revealed that influenza vaccination coverage ranged from low rates of 2.5% to very high rates of 97% while pneumococcal vaccination coverage ranged from 20% to 84.6% (Figure 2).The coverage of both vaccines was much lower than expected in this special group of HF patients.
The studies' populations ranged from a small number of 61 participants to 5,102,568 participants and the majority of the studies were performed in Europe.Specifically, ten studies were performed in European countries, five studies in the US, and two in Israel, while the rest were from Brazil, Korea, Turkey, and India.
studies were performed in European countries, five studies in the US, and two in Israel, while the rest were from Brazil, Korea, Turkey, and India.

Discussion
There are sparse data regarding flu and pneumococcal vaccination rates in patients with HF globally.In the present systematic review, we demonstrated the low rates of vaccination coverage in patients with HF, derived from 23 studies, within the time period from 2005 to 2023.The goal of high vaccination coverage for influenza and pneumococcus

Discussion
There are sparse data regarding flu and pneumococcal vaccination rates in patients with HF globally.In the present systematic review, we demonstrated the low rates of vaccination coverage in patients with HF, derived from 23 studies, within the time period from 2005 to 2023.The goal of high vaccination coverage for influenza and pneumococcus is to increase overall life expectancy in frail patients and to reduce morbidity, mortality, and hospitalizations.
Recent sub-analyses of big clinical trials report a high incidence of pneumococcal infections in patients with HF, with the incidence rates reaching up to 39 per 1000 patientyears [37].Moreover, respiratory infections including pneumonia are associated with higher in-hospital mortality (odds ratio, 1.60) [38] and increased rates of acute HF hospitalizations up to 24% [39].Except for mortality and hospitalizations, patients with HF who are infected by influenza or pneumococcus frequently present with worse clinical symptoms.In a large retrospective study in the US that included 8,189,119 hospitalized HF patients, it was shown that they were at higher risk for worse outcomes such as acute respiratory failure and acute kidney injury [40].
The beneficial effects of influenza and pneumococcal vaccination on the severity of HF and clinical outcomes in patients with HF have been shown in recent studies [20].The PARADIGM-HF trial showed that patients with HF who were vaccinated against influenza had a significant decrease in the relative risk of all-cause mortality (HR, 0.81; 95% CI, 0.67 to 0.97; p = 0.015) [17].In a meta-analysis by Udell et al. [41], influenza-vaccinated patients had a lower risk for a composite of major cardiovascular events compared to the unvaccinated patients (2.9% vs. 4.7%; relative risk 0.64, 95% CI, 0.48-0.86,p = 0.003), with the effect of vaccination being greater in patients with higher-risk coronary disease.In another randomized double-blind placebo-controlled trial, influenza vaccination administered shortly after myocardial infarction reduced the rate of the composite primary endpoint (all-cause death, myocardial infarction, or stent thrombosis) (HR 0.72, 95% CI 0.52-0.99,p = 0.040), the rates of all-cause death (HR 0.59, 95% CI 0.39-0.89,p = 0.010), and the rates of cardiovascular death (HR 0.59, 95% CI 0.39-0.90,p = 0.014) at 12 months compared to the placebo group [42].Another finding observed in our review was that vaccination against influenza before hospital admission was associated with a significant decrease in risk of all-cause mortality and cardiovascular hospitalizations in patients hospitalized with acute HF.In general, 10 out of the 23 studies [14][15][16][17][18][19][20][21][22][23] in our systematic review investigated the effects of vaccination on HF outcomes, including survival, mortality, and hospitalization rates.Influenza vaccination coverage was associated with lower 1-year, 4-year, and allcause mortality rates [14,17,18,21,22] and reduced rates of hospitalizations due to HF symptoms [15,19,23].Only a single study showed no association between vaccination and differences in clinical outcomes [20].Unfortunately, there were no studies assessing the effect of pneumococcal vaccination on HF outcomes.On the contrary, there was a single study where patients who had been vaccinated presented with higher rates of ICU admission and the need for positive pressure ventilation [16].The reason may be the fact that the sample size consisted of hospitalized elderly patients with multiple comorbidities of high severity including COPD, congestive HF, and cancer who had poor prognoses.
On the other hand, pneumococcal disease is associated with significant morbidity and mortality in both developing and developed countries, resulting in 1.6 million deaths annually.By 2040, the burden of pneumococcal disease among the elderly is expected to be double [43].Pneumococcal vaccination in HF is also quite significant, as shown by clinical trials.Specifically, a recent meta-analysis that included 18 studies with 716,108 participants demonstrated the protective effect of 23-valent polysaccharide pneumococcal vaccination (PPV23) in patients with cardiovascular events by reducing the rates of cardiovascular events (RR 0.91; 95% CI 0.84-0.99)and myocardial infarction (RR 0.88; 95% CI 0.79-0.98),as well as the risk of all-cause mortality, in all age groups (RR 0.78; 95% CI 0.68-0.88)[44].This effect seemed to be higher in patients aged ≥65 years.Finally, Jaiswal et al. showed that pneumococcal vaccination was associated with a decrease in the incidence of myocardial infarction (HR, 0.73 (95% CI: 0.56−0.96),p = 0.02), without significant reduction in CV mortality (HR, 0.87 (95% CI: 0.72−1.07),p = 0.18) and stroke (HR, 1.01 (95% CI: 0.93−1.10),p = 0.82) [45].Pneumococcal vaccination is associated with a decreased risk of all-cause mortality in patients at very high cardiovascular risk [46].The CDC and ECDC recommend immunization with polysaccharide and conjugate vaccines against pneumococcal infection for older adults, individuals at risk, and high-risk patients with HF [47][48][49].The protective efficacy of polysaccharide vaccines has been consistently shown in the literature [50][51][52].Systematic reviews and meta-analyses support the effectiveness of conjugate vaccines against pneumococcal disease in adults [53,54].
Another virus infection, the COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has significantly affected public health on a global scale.COVID-19 has been associated with the development of HF via myocardial infarction, myocarditis, microthrombi, and stress cardiomyopathy [55].HF is a common condition among patients with COVID-19, estimated at between 4.9% and 13% of hospitalized patients with COVID-19, leading to poor prognoses [56,57].Johnson et al. performed a study during the pandemic in order to assess the benefits of vaccination against COVID-19 in patients with HF [58].Immunization against COVID-19 was shown to decrease all-cause hospitalizations and death rates in high-risk patients with HF [58].
Clinical applications of the immunization protocols are not limited to the population with HF.The improvement of general health practices and cardiovascular outpatient programs could significantly increase immunization rates among patients with comorbidities.National vaccination programs for the elderly and other special populations are intricate, with socioeconomic and income differences.There are opportunities to expand and improve national immunization programs.The recent COVID-19 pandemic demonstrated the importance of technology and telemedicine, such as vaccine registration systems, in order to support public immunization programs [59].To ensure that HF patients receive the best possible immunization coverage, public health authorities should concentrate their efforts on yearly vaccination campaigns.
Health campaigns need to focus on appropriate planning, easy implementation, and continuous evaluation, which are crucial factors for their success [60].Despite there being significant knowledge about the benefits of vaccinations [61], there are also differences in vaccination programs for adults around the world [62].In the present review, we presented the results of vaccination coverage in HF patients, including rates; however, the rates remain lower than suggested.Influenza vaccination coverage is frequently lower than the World Health Organization (WHO) and European Union (EU) target of 75% of older adults [63].The percentage of pneumococcal vaccination varies in older adults.National guidelines and immunization programs differ, recommending either the polysaccharide vaccine or the conjugate vaccine, or even both.Streptococcus pneumonia remains a major cause of morbidity and mortality in high-risk groups and elderly people, and as a result, recommendations focus on routine vaccination against pneumococcal diseases in these individuals [64].The global target for vaccination coverage against pneumococcus seems to be far from the proposed target of 60% for high-risk adults aged <65 years and 90% for elderly people [31,65].The present review highlighted the difficulties in comparing pneumococcal vaccination coverages in distinct areas due to the different characteristics of national healthcare systems and vaccination programs.We also reported low percentages of immunization against influenza and pneumococcus during the COVID-19 pandemic, as well as major geographic differences in vaccination rates among them.Most likely, the pandemic played a crucial role in the reduction of routine vaccination coverage.It would be quite interesting to perform a sub-analysis of the vaccination coverage rates before and after the COVID-19 period in order to assess its impact on vaccination, as the present review was also a meta-analysis.Comparing vaccination rates in the same countries before and after the pandemic, we observed that in most places, such as the USA, Israel, France, and Denmark, the vaccination rates increased during and after the pandemic, while in other countries such as Spain and Belgium, the rates decreased.However, the sample sizes in the same country are quite different before and after the pandemic, and thus, we cannot extract safe conclusions.
Finally, another finding of the systematic review was that immigrants were less likely to be vaccinated compared to native-born people.Refugees and immigrant groups presented with low immunization rates, putting them at higher risk for infectious diseases which could be prevented by vaccination [66].The fact that the study sample may include high percentages of immigrants and refugees could explain the reason why some studies in our systematic review presented very low vaccination coverage rates amongst HF patients.Furthermore, in developing countries in Africa and Asia, as well as countries with a very large population and low socioeconomic status, people with cardiovascular diseases do not have the opportunity to vaccinate against pneumococcal and influenza, especially when there is not a 100% compensation rate for vaccines and the economic status of the country remains low.As a result, an inadequate vaccine supply is being observed.In these countries, there is a lack of awareness, as educational campaigns about the beneficial effects of vaccination are quite limited.Challenges related to vaccine accessibility, such as geographic barriers, limited healthcare professionals, or transportation issues, may also hinder HF patients' ability to receive vaccination coverage.Finally, the national health policy of each country may be another significant factor for differences in vaccination coverage among countries.Even within the same country, the extensive time range could affect vaccination, as it may have changed several times from 2005 until 2023.

Limitations and Future Directions
The present review has several limitations.Most of the studies were considered as being at a high risk of bias, mainly due to the lack of control for the confounders.Specifically, information bias in observational studies, particularly in those with questionnaires about vaccination coverage, should be taken into consideration.Moreover, due to the heterogeneity of the studies, were could not generalize and compare the results from different studies, nor perform a meta-analysis.Another significant limitation is the fact that the extensive time range brings a bias in interpreting the results.Specifically, within the same country, the national health policy regarding vaccination may have changed several times within this 18-year time period.In addition, the economic level of each country may be an important factor for vaccination coverage, as several countries have a 100% compensation rate for vaccines while others have a price for them, and as a result, many HF patients cannot afford them.Finally, protection from pneumococcal and influenza vaccination in the COVID-19 era may include bias, as a great number of HF patients vaccinated for pneumococcal and influenza infection could have presented with an episode of decompensated HF due to COVID-19 infection.
Future directions of pneumococcal and influenza vaccination coverage in patients with cardiovascular diseases, and especially HF, should involve the implementation of targeted campaigns in order to raise awareness among both patients and healthcare providers about the importance of vaccination in managing HF and reducing complications, as well as collaboration between primary care, public health sectors, and the hospital setting which may be pivotal in establishing comprehensive vaccination programs tailored to the unique needs of HF patients.Finally, ongoing research into vaccine effectiveness and the development of novel delivery methods could offer promising avenues for optimizing protection and reducing disease burden in this population.

Conclusions
Patients with heart failure are vulnerable to virus infections and vaccination against influenza and pneumococcus is necessary to reduce mortality and morbidity.High vaccination coverage in patients with comorbidities is the only way to achieve the desired results.Our systematic review demonstrated a variety of influenza and pneumococcal vaccination coverage rates among patients with HF.In national health systems, further effort is necessary in order to develop effective immunization programs and increase vaccination coverage in these patients.

Figure 1 .
Figure 1.Flowchart of the study screening process in our systematic review.

Figure 1 .
Figure 1.Flowchart of the study screening process in our systematic review.

Figure 2 .
Figure 2. Vaccination coverage rates for pneumococcal and influenza in HF patients in the included studies [14-36].

Figure 2 .
Figure 2.Vaccination coverage rates for pneumococcal and influenza in HF patients in the included studies].

Table 1 .
PICOS criteria for eligibility of articles.
Seroprevalence studies, experimental, descriptive, observational, or studies that included health benefits of adult influenza and pneumococcal vaccination in patients with heart failure.
V, vaccinated; NV, not vaccinated; LVEF, left ventricular ejection fraction; EIV, eligible for influenza vaccination; EPV, eligible for pneumococcal vaccination; HFrEF, heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; NS, not specified.Categorial variables are expressed as absolute numbers (population) or percentages.* Continuous variables are expressed either as mean ± SD or median (25th-75th percentiles).

Table 3 .
Influenza and pneumococcal vaccination coverage among studies from 2005 to 2023, and effects on outcomes in HF patients.