Accepted on 23 Jun 2021
Submitted on 23 Jun 2021
Cardiovascular (CV) mortality continues to be the main cause of death in developed countries as well as in emerging economies. Respiratory infections, particularly those caused by the influenza virus, contribute significantly to morbidity and mortality throughout the world, representing the third cause of mortality in several Latin American nations, particularly in low- to middle-income countries [1]. Analysis of the evidence based on systematic reviews and meta-analysis of epidemiological studies show a consistent association between respiratory infections and the incidence of acute myocardial infarction (AMI) and CV mortality [2, 3, 4, 5, 6, 7, 8, 9, 10, 11].
Numerous deaths and CV complications take place during flu epidemics, especially in vulnerable populations. Patients with chronic CV diseases are particularly at risk during this period and represent a population that could be targeted for vaccination, as one of the main objectives in public health today is to reduce the impact of CV disease in the general population. Current COVID-19 pandemic has reflected the strong link between respiratory infections and CV diseases, both as risk group and as trigger for new events, and that reinforced the purpose of this consensus.
In the last 15 years, influenza vaccination (IV) in high-risk populations has become an effective strategy to reduce the incidence of respiratory infections and therefore associated CV complications. However, the prescription of the IV is not common in routine cardiology practice, and vaccination rates vary widely among high-risk vulnerable populations in different regions of the world [12]. This reluctance of cardiologists to incorporate immunization as a routine CV prevention strategy for their patients has been observed in Latin American countries [13, 14].
The incomplete application of existing recommendations prompted us to perform an in-depth analysis of the literature regarding IV and CV events and the possible barriers to its implementation. Within this framework, the Inter-American Society of Cardiology (SIAC) and the World Heart Federation (WHF) decided to promote the development of a consensus on the role of influenza immunization as a cardiovascular prevention strategy.
The purpose of the document was to critically analyze the contemporary evidence that supports the use of the IV in adults in order to reduce the rate of CV events and its effect on the burden of the disease in our region, as well as to analyze the difficulties and barriers in its implementation. This was done based on the evidence available in the literature and the experience of the participants in clinical practice.
The consensus document was made using the modified RAND/UCLA methodology. This method is based on the available scientific evidence and the collective judgment and clinical experience of a panel of experts. It is a combination of the Delphi technique with that of nominal groups [15, 16].
A multidisciplinary team composed of experts in the management and prevention of CV disease from the Americas was convened by the IASC and participated in the process and the formulation of statements. A coordinating committee of two experts and one scientific secretary was gathered, along with a recommendation-formulating group that included the coordinating committee, fourteen more experts, and two consultants who provided the final review of the document. A content index and a list of seven relevant clinical questions were developed during the kickoff meeting (association between influenza and CV events, efficacy of IV in different risk groups, safety of the vaccination and different vaccination schemes, cost-effectiveness, implementation barriers, and proposals for increasing vaccination rates). A nonsystematic expert search of the available publications related to these clinically relevant questions was conducted in May/Jun 2020 in databases including MEDLINE via PubMed, CENTRAL (Cochrane), Scielo and LILACS. Priority was given to those that were relevant to the Americas or conducted in American countries. A total of 245 publications were retrieved. Question 5 required a systematic review of publications in four databases. To evaluate cost-effectiveness (CE) and the quality of the publications, the list of verifications of the international research society in pharmacoeconomics ISPOR 200 was used. The review was carried out from June to September 2020, on the databases MedLine (via Pubmed, n = 124) DARE, HTA, and EED (via CRD-York, n = 51). Finally, 45 CE studies of influenza vaccination remained for analysis. An extended version of this document, including the full methodology of the systematic review and the results of each article is freely available at IASC website, www.siacardio.com [17].
Statements were debated during a structured virtual meeting. A total of 38 statements and conclusions were included. Statements that achieved unanimity (100% agreement) or consensus (80% agreement) were accepted. Statements were formally categorized with their level of evidence and degree of recommendation according to AHA/ACC Guidelines (Table 1) [18].
Table 1
Class of Recommendation and Level of Evidence, ACC/AHA criteria [19].
| Class of Recommendation (CoR) | ||
|---|---|---|
| I | Strong | Benefit >>> Risk |
| IIa | Moderate | Benefit >> Risk |
| IIb | Weak | Benefit > Risk |
| III | No benefit or harm | Benefit = Risk, or Risk > Benefit |
| Level of Evidence (LoE) | ||
| A | High quality evidence of >1 RCT or meta-analysis of them | |
| B-R | Randomized | Moderate evidence from 1 RCT |
| B-NR | Non-Randomized | Moderate evidence from well-designed nonrandomized trial |
| C-LD | Limited Data | Randomized or nonrandomized clinical studies of limited quality. Meta-analysis of those studies. Mechanistic studies. |
| C-EO | Expert Opinion | Consensus of experts opinion based on clinical experience |
This document was supported by an unrestricted grant to the Inter-American Society of Cardiology provided by Sanofi Pasteur to the World Heart Federation. Funder had no role in the drafting, evidence review, meetings, or publication process.
A recent systematic review reported a consistent association between influenza and AMI, as well as weak evidence of an association with CV death, heart failure (HF), and stroke [19]. Likewise, influenza epidemics are associated with an increase in autopsy-confirmed coronary death [20]. Acute respiratory infections have been considered a trigger for AMI and CV mortality, attributable to a possible inflammatory and prothrombotic effect. Recent respiratory symptoms are associated with the development of AMI (OR 2.1, 95% CI, 1.4–3.2) [5]. Additionally, in patients with laboratory-confirmed influenza infection, the incidence rate of AMI and stroke was six and eight times higher, respectively, during the seven days after infection, compared with control intervals [21, 22]. Influenza as a trigger for CV events meets the Bradford Hill causality criteria (strength of association, biological gradient, temporality, consistency, seasonality, coherence, analogy, and biological plausibility) [23].
Influenza has also been found to be associated with arrhythmias and HF hospitalizations. In 11,374 patients with influenza, an 18% increase in atrial fibrillation (AF) was observed [24], as well as a 24% increase in hospitalization rates for HF (incidence rate, 1.24; 95% CI, 1.11–1.38; p < 0.001) [25]. In an analysis of more than 8 million HF hospitalizations, those with concomitant influenza infection had higher rates of mortality and respiratory and renal failure [26].
The association between influenza and venous thromboembolic events (VTE) is less clear, with the information in the literature showing conflicting results [27, 28, 29, 30, 31]. The current state of knowledge in this domain is additionally complicated by further conflicting results regarding the CV impact of influenza virus types and subtypes in VTE [32, 33, 34]. As pathophysiological hypothesis, cytopathic effects (invasion of endothelial cells), indirect effects mediated by the host’s immune response, virus invasion in atheromatous plaques, infiltration of inflammatory cells, and increased cytokines, with consequent activation of the coagulation cascade, have been described [35, 36, 37]. A recently developed model supports the association between inflammation and arterial thrombosis as a fundamental link in the relationship between influenza and CV mortality [38]. Increased quantity and quality of scientific evidence is required to support this association, since current knowledge is based mainly on retrospective cohorts. Results of prospective clinical trials under development are anticipated and will add substantially to the current body of knowledge [39].
The conclusions related to this issue are summarized in Table 2.
Table 2
Association between respiratory infections and cardiovascular events.
| Conclusions | CoR | LoE | |
|---|---|---|---|
| A | Influenza-like respiratory infections are associated with CV events during follow-up (AMI, stroke, hospitalizations for HF, AF, and CV death). | I | B-NR |
| B | The association between influenza and thromboembolic disease is controversial. | IIb | C-LD |
| C | There is not strong enough evidence to determine the incidence or mortality from CV disease for different types and subtypes of influenza viruses. | IIb | C-LD |
| D | There are proven pathophysiological mechanisms that explain the association of influenza with cardiovascular events. | IIb | C-LD |
Influenza vaccination may be an effective strategy to reduce CV events in patients with pre-existing CV disease. Randomized clinical trials (RCTs) have had dissimilar results regarding cardiovascular death and major cardiovascular events (MACE). However, results of two meta-analyses have shown that influenza vaccine reduced both CV death and MACE, compared to the control group, by approximately 50%.
In the systematic review by LeBras et al. [40], two meta-analyses including the same RCTs were compared [41, 42, 43, 44]. The meta-analysis by Udell et al. compared IV versus placebo or standard treatment in four studies in which 1655 patients had pre-existing CV disease [45]. The primary endpoint was extended MACE, defined as CV death or hospitalization for AMI, unstable angina, stroke, HF, or emergency coronary revascularization. In the subgroup analysis with pre-specified CV disease, IV significantly reduced both MACE (RR 0.57, 95% CI 0.41–0.79, I2 = 14%) and CV death (RR 0.50, 95% CI 0.27–0.95, I2 = 15%). In patients with recent acute coronary syndrome (≤1 year) (n = 815), IV significantly reduced MACE (RR 0.46, 95% CI 0.33–0.64, I2 = 0%) but not CV death (RR 0.44; 95% CI 0.17–1.15; I2 = 38%) or all-cause mortality. The findings are based on a relatively small number of CV events (246 MACE and 97 CV deaths) and arise from trials that varied in study design, expected primary outcomes, and patient populations. There was no difference in MACE or CV death in the subgroup of patients with stable coronary artery disease (n = 840).
A subsequent Cochrane Collaboration meta-analysis of eight RCTs included the same studies, but with a total of 1682 patients with established CV disease [46]. Similar to reported data in the Udell meta-analysis, CV death was significantly lower with IV (RR 0.44, 95% CI 0.26–0.76, I2 = 0%). However, there was no difference in CV death in the subgroup of patients with acute coronary syndrome (n = 350) (RR 0.46, 95% CI 0.04–5.20, I2 = 58%) or stable angina and elective coronary angioplasty (n = 602) (RR 0.35, 95% CI 0.07–1.73, I2 = 0%).
A recent meta-analysis of four RCTs and 12 observational studies demonstrated that IV was associated with a 25% and 18% RR reduction in all-cause mortality and CV mortality, respectively, in patients with previous CV disease. The reduction in mortality was probably driven in part by a 13% RR reduction in MACE [47].
Observational studies have suggested that IV could reduce events during follow-up in patients with HF [12, 48]. Mohseni et al. examined the association between IV and the risk of hospitalization in patients with HF, through a primary care database associated with the registry of hospitalizations in England during the years 1990–2013. In the 52,202 patients analyzed, IV was associated with a lower risk of CV hospitalization (HR = 0.73, 95% CI 0.71–0.76) and all cause hospitalization (HR = 0.90, 95% CI 0.95–0.98) [49]. The effect was somewhat greater in younger patients, without gender differences.
Modin et al., using data from the Danish national patient registry, analyzed the relationship between influenza vaccination and survival in patients with a recent diagnosis of HF, between the years 2003–2015. After adjusting the results for comorbidities, medication, income, and educational level, influenza vaccination was associated with an 18% reduction in total mortality (HR = 0.82, 95% CI 0.81–0.84, p < 0.001) and cardiovascular mortality (HR = 0.82, 95% CI 0.81–0.84, p < 0.001). Annual, timely, and sustained vaccination over the years was associated with a greater risk reduction of death when compared to intermittent vaccination [50].
Rodrigues et al. recently conducted a systematic review and meta-analysis of the HF clinical trials available to date. Six cohort studies with 179,158 patients were included in the analysis. IV was associated with a lower risk of all-cause mortality (HR = 0.83, 95% CI 0.76–0.91, I2 = 75%) and a significant reduction in HF hospitalizations (HR = 0.69, 95% CI 0.55–0.86). No significant effect was observed on CV mortality (HR = 0.92, 95% CI 0.73–1.15) and all-cause hospitalization (HR = 1.01, 95% CI 0.92–1.11). The level of certainty of the evidence was considered low due to the quality of the data obtained in the studies [51].
In conclusion, although there is proven evidence of the benefit of IV in the context of patients with pre-existing CV disease, given the limitations of the data due to the small sample size, low event rate, potential confounders and bias, results of prospective and randomized studies of greater power are required to allow definitive conclusions [39, 52].
Patients with hypertension (HTN), diabetes, and AF have an increased risk of complications associated with influenza. The mostly observational studies done to date have shown a protective effect of IV for these three populations, but due to the limitations of the studies, it is not possible to establish strong recommendations [53, 54, 55].
Although influenza is a universal disease and affects all age groups, 90% of deaths and 50% of hospitalizations are among people over 65 years of age. For this reason, historically vaccination recommendations had been directed at people above that age and those with risk factors (chronic diseases, immunosuppressed, etc.) [56].
The prospective cohort studies carried out by Nichol et al., in health organizations in the United States for patients older than 65 years deserve special mention. In the 1999–2000 epidemic season, the effectiveness of the vaccine was 29% in reducing hospitalizations for influenza-pneumonia, 27% in hospitalizations for HF, 23% in hospital admissions for CV disease, and 24% in all-cause hospitalizations. The reduction in deaths from all-cause mortality was 36%. In those without established CV disease, diabetes, or associated comorbidities (low-risk groups), influenza vaccination was also associated with a significant reduction in CV events at follow-up (CV, cerebrovascular, and all-cause mortality and hospitalizations) [57, 58, 59, 60].
The conclusions and recommendations related to this issue are summarized in Table 3.
Table 3
Clinical efficacy and/or effectiveness of influenza vaccines in cardiovascular events reduction.
| Conclusions | CoR | LoE | |
|---|---|---|---|
| A | IV in patients with coronary artery disease is associated with a reduction in CV events. | I | B – R |
| B | In patients over 65 years of age at low risk (absence of comorbidities, without established CV disease or diabetes) IV is associated with a reduction in CV events. | I | B – NR |
| C | Annual IV in patients with HF is associated with a reduction in all-cause mortality and HF hospitalization. | IIa | B – NR |
| D | In patients with diabetes or hypertension, in the absence of established CV disease, the IV could be associated with a reduction in CV events. | IIb | C – LD |
| Recommendations | |||
| A | IV for patients with a recent acute coronary syndrome (≤1 year) | I | B – R |
| B | Annual IV for patients >65 years even in the absence of CV disease or risk factors. | I | B – NR |
| C | Annual IV for patients with chronic coronary artery disease with or without history of revascularization. | IIa | B – R |
| D | Annual IV for patients with HF. | IIa | B – NR |
| E | Annual IV for patients with diabetes or hypertension without established CV disease. | IIb | C – LD |
The adverse events of IV can be divided into those attributed to the vaccine, its preservatives, inoculation, and the interaction with other drugs and vaccines. The Institute of Medicine (IOM) of the United States National Academy of Sciences found no evidence of causality between IV and a wide range of studied immunologic or neurologic events [61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76].
Currently available evidence suggests that the majority of people can be vaccinated, even with a documented allergy to eggs [77, 78, 79, 80, 81, 82]. In cases of prior anaphylaxis, patients should be monitored for 30 minutes.
Presumed IV adverse events could represent manifestations of other winter respiratory pathogens as a natural disease [73, 74].
Patients with CV diseases often require anticoagulants. There were no significant differences between the subcutaneous or intramuscular routes for administration of the influenza vaccine in the generation of hematomas, although there is a greater local reaction (pain and erythema at the puncture site on the first day) with the former [83]. Patients with higher INR (International Normalized Ratio) values do not present an increased risk of complications. There is no evidence that IV produces considerable changes in the INR of patients, and on the other hand, immunogenicity is similar between individuals who use oral anticoagulants or not [84]. Subdeltoid intramuscular administration produces a slight increase in the incidence of bursitis [85].
Regarding other CV drugs, no interactions have been found between influenza vaccines and antiplatelet agents, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, digitalis, amiodarone, flecainide, and diuretics [86]. The combination of aspirin and live attenuated influenza vaccine (LAIV) has been associated with the risk of Reye’s syndrome [87].
Vaccines for influenza and pneumococcus are mainly recommended in people over 65 years of age, or people with established CV disease given their susceptibility to both diseases [88]. The use of dual vaccination showed additive or synergistic preventive effects compared to separate administration or absence of vaccination, with adequate effectiveness and safety [89]. Concurrent use does not affect immunogenicity or safety, even in people with chronic respiratory diseases [90]. However, it increases the rate of mild local and systemic adverse events related to the injection site [90].
In the context of the COVID-19 pandemic, messenger RNA vaccines, vector vaccines (Adenovirus with Spike protein) and inactivated virus vaccines have been developed and approved to date. In relation to vaccination for influenza, the Argentine Respiratory Medicine Association recently suggested prioritizing vaccination for COVID-19 and waiting for an interval of at least 14 days between vaccines [91].
The formal contraindications are specific to each vaccine label and described elsewhere [92], the conclusions and recommendations related to this issue are summarized in Table 4.
Table 4
Safety of the influenza vaccine in patients with cardiovascular disease.
| Conclusions/Recommendations | CoR | LoE | |
|---|---|---|---|
| A | The different flu vaccines are generally safe; the reduction in the incidence of epidemic influenza is significantly greater than the incidence of adverse effects. | I | A |
| B | Co-administration of injectable IV and warfarin is safe, requiring only longer pressure at the intramuscular injection site. There is insufficient information to support determining the INR before or at the time of administration of the vaccine. |
II a III |
B-R C-EO |
| C | Co-administration of influenza and pneumococcal vaccines is safe and immunogenic. Co-administration was associated with a higher rate of adverse events, albeit mild. |
II a II b |
B-R C-LD |
| D | In the context of COVID-19 pandemic, it may be beneficial the SARS-CoV-2 vaccination and then IV after an interval of at least 14 days. | IIb | C-EO |
| E | It is recommended not to administer the LAIV together with aspirin in children given the risk of Reye’s syndrome. The LAIV is generally not recommended for patients with CV disease. |
III III |
C-EO C-EO |
| F | Individuals with history of severe egg anaphylaxis may receive chicken embryo-based vaccine but should be monitored for at least 30 minutes after the administration. | IIa | B-R |
Both the efficacy in immunological terms and the clinical effectiveness of IV appear to decrease with age. This fact, linked to immune senescence, represents a state of dysregulation of immune function that predispose older patients to a greater susceptibility to infections of any type, in addition to other diseases that compromise the immune system, and the presence of comorbidities.
Although current IVs are immunogenic, mutations in the virus can reduce their effectiveness. Strategies focused on increasing immunogenicity or the spectrum of antiviral coverage include the use of high doses of vaccine, quadrivalent vaccines, adjuvanted vaccines, and those prepared in cell cultures. The elderly and immunocompromised are those who obtain the greatest benefit from these options [72, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107].
The benefit of using higher than conventional doses in older patients has recently been demonstrated. A randomized, double-blind study conducted in the United States and Canada on 31,989 patients over 65 years of age has documented a 24% superior efficacy of high dose trivalent inactivated virus vaccine against lab-confirmed influenza, when compared to standard dose (60 μg vs 15 μg of hemagglutinin) [108]. A recent study reports that high dose vaccine is 14% more effective in reducing cardiovascular hospitalizations [109]. The increased protection of higher dose vaccine against various endpoints is also supported by a recent meta-analysis of data from 34 million older adults over 10 consecutive seasons [110]. The use of high doses induced significantly higher antibody responses and provided better protection against laboratory-confirmed influenza. Patients with a history of CV or chronic respiratory diseases who received high dose vaccine had a lower frequency of pneumonia or cardio-respiratory complications [110].
In a systematic review and meta-analysis of 7 trials in Canada, the authors concluded that in adults older than 65 years, high-dose IV was well tolerated, more immunogenic, and effective in preventing influenza infections than the standard-dose vaccine [111]. However, more pragmatic trials are needed to determine whether higher efficacy translates into greater clinical effectiveness of the vaccine in this population.
Recently, Vardeny et al., in a randomized double-blind study that included 5,260 high-risk patients with CV disease, did not find significant differences in mortality and CV hospitalization when they compared high doses of trivalent vaccine and standard doses of quadrivalent vaccine [93]. Some criticism to that trial rose regarding baseline risk, number of patients, vaccine effectiveness, as well as type of outcomes analyzed [112, 113].
Quadrivalent vaccines have a safety profile similar to that of the trivalent vaccine. In seasons with relatively high influenza B activity, the quadrivalent vaccine appeared more protective than the trivalent [114, 115].
The deep subcutaneous/intramuscular route of administration may reduce morbidity and mortality from seasonal influenza. Higher antibody levels have been identified after boosting with the application of attenuated virus vaccines intradermally (DNA-IIV3) and intramuscularly (IIV3-IIV3), although with greater swelling and local redness, compared to other routes of administration; systemic reactogenicity was similar between regimens [116].
Intranasal application not only induces IgG antibodies, but also activates the secretory IgA antibodies of the respiratory tract epithelium (S-IgA), mimicking natural infection [117]. For this reason, some experts point out that the intranasal route could be a safe and effective strategy [118, 119].
Finally, with regard to the time of vaccination, it is always recommended to use the vaccine prior to the onset of influenza circulation. If such seasonality is not observed in some of the tropical countries, some authors suggest that a fixed administration strategy every six months could be used [120].
The conclusions and recommendations related to this issue are summarized in Table 5.
Table 5
Efficacy of different vaccination schedules.
| Conclusions/Recommendations | CoR | LoE | |
|---|---|---|---|
| A | The vaccine should be administered at least annually before the annual season in which the incidence of influenza increases, or at the beginning of the season. | I | A |
| B | The high-dose inactivated influenza vaccine (IIV3-HD) is recommended compared to the standard dose (IIV3-SD) because it is more immunogenic, effective, and because it reduces cardiorespiratory outcomes | IIa | B-R |
| C | The quadrivalent inactivated influenza vaccine is recommended compared to the trivalent because it offers a broader protection. | IIa | B-NR |
| D | Adjuvant vaccines are indicated in elderly patients, with suboptimal immune responses, or when rapid responses to smaller doses are required during a pandemic. | IIa | B-NR |
| E | Influenza vaccines developed integrally in cell culture are more immunogenic than those developed in chicken embryos, requiring lower doses, and maintaining a comparable biosafety profile. | IIa | B-NR |
| F | The benefit regarding CV outcomes between IIV3-HD and quadrivalent vaccine could not be established due to methodological limitations in the only randomized clinical trial. | IIb | B-R |
| G | In tropical countries where it is proven that there is no seasonal variation in influenza, biannual vaccination could be beneficial, although there are still no studies to support this recommendation. | IIb | C-EO |
Based on the systematic review carried out, 45 cost-effectiveness (CE) studies were identified, and the results were stratified according to the population analyzed [17].
Although our aim was to evaluate the CE of individual vaccination in risk groups, another approach as a preventive measure is mass vaccination, which was shown to be cost-effective in a model carried out in the United States [166, 167]. Compared with other primary prevention strategies such as breast or colon cancer screening, or control of arterial hypertension, the CE of vaccination is of a similar magnitude [168, 169].
In the Americas, we identified CE studies with positive results in eight countries: Canada, United States, Mexico, Costa Rica, Panama, Colombia, Brazil, Argentina and in tropical countries where there are seasonal peaks of influenza [124, 126].
With regard to the types of vaccines, the information about disease costs and formal CE analysis in low- and middle-income countries (like most in the Americas) is of low quality or totally absent for some of the parameters, and therefore, for certain authors [170], it may not be a priority to use more complex vaccines than the conventional trivalent, from an economic point of view. Recently, after our systematic review and during the editorial process, a review was published including economic evaluation of high dose IV for people older than 65 years from USA and Canada. In that review, high-dose IV was cost-effective and cost saving, pulled by the economic benefit of CV events reduction [171].
The conclusions related to this issue are summarized in Table 6.
Table 6
Cost-effectiveness of influenza vaccination.
| Conclusions | CoR | LoE | |
|---|---|---|---|
| A | Vaccination for influenza with a trivalent vaccine is a CE strategy: In adults in general, it is CE for the reduction of ambulatory ILI cases, hospitalizations for pneumonia, quality-adjusted life years and total mortality. |
I | B-NR |
| B | Vaccination for influenza is CE when evaluating CV outcomes: From an economic point of view, vaccination is reasonable in those over 50 years of age, and regardless of age in subjects with diabetes, coronary artery disease, or other established CV diseases. In the United States, mass vaccination was CE compared to vaccination only to risk groups. |
IIa | B-NR |
| C | Vaccination for influenza is as CE as other primary health prevention strategies (colon cancer screening, breast cancer screening, or control of arterial hypertension). Vaccination for influenza is CE in tropical countries. |
IIa | C-LD |
| D | There is little to no information on CE of influenza vaccines with new technologies (with adjuvants, tetravalent, high doses) in low-resource countries, so there is not enough evidence yet to recommend one over the other, from the pharmacoeconomic point of view specifically. | IIb | C-EO |
Despite the benefits related to IV and the recommendations for its prescription by scientific societies and health regulatory agencies, vaccination rates globally, as well as in the Americas, are lower than desired [172]. This fact is explained by the presence of implementation barriers that involve doctors, patients, and health systems. An adequate diagnosis and recognition of each barrier is essential to generate potential strategies that allow increasing vaccination rates.
As with other prevention measures, medical knowledge through continuous education, clear regulations, and conviction regarding the risk-benefit ratio seem to be the main determinants of the implementation of an intervention.
The personal experience of the physician, as well as that of other health workers with influenza immunization, also appears to be a determining factor in future recommendations for patients. When ‘missed opportunities’ were analyzed in unvaccinated patients, lack of recommendation during medical visits was identified as the main cause. Seen in another way, when doctors have a positive attitude and recommend the vaccine, the immunization rate increases considerably, generating an effective vaccination between 50% and 93% of cases in different series [173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183]. A full list of the results of the analyzed studies is available in the large version of this consensus [17].
Specialist physicians may be reluctant to carry out primary prevention interventions [183]. Another great limitation in effective vaccination involves complex behavioral attributes related to the psychological aspects of patients [184, 185, 186]. There are approximately 500 articles that analyze behavioral aspects that determine vacillation in the vaccination decision. These aspects are grouped into complacency (example: low perceived risk of becoming ill or presenting serious complications, or not having presented the disease), inconvenience (self-efficacy, cost, behavioral aspects), lack of confidence (aspects such as distrust in the efficacy and effects adverse effects, psychological aspects related to the link with the authorities and the indications, greater acceptance of negative myths) and calculation (individual and social risk-benefit ratio) [186].
Sociocultural factors were also identified such as economic level, education level (paradoxically, university students reject immunization to a greater extent), religion, and demographics (ethnic differences have been reported in the United States, with a lower immunization rate in Hispanic-Latino populations). Among the countries of the Americas, confidence in vaccination by patients is unevenly distributed. Recent data from the CorCOVID-LATAM study, conducted in 13 Latin American countries, has reported differences in the vaccination rate according to economic income and educational level [187].
In contrast to medical knowledge and conviction, external factors that affect vaccination are grouped together, increasing patients’ hesitancy. Fake news in the media and social networks and people who advocate against vaccination are key aspects in the hesitation process, with potential harmful effects on population health [188]. Years of scientific research can be overshadowed by a simple fake news article developed in one minute and massively disseminated on social media [189].
In an analysis of 450,000 health-related fake news articles collected on social media in Poland, the majority were related to vaccines [190]. Cautious dissemination of recent scientific articles, review of data or publications by experts, social media campaigns and alliances with influential subjects in social networks, as well as public commitment by doctors, are some of the suggestions to overcome this [191, 192, 193, 194, 195].
More recently, the COVID-19 pandemic occurred in a completely virtual era with a high global penetrance rate of the internet and social networks, where skepticism about the disease, as well as the safety and efficacy of new vaccines, could influence short-term influenza vaccination rates. Recently, three of the largest platforms (YouTube, Facebook, and Twitter) unified criteria to prevent the spread of vaccine related fake news [196].
IV coverage is a useful indicator to monitor health interventions. Despite a significant improvement of that indicator in Argentina, Brazil, and Mexico, the expected vaccination rates have not been achieved, reflecting the presence of barriers of all kinds.
In the United States, IV was incorporated as a recommendation for at-risk groups by the CDC expert committee more than a decade ago [197]. In Argentina, despite having policies aimed at free vaccination, the vaccination rate was 51.6% in at-risk groups in 2013 [198, 199]. At the other extreme, Brazil has reported that the vaccination rate between 2018 and 2020 was 90% to 95% of the target population [200]. In a review carried out by PAHO between 2005 and 2015 in Mexico, Brazil and Argentina, countries with vaccination policies for older adults, the existence of structural barriers in populations with lower socioeconomic and educational levels was established [177].
An assessment carried out in 137 countries reveals that only 51 (37%) have included the influenza vaccine in their list of essential drugs [201, 202]. In Latin America and the Caribbean, 30 countries have a list of essential drugs, however in only 11 (36.6%) the influenza vaccine is recognized as essential medicine [201, 202, 17].
The cardiologist’s knowledge about the benefit of IV as a primary and secondary CV prevention strategy is also considered a barrier in the Americas. Only in some countries is IV included in the national cardiology guidelines. Furthermore, a survey among young cardiologists showed low knowledge regarding vaccinations, and therefore a low rate of prescription [13].
The direct cost of the vaccine is a major barrier. However, PAHO has created a revolving fund to facilitate lower-cost access to both trivalent and quadrivalent vaccines. In this way, 41 countries and territories of Latin America and the Caribbean have a facilitated vaccine acquisition program [203].
Finally, the CorCOVID LATAM study recently published by IASC demonstrated that there are profound regional differences in vaccination rates [187]: they were very low in the tropical countries of the Americas compared to the countries of the Southern Cone (approximately 50% less), which may partly reflect medical lack of knowledge regarding the circulation of influenza and seasonal peaks even in tropical countries. Of note, that study also found differences in vaccination rates in relation to economic strata and the educational level of the patients. Figure 1 illustrates the main barriers that involve clinicians, patients and their context and the importance of doctor/patient interaction in relation to vaccination rates.
Doctor’s, context, and patient’s role in effective vaccination.
Red squares: barriers, green squares: facilitators.
The conclusions related to this issue are summarized in Table 7.
Table 7
Barriers to influenza vaccination implementation related to physicians, patients, and their context.
| Conclusions | CoR | LoE | |
|---|---|---|---|
| A | Medical conviction is the main determinant (50–90%) of effective vaccination. Prescription or advice from a physician or healthcare worker is positively associated with effective vaccination. |
I | C-LD |
| B | There are factors beyond access to the vaccine, which psychologically influence the patient’s decision to get vaccinated, encompassed in the concept of hesitancy. Cultural, geographic, economic, religious, and ethnic differences were found as determinants of the vaccination rate. |
I | B-NR |
| C | The growing impact of fake news on mass media and social media contributes to the determinants of non-vaccination. | IIa | C-LD |
From what has been previously discussed, it is understood that physicians’ conviction seems to be more influential than the perceptions of the patient when analyzing effective vaccination rates. The strong and positive attitude by the doctors at the moment of vaccine prescription seems decisive [177, 178, 204, 205, 206, 207].
The implementation of continuous medical education programs aimed at general practitioners and specialists addressing the benefits and opportunities of IV should be considered as a primary objective, as well as its incorporation into clinical practice guidelines.
Immunization should be considered an essential topic of undergraduate medical and nursing schools. The study of immunological aspects, as well as pharmacology, should be expanded and standardized.
The incorporation of advanced medical and nursing students in vaccination campaigns could contribute in this regard.
Patient’s adherence to treatment while undergoing acute-high-mortality diseases such as ACS, is almost complete upon discharge from the coronary care unit, but drastically falls during follow-up [207]. Therefore, implementation of IV prior to discharge or immediately after it would be a highly effective measure to increase vaccination rates.
The access of patients to simple, truthful, and reliable information, carried out through communication campaigns to the community, should also be considered a primary objective. A recent document developed by Vaccines 4 life and by the International Federation of Aging [208], has established a framework for the optimal development of vaccination campaigns for influenza.
The recommendations related to this issue are summarized in Table 8.
Table 8
Strategies for increasing influenza vaccination rate.
| Recommendations | CoR | LoE | |
|---|---|---|---|
| Physicians | Develop continuing medical education programs aimed at general practitioners and specialists that address the benefits and opportunities of IV, as well as its incorporation into the clinical practice guidelines. Incorporate the concept of vaccination as a CV prevention strategy together with other preventive interventions. Generate multimodal interventions aimed at outpatient doctors, nurses and students of both careers that allow the dissemination of this concept. Vaccinate prior to or immediately after discharge in patients with acute coronary syndrome. Increase the availability of vaccines in outpatient clinics. |
IIa | C-EO |
| Patients | Educate patients and have strategies to overcome vaccine related hesitancy with simple, truthful, and reliable information. Carry out effective vaccination campaigns adapted to local or regional needs. Use clear, simple, multimodal communication oriented at the target population. Refute fake news and promote dialogue with anti-vaccines groups. |
IIa | C-EO |
| Context | Improve access to IV, guaranteeing its free provision to target populations. Incorporate IV into the list of essential medicines. Incorporate IV into the annual vaccination calendar. Develop epidemiological surveillance programs to measure results (annual vaccination rates in risk groups). |
IIa | C-EO |
There is a strong causal relationship between acute respiratory infections and the incidence of CV events. The severe morbidity and mortality associated with influenza is due in part to the presence of these complications. Incorporating a practice as simple as vaccination can considerably reduce the risk of CV events in selected populations.
With the existing evidence, scientific societies and governmental health agencies strongly recommend the incorporation of IV in patients with pre-existing CV disease and in high-risk groups (people over 65 years of age, HTN, diabetes). Despite this, vaccination rates are far from the expected rates, globally and particularly in the Americas.
The correct understanding of implementation barriers, which involve doctors, patients, and their context, is essential when designing continuous improvement strategies in order to optimize this reality. The current and unavoidable challenge for our scientific societies is to turn our recommendations into action.
The data presented in this study is available upon request directed to the corresponding author. An extended version of this document including specific methods of the systematic review, consensus processes, and full tables with results and references; is freely available at www.siacardio.com [17].
No patient information was gathered for this study, no IRB was involved.
This research was funded by an unrestricted grant to the Inter-American Society of Cardiology provided by Sanofi Pasteur to the World Heart Federation. Funder had no role in the drafting, evidence review, meetings, or publication process.
The authors have no competing interests to declare.
Conceptualization, Á.S.L.; methodology, Á.S.L., M.I.S.L., P.P., E.J.Z.; validation, all authors; formal analysis, Á.S.L., M.I.S.L., E.J.Z.; investigation, all authors; resources, A.S.L., P.P.; data curation, Á.S.L., M.I.S.L., E.J.Z.; writing—original draft preparation, Á.S.L., M.I.S.L., E.J.Z.; writing—review and editing, Á.S.L., M.I.S.L., A.B., B.A. E.J.Z.; visualization, all authors; supervision, F.J.P, J.R.G.J.; project administration, Á.S.L., M.I.S.L.; funding acquisition, Á.S.L., P.P. All authors have read and agreed to the published version of the manuscript.
GBD Compare|IHME Viz Hub. http://vizhub.healthdata.org/gbd-compare (Accessed Jan 16, 2021).
Warren-Gash C, Smeeth L, Ayward AC. Influenza as a trigger for acute myocardial infarction or death from cardiovascular disease: A systematic review. Lancet Infect Dis. 2009; 9: 601–10. DOI: https://doi.org/10.1016/S1473-3099(09)70233-6
Corrales-Medina VF, Madjid M, Musher DM. Role of acute infection in triggering acute coronary syndromes. Lancet Infect Dis. 2010 Feb; 10(2): 83–92. DOI: https://doi.org/10.1016/S1473-3099(09)70331-7
Madjid M, Aboshady I, Awan I, Litovsky S, Casscells SW. Influenza and cardiovascular disease: Is there a causal relationship? Tex Heart Inst J. 2004; 31(1): 4–13.
Clayton TC, Thompson M, Meade TW. Recent respiratory infection and risk of cardiovascular disease: Case-control study through a general practice database. Eur Heart J. 2007 Dec 8; 29(1): 96–103. DOI: https://doi.org/10.1093/eurheartj/ehm516
Meier CR, Jick SS, Derby LE, Vasilakis C, Jick H. Acute respiratory-tract infections and risk of first-time acute myocardial infarction. Lancet Lond Engl. 1998 May 16; 351(9114): 1467–71. DOI: https://doi.org/10.1016/S0140-6736(97)11084-4
Spodick DH, Flessas AP, Johnson MM. Association of acute respiratory symptoms with onset of acute myocardial infarction: Prospective investigation of 150 consecutive patients and matched control patients. Am J Cardiol. 1984 Feb 1; 53(4): 481–2. DOI: https://doi.org/10.1016/0002-9149(84)90016-X
Clayton TC, Capps NE, Stephens NG, Wedzicha JA, Meade TW. Recent respiratory infection and the risk of myocardial infarction. Heart Br Card Soc. 2005 Dec; 91(12): 1601–2. DOI: https://doi.org/10.1136/hrt.2004.046920
Mattila KJ. Viral and bacterial infections in patients with acute myocardial infarction. J Intern Med. 1989 May; 225(5): 293–6. DOI: https://doi.org/10.1111/j.1365-2796.1989.tb00084.x
Abinader EG, Sharif DS, Omary M. Inferior wall myocardial infarction preceded by acute exudative pharyngitis in young males. Isr J Med Sci. 1993 Dec; 29(12): 764–9.
Spencer FA, Goldberg RJ, Becker RC, Gore JM. Seasonal distribution of acute myocardial infarction in the second National Registry of Myocardial Infarction. J Am Coll Cardiol. 1998 May; 31(6): 1226–33. DOI: https://doi.org/10.1016/S0735-1097(98)00098-9
Vardeny O, Claggett B, Udell JA, Packer M, Zile M, Rouleau J, et al. Influenza vaccination in patients with chronic heart failure: The PARADIGM-HF trial. JACC Heart Fail. 2016 Feb; 4(2): 152–8. DOI: https://doi.org/10.1016/j.jchf.2015.10.012
Zaidel EJ, Cacia SL, Pérez GE, Costabel JP, Failo M, Rosende A, et al. Vacuna antineumocócica en adultos: Encuesta a residentes de cardiología de argentina. Rev CONAREC. 2014; 15: 101–104. http://www.revistaconarec.com.ar/contenido/art.php?recordID=MTA0Mw==.
Martins W de A, Ribeiro MD, Oliveira LB de, Barros L da SN de, Jorge AC da SM, Santos CM dos, et al. Influenza and pneumococcal vaccination in heart failure: A little applied recommendation. Arq Bras Cardiol. 2011 Mar; 96(3): 240–5. DOI: https://doi.org/10.1016/S0048-7120(01)73220-3
Amuedo ME, Vargas MC. Métodos de consenso. Uso adecuado de la evidencia en la toma de decisiones. “Método RAND/UCLA”. Rehabilitación. 2001 Dec 31; 35: 388–92.
Fitch K (ed.). The Rand/UCLA appropriateness method user’s manual. Santa Monica: Rand; 2001. 109 p.
SIAC|GUÍAS|SIAC. http://www.siacardio.com/category/educacion/guias/ (Accessed Mar 28, 2021).
Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019 Jun 25; 73(24): 3168–209.
Kwok CS, Aslam S, Kontopantelis E, Myint PK, Zaman MJS, Buchan I, et al. Influenza, influenza-like symptoms and their association with cardiovascular risks: A systematic review and meta-analysis of observational studies. Int J Clin Pract. 2015 Sep; 69(9): 928–37. DOI: https://doi.org/10.1111/ijcp.12646
Madjid M, Miller CC, Zarubaev VV, Marinich IG, Kiselev OI, Lobzin YV, et al. Influenza epidemics and acute respiratory disease activity are associated with a surge in autopsy-confirmed coronary heart disease death: Results from 8 years of autopsies in 34 892 subjects. Eur Heart J. 2007 May 1; 28(10): 1205–10. DOI: https://doi.org/10.1093/eurheartj/ehm035
Kwong JC, Schwartz KL, Campitelli MA, Chung H, Crowcroft NS, Karnauchow T, et al. Acute Myocardial Infarction after Laboratory-Confirmed Influenza Infection. N Engl J Med. 2018 Jan 25; 378(4): 345–53. DOI: https://doi.org/10.1056/NEJMoa1702090
Warren-Gash C, Blackburn R, Whitaker H, McMenamin J, Hayward AC. Laboratory-confirmed respiratory infections as triggers for acute myocardial infarction and stroke: A self-controlled case series analysis of national linked datasets from Scotland. Eur Respir J. 2018 Mar 1; 51(3). https://erj.ersjournals.com/content/51/3/1701794. DOI: https://doi.org/10.1183/13993003.01794-2017
Hill AB. The Environment and Disease: Association or Causation? Proc R Soc Med. 1965 May; 58(5): 295–300. DOI: https://doi.org/10.1177/003591576505800503
Chang T-Y, Chao T-F, Liu C-J, Chen S-J, Chung F-P, Liao J-N, et al. The association between influenza infection, vaccination, and atrial fibrillation: A nationwide case-control study. Heart Rhythm. 2016 Jun 1; 13(6): 1189–94. DOI: https://doi.org/10.1016/j.hrthm.2016.01.026
Kytömaa S, Hegde S, Claggett B, Udell JA, Rosamond W, Temte J, et al. Association of Influenza-like Illness Activity with Hospitalizations for Heart Failure: The Atherosclerosis Risk in Communities Study. JAMA Cardiol. 2019 Apr 1; 4(4): 363–9. DOI: https://doi.org/10.1001/jamacardio.2019.0549
Panhwar MS, Kalra A, Gupta T, Kolte D, Khera S, Bhatt DL, et al. Effect of Influenza on Outcomes in Patients with Heart Failure. JACC Heart Fail. 2019 Feb 1; 7(2): 112–7. DOI: https://doi.org/10.1016/j.jchf.2018.10.011
van Wissen M, Keller TT, Ronkes B, Gerdes VE, Zaaijer HL, van Gorp EC, et al. Influenza infection and risk of acute pulmonary embolism. Thromb J. 2007 Oct 16; 5(1): 16. DOI: https://doi.org/10.1186/1477-9560-5-16
Bunce PE, High SM, Nadjafi M, Stanley K, Liles WC, Christian MD. Pandemic H1N1 Influenza Infection and Vascular Thrombosis. Clin Infect Dis. 2011 Jan 15; 52(2): e14–7. DOI: https://doi.org/10.1093/cid/ciq125
Avnon LS, Munteanu D, Smoliakov A, Jotkowitz A, Barski L. Thromboembolic events in patients with severe pandemic influenza A/H1N1. Eur J Intern Med. 2015 Oct; 26(8): 596–8. DOI: https://doi.org/10.1016/j.ejim.2015.08.017
Centers for Disease Control and Prevention (CDC). Intensive-care patients with severe novel influenza A (H1N1) virus infection – Michigan, June 2009. MMWR Morb Mortal Wkly Rep. 2009 Jul 17; 58(27): 749–52.
Zhu T, Carcaillon L, Martinez I, Cambou J-P, Kyndt X, Guillot K, et al. Association of influenza vaccination with reduced risk of venous thromboembolism. Thromb Haemost. 2009 Dec; 102(6): 1259–64. DOI: https://doi.org/10.1160/TH09-04-0222
Pearce DC, McCaw JM, McVernon J, Mathews JD. Influenza as a trigger for cardiovascular disease: An investigation of serotype, subtype and geographic location. Environ Res. 2017 Jul; 156: 688–96. DOI: https://doi.org/10.1016/j.envres.2017.04.024
Reichert TA, Simonsen L, Sharma A, Pardo SA, Fedson DS, Miller MA. Influenza and the winter increase in mortality in the United States, 1959–1999. Am J Epidemiol. 2004 Sep 1; 160(5): 492–502. DOI: https://doi.org/10.1093/aje/kwh227
Lichenstein R, Magder LS, King RE, King JC. The relationship between influenza outbreaks and acute ischemic heart disease in Maryland residents over a 7-year period. J Infect Dis. 2012 Sep 15; 206(6): 821–7. DOI: https://doi.org/10.1093/infdis/jis435
Gurevich VS, Pleskov VM, Levaia MV, Bannikov AI, Mitrofanova LB, Urazgil’deeva SA. Influenza virus infection in progressing atherosclerosis. Kardiologiia. 2002; 42(7): 21–4.
Musher DM, Abers MS, Corrales-Medina VF. Acute Infection and Myocardial Infarction. N Engl J Med. 2019 Jan 10; 380(2): 171–6. DOI: https://doi.org/10.1056/NEJMra1808137
Finelli L, Chaves SS. Influenza and acute myocardial infarction. J Infect Dis. 2011 Jun 15; 203(12): 1701–4. DOI: https://doi.org/10.1093/infdis/jir175
McCarthy Z, Xu S, Rahman A, Bragazzi NL, Corrales-Medina VF, Lee J, et al. Modelling the linkage between influenza infection and cardiovascular events via thrombosis. Sci Rep. 2020 Aug 31; 10(1): 14264. DOI: https://doi.org/10.1038/s41598-020-70753-0
Fröbert O, Götberg M, Angerås O, Jonasson L, Erlinge D, Engstrøm T, et al. Design and rationale for the Influenza vaccination After Myocardial Infarction (IAMI) trial. A registry-based randomized clinical trial. Am Heart J. 2017 Jul; 189: 94–102. DOI: https://doi.org/10.1016/j.ahj.2017.04.003
LeBras MH, Barry AR. Influenza Vaccination for Secondary Prevention of Cardiovascular Events: A Systematic Review. Can J Hosp Pharm. 2017 Feb; 70(1): 27–34. DOI: https://doi.org/10.4212/cjhp.v70i1.1626
Gurfinkel EP, de la Fuente RL, Mendiz O, Mautner B. Influenza vaccine pilot study in acute coronary syndromes and planned percutaneous coronary interventions: the FLU Vaccination Acute Coronary Syndromes (FLUVACS) Study. Circulation. 2002 May 7; 105(18): 2143–7. DOI: https://doi.org/10.1161/01.CIR.0000016182.85461.F4
Ciszewski A, Bilinska ZT, Brydak LB, Kepka C, Kruk M, Romanowska M, et al. Influenza vaccination in secondary prevention from coronary ischaemic events in coronary artery disease: FLUCAD study. Eur Heart J. 2008 Jun; 29(11): 1350–8. DOI: https://doi.org/10.1161/01.CIR.0000016182.85461.F4
Phrommintikul A, Kuanprasert S, Wongcharoen W, Kanjanavanit R, Chaiwarith R, Sukonthasarn A. Influenza vaccination reduces cardiovascular events in patients with acute coronary syndrome. Eur Heart J. 2011 Jul; 32(14): 1730–5. DOI: https://doi.org/10.1093/eurheartj/ehr004
Shahid Beheshti University of Medical Sciences. Randomized, Single-Blind, Placebo-Controlled Study of Influenza Vaccine in Preventing Cardiovascular Events in Post-Myocardial Infarction Patients and in Those With Stable Angina Pectoris [Internet]. clinicaltrials.gov; 2009 Jan [cited 2021 Mar 26]. Report No.: NCT00607178. Available from: https://clinicaltrials.gov/ct2/show/NCT00607178
Udell JA, Zawi R, Bhatt DL, Keshtkar-Jahromi M, Gaughran F, Phrommintikul A, et al. Association between influenza vaccination and cardiovascular outcomes in high-risk patients: A meta-analysis. JAMA. 2013 Oct 23; 310(16): 1711–20. DOI: https://doi.org/10.1001/jama.2013.279206
Clar C, Oseni Z, Flowers N, Keshtkar-Jahromi M, Rees K. Influenza vaccines for preventing cardiovascular disease. Cochrane Database Syst Rev. 2015 May 5; 5: CD005050. DOI: https://doi.org/10.1002/14651858.CD005050.pub3
Yedlapati SH, Khan SU, Talluri S, Lone AN, Khan MZ, Khan MS, et al. Effects of Influenza Vaccine on Mortality and Cardiovascular Outcomes in Patients with Cardiovascular Disease: A Systematic Review and Meta-Analysis. J Am Heart Assoc. 2021 Mar 16; 10(6): e019636. DOI: https://doi.org/10.1161/JAHA.120.019636
Wu W-C, Jiang L, Friedmann PD, Trivedi A. Association between process quality measures for heart failure and mortality among US veterans. Am Heart J. 2014 Nov; 168(5): 713–20. DOI: https://doi.org/10.1016/j.ahj.2014.06.024
Mohseni H, Kiran A, Khorshidi R, Rahimi K. Influenza vaccination and risk of hospitalization in patients with heart failure: A self-controlled case series study. Eur Heart J. 2017 Feb 1; 38(5): 326–33.
Modin D, Jørgensen ME, Gislason G, Jensen JS, Køber L, Claggett B, et al. Influenza Vaccine in Heart Failure. Circulation. 2019 Jan 29; 139(5): 575–86. DOI: https://doi.org/10.1161/CIRCULATIONAHA.118.036788
Rodrigues BS, David C, Costa J, Ferreira JJ, Pinto FJ, Caldeira D. Influenza vaccination in patients with heart failure: A systematic review and meta-analysis of observational studies. Heart Br Card Soc. 2020 Mar; 106(5): 350–7. DOI: https://doi.org/10.1136/heartjnl-2019-315193
Loeb M, Dokainish H, Dans A, Palileo-Villanueva LM, Roy A, Karaye K, et al. Randomized controlled trial of influenza vaccine in patients with heart failure to reduce adverse vascular events (IVVE): Rationale and design. Am Heart J. 2019 Jun; 212: 36–44. DOI: https://doi.org/10.1016/j.ahj.2019.02.009
Remschmidt C, Wichmann O, Harder T. Vaccines for the prevention of seasonal influenza in patients with diabetes: Systematic review and meta-analysis. BMC Med. 2015 Mar 17; 13(1): 53. DOI: https://doi.org/10.1186/s12916-015-0295-6
The flu vaccine and mortality in hypertension. A Danish nationwide cohort study. https://esc365.escardio.org/Congress/195110-the-flu-vaccine-and-mortality-in-hypertension-a-danish-nationwide-cohort-study (Accessed Jan 16, 2021).
Kao P-F, Liu J-C, Hsu Y-P, Sung L-C, Yang T-Y, Hao W-R, et al. Influenza vaccination might reduce the risk of ischemic stroke in patients with atrial fibrillation: A population-based cohort study. Oncotarget. 2017 Dec 22; 8(68): 112697–711. DOI: https://doi.org/10.18632/oncotarget.22352
Bridges CB, Fukuda K, Uyeki TM, Cox NJ, Singleton JA, Centers for Disease Control and Prevention, Advisory Committee on Immunization Practices. Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep Morb Mortal Wkly Rep Recomm Rep. 2002 Apr 12; 51(RR-3): 1–31.
Nichol KL. Influenza vaccination in the elderly: Impact on hospitalisation and mortality. Drugs Aging. 2005; 22(6): 495–515. DOI: https://doi.org/10.2165/00002512-200522060-00004
Nichol KL, Nordin J, Mullooly J, Lask R, Fillbrandt K, Iwane M. Influenza Vaccination and Reduction in Hospitalizations for Cardiac Disease and Stroke among the Elderly. N Engl J Med. 2003 Apr 3; 348(14): 1322–32. DOI: https://doi.org/10.1056/NEJMoa025028
Nichol KL, Nordin JD, Nelson DB, Mullooly JP, Hak E. Effectiveness of Influenza Vaccine in the Community-Dwelling Elderly. N Engl J Med. 2007 Oct 4; 357(14): 1373–81. DOI: https://doi.org/10.1056/NEJMoa070844
Nichol KL, Margolis KL, Wuorenma J, Von Sternberg T. The efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community. N Engl J Med. 1994 Sep 22; 331(12): 778–84. DOI: https://doi.org/10.1056/NEJM199409223311206
Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: National Academies Press; 2012. http://www.nap.edu/catalog/13164 (Accessed Jan 16, 2021).
Petráš M, Lesná IK, Dáňová J, Čelko AM. Is an Increased Risk of Developing Guillain-Barré Syndrome Associated with Seasonal Influenza Vaccination? A Systematic Review and Meta-Analysis. Vaccines. 2020 Mar 27; 8(2). DOI: https://doi.org/10.3390/vaccines8020150
Salmon DA, Proschan M, Forshee R, Gargiullo P, Bleser W, Burwen DR, et al. Association between Guillain-Barré syndrome and influenza A (H1N1) 2009 monovalent inactivated vaccines in the USA: a meta-analysis. Lancet Lond Engl. 2013 Apr 27; 381(9876): 1461–8. DOI: https://doi.org/10.1016/S0140-6736(12)62189-8
Moro PL, Woo EJ, Marquez P, Cano M. Monitoring the safety of high-dose, trivalent inactivated influenza vaccine in the vaccine adverse event reporting system (VAERS), 2011–2019. Vaccine. 2020 Aug 18; 38(37): 5923–6. DOI: https://doi.org/10.1016/j.vaccine.2020.07.007
Haber P, Moro PL, Lewis P, Woo EJ, Jankosky C, Cano M. Post-licensure surveillance of quadrivalent inactivated influenza (IIV4) vaccine in the United States, Vaccine Adverse Event Reporting System (VAERS), July 1, 2013-May 31, 2015. Vaccine. 2016 May 11; 34(22): 2507–12. DOI: https://doi.org/10.1016/j.vaccine.2016.03.048
Li-Kim-Moy J, Yin JK, Rashid H, Khandaker G, King C, Wood N, et al. Systematic review of fever, febrile convulsions and serious adverse events following administration of inactivated trivalent influenza vaccines in children. Euro Surveill Bull Eur Sur Mal Transm Eur Commun Dis Bull. 2015 Jun 18; 20(24). DOI: https://doi.org/10.2807/1560-7917.ES2015.20.24.21159
Lee KR, Bae JH, Hwang IC, Kim KK, Suh HS, Ko KD. Effect of Influenza Vaccination on Risk of Stroke: A Systematic Review and Meta-Analysis. Neuroepidemiology. 2017; 48(3–4): 103–10. DOI: https://doi.org/10.1159/000478017
Kamath A, Maity N, Nayak MA. Facial Paralysis Following Influenza Vaccination: A Disproportionality Analysis Using the Vaccine Adverse Event Reporting System Database. Clin Drug Investig. 2020 Sep 1; 40(9): 883–9. DOI: https://doi.org/10.1007/s40261-020-00952-0
Mutsch M, Zhou W, Rhodes P, Bopp M, Chen RT, Linder T, et al. Use of the inactivated intranasal influenza vaccine and the risk of Bell’s palsy in Switzerland. N Engl J Med. 2004 Feb 26; 350(9): 896–903. DOI: https://doi.org/10.1056/NEJMoa030595
Stowe J, Andrews N, Wise L, Miller E. Bell’s palsy and parenteral inactivated influenza vaccine. Hum Vaccin. 2006 Jun; 2(3): 110–2. DOI: https://doi.org/10.4161/hv.2790
Turner PJ, Southern J, Andrews NJ, Miller E, Erlewyn-Lajeunesse M. Safety of live attenuated influenza vaccine in young people with egg allergy: Multicentre prospective cohort study. BMJ. 2015 Dec 8; h6291. DOI: https://doi.org/10.1136/bmj.h6291
Rouleau I, De Serres G, Skowronski DM, Drolet JP, Lemire C, Toth E, et al. Risk factors associated with anaphylaxis and other allergic-like events following receipt of 2009 monovalent AS03-adjuvanted pandemic influenza vaccine in Quebec, Canada. Vaccine. 2014 Jun 12; 32(28): 3480–7. DOI: https://doi.org/10.1016/j.vaccine.2014.04.059
Hayase Y, Tobita K. Influenza virus and neurological diseases. Psychiatry Clin Neurosci. 1997 Aug; 51(4): 181–4. DOI: https://doi.org/10.1111/j.1440-1819.1997.tb02580.x
Cárdenas G, Soto-Hernández JL, Díaz-Alba A, Ugalde Y, Mérida-Puga J, Rosetti M, et al. Neurological events related to influenza A (H1N1) pdm09. Influenza Other Respir Viruses. 2014 May; 8(3): 339–46. DOI: https://doi.org/10.1111/irv.12241
Ludvigsson JF, Winell H, Sandin S, Cnattingius S, Stephansson O, Pasternak B. Maternal Influenza A(H1N1) Immunization During Pregnancy and Risk for Autism Spectrum Disorder in Offspring: A Cohort Study. Ann Intern Med. 2020 Oct 20; 173(8): 597–604. DOI: https://doi.org/10.7326/M20-0167
Mitkus RJ, King DB, Walderhaug MO, Forshee RA. A Comparative Pharmacokinetic Estimate of Mercury in U.S. Infants Following Yearly Exposures to Inactivated Influenza Vaccines Containing Thimerosal. Risk Anal. 2014; 34(4): 735–50. DOI: https://doi.org/10.1111/risa.12124
Grohskopf LA, Sokolow LZ, Olsen SJ, Bresee JS, Broder KR, Karron RA. Prevention and Control of Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices, United States, 2015–16 Influenza Season. MMWR Morb Mortal Wkly Rep. 2015 Aug 7; 64(30): 818–25. DOI: https://doi.org/10.15585/mmwr.mm6430a3
Erlewyn-Lajeunesse M, Brathwaite N, Lucas JS, Warner JO. Recommendations for the administration of influenza vaccine in children allergic to egg. BMJ. 2009 Sep 15; 339: b3680. DOI: https://doi.org/10.1136/bmj.b3680
Greenhawt MJ, Spergel JM, Rank MA, Green TD, Mansoor D, Sharma H, Bird JA, Chang JE, Parikh DS, Teich E, Kelso JM, Sanders GM. Safe administration of the seasonal trivalent influenza vaccine to children with severe egg allergy. Ann Allergy Asthma Immunol. 2012 Dec; 109(6): 426–30. DOI: https://doi.org/10.1016/j.anai.2012.09.011
McNeil MM, Weintraub ES, Duffy J, Sukumaran L, Jacobsen SJ, Klein NP, Hambidge SJ, Lee GM, Jackson LA, Irving SA, King JP, Kharbanda EO, Bednarczyk RA, DeStefano F. Risk of anaphylaxis after vaccination in children and adults. J Allergy Clin Immunol. 2016 Mar; 137(3): 868–78. DOI: https://doi.org/10.1016/j.jaci.2015.07.048
Haber P, Moro PL, Lewis P, Woo EJ, Jankosky C, Cano M. Post-licensure surveillance of quadrivalent inactivated influenza (IIV4) vaccine in the United States, Vaccine Adverse Event Reporting System (VAERS), July 1, 2013–May 31, 2015. Vaccine. 2016 May 11; 34(22): 2507–12. Epub 2016 Mar 23. PMID: 27015735; PMCID: PMC4916262. DOI: https://doi.org/10.1016/j.vaccine.2016.03.048
García-Zamora S, Sosa Liprandi MI, Picco JM, Matta MG, Villarreal R, Pulido L, et al. Inmunizaciones en adultos con cardiopatías. Resumen del Consenso de la Sociedad Argentina de Cardiología [Immunizations in adults with cardiovascular disease. Summary of the Consensus of the Argentine Cardiology Society]. Medicina (B Aires). 2020; 80(5): 541–553. Spanish.
Marra F, Young F, Richardson K, Marra CA. A meta-analysis of intradermal versus intramuscular influenza vaccines: immunogenicity and adverse events. Influenza Other Respir Viruses. 2013 Jul; 7(4): 584–603. DOI: https://doi.org/10.1111/irv.12000
Kuo AM, Brown JN, Clinard V. Effect of influenza vaccination on international normalized ratio during chronic warfarin therapy. J Clin Pharm Ther. 2012 Oct; 37(5): 505–9. DOI: https://doi.org/10.1111/j.1365-2710.2012.01341.x
Hesse EM, Navarro RA, Daley MF, Getahun D, Henninger ML, Jackson LA, et al. Risk for Subdeltoid Bursitis After Influenza Vaccination. Ann Intern Med. 2020 Jun 23; 173(4): 253–61. DOI: https://doi.org/10.7326/M19-3176
Drug Interactions. Drugs.com. https://www.drugs.com/interaction/list/?drug_list=243-0,3227-0 (Accessed Jan 16, 2021).
Morens DM, Halsey NA, Schonberger LB, Baublis JV. Reye syndrome associated with vaccination with live virus vaccines. An exploration of possible etiologic relationships. Clin Pediatr (Phila). 1979 Jan; 18(1): 42–4. DOI: https://doi.org/10.1177/000992287901800105
Walter ND, Taylor TH, Shay DK, Thompson WW, Brammer L, Dowell SF, et al. Influenza circulation and the burden of invasive pneumococcal pneumonia during a non-pandemic period in the United States. Clin Infect Dis Off Publ Infect Dis Soc Am. 2010 Jan 15; 50(2): 175–83. DOI: https://doi.org/10.1086/649208
Yin M, Huang L, Zhang Y, Yu N, Xu X, Liang Y, et al. Effectiveness and safety of dual influenza and pneumococcal vaccination versus separate administration or no vaccination in older adults: a meta-analysis. Expert Rev Vaccines. 2018 Jul; 17(7): 653–63. DOI: https://doi.org/10.1080/14760584.2018.1495077
Seo YB, Choi WS, Lee J, Song JY, Cheong HJ, Kim WJ. Comparison of immunogenicity and safety of an influenza vaccine administered concomitantly with a 13-valent pneumococcal conjugate vaccine or 23-valent polysaccharide pneumococcal vaccine in the elderly. Clin Exp Vaccine Res. 2017 Jan; 6(1): 38–44. DOI: https://doi.org/10.7774/cevr.2017.6.1.38
vacunacion_2021.pdf. https://www.aamr.org.ar/secciones/coronavirus/vacunacion_2021.pdf (Accessed Mar 26, 2021).
Seguridad de la vacuna contra la influenza estacional: Un resumen para médicos|CDC. 2020. https://espanol.cdc.gov/flu/professionals/vaccination/vaccine_safety.htm (Accessed Jan 16, 2021).
Vardeny O, Kim K, Udell JA, Joseph J, Desai AS, Farkouh ME, et al. Effect of High-Dose Trivalent vs Standard-Dose Quadrivalent Influenza Vaccine on Mortality or Cardiopulmonary Hospitalization in Patients with High-risk Cardiovascular Disease: A Randomized Clinical Trial. JAMA. 2021 Jan 5; 325(1): 39–49. DOI: https://doi.org/10.1001/jama.2020.23649
Tregoning JS, Russell RF, Kinnear E. Adjuvanted influenza vaccines. Hum Vaccines Immunother. 2018 Mar 4; 14(3): 550–64. DOI: https://doi.org/10.1080/21645515.2017.1415684
Soema PC, Kompier R, Amorij J-P, Kersten GFA. Current and next generation influenza vaccines: Formulation and production strategies. Eur J Pharm Biopharm Off J Arbeitsgemeinschaft Pharm Verfahrenstechnik EV. 2015 Aug; 94: 251–63. DOI: https://doi.org/10.1016/j.ejpb.2015.05.023
Manzoli L, De Vito C, Salanti G, D’Addario M, Villari P, Ioannidis JPA. Meta-analysis of the immunogenicity and tolerability of pandemic influenza A 2009 (H1N1) vaccines. PloS One. 2011; 6(9): e24384. DOI: https://doi.org/10.1371/journal.pone.0024384
Bernstein DI, Edwards KM, Dekker CL, Belshe R, Talbot HKB, Graham IL, et al. Effects of adjuvants on the safety and immunogenicity of an avian influenza H5N1 vaccine in adults. J Infect Dis. 2008 Mar 1; 197(5): 667–75. DOI: https://doi.org/10.1086/527489
Van Buynder PG, Konrad S, Van Buynder JL, Brodkin E, Krajden M, Ramler G, et al. The comparative effectiveness of adjuvanted and unadjuvanted trivalent inactivated influenza vaccine (TIV) in the elderly. Vaccine. 2013 Dec; 31(51): 6122–8. DOI: https://doi.org/10.1016/j.vaccine.2013.07.059
Della Cioppa G, Vesikari T, Sokal E, Lindert K, Nicolay U. Trivalent and quadrivalent MF59(®)-adjuvanted influenza vaccine in young children: a dose- and schedule-finding study. Vaccine. 2011 Nov 3; 29(47): 8696–704. DOI: https://doi.org/10.1016/j.vaccine.2011.08.111
Vesikari T, Pellegrini M, Karvonen A, Groth N, Borkowski A, O’Hagan DT, et al. Enhanced Immunogenicity of Seasonal Influenza Vaccines in Young Children Using MF59 Adjuvant. Pediatr Infect Dis J. 2009 Jul; 28(7): 563–71. DOI: https://doi.org/10.1097/INF.0b013e31819d6394
Schwarz TF, Horacek T, Knuf M, Damman H-G, Roman F, Dramé M, et al. Single dose vaccination with AS03-adjuvanted H5N1 vaccines in a randomized trial induces strong and broad immune responsiveness to booster vaccination in adults. Vaccine. 2009 Oct; 27(45): 6284–90. DOI: https://doi.org/10.1016/j.vaccine.2009.01.040
McElhaney JE, Beran J, Devaster J-M, Esen M, Launay O, Leroux-Roels G, et al. AS03-adjuvanted versus non-adjuvanted inactivated trivalent influenza vaccine against seasonal influenza in elderly people: a phase 3 randomised trial. Lancet Infect Dis. 2013 Jun; 13(6): 485–96. DOI: https://doi.org/10.1016/S1473-3099(13)70046-X
Durier C, Desaint C, Lucht F, Girard P-M, Lévy Y, May T, et al. Long-term immunogenicity of two doses of 2009 A/H1N1v vaccine with and without AS03A adjuvant in HIV-1-infected adults. AIDS. 2013 Jan; 27(1): 87–93. DOI: https://doi.org/10.1097/QAD.0b013e328359f27a
Rimmelzwaan G. A randomized, double blind study in young healthy adults comparing cell mediated and humoral immune responses induced by influenza ISCOM? vaccines and conventional vaccines. Vaccine. 2000 Dec; 19(9–10): 1180–7. DOI: https://doi.org/10.1016/S0264-410X(00)00310-8
Fries LF, Smith GE, Glenn GM. A Recombinant Viruslike Particle Influenza A (H7N9) Vaccine. N Engl J Med. 2013 Dec 26; 369(26): 2564–6. DOI: https://doi.org/10.1056/NEJMc1313186
Treanor JJ, Taylor DN, Tussey L, Hay C, Nolan C, Fitzgerald T, et al. Safety and immunogenicity of a recombinant hemagglutinin influenza–flagellin fusion vaccine (VAX125) in healthy young adults. Vaccine. 2010 Dec; 28(52): 8268–74. DOI: https://doi.org/10.1016/j.vaccine.2010.10.009
Taylor DN, Treanor JJ, Sheldon EA, Johnson C, Umlauf S, Song L, et al. Development of VAX128, a recombinant hemagglutinin (HA) influenza-flagellin fusion vaccine with improved safety and immune response. Vaccine. 2012 Aug; 30(39): 5761–9. DOI: https://doi.org/10.1016/j.vaccine.2012.06.086
Diaz Granados CA, Dunning AJ, Kimmel M, Kirby D, Treanor J, Collins A, et al. Efficacy of High-Dose versus Standard-Dose Influenza Vaccine in Older Adults. N Engl J Med. 2014 Aug 14; 371(7): 635–45. DOI: https://doi.org/10.1056/NEJMoa1315727
van Aalst R, Russo EM, Neupane N, Mahmud SM, Wilschut J, Samson SI, Chit A, Postma M, Young-Xu Y. Comparing the impact of high-dose versus standard dose influenza vaccines on hospitalization cost for cardiovascular and respiratory diseases: Economic assessment in the US Veteran population during 5 respiratory seasons using an instrumental variable method. Vaccine. 2021 Mar 15; 39(Suppl 1): A51–A55. DOI: https://doi.org/10.1016/j.vaccine.2020.05.080
Lee JKH, Lam GKL, Shin T, Samson SI, Greenberg DP, Chit A. Efficacy and effectiveness of high-dose influenza vaccine in older adults by circulating strain and antigenic match: An updated systematic review and meta-analysis. Vaccine. 2021 Mar 15; 39(Suppl 1): A24–A35. DOI: https://doi.org/10.1016/j.vaccine.2020.09.004
Wilkinson K, Wei Y, Szwajcer A, Rabbani R, Zarychanski R, Abou-Setta AM, et al. Efficacy and safety of high-dose influenza vaccine in elderly adults: A systematic review and meta-analysis. Vaccine. 2017 May; 35(21): 2775–80. DOI: https://doi.org/10.1016/j.vaccine.2017.03.092
Bhatt AS, Vardeny O, Udell JA, et al. Influenza vaccination: A ‘shot’ at INVESTing in cardiovascular health. European Heart Journal. 2021; 1–4.
Patel MM, Uyeki TM. Influenza Vaccine for Patients with High-risk Cardiovascular Disease. JAMA. 2021 Jan 5; 325(1): 33–35. DOI: https://doi.org/10.1001/jama.2020.23948
Grohskopf LA. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices — United States, 2020–21 Influenza Season. MMWR Recomm Rep. 2020; 69. https://www.cdc.gov/mmwr/volumes/69/rr/rr6908a1.htm (Accessed Jan 17, 2021). DOI: https://doi.org/10.15585/mmwr.rr6908a1
Shasha D, Valinsky L, Hershkowitz Sikron F, Glatman-Freedman A, Mandelboim M, Toledano A, et al. Quadrivalent versus trivalent influenza vaccine: clinical outcomes in two influenza seasons, historical cohort study. Clin Microbiol Infect. 2020 Jan; 26(1): 101–6. DOI: https://doi.org/10.1016/j.cmi.2019.05.003
Carter C, Houser KV, Yamshchikov GV, Bellamy AR, May J, Enama ME, et al. Safety and immunogenicity of investigational seasonal influenza hemagglutinin DNA vaccine followed by trivalent inactivated vaccine administered intradermally or intramuscularly in healthy adults: An open-label randomized phase 1 clinical trial. Fast PE, (ed.). PLOS ONE. 2019 Sep 18; 14(9): e0222178. DOI: https://doi.org/10.1371/journal.pone.0222178
van Riet E, Ainai A, Suzuki T, Hasegawa H. Mucosal IgA responses in influenza virus infections: Thoughts for vaccine design. Vaccine. 2012 Aug 31; 30(40): 5893–900. DOI: https://doi.org/10.1016/j.vaccine.2012.04.109
Ainai A, Suzuki T, Tamura S, Hasegawa H. Intranasal Administration of Whole Inactivated Influenza Virus Vaccine as a Promising Influenza Vaccine Candidate. Viral Immunol. 2017 Jul; 30(6): 451–62. DOI: https://doi.org/10.1089/vim.2017.0022
Sano K, Ainai A, Suzuki T, Hasegawa H. Intranasal inactivated influenza vaccines for the prevention of seasonal influenza epidemics. Expert Rev Vaccines. 2018 Aug 3; 17(8): 687–96. DOI: https://doi.org/10.1080/14760584.2018.1507743
Young B, Sadarangani S, Jiang L, Wilder-Smith A, Chen MI-C. Duration of Influenza Vaccine Effectiveness: A Systematic Review, Meta-analysis, and Meta-regression of Test-Negative Design Case-Control Studies. J Infect Dis. 2018 Feb 14; 217(5): 731–41. DOI: https://doi.org/10.1093/infdis/jix632
Nguyen VH, Vizzotti C, Uruena A, Giglio N, Magneres C, Richmond H. Cost-effectiveness of introducing an MF59-adjuvanted trivalent influenza vaccine for older adults in Argentina. Vaccine. 2020 Apr; 38(20): 3682–9. DOI: https://doi.org/10.1016/j.vaccine.2020.02.081
Nichol KL, Goodman M. Cost effectiveness of influenza vaccination for healthy persons between ages 65 and 74 years. Vaccine. 2002 May; 20: S21–4. DOI: https://doi.org/10.1016/S0264-410X(02)00124-X
Gutiérrez JP, Bertozzi SM. Vacunación contra influenza para adultos mayores en México: consideraciones económicas. Salud Pública México. 2005 Jun; 47(3): 234–9. DOI: https://doi.org/10.1590/S0036-36342005000300007
PAHO. EPI Newsletter: Expanded Program on Immunization in the Americas. 2004: 26(6): 2–4. https://www.paho.org/hq/dmdocuments/2012/Influenza-Cost-Effectiveness-Costa-Rica.pdf (Accessed Jan 17, 2021).
Porras-Ramírez A, Alvis-Guzmán N, Rico-Mendoza A, Alvis-Estrada L, Castañeda-Orjuela CA, Velandia-González MP, et al. Costo efectividad de la vacunación contra influenza en menores de 2 años y mayores de 65 años en Colombia. Rev Salud Pública. 2009 Oct; 11(5): 689–99. DOI: https://doi.org/10.1590/S0124-00642009000500002
Yue M, Dickens BL, Yoong JS, I-Cheng Chen M, Teerawattananon Y, Cook AR. Cost-Effectiveness Analysis for Influenza Vaccination Coverage and Timing in Tropical and Subtropical Climate Settings: A Modeling Study. Value Health. 2019 Dec; 22(12): 1345–54. DOI: https://doi.org/10.1016/j.jval.2019.07.001
Fisman DN, Tuite AR. Estimation of the Health Impact and Cost-Effectiveness of Influenza Vaccination with Enhanced Effectiveness in Canada. Cowling BJ (ed.). PLoS ONE. 2011 Nov 14; 6(11): e27420. DOI: https://doi.org/10.1371/journal.pone.0027420
Allsup S, Haycox A, Regan M, Gosney M. Is influenza vaccination cost effective for healthy people between ages 65 and 74 years? Vaccine. 2004 Dec; 23(5): 639–45. DOI: https://doi.org/10.1016/S0264-410X(04)00519-5
Kosteneffectiviteit van influenzavaccinatie in Nederland|Nederlands Tijdschrift voor Geneeskunde. https://www.ntvg.nl/artikelen/kosteneffectiviteit-van-influenzavaccinatie-nederland/volledig (Accessed Jan 17, 2021).
Mullooly JP. Influenza Vaccination Programs for Elderly Persons: Cost-Effectiveness in a Health Maintenance Organization. Ann Intern Med. 1994 Dec 15; 121(12): 947. DOI: https://doi.org/10.7326/0003-4819-121-12-199412150-00008
Wang C-S, Wang S-T, Chou P. Efficacy and cost-effectiveness of influenza vaccination of the elderly in a densely populated and unvaccinated community. Vaccine. 2002 Jun; 20(19–20): 2494–9. DOI: https://doi.org/10.1016/S0264-410X(02)00181-0
Hoshi S-L, Kondo M, Honda Y, Okubo I. Cost-effectiveness analysis of influenza vaccination for people aged 65 and over in Japan. Vaccine. 2007 Aug; 25(35): 6511–21. DOI: https://doi.org/10.1016/j.vaccine.2007.05.067
Schooling CM, Wong LC, Chau J, Cheung A, Ho A, McGhee SM. Cost-effectiveness of influenza vaccination for elderly people living in the community. Hong Kong Med J Xianggang Yi Xue Za Zhi. 2009 Oct; 15(Suppl 6): 44–7.
You JH, Ming W, Chan PK. Cost-effectiveness analysis of quadrivalent influenza vaccine versus trivalent influenza vaccine for elderly in Hong Kong. BMC Infect Dis. 2014 Dec; 14(1): 618. DOI: https://doi.org/10.1186/s12879-014-0618-9
Chit A, Roiz J, Briquet B, Greenberg DP. Expected cost effectiveness of high-dose trivalent influenza vaccine in US seniors. Vaccine. 2015 Jan; 33(5): 734–41. DOI: https://doi.org/10.1016/j.vaccine.2014.10.079
Brydak L, Roiz J, Faivre P, Reygrobellet C. Implementing an Influenza Vaccination Programme for Adults Aged ≥65 Years in Poland: A Cost-Effectiveness Analysis. Clin Drug Investig. 2012 Feb; 32(2): 73–85. DOI: https://doi.org/10.2165/11594030-000000000-00000
Van Bellinghen L-A, Meier G, Van Vlaenderen I. The Potential Cost-Effectiveness of Quadrivalent versus Trivalent Influenza Vaccine in Elderly People and Clinical Risk Groups in the UK: A Lifetime Multi-Cohort Model. Ho PL (ed.). PLoS ONE. 2014 Jun 6; 9(6): e98437. DOI: https://doi.org/10.1371/journal.pone.0098437
Duru G, Carrat F, Pribil C, Bricaire F, Pujol P, Robert J, et al. Cost Effectiveness of Quadrivalent Influenza Vaccine Over Trivalent Vaccine in France. Value Health J Int Soc Pharmacoeconomics Outcomes Res. 2014 Nov; 17(7): A678. DOI: https://doi.org/10.1016/j.jval.2014.08.2525
Raviotta JM, Smith KJ, DePasse J, Brown ST, Shim E, Nowalk MP, et al. Cost-Effectiveness and Public Health Effect of Influenza Vaccine Strategies for U.S. Elderly Adults. J Am Geriatr Soc. 2016 Oct; 64(10): 2126–31. DOI: https://doi.org/10.1111/jgs.14323
Capri S, Barbieri M, de Waure C, Boccalini S, Panatto D. Cost-effectiveness analysis of different seasonal influenza vaccines in the elderly Italian population. Hum Vaccines Immunother. 2018 Jun 3; 14(6): 1331–41. DOI: https://doi.org/10.1080/21645515.2018.1438792
Jamotte A, Clay E, Macabeo B, Caicedo A, Lopez JG, Bricks L, et al. Public health impact and economic benefits of quadrivalent influenza vaccine in Latin America. Hum Vaccines Immunother. 2017 Apr 3; 13(4): 877–88. DOI: https://doi.org/10.1080/21645515.2016.1256928
Kim Y-K, Song JY, Jang H, Kim TH, Koo H, Varghese L, et al. Cost Effectiveness of Quadrivalent Influenza Vaccines Compared with Trivalent Influenza Vaccines in Young Children and Older Adults in Korea. PharmacoEconomics. 2018 Dec; 36(12): 1475–90. DOI: https://doi.org/10.1007/s40273-018-0715-5
Chen C, Liu GE, Wang MJ, Gao TF, Jia HP, Yang H, et al. Cost-effective analysis of seasonal influenza vaccine in elderly Chinese population. Zhonghua Yu Fang Yi Xue Za Zhi. 2019 Oct 6; 53(10): 993–9.
Jiang M, Li P, Wang W, Zhao M, Atif N, Zhu S, et al. Cost-effectiveness of quadrivalent versus trivalent influenza vaccine for elderly population in China. Vaccine. 2020 Jan; 38(5): 1057–64. DOI: https://doi.org/10.1016/j.vaccine.2019.11.045
Yang J, Atkins KE, Feng L, Baguelin M, Wu P, Yan H, et al. Cost-effectiveness of introducing national seasonal influenza vaccination for adults aged 60 years and above in mainland China: a modelling analysis. BMC Med. 2020 Dec; 18(1): 90. DOI: https://doi.org/10.1186/s12916-020-01545-6
Aballéa S, Chancellor J, Martin M, Wutzler P, Carrat F, Gasparini R, et al. The Cost-Effectiveness of Influenza Vaccination for People Aged 50 to 64 Years: An International Model. Value Health. 2007 Mar; 10(2): 98–116. DOI: https://doi.org/10.1111/j.1524-4733.2006.00157.x
Newall AT, Scuffham PA, Kelly H, Harsley S, MacIntyre CR. The cost-effectiveness of a universal influenza vaccination program for adults aged 50–64 years in Australia. Vaccine. 2008 Apr; 26(17): 2142–53. DOI: https://doi.org/10.1016/j.vaccine.2008.01.050
Mogasale V, Barendregt J. Cost-effectiveness of influenza vaccination of people aged 50–64 years in Australia: results are inconclusive. Aust N Z J Public Health. 2011 Apr; 35(2): 180–6. DOI: https://doi.org/10.1111/j.1753-6405.2010.00639.x
Aballea S, Dejuanes J, Barbieri M, Martin M, Chancellor J, Oyaguez I, et al. The cost effectiveness of influenza vaccination for adults aged 50 to 64 years: A model-based analysis for Spain. Vaccine. 2007 Sep 28; 25(39–40): 6900–10. DOI: https://doi.org/10.1016/j.vaccine.2007.07.033
Choi EJ, Park JH, Chun BC. Cost effectiveness of trivalent and quadrivalent influenza vaccines in 50- to 64-year-old adults in Korea. Vaccine. 2020 Jul; 38(32): 5002–8. DOI: https://doi.org/10.1016/j.vaccine.2020.05.065
Turner DA, Wailoo AJ, Cooper NJ, Sutton AJ, Abrams KR, Nicholson KG. The cost-effectiveness of influenza vaccination of healthy adults 50–64 years of age. Vaccine. 2006 Feb; 24(7): 1035–43. DOI: https://doi.org/10.1016/j.vaccine.2004.12.033
Maciosek MV, Solberg LI, Coffield AB, Edwards NM, Goodman MJ. Influenza Vaccination. Am J Prev Med. 2006 Jul; 31(1): 72–9. DOI: https://doi.org/10.1016/j.amepre.2006.03.008
Akın L, Macabéo B, Caliskan Z, Altinel S, Satman I. Cost-Effectiveness of Increasing Influenza Vaccination Coverage in Adults with Type 2 Diabetes in Turkey. Borrow R (ed.). PLOS ONE. 2016 Jun 20; 11(6): e0157657. DOI: https://doi.org/10.1371/journal.pone.0157657
Yang J, Yan H, Feng LZ, Yu HJ. [Cost-effectiveness of potential government fully-funded influenza vaccination in population with diabetes in China]. Zhonghua Yu Fang Yi Xue Za Zhi. 2019 Oct 6; 53(10): 1000–6.
Bui AL, Horwich TB, Fonarow GC. Epidemiology and risk profile of heart failure. Nat Rev Cardiol. 2011 Jan; 8(1): 30–41. DOI: https://doi.org/10.1038/nrcardio.2010.165
Conrad N, Judge A, Canoy D, Tran J, Pinho-Gomes A-C, Millett ERC, et al. Temporal Trends and Patterns in Mortality After Incident Heart Failure: A Longitudinal Analysis of 86 000 Individuals. JAMA Cardiol. 2019 Nov 1; 4(11): 1102. DOI: https://doi.org/10.1001/jamacardio.2019.3593
Sribhutorn A, Phrommintikul A, Wongcharoen W, Chaikledkaew U, Eakanunkul S, Sukonthasarn A. Influenza vaccination in acute coronary syndromes patients in Thailand: The cost-effectiveness analysis of the prevention for cardiovascular events and pneumonia. J Geriatr Cardiol JGC. 2018 Jun; 15(6): 413–21.
Peasah SK, Meltzer MI, Vu M, Moulia DL, Bridges CB. Cost-effectiveness of increased influenza vaccination uptake against readmissions of major adverse cardiac events in the US. Lazzeri C (ed.). PLOS ONE. 2019 Apr 29; 14(4): e0213499. DOI: https://doi.org/10.1371/journal.pone.0213499
Suh J, Kim B, Yang Y, Suh D-C, Kim E. Cost effectiveness of influenza vaccination in patients with acute coronary syndrome in Korea. Vaccine. 2017 May; 35(21): 2811–7. DOI: https://doi.org/10.1016/j.vaccine.2017.04.016
Thorrington D, van Leeuwen E, Ramsay M, Pebody R, Baguelin M. Cost-effectiveness analysis of quadrivalent seasonal influenza vaccines in England. BMC Med. 2017 Dec; 15(1): 166. DOI: https://doi.org/10.1186/s12916-017-0932-3
Blommaert A, Bilcke J, Vandendijck Y, Hanquet G, Hens N, Beutels P. Cost-effectiveness of seasonal influenza vaccination in pregnant women, health care workers and persons with underlying illnesses in Belgium. Vaccine. 2014 Oct; 32(46): 6075–83. DOI: https://doi.org/10.1016/j.vaccine.2014.08.085
García A, Ortiz de Lejarazu R, Reina J, Callejo D, Cuervo J, Morano Larragueta R. Cost-effectiveness analysis of quadrivalent influenza vaccine in Spain. Hum Vaccines Immunother. 2016 Sep; 12(9): 2269–77. DOI: https://doi.org/10.1080/21645515.2016.1182275
Nagy L, Heikkinen T, Sackeyfio A, Pitman R. The Clinical Impact and Cost Effectiveness of Quadrivalent Versus Trivalent Influenza Vaccination in Finland. PharmacoEconomics. 2016 Sep; 34(9): 939–51. DOI: https://doi.org/10.1007/s40273-016-0430-z
Yang M-C, Tan EC-H, Su J-J. Cost-effectiveness analysis of quadrivalent versus trivalent influenza vaccine in Taiwan: A lifetime multi-cohort model. Hum Vaccines Immunother. 2017 Jan 2; 13(1): 81–9. DOI: https://doi.org/10.1080/21645515.2016.1225636
Mennini FS, Bini C, Marcellusi A, Rinaldi A, Franco E. Cost-effectiveness of switching from trivalent to quadrivalent inactivated influenza vaccines for the at-risk population in Italy. Hum Vaccines Immunother. 2018 Aug 3; 14(8): 1867–73. DOI: https://doi.org/10.1080/21645515.2018.1469368
Nichol KL, Lind A, Margolis KL, Murdoch M, McFadden R, Hauge M, et al. The Effectiveness of Vaccination against Influenza in Healthy, Working Adults. N Engl J Med. 1995 Oct 5; 333(14): 889–93. DOI: https://doi.org/10.1056/NEJM199510053331401
Clements KM, Chancellor J, Nichol K, DeLong K, Thompson D. Cost-Effectiveness of a Recommendation of Universal Mass Vaccination for Seasonal Influenza in the United States. Value Health. 2011 Sep; 14(6): 800–11. DOI: https://doi.org/10.1016/j.jval.2011.03.005
Dabestani NM, Leidner AJ, Seiber EE, Kim H, Graitcer SB, Foppa IM, et al. A review of the cost-effectiveness of adult influenza vaccination and other preventive services. Prev Med. 2019 Sep; 126: 105734. DOI: https://doi.org/10.1016/j.ypmed.2019.05.022
MacIntyre CR, Mahimbo A, Moa AM, Barnes M. Influenza vaccine as a coronary intervention for prevention of myocardial infarction. Heart. 2016 Dec 15; 102(24): 1953–6. DOI: https://doi.org/10.1136/heartjnl-2016-309983
Hendriks J, Hutubessy RCW, Grohmann G, Torelli G, Friede M, Kieny M-P. Quadrivalent influenza vaccines in low and middle income countries: Cost-effectiveness, affordability and availability. Vaccine. 2018 Jun; 36(28): 3993–7. DOI: https://doi.org/10.1016/j.vaccine.2018.05.099
Colrat F, Thommes E, Largeron N, Alvarez FP. Economic evaluation of high-dose inactivated influenza vaccine in adults aged ≥65 years: A systematic literature review. Vaccine. 2021 Mar 15; 39(Suppl 1): A42–A50. DOI: https://doi.org/10.1016/j.vaccine.2020.12.036
Ropero-Álvarez AM, El Omeiri N, Kurtis HJ, Danovaro-Holliday MC, Ruiz-Matus C. Influenza vaccination in the Americas: Progress and challenges after the 2009 A(H1N1) influenza pandemic. Hum Vaccines Immunother. 2016 May 19; 12(8): 2206–14. DOI: https://doi.org/10.1080/21645515.2016.1157240
Fica CA, Antunez RM, Cuevas AK, Rodriguez NA, Aravena RP. Prescripción de la vacuna anti influenza por médicos institucionales y estudiantes de especialidades médicas en un hospital docente. Rev Chil Infectol. 2001; 18(1). http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0716-10182001000100003&lng=en&nrm=iso&tlng=en. DOI: https://doi.org/10.4067/S0716-10182001000100003
Hershey CO, Karuza J. Delivery of Vaccines to Adults: Correlations with Physician Knowledge and Patient Variables. Am J Med Qual. 1997 Sep; 12(3): 143–50. DOI: https://doi.org/10.1177/106286069701200302
Baron G, De Wals P, Milord F. Vaccination practices of Quebec family physicians. Influenza vaccination status and professional practices for influenza vaccination. Can Fam Physician Med Fam Can. 2001 Nov; 47: 2261–6.
Olasupo OO, Brown J, Segal R. Missed Opportunities for Influenza and Pneumococcal Vaccinations in the Elderly in the US – A Cross-Sectional Analysis. Value Health. 2018 May 1; 21: S158. DOI: https://doi.org/10.1016/j.jval.2018.04.1083
Davis BM, Black D. Identifying the Challenges to Adult Influenza Vaccination in Latin America. Value Health. 2017 Oct 1; 20(9): A934. DOI: https://doi.org/10.1016/j.jval.2017.08.2951
Zimmerman RK, Santibanez TA, Janosky JE, Fine MJ, Raymund M, Wilson SA, et al. What affects influenza vaccination rates among older patients? An analysis from inner-city, suburban, rural, and Veterans Affairs practices. Am J Med. 2003 Jan; 114(1): 31–8. DOI: https://doi.org/10.1016/S0002-9343(02)01421-3
Centers for Disease Control and Prevention (CDC). Reasons reported by Medicare beneficiaries for not receiving influenza and pneumococcal vaccinations—United States, 1996. MMWR Morb Mortal Wkly Rep. 1999 Oct 8; 48(39): 886–90.
Centers for Disease Control (CDC). Adult immunization: Knowledge, attitudes, and practices—DeKalb and Fulton Counties, Georgia, 1988. MMWR Morb Mortal Wkly Rep. 1988 Nov 4; 37(43): 657–61.
Bovier PA, Chamot E, Bouvier Gallacchi M, Loutan L. Importance of patients’ perceptions and general practitioners’ recommendations in understanding missed opportunities for immunisations in Swiss adults. Vaccine. 2001 Sep; 19(32): 4760–7. DOI: https://doi.org/10.1016/S0264-410X(01)00223-7
Srivanichakom W, Asavathitanonta K, Washirasaksiri C, Chaisathaphon T, Chouriyagune C, Phisalprapa P, et al. Prescribing rate of influenza vaccine among internal medicine residents for outpatient continuum care. J Med Assoc Thail Chotmaihet Thangphaet. 2014 Dec; 97(12): 1281–9.
Jaiyeoba O, Villers M, Soper DE, Korte J, Salgado CD. Association between health care workers’ knowledge of influenza vaccine and vaccine uptake. Am J Infect Control. 2014 Jan; 42(1): 69–70. DOI: https://doi.org/10.1016/j.ajic.2013.06.020
Larson HJ, de Figueiredo A, Xiahong Z, Schulz WS, Verger P, Johnston IG, et al. The State of Vaccine Confidence 2016: Global Insights Through a 67-Country Survey. EBioMedicine. 2016 Oct; 12: 295–301. DOI: https://doi.org/10.1016/j.ebiom.2016.08.042
Bertoldo G, Pesce A, Pepe A, Pelullo CP, Di Giuseppe G, The Collaborative Working Group. Seasonal influenza: Knowledge, attitude and vaccine uptake among adults with chronic conditions in Italy. Manzoli L (ed.). PLOS ONE. 2019 May 1; 14(5): e0215978. DOI: https://doi.org/10.1371/journal.pone.0215978
Schmid P, Rauber D, Betsch C, Lidolt G, Denker M-L. Barriers of Influenza Vaccination Intention and Behavior – A Systematic Review of Influenza Vaccine Hesitancy, 2005 – 2016. Cowling BJ (ed.). PLOS ONE. 2017 Jan 26; 12(1): e0170550. DOI: https://doi.org/10.1371/journal.pone.0170550
Sosa Liprandi Á, Zaidel EJ, Lopez Santi R, Araujo JJ, Baños González MA, Busso JM, et al. Influenza and Pneumococcal Vaccination in Non-Infected Cardiometabolic Patients from the Americas during the COVID-19 Pandemic. A Sub-Analysis of the CorCOVID-LATAM Study. Vaccines. 2021 Feb 4; 9(2). DOI: https://doi.org/10.3390/vaccines9020123
Burki T. Vaccine misinformation and social media. Lancet Digit Health. 2019 Oct; 1(6): e258–9. DOI: https://doi.org/10.1016/S2589-7500(19)30136-0
Medical Misinformation. Vet the Message! Int J Cardiol. 2019 Feb; 277: 1–2. DOI: https://doi.org/10.1016/j.ijcard.2018.12.071
Waszak PM, Kasprzycka-Waszak W, Kubanek A. The spread of medical fake news in social media – The pilot quantitative study. Health Policy Technol. 2018 Jun; 7(2): 115–8. DOI: https://doi.org/10.1016/j.hlpt.2018.03.002
Chan M-PS, Jamieson KH, Albarracin D. Prospective associations of regional social media messages with attitudes and actual vaccination: A big data and survey study of the influenza vaccine in the United States. Vaccine. 2020 Sep 11; 38(40): 6236–47. DOI: https://doi.org/10.1016/j.vaccine.2020.07.054
Guidry JPD, Coman IA, Vraga EK, O’Donnell NH, Sreepada N. (S)pin the flu vaccine: Recipes for concern. Vaccine. 2020 Jul 22; 38(34): 5498–506. DOI: https://doi.org/10.1016/j.vaccine.2020.06.012
Pulido C, Ruiz-Eugenio L, Redondo-Sama G, Villarejo-Carballido B. A New Application of Social Impact in Social Media for Overcoming Fake News in Health. Int J Environ Res Public Health. 2020 Apr 3; 17(7): 2430. DOI: https://doi.org/10.3390/ijerph17072430
Trethewey SP. Strategies to combat medical misinformation on social media. Postgrad Med J. 2020 Jan; 96(1131): 4–6. DOI: https://doi.org/10.1136/postgradmedj-2019-137201
Steffens MS, Dunn AG, Wiley KE, Leask J. How organisations promoting vaccination respond to misinformation on social media: A qualitative investigation. BMC Public Health. 2019 Dec; 19(1): 1348. DOI: https://doi.org/10.1186/s12889-019-7659-3
YouTube, Facebook and Twitter align to fight Covid vaccine conspiracies. BBC News. 2020 Nov 20. https://www.bbc.com/news/technology-55005385 (Accessed Mar 26, 2021).
Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5306a1.htm (Accessed Jan 17, 2021).
Vizzotti C, Katz N, Stecher D, Aquino A, Juárez MDV, Urueña A. Assessment of the use in adults of four vaccines: A population survey in Argentina. Medicina (Mex). 2018; 78(2): 76–82.
Galante M, Konfino J, Ondarsuhu D, Goldberg L, O’Donnell V, Begue G, et al. Principales resultados de la Tercera Encuesta Nacional de Factores de Riesgo de Enfermedades No Transmisibles en Argentina. Rev Argent Salud Pública. 2019 Jan 25; 6.
SI-PNI Web. http://sipni.datasus.gov.br/si-pni-web/faces/inicio.jsf (Accessed Jan 17, 2021).
Jarvis JD, Woods H, Bali A, Oronsaye E, Persaud N. Selection of WHO-recommended essential medicines for non-communicable diseases on National Essential Medicines Lists. Daivadanam M (ed.). PLOS ONE. 2019 Aug 9; 14(8): e0220781. DOI: https://doi.org/10.1371/journal.pone.0220781
EMLs Around The World. https://global.essentialmeds.org/dashboard/medicines/964 (Accessed Jan 17, 2021).
PAHO|Fondo Rotatorio. https://www.paho.org/hq/index.php?option=com_topics&view=article&id=396&Itemid=42192&lang=es (Accessed Jan 17, 2021).
Gopal S, Davis MM. Delivery of influenza vaccine to non-elderly persons with cardiovascular disease, with varying national supply of vaccine: A decision analysis. Hum Vaccin. 2005 Dec; 1(6): 217–23. DOI: https://doi.org/10.4161/hv.1.6.2225
Nowalk MP, Zimmerman RK, Shen S, Jewell IK, Raymund M. Barriers to pneumococcal and influenza vaccination in older community-dwelling adults (2000–2001). J Am Geriatr Soc. 2004 Jan; 52(1): 25–30. DOI: https://doi.org/10.1111/j.1532-5415.2004.52006.x
Chi R-C, Neuzil KM. The association of sociodemographic factors and patient attitudes on influenza vaccination rates in older persons. Am J Med Sci. 2004 Mar; 327(3): 113–7. DOI: https://doi.org/10.1097/00000441-200403000-00001
Villarreal R, Zaidel EJ, Cestari HG, Mele EF, Sosa Liprandi MI, Sosa Liprandi A. Influenza and Pneumococcal Vaccination in Patients with Cardiovascular Disease: Pilot Project. Rev Argent Cardiol. 2016; 84: 582–583.
Changing the Conversation on Adult Influenza Vaccination – Vaccines 4 Life. https://www.vaccines4life.com/changing-the-conversation/ (Accessed Jan 17, 2021).