Does influenza vaccination influence cardiovascular complications?

Abstract

Each year, influenza infection is responsible for substantial morbidity and mortality across the globe. Because confirmatory testing is often not performed, the total burden of influenza on annual cardiopulmonary (respiratory and cardiac) hospitalizations is likely even higher.

Keywords:

• influenza
• vaccination
• ischemic heart disease
• heart failure
• prevention
• randomized controlled trial

Potential mechanism of influenza infection as a trigger for acute cardiovascular events

A large body of data support the notion that influenza itself may be a trigger for major adverse cardiovascular events (MACE) and heart failure (HF) exacerbations, further adding to the morbidity and mortality associated with this infection [1–4]. Observational studies have shown an elevated short-term risk for acute myocardial infarction (MI; incidence ratio 4.95; 95% CI: 4.43–5.53), and stroke (incidence ratio 3.19; 95% CI: 2.81–3.62), within the first few days after a respiratory infection that gradually declines over time [3–5]. A number of proposed mechanisms support a potential causal association between influenza infection and cardiovascular risk: systemic immune stimulation and inflammation as triggers of acute plaque rupture; cardiovascular consequences of increase in metabolic demand, adrenergic surge, endothelial dysfunction, hypercoagulability and hypoxia; direct myocardial and/or arterial toxicity with myocarditis, arteritis, thrombosis and capillary permeability. Influenza can act to produce a potent inflammatory and thrombotic stimulus, with either direct myocardial injury or indirect influence by activation of circulating procoagulants, elevation in cytokine levels, endothelial dysfunction, fluid shifts and sympathetic stimulation as observed in patients with coronary artery disease, stroke and HF [6,7]. Influenza infection also predisposes patients to develop opportunistic pneumonia, which in itself is associated with increased cardiovascular events due to prolonged elevation in cytokine levels and a procoagulant state [5,7]. When compounded by hypoxemia, influenza may exacerbate underlying cardiovascular disease, resulting in volume overload HF, plaque rupture, arrhythmia, with potentially lethal cardiovascular consequences. Influenza infection has also been associated within direct myocardial depression [8], which has been ascribed to an increase in pro-inflammatory cytokines; with histologic evidence of myocardial injury, myocarditis and myocyte necrosis after influenza-related deaths [6].

The influence of standard-dose influenza vaccination on cardiovascular complications

A recent systematic review and meta-analysis of randomized controlled trials showed that the cardiovascular risk attributable to influenza may be a modifiable risk factor through influenza vaccination. Specifically, annual influenza vaccination reduced the risk for MACE in patients with or at risk for cardiovascular disease by 36% compared with placebo or standard care (2.9 vs 4.7%; risk ratio [RR] 0.64; 95% CI: 0.48–0.86; p = 0.003). A treatment interaction was detected such that those with recent acute MI derived the greatest cardioprotective benefit from influenza vaccine (RR: 0.45; 95% CI: 0.32–0.63) compared with patients with stable coronary disease (RR: 0.94; 95% CI: 0.55–1.61; p interaction = 0.02) [9]. Limitations of this meta-analysis are that the randomized controlled trials included patients of varied risk and were underpowered to detect beneficial effects in individual cardiovascular endpoints or key subgroups. Confirmation of these results in an adequately powered outcomes trial is warranted.

Potential mechanism of cardioprotection with influenza vaccination

The mechanism by which influenza vaccination protects against cardiovascular events is multifactorial. In addition to preventing infection and thus avoiding disruptions in homeostasis, the immune response to vaccination itself may result in non-infectious cardiovascular benefits. For instance, vaccine-induced antibodies may promote plaque or hemodynamic stabilization via activation of the bradykinin 2 receptor, which induces nitric oxide production, vasodilation and natriuresis [10]. Moreover, influenza vaccination may promote atherosclerotic plaque stabilization. A study in apoE knockout mice showed that influenza-vaccinated mice developed smaller atherosclerotic regions with lower lipid content and higher concentrations of smooth muscle cells and collagen compared with control-treated animals [11]. However, optimal effectiveness from influenza vaccination relies upon intact immune responses, which may be compromised in those with cardiovascular conditions.

Variation in immune response to influenza vaccination

There is considerable heterogeneity among patients in antibody response to influenza vaccine, thus a substantial proportion of vaccinated patients remains at high residual risk for influenza infection and influenza-attributable cardiopulmonary complications despite receiving a standard dose (SD) of trivalent-inactivated influenza vaccination, the current standard of care [12]. Risk factors for a decline in innate immune function and insufficient antibody responsiveness to vaccination (i.e., immunosenescence) include advancing age, obesity and comorbidities, including patients with or at risk for cardiovascular disease [13]. For instance, patients with ischemic and non-ischemic HF exhibit reduced humoral immune responses to influenza vaccination evidenced by lower antibody titers, a widely accepted measure of vaccine efficacy, compared with healthy controls [14]. Another study in patients with stable coronary artery disease did not find differences in antibody response compared with healthy controls [15]. It is possible that more pronounced beta adrenergic stimulation occurring in HF, which has been associated with blunted immune responses, may account for the differences observed in patients with varying cardiovascular risk. Cell-mediated responses to influenza vaccination are also crucial for mounting adequate protection from influenza infection, and these have been shown to be altered with advancing age. Specifically, reduced T-cell proliferation and cytokine production were observed after influenza vaccine challenge in older individuals [13]. Although not routinely measured due to a lack of consensus for the most appropriate assay, cell-mediated responses may be more representative of the immune system dysfunction that occurs with aging. There are several new vaccine formulations and/or strategies that have been tested predominantly in elderly patients or are in development to boost the immune response. One recently demonstrated strategy to enhance immune response in elderly patients, including those with established heart disease, is vaccination with a more concentrated dose of trivalent inactivated influenza vaccination.

High-dose influenza vaccination in HF patients & influenza protection

In a single-centre, double-blind, pilot RCT, antibody responses in patients with ischemic and non-ischemic HF were augmented using a higher dose of influenza vaccine [16]. Participants (n = 28) were randomized during the 2009/2010 influenza season to receive double dose (30 μg/strain) or SD (15 μg/strain) influenza vaccine. At 2–4 weeks, double dose antibody titers were significantly higher than those of SD in both influenza A strains tested, A/H3N2 (p < 0.001) and A/H1N1 (p = 0.009). Three individuals in each group experienced mild injection site soreness, and two participants in the double dose group noted severe injection site soreness. There were no serious adverse events observed.

Recently, a Phase III multicenter randomized double-blind active control trial of 31,989 medically stable adults aged ≥65 years demonstrated a 24% reduced risk of laboratory-confirmed influenza among participants randomized to a fourfold higher dose (60 g/strain) of influenza vaccine compared with the SD (15 g/strain) of influenza vaccine (1.43 vs 1.89%; RR: 0.76, 95% CI: 0.64–0.90) [17]. Preliminary results also suggest that the high-dose vaccine trended toward reduced risk of pneumonia, all-cause hospitalization, and cardiopulmonary events with no increase in serious adverse events compared with standard-dose vaccine. Although the trial included a limited number of patients with stable coronary disease and stable HF, individuals with recent acute coronary syndrome or acute HF were not included; the trial was also underpowered to assess cardiopulmonary events. Thus, it is possible that the benefit of high-dose influenza vaccine in patients with recent MI or HF could be more pronounced [17].

The benefit of high-dose influenza vaccination on cardiovascular complications

To address the core hypothesis of whether more influenza protection may provide additional cardiovascular benefit, the previously described systematic review also considered the comparative effectiveness of different strategies of influenza vaccination, that is, intensive compared with standard vaccination. An intensive strategy encompassed either a more concentrated dose of an annual trivalent inactivated influenza vaccine, re-administration of standard-dose trivalent inactivated vaccine in patients with a suboptimal antibody response (i.e., a booster shot), compared with an intranasal live attenuated influenza vaccine, use of both a standard-dose trivalent inactivated vaccine and an intranasal live attenuated influenza vaccine and other strategies. The meta-analysis of active control randomized controlled trials suggested a trend toward a further 27% reduced risk for MACE in which patients were treated with intensive versus standard influenza vaccination (0.39 vs 0.60%; RR: 0.72; 95% CI: 0.46–1.13) [9]. This finding should be considered hypothesis generating, as it was determined from several small, individually underpowered trials that were not designed as cardiovascular outcomes studies, with varying risk patient populations, influenza vaccines tested, seasons of study and duration of follow-up.

Safety of high-dose influenza vaccination

High-dose influenza vaccine is well tolerated and safe with no increase in serious adverse events when compared with standard-dose vaccines [18]. Mild-to-moderate injection-site reactions, but not systemic reactions or unsolicited adverse events, were reported more commonly in clinical trials of high-dose versus SD vaccine.

Definition of the standard influenza vaccine: a moving target

In addition to increased antigen amounts in the high-dose trivalent influenza vaccine (TIV) formulation, alternative influenza vaccine strategies are available, including the SD quadrivalent influenza vaccine. The quadrivalent formulation contains an additional influenza B strain, as opposed to TIV, which includes three components: A/H1N1, A/H3N2, and only one B-serotype. In recent years, two different influenza B lineages have been in circulation. Quadrivalent offers added protection by reducing potential mismatch between circulating and vaccine lineages, and although the A-type viruses predominate most years, a B-type virus rises above epidemic threshold every 2–4 years. Adoption of quadrivalent vaccine has been on the rise over the past few influenza seasons and is expected to continue to expand and become standard of care. Currently, there is not a high-dose quadrivalent vaccine formulation available.

Conclusion

A substantial proportion of the estimated morbidity and cost of treating heart disease may be attributable to elevated cardiopulmonary hospitalizations during influenza season. As such, effective influenza immunization in high-risk patients with cardiovascular disease is of paramount importance and could prevent influenza-related hospitalizations, reduce MACE and acute HF and decrease mortality. If preliminary findings in patients with recent MI and HF can be confirmed, a simple, once annual influenza vaccine may have the ability to impact a major population attributable cardiovascular risk, inform policy and boost its use in routine practice.

Financial & competing interests disclosure

The authors were supported by the Peter Munk Chair in Multinational Clinical Trials, Peter Munk Cardiac Centre and Department of Medicine, University Health Network; Heart and Stroke Foundation of Canada; Canadian Institutes for Health Research; Women’s College Research Institute and Department of Medicine, Women’s College Hospital; Department of Medicine and Heart and Stroke/Richard Lewar Centres of Excellence in Cardiovascular Research, University of Toronto. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.