In this study, we compared humoral and CTL immune responses to influenza vaccination in patients with heart failure compared to healthy individuals. Our results were threefold.
First, participants with HF exhibited higher IL-10 production in response to influenza vaccination compared with healthy controls. Additionally, HF participants had a lower IFNγ:IL:10 ratio compared with healthy controls, indicating a Th2 dominant phenotype. There were no differences in IFNγ production between groups. CTL responses are critical for recovery from influenza infection; particularly Th1 responses. CTL responses to influenza vaccine depend on IFNγ which in turn stimulate influenza-specific memory T cells. A shift from Th1 cytokines (involving IFNγ) to Th2 cytokines (involving IL-10) with aging has been associated with reduced CTL activity and diminished protection against influenza virus challenge.[22
] Although influenza-specific Th2 cytokines such as IL-10 do not promote recovery from influenza infection, these cytokines continue to be expressed in high levels at the site of influenza infection, indicating that a balance between Th1 and Th2 cytokines may be important for viral clearance.[24
] Our study suggests that Th1 responses are preserved in patients with heart failure, and that overall CTL responses are shifted toward involvement of Th2 cytokines. Our cohort was significantly younger than those included in the abovementioned CTL response study, suggesting that perhaps certain chronic conditions may influence response phenotype in addition to age.
Second, participants with HF mounted a less vigorous antibody response to the vaccine viral strain A/H3N2 compared with healthy individuals. The composition of the trivalent influenza vaccine changes with each influenza season. The A/H3N2 strain was the newest strain to be incorporated into the vaccine for the 2006/2007 season. Evaluation of influenza vaccine relies heavily on serologic responses. The most widely accepted measures that indicate appropriate immune responses are seroprotection (antibody titer ≥40) and seroconversion (4 fold increase in antibody titer). However, these require demonstration of an antibody mediated response to just one of the three vaccine viral strains. It may be advantageous to measure responses to each individual vaccine viral strain in order to gain a better understanding of high rates of influenza infection in patients with heart failure despite growing and widespread immunization rates. Although rates of seroprotection and seroconversion were similar between groups, HF patients were not able to mount as vigorous of a humoral response to the newest vaccine viral strain compared with healthy individuals. As such, measurement of seroconversion and seroprotection rates alone may not capture individuals who remain at high risk for infection due to varying responses to specific viral strains. Our results suggest that patients with HF may rely on immunologic memory to mount appropriate antibody-mediated immune responses to an antigen, whereas healthy individuals are able to mount a vigorous immune response upon first exposure to a new antigen. It is also of note that as a group, participants with HF were only mildly symptomatic, had a mean ejection fraction near 40%, and were maximized on goal doses of both ACE inhibitors or ARBs and beta blockers. Our study suggests that even patients with mild heart failure may not be adequately protected against influenza infection despite annual vaccination. Future studies should explore alternate influenza vaccination strategies for patients with heart failure.
Lastly, when stratifying the HF group by beta blocker and examining immune responses, we found a non-significant trend toward better antibody responses to A/H3N2 with participants taking carvedilol compared to those taking metoprolol. Integral to the treatment of an upregulated adrenergic system in heart failure is the use of beta adrenergic blockers, proven to significantly decrease all cause mortality.[25
] As mentioned previously, the sympathetic nervous system influences immune response via activation β2
] In particular, human T and B lymphocytes express β2
-AR. Stimulation of the β2
-AR leads to decreased immune responses, therefore high concentrations of epinephrine and norepinephrine in heart failure may inhibit production of cytokines necessary for appropriate vaccine response.[9
] Logically, it may be reasonable to predict that blockade of β2
-AR affects immune response to influenza vaccine, and may therefore preserve an appropriate vaccine-induced protection to influenza infection. More complete β2
-AR blockade with carvedilol may account for the antibody-mediated findings. We did not observe differences in CTL responses within patients with heart failure based on beta blocker stratification, although sample sizes were small. Although we consider this trend intriguing, we consider these data hypothesis generating, requiring confirmation in future larger studies designed to examine differences in immune responses by beta blocker. To our knowledge, this study is the first to examine an association of beta blocker on immune responses in patients with HF.
Several limitations to our study need to be considered. First, immune responses to influenza vaccination are known to decrease with age, and our healthy control group was significantly younger than our HF group. Declining antibody responses to influenza vaccine have been observed in the elderly,[26
] however both groups in our study had mean and median ages well below 65 years. Additionally, study participants had mildly symptomatic, stable heart failure. The generalizability of our results to a wider group of patients, especially those with more advanced HF, is unknown. We cannot rule out that our findings among heart failure patients taking carvedilol are due to chance based on our small sample size and limited power to examine an interaction of beta-blocker effects on immune function. We did not specifically measure adrenergic activity as it relates to immune function in our participants. As such, we cannot rule out other potential contributors to differences in immune responses between the two groups, such as differences in nitric oxide availability. Lastly, we were unable to correlate differences in immune responses between the study groups to subsequent rates of influenza infection within that season as we were not powered to perform these analyses. Future work should address the issue of individual strain vaccine-induced antibody responses and clinical correlations with influenza infection rates more specifically.
In conclusion, patients with heart failure demonstrated Th2-weighted cell mediated responses to influenza vaccination. Moreover, HF patients did not mount as vigorous of an antibody immune response to the newest vaccine viral strain compared to healthy individuals, despite similar rates of seroprotection and seroconversion. Immunologic memory may be important for vaccine protection among those with HF. Lastly, future explorations are warranted involving therapeutic agents for heart failure with actions at the β2-AR and potential benefits in preserving antibody-mediated immune responses in patients with heart failure.