Burden of Influenza Infection

Influenza infection is a major cause of recurrent hospitalization, increased mortality, and morbidity especially among individuals with diabetes mellitus (DM) and atherosclerotic cardiovascular disease (ASCVD) due to increased underlying disease burden. Acute myocardial infarction (AMI) is a serious complication of acute influenza infection. Patients were ten-times and five-times more likely to have AMI within 7 days of laboratory confirmed infection with influenza B and influenza A virus, respectively when compared to 7 days after or before infection.¹ Influenza infection increases inflammatory activity within the plaque, to which the host responds with oxidative bursts and release of metalloproteinases and peptidases, all of which destabilize plaque and predisposing to rupture. Additionally, the systemic inflammation and pro-thrombotic state during acute infection further promotes thrombosis of ruptured plaque causing AMI.^2,3 Therefore, influenza vaccination reduces the likelihood of influenza infection, thereby protecting against AMI by preventing the above-mentioned mechanism.

Efficacy/Effectiveness of Influenza Vaccination

While influenza vaccination is shown to reduce all-cause mortality and hospitalization among individuals with DM, data on cardiovascular mortality benefits are limited.^4,5 Findings from a recent study by Modin et al. published in Diabetes Care demonstrated that influenza vaccination is associated with reduced cardiovascular and all-cause mortality.⁶ Using the Danish nationwide registry data, the authors included 241,551 individuals with DM over nine consecutive influenza seasons between 2007 and 2016, with a total follow-up of 425,318 person-years. Overall, 119,397 individuals had ever received vaccination (at least once) and 122,154 had never received vaccination during the study period. Average vaccination coverage of all seasons was 33% with a range of 24% to 36% during the study period. About 3.4% (8,207) of the patients died of any cause, of which 4,127(1.7%) deaths were attributed to CVD causes (1,439 [35%] were due to AMI/stroke). On adjusted analysis, influenza vaccination was associated with a significant reduction in all-cause mortality (hazards ratio [HR] 0.83, 95% confidence interval [CI] 0.78-0.88), CVD mortality (HR 0.84, 95% CI 0.77-0.91), and AMI/stroke mortality (HR 0.85, 95% CI 0.74, 0.98). Additionally, the number needed to treat (NNT) with influenza vaccination to prevent one death was 1,133 (95% CI 876-1,606).

These important findings should further guide influenza vaccination recommendations among individuals with DM since the 2020 American Diabetes Association guidelines are based on low level of evidence (level C; observational studies of low quality) and without a class of recommendation.⁷ Additionally, Modin et al. excluded individuals with ASCVD from the study; therefore these findings further strengthen the evidence of influenza vaccination for primary prevention of ASCVD among individuals with established CVD risk factors which was not been addressed by the 2019 American College of Cardiology (ACC)/American Heart Association (AHA) primary prevention guidelines.⁸

The utility of influenza vaccination in preventing mortality (all-cause and CVD), morbidity (complications and disease severity), and recurrent hospitalizations has been thoroughly studied among individuals with ASCVD.⁹ Additionally, in a meta-analysis of case-control studies, influenza vaccination was found to have a combined efficacy of 29% (range: 19%-45%) similar to those of smoking cessation (32%-43%), statin therapy (19%-30%), and antihypertensive medication (17%-25%).^3,9 Moreover, this evidence supports the guidelines by the ACC/AHA, which recommend annual influenza vaccination among individuals with ASCVD (class I, level B) for secondary prevention.¹⁰

Prevalence of and Disparities in Influenza Vaccination in the US

Despite the well-established evidence and current recommendations, the prevalence of annual influenza vaccination among individuals with ASCVD and DM are sub-optimal.^11,12 Hung et al. evaluated the US national influenza vaccination rates among adults aged 18 years and older with DM between 2007 and 2018.¹¹ In this study, the annual influenza vaccination coverage among adults with DM ranged from 63% to 65% without much improvement in the vaccination rate over the eleven influenza seasons. Relatively younger age (18-65 years), non-Hispanic Black race/ethnicity, lack of usual source of care, and lower relative socioeconomic status were independently associated with increased prevalence of lacking influenza vaccination.

Using a nationally representative sample from 2008 to 2016, Grandhi and colleagues reported the prevalence of annual influenza vaccination among adults aged 40 years and older with ASCVD to be only 67% in the US.¹² This proportion represents nearly 7.4 million adults with ASCVD not receiving yearly influenza vaccination. These rates of lacking vaccination are particularly high among individuals with the following sociodemographic characteristics: 40-64 years (46%), non-Hispanic Blacks (41%), without usual source of care (57%), and without insurance coverage (65%). Additionally, the following individuals were found to have increased odds of not receiving influenza vaccination: 40-64 years (odds ratio [OR] 2.32, 95% CI 2.06-2.62), without usual source of care (OR 2.00, 95% CI 1.71-2.33), uninsured (OR 2.05, 95% CI 1.63-2.58), lower education level (OR 1.25, 95% CI 1.12-1.40), lower income level (OR 1.14, 95% CI 1.01-1.27), and non-Hispanic Black race/ethnicity (OR 1.24, 95% CI 1.10-1.41). Among individuals with four or more of the above mentioned higher-risk sociodemographic characteristics, rates of lacking vaccination were 60% corresponding to 732,524 US adults with ASCVD annually. These individuals were six times more likely to not receive influenza vaccination (OR 6.06, 95% CI 4.88-7.53) compared with individuals without any of these high-risk characteristics.

Individuals with chronic diseases, especially those with DM, are largely affected by the novel coronavirus disease 2019 (COVID-19) infection which predispose these patients to a large number of thrombotic complications including AMI.¹³ Coinfection with influenza among individuals with DM and ASCVD will cause considerable adverse outcomes especially in low-resource settings.¹⁴ Given the sub-optimal rates of annual influenza vaccination among DM and increased risk of coinfection with COVID-19 this influenza season, vaccination against influenza among these high-risk individuals is critical until an effective vaccine against COVID-19 is made available and accessible to everyone. Since the onset of COVID-19, non-emergent hospital and routine primary care visits have decreased substantially, which might affect delivery of influenza vaccination rates. In the process of safely reopening of schools, universities, and workplaces, it is imperative to provide vaccination access at alternate and non-traditional sites (grocery stores, schools, universities, senior centers, public housing, parks, mobile clinics, etc.) to enhance equitable vaccination coverage while maintaining appropriate social-distancing and infection-control measures. Apart from these, extensive evidence-based mass media campaigns emphasizing vaccine efficacy and safety, and mandates requiring influenza vaccination with necessary exceptions, are essential.¹⁴

References

1. Kwong JC, Schwartz KL, Campitelli MA, et al. Acute myocardial infarction after laboratory-confirmed influenza infection. N Engl J Med 2018;378:345-53.
2. Musher DM, Abers MS, Corrales-Medina VF. Acute infection and myocardial infarction. N Engl J Med 2019;380:171-6.
3. MacIntyre CR, Mahimbo A, Moa AM, Barnes M. Influenza vaccine as a coronary intervention for prevention of myocardial infarction. Heart 2016;102:1953-6.
4. 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;13:53.
5. Goeijenbier M, van Sloten TT, Slobbe L, et al. Benefits of flu vaccination for persons with diabetes mellitus: a review. Vaccine 2017;35:5095-5101.
6. Modin D, Claggett B, Køber L, et al. Influenza vaccination is associated with reduced cardiovascular mortality in adults with diabetes: a nationwide cohort study. Diabetes Care 2020;43:2226-33.
7. 4. Comprehensive Medical Evaluation and Assessment of Comorbidities: Standards of Medical Care in Diabetes—2020. Diabetes Care 2020;43:S37-S47.
8. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;74:e177-e232.
9. Barnes M, Heywood AE, Mahimbo A, Rahman B, Newall AT, Macintyre CR. Acute myocardial infarction and influenza: a meta-analysis of case-control studies. Heart 2015;101:1738-47.
10. Davis MM, Taubert K, Benin AL, et al. Influenza vaccination as secondary prevention for cardiovascular disease: a science advisory from the American Heart Association/American College of Cardiology. J Am Coll Cardiol 2006;48:1498-502.
11. Hung MC, Lu PJ, Srivastav A, Cheng YJ, Williams WW. Influenza vaccination coverage among adults with diabetes, United States, 2007-08 through 2017-18 seasons. Vaccine 2020;38:6545-52.
12. Grandhi GR, Mszar R, Vahidy F, et al. Sociodemographic disparities in influenza vaccination among adults with atherosclerotic cardiovascular disease in the United States. JAMA Cardiol 2020;Sept 9:[Epub ahead of print].
13. Gupta A, Madhavan MV, Sehgal K, et al. Extrapulmonary manifestations of COVID-19. Nat Med 2020;26:1017-32.
14. Gostin LO, Salmon DA. The dual epidemics of COVID-19 and influenza: vaccine acceptance, coverage, and mandates. JAMA 2020;324:335-6.

Clinical Topics: COVID-19 Hub, Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Nonstatins, Novel Agents, Statins

Keywords: Diabetes Mellitus, Metabolic Syndrome, Influenza, Human, Influenza Vaccines, COVID-19, Coronavirus, severe acute respiratory syndrome coronavirus 2, Influenza A virus, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Antihypertensive Agents, Risk Factors, Prevalence, American Heart Association, Secondary Prevention, Odds Ratio, Mobile Health Units, Medically Uninsured, Senior Centers, Confidence Intervals

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