Author + information
- Published online January 28, 2019.
- aCenter for Care Delivery and Outcomes Research, VA Health Care System, Minneapolis, Minnesota
- bDepartment of Medicine, University of Minnesota, Minneapolis, Minnesota
- cDivision of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard University, Boston, Massachusetts
- ↵∗Address for correspondence:
Dr. Orly Vardeny, Minneapolis VA Center for Care Delivery and Outcomes Research, 1 Veterans Drive, Minneapolis, Minnesota 55417.
The World Health Organization estimates that 3 to 5 million cases of influenza and approximately 300,000 to 650,000 respiratory deaths worldwide are attributable to influenza each year. Individuals of older age, those with comorbidities such as respiratory and cardiac conditions, infants, pregnant women, and patients who are immunocompromised are at a magnified risk for incurring influenza-related complications and are more likely to be hospitalized when infected with influenza, thus leading to increased health care resource use and burden.
A spike in hospitalizations for acute myocardial infarction has been tied to influenza, particularly in patients with influenza diagnosed in the week before the cardiac event, thereby establishing a temporal association between these 2 outcomes (1). Data linking influenza to hospitalizations for heart failure are less robust, but Medicare and national discharge data suggest higher rates of hospitalization for heart failure during influenza epidemic periods compared with nonepidemic time periods. Additionally, an analysis of participants with heart failure enrolled in the SOLVD (Studies of Left Ventricular Dysfunction) trials revealed a higher risk of both heart failure–related and non–heart failure–related hospitalizations during the influenza season compared with noninfluenza seasons, even after adjustment for comorbidities and cold temperature (2). Therefore, special care of patients with heart failure during winter months cannot be overemphasized.
In this issue of JACC: Heart Failure, Panhwar et al. (3) examine associations between influenza and clinical outcomes among patients hospitalized for heart failure on the basis of the presence of influenza infection, as defined by International Classification of Diseases-Ninth Revision codes. Data from the National Inpatient Sample from 2013 to 2014 were used, and propensity score matching was used to match ∼55,000 cases of hospitalized heart failure and influenza with cases of heart failure without influenza. Panhwar et al. (3) reported increased rates of in-hospital mortality, adverse clinical outcomes including acute kidney injury (with and without need for dialysis), respiratory failure (with and without necessitation of mechanical ventilation), and prolonged length of stay among those with influenza compared with individuals without influenza. These results carry wide public health implications and substantially add to the body of evidence linking respiratory infections with adverse cardiovascular sequelae.
Data on predictors and outcomes among patients with influenza and hospitalized heart failure are sparse. An analysis of OPTIMIZE-HF (the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) revealed that pneumonia or other respiratory process precipitated 15.3% of hospitalizations and increased the risk for in-hospital mortality by 60% (4). Pneumonia was the fourth leading cause of noncardiovascular hospitalization in a Canadian cohort of patients with heart failure. A well-recognized complication of influenza is secondary pneumonia. Alon et al. (5) reported that patients with heart failure who were admitted for infectious causes, particularly respiratory infections, bacteremia, and sepsis, were significantly more likely to be readmitted at 6 months and exhibited higher 30-day mortality rates compared with patients with heart failure who were admitted for a noninfectious cause. As with the current study, predictors of infection included older age and female sex. Nonetheless, key missing data from previous studies of patients with heart failure include capture of influenza diagnosis, thus underscoring the importance of the current study.
It is not surprising that acute kidney injury and respiratory failure were more frequent among patients with heart failure and influenza. Influenza often leads to dehydration, and the use of diuretics and renin-angiotensin-aldosterone system inhibitors by patients with heart failure would decrease renal reserve and predispose these patients to acute kidney injury. Similarly, there is an association between acute exacerbations of chronic obstructive pulmonary disease and cardiac events, and the reverse association is also likely. The pathophysiological interplay between influenza infection and detrimental cardiac effects is complex. Influenza increases metabolic demand and, when accompanied by hypoxemia, may exacerbate underlying cardiac conditions. Up-regulated sympathetic nervous system activity during infection can be detrimental for patients with heart failure who are especially sensitive to neurohormone system activation, and infection concurrent with cardiorenal function changes may lead to volume overload. Inflammatory responses, specifically elevations in proinflammatory cytokines during infection, may precipitate plaque rupture and are associated with myocardial depression. Histological evidence from myocardial tissue samples from autopsies following influenza-related deaths has supported findings of acute myocarditis and myocyte necrosis.
The study by Panhwar et al. (3) evaluates influenza-related hospitalizations during the 2013 to 2014 influenza season, which was a virulent season driven by the A/H1N1 influenza virus subtype. Influenza A/H3N2 is usually associated with more severe morbidity compared with other influenza sub-types. Given that influenza activity varies both within and among seasons, it would be informative to investigate associations between influenza and heart failure–related hospital morbidity during other seasons, specifically those driven by A/H3N2, as well as within the influenza season by month. Outcomes specifically attributable to influenza cannot be confirmed in this cohort in the absence of laboratory confirmation of influenza because other respiratory viruses, such as respiratory syncytial virus, often cocirculate with influenza during the winter months.
Influenza vaccination has been shown in several meta-analyses to reduce acute cardiovascular events (6). Annual vaccination is recommended in patients with heart failure by the Centers for Disease Control and Prevention as well as by several cardiovascular societies. Implementation of these recommendations has been suboptimal in patients with heart failure, for unclear reasons. In an analysis of the Get With the Guidelines Heart Failure registry, one-third of patients hospitalized with heart failure did not receive the influenza vaccination, a percentage that remained stable between the years 2012 and 2017 (7). Worldwide variations in influenza vaccination have also been demonstrated in an analysis of the contemporary PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) study (8), whereby participants were well managed with other heart failure therapies. Of note, patients with heart failure have been shown to mount less robust immune responses to influenza vaccine, and exhibit more pronounced waning of antibody titer levels compared with individuals of similar ages without heart failure. As such, the optimal influenza vaccine formulation in patients with heart failure is unclear, and this question is currently being tested in a clinical trial (INfluenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure [INVESTED]; NCT02787044) (9).
Although the exact extent to which influenza infection contributes to morbidity, and mortality, in already compromised patients with heart failure has been difficult to estimate, the results of this study make it clear that during the winter months this contribution is neither negligible nor neglectable. Despite a growing armamentarium for treating patients with heart failure, traditional therapies cannot modify this increased risk. Although vaccination remains the best way to reduce the added risk conferred by influenza, the strikingly low vaccination rates of some of our most vulnerable patients represent both a significant public health challenge and a substantial opportunity.
↵∗ Editorials published in JACC: Heart Failure reflect the views of the authors and do not necessarily represent the views of JACC: Heart Failure or the American College of Cardiology.
Dr. Vardeny has received research support from Sanofi Pasteur. Dr. Solomon has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bristol-Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, and Theracos; and has consulted for Akros, Alnylam, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardior, Corvia, Cytokinetics, Gilead, GlaxoSmithKline, Ironwood, Merck, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, and Cardiac Dimensions.
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