During influenza seasons from 2010 through 2018, FluSurv-NET received reports of 89 999 adults hospitalized with laboratory-confirmed influenza (Figure 1). We excluded 1854 patients with no ICD discharge codes. Among 80 261 adults sampled for medical record review and included in our analysis (median age, 69 years [interquartile range, 54 to 81 years]), 11.7% had an ICD discharge code for an acute cardiovascular event, most commonly aHF (6.2%) or aIHD (5.7%) and less commonly hypertensive crisis (1.0%), cardiogenic shock (0.3%), acute myocarditis (0.1%), acute pericarditis (0.05%), or cardiac tamponade (0.02%).

The unadjusted weighted prevalence of acute cardiovascular events was higher in patients who had underlying medical conditions–particularly chronic cardiovascular conditions, chronic metabolic conditions, chronic renal disease, and chronic hematologic conditions-than in those without acute cardiovascular events (data not shown). In this study, 20.6% of those with chronic cardiovascular disease, 19.3% of those with chronic renal disease, and 14.8% of those with diabetes had an acute cardiovascular event (Appendix Table 2, available at Annals.org). Overall, 47.2% of patients received an influenza vaccine in the current season, 39.2% did not receive it, and 13.6% had unknown vaccination status (data not shown).

Among patients with an acute cardiovascular event, 53.5% had aHF, 49.3% aIHD, 8.3% hypertensive crisis, 2.7% cardiogenic shock, 0.8% acute myocarditis, 0.5% acute pericarditis, and 0.2% cardiac tamponade. Most patients with acute myocarditis, acute pericarditis, or cardiogenic shock were aged 18 to 64 years, whereas most with aHF or aIHD were aged 65 years or older (Figure 2).

Overall, patients with acute cardiovascular events had a median length of hospital stay of 5 days, 31.2% were admitted to the intensive care unit, 14.0% required mechanical ventilatory support, and 7.3% died in the hospital (Table 1). Patients with cardiogenic shock had the longest median length of stay (9 days), and 38.9% died during the hospitalization. When we excluded cardiogenic shock from the analysis, 6.4% of patients with another acute cardiovascular event died in the hospital. Among the 2683 patients who died in the hospital, 23.7% had an associated acute cardiovascular event, excluding the diagnosis of cardiogenic shock (data not shown). In-hospital outcomes did not differ substantively between male and female patients with acute cardiovascular events (data not shown).

After excluding patients who received antiviral treatment 2 days or more before hospital admission; those with missing data on antiviral treatment, vaccination status for the current season, and BMI; and those for whom influenza subtype was not imputed, we included 61 856 patients (Figure 1) in the multivariable logistic regression models to examine factors associated with aHF and aIHD.

Compared with patients aged 18 to 49 years, older patients had increased risk for aHF (50 to 64 years: adjusted risk ratio [aRR], 1.40 [95% CI, 1.22 to 1.61]; 65 to 74 years: aRR, 1.58 [CI, 1.36 to 1.84]; 75 to 84 years: aRR, 1.88 [CI, 1.62 to 2.18]; and ≥85 years: aRR, 2.32 [CI, 2.00 to 2.70]) (Table 2). Other factors associated with increased risk for aHF included extreme obesity (aRR, 1.19 [CI, 1.06 to 1.33]), current tobacco use (aRR, 1.17 [CI, 1.07 to 1.28]), atrial fibrillation (aRR, 1.40 [CI, 1.30 to 1.52]), chronic heart failure or cardiomyopathy (aRR, 8.33 [CI, 7.60 to 9.12]), coronary artery disease (aRR, 1.18 [CI, 1.10 to 1.27]), diabetes mellitus (aRR, 1.09 [CI, 1.01 to 1.17]), and chronic renal disease (aRR, 1.22 [CI, 1.14 to 1.32]). Risk for aHF was significantly lower for patients vaccinated against influenza at least 2 weeks before hospitalization than for unvaccinated patients (aRR, 0.86 [CI, 0.80 to 0.92]).

Older age was also significantly associated with higher risk for aIHD compared with age 18 to 49 years (50 to 64 years: aRR, 2.04 [CI, 1.72 to 2.43]; 65 to 74 years: aRR, 2.93 [CI, 2.44 to 3.51]; 75 to 84 years: aRR, 3.43 [CI, 2.85 to 4.12]; and ≥85 years: aRR, 4.37 [CI, 3.64 to 5.25]) (Table 2). Other factors associated with higher risk for aIHD included current tobacco use (aRR, 1.33 [CI, 1.20 to 1.48]), chronic heart failure or cardiomyopathy (aRR, 2.11 [CI, 1.93 to 2.31]), coronary artery disease (aRR, 1.75 [CI, 1.61 to 1.91]), diabetes mellitus (aRR, 1.15 [CI, 1.06 to 1.24]), and chronic renal disease (aRR, 1.25 [CI, 1.15 to 1.36]). Women (aRR, 0.87 [CI, 0.80 to 0.93]) and obese patients (aRR, 0.84 [CI, 0.77 to 0.93]) had lower risk for aIHD, as did patients who were vaccinated against influenza at least 2 weeks before hospitalization compared with those who were not vaccinated (aRR, 0.80 [CI, 0.74 to 0.87]).

Patients who received late antiviral treatment had higher risk for aHF and aIHD than those who received early antiviral treatment; however, information on the timing of antiviral treatment in relation to that of acute cardiovascular events was not available.

In this study of more than 80 000 adults hospitalized with laboratory-confirmed influenza in the United States, approximately 12% of patients had acute cardiovascular events, most commonly aHF and aIHD. Although respiratory tract diagnoses are most commonly associated with influenza (28), acute cardiovascular events are important contributors to influenza-related morbidity and mortality. Almost one third of patients with an acute cardiovascular event were admitted to the intensive care unit, and 7% (6% excluding those with cardiogenic shock) ultimately died during hospitalization, underscoring the severity of cardiovascular complications with concomitant influenza virus infection. Underlying cardiovascular disease was strongly associated with both aHF and aIHD among patients hospitalized with influenza. Our findings highlight the importance of preventing influenza virus infection, especially in those with underlying chronic conditions.

Influenza may be an important but underrecognized contributor to the health care burden of hospitalized cardiovascular disease. In 1 prospective study in which all patients admitted to a coronary care unit were systematically tested for influenza, 8% were found to have influenza virus infection (30). Another study estimated the proportion of myocardial infarction–associated hospitalizations that are related to influenza to be 3% to 5% in England and Wales and 8% in Hong Kong at the peak of influenza circulation (31). Costs associated with cardiovascular disease may increase in the next 20 years, with lost productivity from illness and premature death (32). Public health interventions should include focused attention on preventable causes of this health care burden, including prevention of influenza virus infection.

Although this analysis was not designed to assess the effectiveness of influenza vaccination or antiviral medications, evidence suggests that these interventions may have benefits in attenuating disease severity. Several studies have found that vaccination (33, 34) and influenza antiviral medication (35, 36) help decrease severity of disease and symptom duration. Yet despite these benefits, influenza vaccination rates are suboptimal: Only 33.9% to 56.3% of U.S. adults (varying by state) received the influenza vaccine in the 2018-to-2019 season (37). Especially among patients with risk factors for acute cardiovascular events, practitioners may play an essential role in mitigating the burden of cardiovascular disease by maintaining high rates of annual influenza vaccination (38-41) and providing early antiviral treatment to patients with suspected or confirmed influenza (42-44).

The most common acute cardiovascular events among adults hospitalized with influenza were aHF and aIHD. Although causality cannot be determined from our study alone, the pathophysiologic mechanisms that lead to cardiovascular events after influenza virus infection have been described. For example, systemic inflammatory response in the setting of influenza virus infection promotes oxidative stress, leading to hemodynamic consequences and activation of prothrombotic pathways (13, 15, 45-47) as evidenced by increased levels of serum troponin (48) and myosin light chains (49) in some patients hospitalized with influenza. Patients with preexisting conditions may be at greater risk for cardiovascular decompensation because decreased circulatory reserve at baseline leads to increased risk for in-hospital morbidity and mortality in the setting of influenza infection (50, 51). In patients with aIHD, various factors—including direct results of plaque disruption (3), vasoconstrictive effects of systemic inflammation (46), increased metabolic demand from systemic inflammation (15), and ambient temperature (52, 53)—may be the basis for these acute cardiovascular events in the setting of influenza infection. Although direct associations between heart failure exacerbation and influenza have not been well characterized (54), aHF-associated hospitalizations correlate with influenza activity (55, 56). During the influenza season, practitioners should consider an influenza diagnosis when a patient is hospitalized with an exacerbation of or new-onset cardiovascular event (57). Early identification of influenza, especially in those at greater risk for complications like acute cardiovascular events, could lead to earlier treatment with antiviral medication, reduce unnecessary antibiotic use, and lessen the morbidity and mortality of disease (57).

We found that older patients may have a higher risk for aHF and aIHD when hospitalized with influenza, a finding supported by previous studies (4, 31, 58, 59). We showed that patients with preexisting cardiovascular conditions, namely chronic heart failure or cardiomyopathy, and known cardiovascular risk factors, such as tobacco use, diabetes, and renal disease, had the highest risk for aHF or aIHD with influenza. In fact, 1 in 5 patients with a chronic cardiovascular condition who were hospitalized with influenza also had an acute cardiovascular event during the hospitalization. Of note, extreme obesity was found to be associated with higher risk for aHF, but obesity was associated with lower risk for aIHD in patients hospitalized with influenza virus infection. In observational studies, this finding may be related to the previously described obesity paradox, whereby certain subgroups of patients who are obese have better cardiovascular outcomes than those with lower BMI (60). Other explanations that contribute to these findings may include nonpurposeful weight loss associated with chronic disease (61), changes in inflammatory response due to obesity (62), increased muscle mass interpreted as obesity (61), or a practitioner's threshold for admission of patients who are obese or have a history of chronic comorbid conditions. Ultimately, the reasons for the reduced association between obesity and aIHD in patients with influenza are not clear, and additional studies are required to better understand these associations.

Our study adds to the growing body of literature on the effect of acute cardiovascular events on the morbidity and mortality associated with influenza. These include long hospital stays and severe in-hospital outcomes, including death. Previous studies have shown that patients with influenza virus infection and cardiovascular complications, such as heart failure (50) and acute myocardial infarction (63), had higher mortality than those without influenza. They demonstrate that cardiovascular complications related to influenza may be significant outcomes of infection and that estimations of influenza burden relying solely on respiratory diagnoses are likely to underestimate the true burden of influenza-related complications.

Our study has limitations to consider. First, patients were identified from practitioner-initiated influenza testing. Practitioners are more likely to test for influenza in patients presenting with symptoms of respiratory infection and other influenza-like illness (64); thus, we may have underestimated the true prevalence of influenza-associated cardiovascular events (65). Second, because our study included only hospitalized patients with laboratory-confirmed influenza, uncontrolled collider bias is possible if influenza testing is a common effect of the exposures we considered (66). Third, we used ICD discharge codes to classify acute cardiovascular event groups, and diagnoses were not based on laboratory confirmation of a cardiovascular event. Although ICD codes are a common method to identify cardiovascular complications (4, 15, 31, 55), administrative codes may be subject to misclassification bias if they are carried over from recent hospitalizations or if ICD coding is affected by billing practices, the experience of medical coders, or incomplete capture of medical information documented by the clinician (67). Using ICD discharge codes also limits our ability to distinguish between acute and chronic conditions and may bias the observed association between acute and underlying cardiovascular diseases. We attempted to lessen this risk for misclassification by selecting ICD discharge codes of diagnoses that were most likely limited to the current hospital stay. In addition, FluSurv-NET captures only the first 9 ICD codes listed in the medical record, and diagnoses listed thereafter are not included in the analysis. Fourth, we could not assess the timing of antiviral therapy relative to the onset of aHF or aIHD; thus, our finding of higher odds of aHF and aIHD among those who received late antiviral treatment should be interpreted with caution. Antiviral therapy was included in the model to control for confounding, and the aRRs should not be interpreted as a measure of antiviral effectiveness against aHF or aIHD. Last, we may not have captured all confounders within our regression models for aHF and aIHD. For example, hypertension and hyperlipidemia are known risk factors for heart failure and ischemic heart disease but were not collected as underlying conditions in FluSurv-NET.

In this study, acute cardiovascular events were common diagnoses among adults hospitalized with influenza, particularly among older patients and those with underlying chronic disease. A high percentage of patients with acute cardiovascular events experienced in-hospital morbidity and mortality. Increasing rates of influenza vaccination, especially among those with cardiovascular risk factors, is essential in preventing infection and potentially attenuating influenza-related cardiovascular complications and adverse outcomes.