Flu's Added CV Risk Shows Need to Distinguish It From COVID-19

August 24, 2020

Almost 12% of about 80,000 adults in the United States admitted with laboratory-confirmed influenza then suffer an acute cardiovascular (CV) event that likely prolongs hospitalization and worsens their risk of dying, suggests a new analysis from the Centers for Disease Control and Prevention (CDC).

The data cover flu seasons from late 2010 to early 2017, well before the advent of SARS-CoV-2 but with warnings for clinicians in 2020 facing the double threat of seasonal flu during a COVID-19 pandemic that remains a poorly understood menace.

The breakthrough CV events consisted overwhelmingly of heart failure (HF) decompensation and ischemic events, and were mostly likely to strike older patients and those with preexisting CV disease, diabetes, or chronic kidney disease.

And they added considerably to patients' burden of disease. Almost one quarter of deaths in the overall cohort were in patients who had experienced a CV event, not even counting the few who went into cardiogenic shock.

About 31% of those with a CV event went to the intensive care unit, and 14% required mechanical ventilation. About 7% died in the hospital, "underscoring the severity of cardiovascular complications with concomitant influenza virus infection," write the authors, led by the CDC's Eric J. Chow, MD, in their report published online today in the Annals of Internal Medicine.

Notably, CV events were 14% to 20% less likely among patients who had received the year's appropriate vaccination. And there was evidence for a limited but protective obesity-paradox effect.

The data certainly don't reflect the true extent of influenza cases during those years, as nonhospitalized patients and those without laboratory confirmation weren't included, an obvious limitation of the analysis, the authors point out.

Still, the findings carry big messages, especially about seasonal flu vaccination, researchers say. For starters, they "highlight the importance of preventing influenza virus infection, especially in those with underlying chronic conditions," the report says.

Only 47% of the cohort was known to have been vaccinated for the respective flu season; 39% were not vaccinated, and the status was unknown in the remainder, the group reported.

Also, early influenza diagnosis, especially in patients deemed at high CV risk, "could lead to earlier treatment with antiviral medication, reduce unnecessary antibiotic use, and lessen the morbidity and mortality of disease."

The Data for Influenza vs COVID-19

The current analysis is "rigorously done," Jacob A. Udell, MD, MPH, not associated with the study, told theheart.org | Medscape Cardiology. "It's a very comprehensive dataset with really important clinical information," and the authors "did a good job of teasing out the different risk groups, and making adjustments for competing risk factors."

Those higher-risk groups, "mirror what we're seeing with the pandemic at the moment," said Udell, who studies the nexus of influenza and CV disease at the University of Toronto, Canada, and is co-principal investigator of the ongoing randomized INVESTED trial exploring the CV effects of high-dose compared with standard-dose influenza vaccination in more than 5300 patients.

Strikingly, in the current study, Udell said, the 12% risk of CV events during flu hospitalization was "pretty in line with what we're seeing for COVID-19."

That isn't to dismiss the risk of CV events in patients with the new coronavirus, for which there is currently no good treatment, but to underscore the CV risks of respiratory infections that have been around longer and can resemble COVID-19, he said.

"Flu and respiratory syncytial virus [RSV] are actually just as, if not more common, and just as deadly in their morbidity and mortality from cardiovascular disease," he said. "We're looking for rapid COVID-19 tests, and we may or may not have those in time for the fall and winter. But we do have rapid tests for flu and for RSV."

With the "twindemic" approaching, he said, those tests will be important for differentiating between COVID-19 and other respiratory infections that actually have established therapies.

"Not only do we have shots to prevent flu, we have antivirals that can mitigate some of the symptoms and complications if given early enough." Although flu vaccination is never totally protective, he said, it's much better than nothing.

The Data in Cardiovascular Context

Whereas most relevant published studies "have looked at the prevalence of influenza in patients with acute cardiovascular events," notes an accompanying editorial, the current study shows that "among all diagnosed influenza admissions, acute cardiovascular disease is common."

The findings, writes Chandini Raina MacIntyre, MBBS, PhD, University of New South Wales, Sydney, Australia, "confirm that cardiovascular events are an important contributor to the morbidity and mortality associated with influenza."

They also showed that "vaccination was beneficial even when it did not prevent influenza," in that the vaccinated patients were less likely to develop acute HF and acute ischemic heart disease than those who were not vaccinated. "This finding shows that the benefit of influenza vaccination extends beyond simply preventing infection," MacIntyre writes.

"Influenza may unmask undiagnosed cardiovascular disease and may exacerbate known disease," underscoring the importance of flu vaccination for CV secondary prevention and that "all patients with influenza should be assessed for cardiovascular health and vaccination status," the editorial recommends.

Of 80,261 patients admitted with laboratory-confirmed influenza for whom complete medical records were available, 11.7% experienced an in-hospital CV event, according to discharge codes; 6.2% of the total experienced acute HF and 5.7% an acute ischemic event.

Solely among the patients with a CV event, 53.5% experienced acute HF, 49.3% an acute ischemic event, 8.3% experienced a hypertensive crisis, 2.7% went into cardiogenic shock, 0.8% showed acute myocarditis and 0.5% acute pericarditis, and 0.2% experienced cardiac tamponade, the group reports.

Advanced age, CV risk factors, and underlying cardiac, diabetic, and renal disease at admission were significant predictors of acute HF and acute ischemic events during hospitalization.

Adjusted* Relative Risk (RR) for Acute CV Events by Patient Features at Hospitalization for Laboratory-Confirmed Influenza
Risk Factors Acute HF, RR (95% CI) Acute Ischemic Event, RR (95% CI)
Age 75–84 (vs 18-49 y ) 1.88 (1.62–2.18) 3.43 (2.85–4.12)
Age ≥85 (vs 18-49 y ) 2.32 (2.00–2.70) 4.37 (3.64–5.25)
Current tobacco use 1.17 (1.07–1.28) 1.33 (1.20–1.48)
Atrial Fibrillation 1.40 (1.30–1.52) 1.08 (0.97–1.19)
Chronic HF or Cardiomyopathy 8.33 (7.60–9.12) 2.11 (1.93–2.31)
Coronary Artery Disease 1.18 (1.10–1.27) 1.75 (1.61–1.91)
Diabetes 1.09 (1.01–1.17) 1.15 (1.06–1.24)
Chronic Kidney Disease 1.22 (1.14–1.32) 1.25 (1.15–1.36)

*adjusted for season, surveillance site, age group, sex, race/ethnicity, body mass index, tobacco-use history, medical history of atrial fibrillation, chronic congestive heart failure or cardiomyopathy, coronary artery disease, diabetes mellitus, chronic renal disease, influenza vaccination status, antiviral therapy, and influenza type or subtype


"Overweight" and "obesity" by conventional body-mass index (BMI) standards were not associated with increased risk of acute CV events, but "extreme obesity," BMI of at least 40, posed an adjusted RR of 1.19 (1.06–1.33) for an acute HF event.

Notably, however, obesity — defined as a BMI of 30 to 39.9 — was protective from acute ischemic events at an adjusted RR of 0.84 (0.77–0.93).

Risk Reductions in Context

That 16% risk reduction with obesity, the authors point out, was on par with the protective effects of influenza vaccination, for which the RR for acute HF was 0.86 (0.80–0.92) and for ischemic events was 0.80 (0.74–0.87) compared with no vaccination.

"The estimated efficacy of influenza vaccines for secondary prevention of cardiovascular events is 15% to 45%, similar to that of statins, antihypertensive agents, and smoking cessation," the MacIntyre editorial states.

"We accept the important role of the latter interventions in secondary prevention of cardiovascular disease, but influenza vaccination continues to be overlooked," it says. "It is time to view influenza vaccination as a routine secondary preventive measure for cardiovascular events."

The CDC funded the study. Chow has disclosed no relevant financial relationships; information about any potential conflicts for the other authors is available with the report. MacIntyre reports receiving grants from Sanofi and Seqirus. Udell reports advisory relationships with Amgen, Boehringer Ingelheim, Janssen, Novartis, and Sanofi Pasteur; and receiving grants from AstraZeneca and Novartis.

Ann Intern Med. Published online August 24, 2020. Report, Editorial

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