Friday, February 09, 2024

Risk of Cardiovascular Events After Influenza: A Population-based Self Controlled Case Series Study



While most people regard influenza as a fairly minor illness in a healthy adult, over the past few years we've seen a lot of research showing an apparent link between current (or recent) influenza infection and cardiovascular complications, including heart attacks.   

A few of many examples include:

While the influenza-cardiac link grows stronger with each year, most people consider it primarily a concern for elderly (> 65)  patients, who are more likely to already have some cardiovascular deficits.

Today, however, we have a population-based study from Spain which looks at the rate of atherothrombotic events (heart attack or ischemic stroke) in adults aged 50 and over, both with or without recent influenza infection. 

Even for those with fewer risk factors and mild influenza illness the risk of experiencing an acute cardiovascular event (ACVE) was doubled for the first 14 days, and in severe flu cases among more vulnerable patients, that risk increased 4-fold for 2 weeks and remained doubled for 60 days.  

I've only posted some excerpts from the open-access study, so you'll want to follow the link to read it in its entirety.  I'll have a postscript after the break. 

Risk of cardiovascular events after influenza: A population-based Self Controlled Case Series study, Spain 2011-2018
Cintia Muñoz-Quiles, Mónica López-Lacort, Arantxa Urchueguía, Javier Díez-Domingo, Alejandro Orrico-Sánchez

The Journal of Infectious Diseases, jiae070,
Published: 08 February 2024 

This study explores the relationship between influenza infection, both clinically diagnosed in primary-care and laboratory confirmed in hospital, and atherothrombotic events (acute myocardial infarction and ischemic stroke) in Spain. A population-based self-controlled case series design was used with individual-level data from electronic registries (n = 2,230,015). 

The risk of atherothrombotic events in subjects ≥50 years old increased more than 2-fold during the 14 days after the mildest influenza cases in patients with fewer risk factors and more than 4-fold after severe cases in the most vulnerable patients, remaining in them more than 2-fold for 2 months.

The transient increase of the association, its gradient after influenza infection and the demonstration by 4 different sensitivity analyses provide further evidence supporting causality. This work reinforces the official recommendations for influenza prevention in at-risk groups and should also increase the awareness of even milder influenza infection and its possible complications in the general population.



Cardiovascular diseases (CVDs) are the leading cause of death globally, accounting for 32% of all deaths worldwide in 2019 (1). There is growing evidence that respiratory infections, especially influenza, can trigger or aggravate CVDs (2–5). Influenza affects 5-15% of the population yearly (6) and 290,000 - 650,000 of cases result in death (7). These estimates do not consider deaths from other diseases such as CVDs, which can be influenza-related (8).

Although the association between influenza and acute cardiovascular events (ACVEs) seems to be well established, there are significant methodological aspects that could be biasing the results (3,9– 16). First, some studies lacked individual-level information of influenza and ACVE (17,18). Second, studies restricting to laboratory-confirmed influenza (LCI) cases are prone to selection bias and therefore, not generalizable for two main reasons: 1) laboratory testing is mainly performed on individuals with a severe infection or underlying risk factors for severe disease (3,10–12,19), and 2) likelihood of undergoing an influenza test (exposure) may be linked to an ACVE (outcome) by clinical practice (20). Therefore, studies with robust methodologies, and including severe and milder cases of influenza would provide further evidence of possible causality between influenza and increased ACVEs risk.

The biological mechanism by which influenza virus triggers ACVEs is still unknown (21). Among the postulated hypotheses, influenza might exacerbate vascular atherosclerosis by activating inflammatory pathways (22), destabilising pre-existing atherosclerosis plaques, or elevating macrophage circulation in arteries (23,24). Experiments on apolipoprotein-deficient mice (a wellestablished mouse model of atherosclerosis) showed that infection with influenza virus promotes inflammatory cell infiltration, smooth muscle cell proliferation and fibrin deposition in atherosclerotic plaques (25). 



The study shows a robust association between influenza infection and an increased risk of acute atherothrombotic events in subjects ≥50 years old in Spain. The transient increase in the risk of ACVE and its gradient after influenza infection provides further evidence supporting causality. The risk of ACVE was more than twofold during the 14 days after milder influenza cases in patients with fewer risk factors and more than fourfold after severe cases in more vulnerable patients, remaining in them more than twofold for 2 months. Our findings reinforce official recommendations for influenza prevention in at-risk groups and should also increase the awareness of even milder influenza infection and its possible complications in the general population.

(Continue . . . )

The link between influenza infection and heart attacks seems pretty solid, and while not quite as robust, there is growing evidence to suggest that getting the flu vaccine every year can significantly reduce your risk of heart attack or stroke (see here, here, here and here).  

Last November, in Nature: Influenza Vaccination & Major Cardiovascular Risk: a Systematic Review & Meta-Analysis, we looked at a major review study which the authors found provided `. . . compelling evidence that influenza vaccination is associated with a decreased risk of major cardiovascular events'.

Specifically, the authors found that ". . . patients who received the influenza vaccine experienced a remarkable risk reduction of over 20% in cardiovascular death". This particular analysis focused on patients with an existing diagnosis of CVDs (Cardiovascular diseases).

There is admittedly much we still don't know about the long-term impacts of various viral infections, or through what mechanisms the flu shot might mitigate some of those risks. 

While we have substantial statistical evidence suggesting correlation, proving causality is notoriously difficult. Still, there is enough here to suggest that the flu vaccine may have some hidden health benefits beyond its modest ability to prevent seasonal influenza infection. 

Given the devastating impacts of heart attacks and strokes, even a small reduction in cardiovascular events would be welcome news.