Flu-like Illness Linked to Stroke, Cervical Dissection

Pauline Anderson

February 06, 2019

HONOLULU — Having an influenza-like illness (ILI) is associated with an increased risk of ischemic stroke on the order of 40%, regardless of sex, race, or geographical setting, new research suggests.

"The study shows that influenza-like illness increases the risk of stroke, particularly in the first 30 days," study author Amelia Boehme, PhD, assistant professor, Epidemiology and Neurology, Columbia University, New York City, told Medscape Medical News.  

"More research is needed to determine the mechanism behind this association, and to determine if there are specific populations more susceptible to these effects." 

Dr Amelia Boehme

A related study shows an association between ILI and non-traumatic cervical artery dissection (CeAD), a leading cause of ischemic stroke in patients ages 15 to 45 years.

Results of these two preliminary studies will be presented here at the American Stroke Association's International Stroke Conference (ISC) 2019.

For the stroke study, researchers used the New York Statewide Planning And Research Cooperative System (SPARCS), a dataset that captures about 97% of all hospitalizations across the state.

The researchers used a case crossover design, said Boehme. "We identified all the stroke cases and then looked at the time period just before the stroke and then in the years prior to that."

For example, if a patient presented on March 1, 2014 with a stroke, researchers went back from February 15 to March 1 to see if that patient had influenza. Then they looked at those same calendar dates in 2013 and 2012.

"So each person served as their own control," said Boehme. "That way, you don't have to worry about issues with confounding, and comorbid conditions."

ILI is a term used for surveillance and includes more than just influenza, the codes for which have not been validated with regard to sensitivity and specificity, said Boehme. ILI captures a number of other infections, including severe viral rhinitis.

Researchers calculated the estimated odds of ischemic stroke up to 1 year after presentation with ILI. They used logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs).

Urban vs Rural

Investigators stratified analyses by urban and rural status based on residential zip codes, and by sex and race. Also, they adjusted for influenza prevalence as this can influence whether patients are more likely to seek care, said Boehme.

The study included 30,912 patients with an ischemic stroke in 2014, mean age 71.9 years, 49% male, 20% black, and 84% living in an urban area.

ILI in the 15 days before a stroke was associated with an overall increase in odds of stroke (OR 1.39, 95% CI 1.09 - 1.77). This association remained for several months.

"The vast majority of the increased risk happened in the first 30 days," said Boehme. "The risk starts to decrease as you go out from the influenza-like event, but it remains all the way up to a year."

Boehme noted that the majority of ILI cases were emergency department (ED) visits. "Less than 1% were actually hospitalized," she said.

There was no significant interaction between ILI and sex (P = .81), race (P = .85), or urbanicity (P = .29).

Boehme had thought there might be a stronger relationship between ILI and stroke in rural areas since patients in these districts have less access to primary care. On the other hand, influenza spreads more rapidly in a more crowded urban center, so the relationship might be stronger in those areas.

In any case, said Boehme, "geographic location played no role in the association, which was really interesting."

Boehme surmised that flu vaccinations may have helped prevent some older subjects with ILI from suffering a stroke. Past studies from Taiwan have shown a direct relationship between influenza vaccinations and decreased stroke risk, she said.

And the research suggests that if patients contract influenza after receiving a vaccine, it's a milder case, and that if they suffer a stroke, it's less severe.

Most patients over age 65 years get a yearly flu shot, which is not always the case with other age groups. "Those aged 18 to 40 years are the least likely to be vaccinated, unless they're a teacher or healthcare worker," said Boehme.

The possible mechanism connecting ILI to stroke isn't clear, although there are a number of hypotheses, including increased inflammation.

Boehme noted that mouse models have shown that influenza crosses the blood-brain barrier, but it's unknown if that's the case in humans.

It is unclear whether those with ILI who don't go to the hospital will also be at a higher risk for stroke, but Boehme pointed to reports elsewhere that seem to indicate that this is the case.

Commenting for Medscape Medical News, Shyam Prabhakaran, MD, professor and chair of Neurology, The University of Chicago Biological Sciences, said this new study provides more supportive evidence of an inflammatory trigger for stroke.

For some years now, researchers have been searching for what triggers a stroke, said Prabhakaran. Patients with several stroke risk factors may wonder why they suffered a stroke on a particular day rather than the day before or year before.  

"We talk a lot about risk factors for stroke, such as hypertension and diabetes," said Prabhakaran. "Those are things that increase your chance of having a stroke, but they don't necessarily trigger a stroke in a time-locked way, meaning they don't trigger it over a specific period of time."

He stressed that the new study does not provide conclusive evidence of a relationship between flu and stroke. "It's hard to study this because you're looking backwards; you're not looking forward and doing a real observational study."

Non-traumatic CeAD

The second study, led by Madeleine D. Hunter, a medical student at Vagelos College of Physicians and Surgeons at Columbia University, New York City, showed that ILI is associated with increased risk of non-traumatic CeAD for up to a month.

Hunter and colleagues used the same SPARCS database as the stroke study to identify 3861 adult patients with a first non-traumatic CeAD, mean age 52 years and 55.5% male.

Researchers compared ILI and influenza preceding CeAD. They calculated ORs and 95% CIs and adjusted for annual population estimates of the influenza prevalence rate.

There were 1736 instances of ILI and 113 of influenza during the 3 years preceding CeAD.

Patients were more likely to have ILI within 30 days of CeAD compared with the same time 1 and 2 years before (0-15 days: adjusted OR 1.53, 95% CI 1.02 - 2.30; 0-30 days: adjusted OR 1.60, 95% CI 1.14 - 2.23).

Influenza was associated with CeAD between 31 and 90 days after CeAD, but this effect was no longer significant after adjusting for prevalence rate of influenza, perhaps due the small number of patients with confirmed influenza.

"Our results suggest that the risk of dissection fades over time after the flu," said Hunter in a press release. "This trend indicates that flu-like illnesses may indeed trigger dissection."

Hunter noted an important limitation of the study was that it used an administrative dataset. This meant that researchers had to rely on billing codes to determine who had cervical artery dissections, influenza, and flu-like illnesses.

CeAD can occur as a result of blunt trauma, such as a fall or car accident. A non-traumatic dissection could be caused by rapid head turning such as during a chiropractic treatment.

A dissection can cause pain, discomfort, and even a stroke, most often in relatively young adults.

Prabhakaran described this new research as interesting and said it again raises the question of timing. For example, people often get chiropractic neck manipulations but don't get a tear. "So why doesn't it cause a dissection every single time?"

Some experts have speculated that the artery has to be weakened or inflamed "for conditions to be just right to lead to a dissection," said Prabhakaran.

In addition to inflammation possibly causing CeAD, the unrelenting coughing associated with the flu could also play a role.

"Influenza is associated with lot of coughing, and violent coughing is known to cause dissection in and of itself," said Prabhakaran.

The stroke study was funded by the National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke, and NIH National Institute on Minority Health and Health Disparities. The CeAd study was funded by National Institutes of Health and the Giordano Family Foundation. The study investigators and Prabhakaran have disclosed no relevant financial relationships.

International Stroke Conference (ISC) 2019: Abstract 189, to be presented February 8, 2019. Poster WMP49, to be presented February 6, 2019.

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