Stroke risk linked to infections in children

Pauline Anderson

February 01, 2012

New Orleans, LA - The risk of ischemic stroke is greatly elevated in children who seek medical attention for an infection, especially within the first few days following the infection, a new study shows [1].

"It seems to be less an issue of a chronic infection and more an issue of an acute infection transiently increasing a child's risk of stroke," the study's principal investigator, Dr Heather Fullerton (University of California, San Francisco), said in an interview. "So the risk is probably for a pretty brief period, just a handful of days, then it really seems to taper off."

The study was presented here at the International Stroke Conference 2012.

"Dose-dependent" effect

Researchers used administrative databases and medical charts to find cases of stroke and infection exposures. Within a cohort of about 2.5 million children who received care in a northern California health maintenance organization, they identified 126 children who had suffered an ischemic stroke outside of the neonatal period (mean age 10.5 years). They also randomly selected 378 age-matched controls, or three per case.

Looking at a time window that extended two years prior to the stroke, the researchers found that children who had strokes were more likely to have had a medical encounter for an infection compared with those who didn't suffer a stroke: 79% of cases vs 62% of controls.

According to Fullerton, there was almost a "dose-dependent" effect. "The more visits for an infection you had in those prior two years, the higher your risk of stroke." Although it's difficult to determine whether the children were actually getting more infections or just coming in more for the same infection, the medical visits were generally spread out, so the researchers believe that it's having more infections that raises the stroke risk.

The risk was higher closer to the time of the infection. In the first two days prior to stroke, 29% of cases had infections vs 1% of controls (p<0.001) during the same time window. In the three to seven days prior to a stroke, 13% of cases and 2% of controls had a visit for infection (p<0.001)

After adjustment for gender and hematologic, autoimmune, and cardiac disease factors, a visit for infection in the two days prior to stroke was associated with a relative hazard of 182 (p<0.001), which fell to 10 (p<0.001) and 2 (p=0.046) for the three to seven days and eight to 28 days prior to the stroke, respectively.

Although studies in adults have generally looked at one-week or one-month time periods, the results in terms of overall odds ratios appear similar, said Fullerton.

Infection types

The types of infections bringing these children to an urgent-care center or to their pediatrician "run the gamut" of common infections, with most being viral, said Fullerton. They included upper-respiratory infections, otitis media, urinary-tract infections, and acute gastroenteritis.

The infection likely causes some sort of systemic inflammation, which contributes to stroke risk in a number of possible ways. Research shows that inflammatory cytokines and inflammatory response can contribute to coagulation and that circulating inflammatory molecules can injure endothelial cells.

In adults, "it's fairly well accepted that inflammation plays a large role in the development of atherosclerotic plaques," which can contribute to strokes, said Fullerton. "So I think the general idea is that something similar might be happening in children, that these circulating inflammatory molecules could be causing injury to the endothelium."

Since infections are exceedingly common in children, and stroke is a rare sequela, Fullerton believes there's something unique about children who have strokes in the setting of infections. One of her research goals is to determine whether they have a genetic abnormality or a defect in their inflammatory response.

"They could have a heightened inflammatory response that's particularly damaging to the cerebral blood vessels or something genetically different about their cerebral blood vessels that makes them more sensitive to the normal inflammatory response that a child would develop after an infection," she said.

The nagging research question is, if inflammation contributes to stroke risk, would anti-inflammatory medications prevent a stroke? Fullerton stressed that stroke occurs only in a small group of children and that anti-inflammatory drugs have side effects, so it doesn't make sense to treat all kids who come in with an infection with an anti-inflammatory agent.

Stroke recurrence

But it might be a different story for those who do suffer a stroke. For these children, the risk of a recurrent stroke is about 15%, with most of the risk being in the first two years, said Fullerton. The risk is particularly high in children who have an abnormality to the blood vessels leading to their brain—two-thirds of them will have a recurrent stroke within a few years.

"The question is, if inflammation is playing a role in those arteriopathies, by the time they have a stroke, is that inflammatory process still active and so it makes sense to give them anti-inflammatory medications? Or, by time they have stroke is that kind of a burnt-out process and too late now to treat them?"

While some experts advocate "presumptively" treating these kids with steroids, this approach can lead to complications. "They can develop fatal sepsis because it depresses the immune response," said Fullerton.

A randomized controlled trial of an anti-inflammatory medication might help answer these questions, especially now that new magnetic resonance imaging can help identify children in whom inflammation is the main culprit.

"Once we feel we can select out the kids where arteriopathy seems to be inflammatory and it's not a dissection, I think we could design a study to use steroids and see whether that changes the course of their arteriopathy and also their recurrent stroke risk."

Identifying risk

Dr E Steve Roach (Ohio State University College of Medicine, Columbus) commented on the study on behalf of the American Stroke Association.

"I could see that if this holds up, it could deepen our understanding of the pathophysiology of stroke in children, and I could see this leading later to discoveries that might actually help us prevent the stroke or possibly identify a subgroup of people who are at more risk for a stroke in the setting of infection," Roach said in comments released by the association.

"I don't think this will impact what we do now, but if this holds up and is bolstered by additional studies, I could actually see this maybe altering what we do in the future based on future discoveries."

There is already a study under way that should provide more data on this, he noted, the Vascular Effects of Infection in Pediatrics (VIPS), a prospective study looking at this same relationship; Fullerton is also the principal investigator.

"So the VIPS trial will give us a little more precise information about this. Is the relationship real? Is the percentage lower or higher?" he added. The data should be available in the next year or two, "so we're going to have some more extensive and arguably more rigorous information about this topic in the immediate future."

The researchers report no conflicts of interest.


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