February 1, 2012 (New Orleans, Louisiana) — 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.
"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, Heather Fullerton, MD, director of the Pediatric Stroke and Cerebrovascular Disease Center, University of California, San Francisco, told Medscape Medical News. "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 (ISC) 2012.
Dose Dependent
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 when they were no longer in the neonatal period (mean age, 10.5 years). They also randomly selected 378 age-matched control participants, or 3 per case.
Within a time window that extended 2 years before the stroke, the researchers found that children who had strokes were more likely to have had a medical encounter for treatment of an infection compared with those who did not suffer a stroke: 79% of patients who had strokes vs 62% of control participants.
According to Dr. Fullerton, there was almost a "dose-dependent" effect. "The more visits for an infection you had in those prior 2 years, the higher your risk of stroke," Dr. Fullerton said. Although it is difficult to determine whether the children were getting more infections or were presenting repeatedly for treatment of the same infection, the medical visits were generally spread out. This led the researchers to believe that having more infections raises the stroke risk.
The risk was higher closer to the time of the infection. In the first 2 days before stroke, 29% of patients had infections vs 1% of control participants (P < .001) during the same time window. In the 3 to 7 days before a stroke, 13% of patients and 2% of control participants had a healthcare visit for treatment of infection (P < .001).
After adjusting for gender as well as hematologic, autoimmune, and cardiac disease factors, a visit for infection in the 2 days before stroke was associated with a relative hazard of 182 (P < .001). The relative hazard fell to 10 (P < .001) and 2 (P = .046) for the periods from 3 to 7 days and from 8 to 28 days before the stroke, respectively.
Although studies in adults have generally investigated either the 1-week or the 1-month period, the results in terms of overall odds ratios appear similar, said Dr. Fullerton.
Infection Types
The types of infections bringing these children to an urgent care center or to their pediatrician "runs the gamut" of common infections, with most being viral, said Dr. 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 the 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 Dr. 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."
Because infections are exceedingly common in children and because stroke is a rare sequela, Dr. Fullerton believes there is 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 that if inflammation contributes to stroke risk, would anti-inflammatory medications prevent a stroke? Dr. Fullerton stressed that stroke occurs only in a small group of children and that anti-inflammatory drugs have side effects, so it does not 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 2 years, said Dr. Fullerton. The risk is particularly high in children who have an abnormality in the blood vessels leading to their brain — two thirds of these children 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?” said Dr. Fullerton.
Although 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 Dr. 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, then 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
E. Steve Roach, MD, chief of pediatric neurology and vice-chair of pediatrics at Nationwide Children's Hospital, Columbus, Ohio, and professor of pediatrics and neurology at the Ohio State University College of Medicine, 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," Dr. 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 underway that should provide more data on this, he noted, referring to the Vascular Effects of Infection in Pediatrics (VIPS), a prospective study examining this relationship; Dr. 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 1 or 2 years, "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 relevant financial relationships.
"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, Heather Fullerton, MD, director of the Pediatric Stroke and Cerebrovascular Disease Center, University of California, San Francisco, told Medscape Medical News. "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 (ISC) 2012.
Dose Dependent
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 when they were no longer in the neonatal period (mean age, 10.5 years). They also randomly selected 378 age-matched control participants, or 3 per case.
Within a time window that extended 2 years before the stroke, the researchers found that children who had strokes were more likely to have had a medical encounter for treatment of an infection compared with those who did not suffer a stroke: 79% of patients who had strokes vs 62% of control participants.
According to Dr. Fullerton, there was almost a "dose-dependent" effect. "The more visits for an infection you had in those prior 2 years, the higher your risk of stroke," Dr. Fullerton said. Although it is difficult to determine whether the children were getting more infections or were presenting repeatedly for treatment of the same infection, the medical visits were generally spread out. This led the researchers to believe that having more infections raises the stroke risk.
The risk was higher closer to the time of the infection. In the first 2 days before stroke, 29% of patients had infections vs 1% of control participants (P < .001) during the same time window. In the 3 to 7 days before a stroke, 13% of patients and 2% of control participants had a healthcare visit for treatment of infection (P < .001).
After adjusting for gender as well as hematologic, autoimmune, and cardiac disease factors, a visit for infection in the 2 days before stroke was associated with a relative hazard of 182 (P < .001). The relative hazard fell to 10 (P < .001) and 2 (P = .046) for the periods from 3 to 7 days and from 8 to 28 days before the stroke, respectively.
Although studies in adults have generally investigated either the 1-week or the 1-month period, the results in terms of overall odds ratios appear similar, said Dr. Fullerton.
Infection Types
The types of infections bringing these children to an urgent care center or to their pediatrician "runs the gamut" of common infections, with most being viral, said Dr. 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 the 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 Dr. 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."
Because infections are exceedingly common in children and because stroke is a rare sequela, Dr. Fullerton believes there is 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 that if inflammation contributes to stroke risk, would anti-inflammatory medications prevent a stroke? Dr. Fullerton stressed that stroke occurs only in a small group of children and that anti-inflammatory drugs have side effects, so it does not 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 2 years, said Dr. Fullerton. The risk is particularly high in children who have an abnormality in the blood vessels leading to their brain — two thirds of these children 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?” said Dr. Fullerton.
Although 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 Dr. 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, then 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
E. Steve Roach, MD, chief of pediatric neurology and vice-chair of pediatrics at Nationwide Children's Hospital, Columbus, Ohio, and professor of pediatrics and neurology at the Ohio State University College of Medicine, 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," Dr. 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 underway that should provide more data on this, he noted, referring to the Vascular Effects of Infection in Pediatrics (VIPS), a prospective study examining this relationship; Dr. 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 1 or 2 years, "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 relevant financial relationships.
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