Background and Purpose Prior studies have demonstrated that infections might precipitate ischemic strokes (IS), but the role of infection as a risk factor remains unclear. We conducted a case-control study to investigate this issue.
Methods Consecutive patients (n=182) with acute IS were examined within 48 hours after admission to our center. A history of acute infections within 2 months before the IS was assessed by means of a specially designed questionnaire that was also given to a control group consisting of 194 consecutive patients who were seen in our outpatient clinic and had suffered IS at least 6 months previously.
Results The prevalence of acute infection in the study group was significantly higher (44193/=24.2%) than in the control group (19193/=9.7%; odds ratio, 2.93; 95% confidence interval, 1.64 to 5.26; P=.0002) and infection occurred mostly within 1 week before the IS (41/44). Neither the severity of the IS nor the type of the infection was significantly different in patients and control subjects.
Conclusions Acute infections of different types constitute a risk factor for IS, particularly within 1 week of the event. However, the severity of the stroke is not related to this factor.
Hypertension, ischemic heart disease, diabetes mellitus, and smoking are among the well-known risk factors for acute IS. Several case-control studies with IS patients and matched control subjects indicated that recent infections, primarily of bacterial origin, are a possible risk factor for cerebrovascular ischemia,1 2 3 4 possibly related to concentrations of anti-inflammatory cytokine protein C and tissue plasminogen activator in patients who had an infection-associated stroke.2 5 However, because of the difficulties in the selection of a control group, the role of infection as a risk factor for stroke has not been unanimously accepted (D. Inzitari, Q. Pracucci, M. Lamassa, R. Innocenti, P. Nencini, A. Di Carlo, P. Vanni, G. Trefoloni, S. Spolveri, M. C. Barufft, P. Adriani, C. Bianco, unpublished observations, 1995). In an attempt to shed more light on this problem, we conducted a prospective epidemiological study on consecutive stroke patients and a matched control group. The latter included patients who had undergone a stroke and were followed up at our stroke outpatient clinic. This control group was chosen because of the similarity of their medical background to that of the study group.
Subjects and Methods
Between August and October 1994, 182 consecutive patients (98 males) with acute IS were admitted to our hospital. The diagnosis of IS was made by experienced neurologists in all cases and was frequently (85%) confirmed by CT brain scans. Patients with cerebral hemorrhage and those for whom there was uncertainty about the diagnosis were excluded. Patients or close relatives were interviewed within 48 hours after admission. The presence of acute infections within 2 months before the IS was assessed by means of a special questionnaire that listed symptoms of infectious diseases. The same questionnaire was given to a control group that consisted of 194 consecutive patients (103 males) living in the same region who were seen in our outpatient clinic after suffering an IS at least 6 months previously. It should be noted that the weather from August to October in Tel Aviv is very consistent, with the temperature and humidity barely changing. The diagnosis of infection for both groups was based on either fever alone or a minimum of one cardinal manifestation (bacterial isolation and/or x-ray verification) and two additional presentations (leukocytosis, sore throat lymphadenitis, cough with purulent sputum, vomiting, urinary frequency, hematuria, dysuria, diarrhea, and/or pressure sores). The results of urinary and hematological counts were analyzed, and additional culture analyses of sputum, blood, urine, and stools for definition of bacterial origin were carried out for specific patients when indicated. Bacterial infection was diagnosed only when there was positive culture of blood, urine, or sputum. Viral tests were not performed, and if the origin of infection could not be determined, the diagnosis was classified as “unknown.” All IS patients and the control subjects were also evaluated for the presence of the usual risk factors for cerebrovascular ischemia. All patients were evaluated with the Unified Neurological Stroke Scale6 as previously verified by us.7 Stroke severity was defined according to capability of carrying out activities of daily living within 24 hours after admission: mild stroke (independence in daily activities), moderate stroke (partial dependency for daily activities), and severe stroke (complete dependency).
Data are given as mean±SD for continuous variables, proportions, and OR estimates and 95% CI. Statistical analysis was performed with χ2 analysis and t tests as appropriate.
The prevalence of acute infection in the study group was significantly higher than in the control group (44/182=24.2% versus 19193/=9.7%; OR, 2.93; 95% CI, 1.64 to 5.26; P=.0002; Table 1⇓). In most of the patients who had infections, the infections occurred within 1 week before the IS (41/44). Bacterial infections were diagnosed in 34 cases (18.7%) of the study group and in 13 cases (6.7%) of the control group (P<.005). The distribution of different infection types was similar in both groups, with respiratory and urinary tract infections being more prevalent in both groups (Table 2⇓). The chest x-ray confirmed pneumonia in 10 cases of the study group and in 2 cases of the control group. Infection was more common in the study groups among all age groups (Table 3⇓), but because of the small numbers, this reached significance only for subjects aged 65 to 84 years. Comparison of the severity of the IS as determined by the Unified Neurological Stroke Scale and the type of infection did not reveal significant differences in the mild and severe groups (Table 4⇓). The effect of infection remained significant when other risk factors for stroke were adjusted (Table 1⇓).
Prior studies have demonstrated that infection might increase the risk of IS.1 2 3 4 However, all recent reports are based on various control groups of patients with a low frequency of strokes. In the present study, the control subjects were patients seen in our outpatient clinic who had suffered an IS at least 6 months previously, thus eliminating the possibility that differences were related to differences among patients and control subjects because of risk factors. Although it appeared that the patients had slightly more hypertension, peripheral vascular disease, and ischemic heart disease and more often smoked and therefore would be more likely than control subjects to experience preceding infection, the differences were not statistically significant, and these risk factors could not be considered as being directly related to infection. Our results are in accordance with other studies reporting that acute infection during the preceding week is more frequent among IS patients.1 3 4
When all the subjects were analyzed together, infection was shown to have increased the risk of IS in all previously studied groups.1 2 3 4 8 Infections among our patients were mainly of bacterial origin. Recent studies2 3 4 on the possible mechanisms of infection-associated stroke revealed that there was significant elevation in peripheral blood of interleukin-1 and interleukin-6 and inhibition of polymorphonuclear activity. In a small series of stroke patients who had an associated infection, increased levels of TNF-α were detected, and TNF-α was suspected as a potential mediator in infection-associated stroke. Other factors have been studied, including common and specific pathways of induction of the endothelial adhesion proteins (ICAM-1, VCAM-1, and E-selectin). Differences in the kinetics of endothelial expression of E-selectin, VCAM-1, and ICAM-1 may also contribute to the selective recruitment of leukocyte subtypes to the site of inflammation. Combinations of cytokines may produce additive or synergistic (eg, interleukin-4 and TNF-α for VCAM-1) or antagonistic (eg, interleukin-4 and TNF-α for E-selectin) effects. These multiple levels of regulation provide for precise modulation of expression of endothelial adhesion proteins that are involved in recruitment of leukocytes to sites of inflammation. Another possible coagulative mechanism that may be a relevant factor in IS triggered by infection is an increase of fibrinogen concentration during infection, which increases the blood viscosity.2 3 4 5 12 16 Other authors did not find differences in the severity of the neurological deficit between patients with and without prior infections,2 8 and neither the severity of the IS nor the type of the bacterial infection was significantly different in our two groups (Table 4⇑).
In summary, acute infection of different types constitutes a risk factor for IS, particularly during the first week of the disease. However, the severity of the stroke was apparently not related to this factor. The retrospective ascertainment of the type of infection may of course lead to inaccuracies. However, we do not think that recall bias or differences in motivation could explain the results, particularly the strikingly high frequency of infections during the week preceding the infection.
Selected Abbreviations and Acronyms
|ICAM-1||=||intercellular adhesion molecule-1|
|TNF||=||tumor necrosis factor|
|VCAM-1||=||vascular cell adhesion molecule-1|
- Received May 17, 1996.
- Revision received September 9, 1996.
- Accepted September 16, 1996.
- Copyright © 1996 by American Heart Association
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