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Fever and infection early after ischemic stroke
Journal of the Neurological Sciences 171 (1999) 115–120 www.elsevier.com / locate / jns
Fever and infection early after ischemic stroke a, a b a a Armin J. Grau *, Florian Buggle , Paul Schnitzler , Maike Spiel , Christoph Lichy , Werner Hacke a
b
a Department of Neurology, University of Heidelberg, Heidelberg, Germany Department of Microbiology University of Heidelberg, Heidelberg, Germany
Received 31 May 1999; received in revised form 5 August 1999; accepted 21 September 1999
Abstract Previous studies showed that elevated body temperature early after ischemic stroke is associated with severe neurological deficit and a poor outcome. The aim of this study was to analyse the prevalence and putative etiology of febrile body temperature ($38.08C) early after stroke and to investigate the association between body temperature, stroke severity and outcome. We investigated 119 consecutive patients who were admitted within 24 h after ischemic stroke. Patients were examined for infection before ischemia using a standardized questionnaire and received daily clinical examination after stroke. In case of fever, standardized radiological and microbiological examinations were performed. Fever within 48 h after stroke was observed in 30 (25.2%) patients. The probable cause of fever was infective or chemical aspiration pneumonia (n512), other respiratory tract infection (n57), urinary tract infection (n54), viral infections (n53) or insufficiently defined (n55). (One patient had two potential causes of fever.) In thirteen of these patients, infection was most probably acquired before stroke. Fever newly developed more often during day 1 to 2 than day 3 to 7 after stroke (P50.016). Fever was associated with a more severe deficit on admission independent from age, vascular diseases and risk factors (odds ratio 9.6; 95% confidence interval 3.1–29). Fever is a frequent complication early after stroke and in the majority of cases, it can be explained by infection or chemical aspiration pneumonia. In about half of the infected patients, infection was most probably acquired before stroke. Fever was associated with a more severe neurological deficit on admission. 1999 Elsevier Science B.V. All rights reserved. Keywords: Ischemic stroke; Infection; Fever
1. Introduction Previous studies showed that infection shortly before ischemia is an important risk factor for ischemic stroke [1–5]. Furthermore, fever and infection are frequent complications after stroke which are associated with increased mortality and a worse outcome [6–10]. Fever after stroke can be attributed to infection acquired past ischemia. Infection may be caused by aspiration and later *Corresponding author. Tel.: 149-6221-567-559; fax: 149-6221-565348. E-mail address: armin [email protected] (A.J. Grau) ]
by immobilization and use of indwelling catheters. Alternatively, fever may be the sequel of infection acquired before ischemia. Thirdly, other diseases and mechanisms, particularly the ischemic cerebral tissue damage itself may cause increased body temperature [9]. Previous studies on fever after stroke have not intensively studied the etiology of fever and in particular, they did not differentiate between infection acquired before and after ictus. The aim of this study was to analyse the prevalence and putative etiology of fever early after stroke and to investigate the association between early fever and stroke severity and outcome. This analysis is based on the patients’ group of a recently performed case-control study in which bacterial
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A. J. Grau et al. / Journal of the Neurological Sciences 171 (1999) 115 – 120
and viral infection within the preceding week were shown to be an important and independent risk factor for acute cerebral ischemia [5].
2. Subjects and methods We included consecutive patients who were admitted within 24 h after ischemic stroke. In patients who awoke with stroke the last time point when patients were awake and without symptoms was considered. Patients with transient ischemic attack (TIA) were excluded. All patients received cranial computed tomography in order to exclude cerebral hemorrhage. We took a detailed history from all patients using a standardized questionnaire that focuses on signs and symptoms of infection during the last four weeks. If information could not be obtained from the patient, a next-of-kin was interviewed. Criteria for the diagnosis of infection before ischemia were detailed previously [2,5]. Briefly, diagnosis of preceding infection required the report of $1 typical symptom in combination with fever ($38.08C), subfebrile temperature (37.6– 37.98C), or a corresponding serological or cultural finding that indicated an acute infection, or the combination of $2 symptoms typical of a local infection. Combinations of signs and symptoms that may have been caused by diseases other than infection (e.g., by an allergy) were not accepted. The patients received daily physical examinations and oral measurements of body temperature on admission and $2 times per day during hospitalization (Temp Plus II, Ivac, Giessen, Germany). Fever was diagnosed when $1 measurement was $38.08C (subfebrile temperature: 37.6– 37.98C). We assessed the neurological deficit daily using the NIH stroke scale (NIH-SS) [11]. Follow-up examination was done $3 months after stroke and outcome was rated using Barthel-index and NIH-SS. We defined a severe neurological deficit as NIH-SS score values .6 and poor outcome as death or Barthel index ,70. Etiologic subtypes of ischemic stroke were based on the TOAST criteria [12]. In case of fever ($388C), a chest X-ray and an investigation of a urine specimen were performed. If related symptoms were present, additional cultures of sputum, transtracheal aspirate, stools or local swabs were done. Fever .38.58C and fever of unknown origin prompted repeated blood cultures. In case of suspected respiratory tract infection or in case of fever of unknown origin we performed tests for the detection of specific antibodies against adeno virus [enzyme linked immunosorbent assay (ELISA) for Ig M and complement fixation assay (CFA)], influenza virus A and B [immunofluorescence assay (IFA) for Ig G and Ig A and CFA], parainfluenza virus (CFA), picorna virus (CFA), respiratory syncytial virus (ELISA for IgM and CFA), echo virus (CFA), Mycoplasma pneumoniae (ELISA for IgM and CFA) and Chlamydia pneumoniae. (CFA). If possible a second serum sample was
analysed $10 days later. Presence of IgM (or IgA) type antibodies or changes of antibody titers of two or more steps were taken as diagnostic. In case only one sample was available for analysis infection was supposed if titers were above cut-off values according to both data from the manufacturer and values established by the Institute of Virology, Heidelberg. In patients with fever or subfebrile temperature criteria for the diagnosis of infection were as follows: Diagnosis of pneumonia (either infectious or chemical aspiration pneumonitis) required an infiltrate, consolidation, or pleural effusion on chest X-ray or rales or dullness to percussion. In case of cough and purulent sputum in the absence of signs indicative of pneumonia, we diagnosed purulent bronchitis. Upper respiratory infection was diagnosed when cough, sneezing or hoarseness were present in addition to fever and criteria for pneumonia or purulent bronchitis were not met. Diagnosis of urinary tract infection required either typical symptoms (urgency, dysuria or suprapubic tenderness) and a urine culture of $10 5 colonies / ml urine or a dip stick test positive for leukocyte esterase and / or nitrate. Non-infectious sources of increased temperature, mainly venous thrombosis or pulmonary embolism, myocardial infarction, severe dehydration, hyperthyroidism, a history of metastasizing carcinoma or systemic vasculitis were considered in febrile patients and special investigations were performed when indicated clinically. Leukocyte count, C-reactive protein and erythrocyte sedimentation rate were not considered for the differential diagnosis of fever as ischemic stroke itself may lead to an acute phase reaction with an increase of these parameters. During the study period, it was part of the standard treatment of stroke in our hospital to rapidly administer antipyretics in case of fever (.388C) and when an infectious origin was suspected antibiotics were given without delay. To compare sample proportions, we applied the Chisquare test and Fisher’s exact test as appropriate. NIH score values were compared using the Mann–Whitney U-test. We used multivariate analyses to simultaneously assess the influence of various factors on NIH score values. The statistical software package SAS (SAS Institute Inc., Cary, NC) was used for the analyses.
3. Results Among 130 consecutive patients with ischemic stroke, 119 (40 women, 79 men, age 61614 years, mean6S.D.) were admitted within 24 h and were eligible for the present study. In 30 out of 119 patients (25.2%), fever was measured within 48 h after stroke, in nine patients within 24 h and in 21 patients between 24 and 48 h after ischemia. Eight out of these 30 patients (26.7%) had a history of infection during the week before stroke with
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Table 1 Probable cause of fever ($38.08C) within 48 h after ischemic stroke Probable cause of fever
History of infection before stroke a
No history of infection before stroke
Total a
Pneumonia / aspiration pneumonitis b Bronchitis or upper respiratory infection c Urinary tract infection d Viral infection e Fever of unknown origin Total
n52 n54 n52 n51 – n58 a
n510 n53 n52 n52 n55 n522
n512 n57 n54 n53 n55 n530
a
One patient had both bronchitis and urinary tract infection. Probably causative bacteria (pneumococci) were detected in one patient. c Probably causative bacteria (streptococci) were detected in two patients. d Probably causative bacteria [E. coli (n52), enterococci] were detected in three patients. e This group includes one patient with Parainfluenza (complement fixation titers: day 2: 1:20; day 5: 1:160; 6 months: 1:10), Mumps (parotitis and orchitis in the first week, anti Mumps IgM positive on day 7; for more detailed report on this patient see Ref. [13]) and Influenza A infection (Ig A positive on day 2; IgG 1:320 on day 17), respectively. b
signs or symptoms of infection persisting until ischemia (Table 1). Pneumonia was the most common origin of fever (n5 12), (Table 1). Ten of the patients with pneumonia had reduced consciousness on or early after admission, six received ICU treatment and three were artificially ventilated. In eight patients with pneumonia fever developed during the second and in four patients within the first day after stroke; three of these four patients were somnolent and two vomited on admission. Three patients without history of preceding infection had fever and cough without evidence of pneumonia and were diagnosed to have bronchitis or upper respiratory tract infection. Two of these patients were alert and without reason for silent aspiration and one of them had a borderline IgA titer against Influenza A or B virus (1:160; cut-off value: 1:160) on the third day after ischemia, however, a second serum sample was not available. Two patients developed urinary tract infections within 48 h; in one of them the diagnosis was established within less than 24 h after stroke and before the use of a urinary catheter. Three patients had evidence of viral infections caused by parainfluenza, influenza and mumps virus, infections that were acquired before stroke (Table 1). In five patients, four of whom had fever above 398C, a definite cause of fever could not be certified; in two of these patients borderline Ig A titers against Influenza virus (1:160) were detected. In one patient with high fever (39.98C), hyperthyroidism [triiodothyronine (T3) 2.73 (normal range 0.6–1.7) ng / ml; thyroxine (T4)
175 (normal range 45–126) ng / ml] may have contributed to the pathogenesis of fever. She also had a borderline IgM titer against respiratory syncytial virus. Between day 3 and 7 after stroke fever developed in six of 65 patients (9.1%) who were afebrile within the first 48 h and could be followed for >7 days on our wards. Therefore, fever was newly diagnosed more often during the first two days after stroke (30 / 119; 25.2%) than during the longer period between day 3 and 7 (P50.016). However, 24 patients without initial fever could not be followed until the end of the first week and this may limit our analysis. In six additional patients, the maximum body temperature within the first 48 h was between 37.6 and 37.98C. Two patients had symptoms of upper respiratory infection (cough and sneezing), one patient had a urinary tract infection with significant bacteriuria and one patient had serologic evidence of acute picorna virus infection (CF titer of 1:160; cut-off value 1:160), however a second serum sample was not available. In the other two patients, there was no evidence of infection or any other source of increased body temperature. Patients with fever within 48 h were older and had a more severe deficit on admission and after $3 months and a higher mortality than patients without fever (Table 2). Fifty percent of the patients with fever within 48 h (15 out of 30) but only 20.2% of the afebrile patients (18 out of 89) required ICU treatment during the first week (P5 0.002). The prevalence of vertebrobasilar artery territory
Table 2 Univariate analysis of demographic data, risk factors, stroke severity and outcome in patients with and without fever within 48 h after stroke
Age (years) NIH-SS on admission a NIH-SS after $3 months Barthel-Index $3 months Mortality after $3 months a
Patients without fever within 48 h
Patients with fever within 48 h
P-value
n589 59615 n587; 4; 2–10 n575; 1; 0–3 n574; 100; 85–100 9 / 89 (10.1%)
n530 67613 n529; 19; 10–25 n523; 12; 2–42 n522; 60; 0–95 10 / 30 (33.3%)
P50.02 P#0.0001 P50.002 P#0.0001 P50.003
NIH-SS5NIH Stroke Scale. Data on NIH stroke scale and Barthel Index are given as median and 25–75% quartile.
A. J. Grau et al. / Journal of the Neurological Sciences 171 (1999) 115 – 120
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Table 3 Multiple logistic regression analysis of severe deficit on admission and poor outcome Parameter
Fever (48 h) Age .60 years Diabetes mellitus Hypertension Current smoking CHD and / or PAD a a
Poor outcome after $3 months (Barthel Index ,70)
Severe deficit on admission (NIH-SS .6) Odds ratio (95% c.i.)
P-value
Odds ratio (95% c.i.)
P-value
9.6 1.0 0.9 0.7 0.7 1.3
#0.0001 0.94 0.79 0.37 0.56 0.57
3.9 3.6 2.4 1.1 0.8 2.5
0.024 0.062 0.15 0.91 0.77 0.12
(3.1–29) (0.37–2.5) (0.31–2.4) (0.27–1.6) (0.26–2.1) (0.50–3.5)
(1.20–13) (0.94–14) (0.73–7.8) (0.31–3.8) (0.16–3.8) (0.79–7.9)
CHD5Coronary heart disease; PAD5peripheral arterial disease
stroke was not different between patients with (8 / 30; 26.7%) and without early fever (31 / 83; 37.4%). Fever within 48 h after stroke was associated with a more severe deficit on admission independent from age, stroke risk factors and concomitant vascular diseases (Table 3). Early fever was also correlated with poor outcome after $3 months (Table 3). However, when stroke severity on admission was included in the multivariate analysis, severe deficit on admission (NIH-SS .6) was a predictor for poor outcome [odds ratio (OR) 11.8; 95% confidence interval (ci) 2.7–52] but early fever (OR 2.0; 95% ci 0.53–7.4) and the other covariates of Table 3 were not significant. Patients with cardioembolic stroke had more often fever within 48 h (16 out of 42; 38.1%) than the other patients (14 out of 77; 18.2%; P50.018). Cardioembolic stroke was also associated with a trend to a more severe deficit on admission (NIH-SS, 10; 3–21 versus 4.5; 2–12.5 [median; 25–75% quartile; P50.082]. Other stroke etiologies were not associated with a high prevalence of fever or a more severe deficit.
4. Discussion In our study approximately 25% of the patients had fever and 32% had a body temperature $37.58C within 48 h after ischemic stroke. Previous studies reported fever ($38.38C) in 22% of patients within five days after stroke [14] and elevated body temperature (.37.28C on axilar measurement) in 43% of patients within one week after stroke [8]. In contrast, a recent study found increased body temperature ($37.58C on axilar measurement) in as much as 61% of patients within 72 h after stroke [10]. Due to less frequent temperature monitoring, mild (,38.08C) and short-lasting elevation of temperature may have been missed in some of our patients. However, it is unlikely that we underestimated the prevalence of febrile temperature. Similar to previous studies, fever occurred most often within the first two days after stroke [8,14]. Thus, febrile temperature is a frequent complication in the early stages after stroke. In the majority of febrile patients (83%), early fever can
be explained by infection (or by aspiration chemical pneumonitis) in our study. This result justifies the use of the word ‘fever’ which points to a shift in the hypothalamic setpoint of temperature regulation instead of the term ‘hyperthermia’ which denominates increased body temperature from excessive heat production or inability to lose heat. Previous studies found an association between increased body temperature and infection in 65% [14] and 58% [10] of patients, however, screening for antimicrobial antibodies and a search for pre-stroke infection was not performed in these investigations. Our study was still limited with respect to microbiological techniques, e.g. we did not perform viral antigen detection assays. Due to the present evidence that fever after stroke is harmful for the patient, antibiotics are administered early if an infectious origin is suspected and cultural tests are not repeated several times before antibiotic treatment. This practice limits the probability of cultural detection of bacteria and may explain the low detection rate of bacteria in our study. During the study period, antipyretics were not given to patients with subfebrile temperature (,38.08C). Thus, the prevalence of fever was not influenced by antipyretic treatment. However, antipyretics may have altered the course of fever after temperature of more than 38.08C had been measured. Therefore, we did not include parameters such as duration of fever and maximum temperature in our analyses. Our data indicate that in most cases, infection can explain fever after stroke. In principle, there is a multitude of non-infectious sources of febrile temperature, including drug fever, neoplastic, endocrinological, inflammatory and immunologically mediated disorders. In only one of our patients with fever, was there evidence that any of these alternative conditions (hyperthyroidism) may have contributed to elevated body temperature. Presently it is discussed whether cerebral ischemia and tissue necrosis itself may cause increased body temperature [9]. Interleukin (IL)-1b and IL-6, both important contributors to the induction of fever, are increased in the cerebrospinal fluid after stroke. This intrathecal production showed a timerelated variation with a peak two to three days after stroke; on the day of ischemia and the first day thereafter no
A. J. Grau et al. / Journal of the Neurological Sciences 171 (1999) 115 – 120
(IL-1b) or only a minor (IL-6) increase over chronic levels could be found [15]. Thus, intrathecal production of these major pyrogens may not be an important contributor to fever early after stroke. However, a role of these endogenous pyrogens cannot be completely excluded and other pyrogenic factors (e.g. interferons or tumor necrosis factora) could also contribute to fever. In our study five patients had early fever without definite identification of an infectious cause. Four of these patients had high fever (.39.08C), one had evidence of hyperthyroidism and in three patients borderline antiviral antibody titers were present. Infection is the most likely cause of fever in these patients with hyperthyroidism also contributing in one patient. As the diagnosis of infection could not be proven, other etiologies such as a reaction to brain infarction can not be excluded, however. The frequent use of indwelling catheters and the immobility after stroke increase the risk of infection. Therefore, infection after stroke is often regarded as a consequence of cerebral ischemia and its treatment. Most of the patients with pneumonia required artificial ventilation or had reduced consciousness or both. In the majority of these patients, silent aspiration or aspiration after vomiting may have caused pneumonia. Pneumonitis after aspiration can cause fever and is frequently followed by early bacterial infection even within the first 48 h [16,17]. In the patients with pneumonia, fever is most likely a sequel of stroke. In contrast, 27% of the patients with early fever had a history of infection which started before ischemia. These infections are not a sequel of stroke. In addition, two patients with viral infections, one of the patients with urinary tract infection and at least two of the patients with bronchitis or upper respiratory tract infection had certainly or most likely acquired their infection before ischemia although related symptoms were not present or reported for the period before stroke. Therefore, 13 out of 30 patients (43%) with early fever had probably acquired infection before ischemia. To the best of our knowledge, this is the first study showing that fever early after stroke is frequently caused by community acquired infection. This result indicates that the role of infection as a stroke risk factor may be even more important than estimated in previous analyses where only patients with signs and symptoms of infection before ischemia were considered. In parallel with previous studies [6–10], we found that early fever was independently associated with a severe deficit in the acute stage after stroke. It was also a predictor for poor outcome but this association was not independent from initial stroke severity. High fever can itself lead to confusion, reduced alertness and disturbed orientation and can therefore worsen the neurological score independent from any interaction with cerebral ischemia. This may have an influence on the particularly strong association between fever and deficit on admission. However, it does certainly not explain the whole association between stroke severity and fever. Several studies showed
119
that even a mild elevation of body temperature causes larger infarcts and more severe deficits in experimental stroke (for review see [18]). This and results from clinical studies [10] clearly indicate that high temperature is a negative predictor independent from its etiology. Hyperthermia worsens cerebral ischemia by enhanced release of neurotransmitters, increased oxygen free radical production, worsening of blood–brain barrier break-down and cytoskeletal proteolysis and other mechanisms [18]. As shown in our study, fever in the clinical setting can be both cause and sequel of severe stroke. Febrile infection is often acquired before ictus, but severe stroke also predisposes to early aspiration causing febrile infection that in turn may worsen the neurological deficit. In summary, fever is a frequent early complication after stroke and is most common within the first two days after ischemia. In the majority of cases, early fever can be explained by infection or by chemical aspiration pneumonia. Pneumonia, the most common cause of fever early after stroke, is mostly caused by early aspiration. In few cases it is community acquired. More than 40% of patients with early fever had an infection acquired before stroke. In accordance with previous reports we found that increased body temperature early after stroke is associated with a more severe neurological deficit in the acute stage. Based on these findings we conclude that fever in a patient with acute stroke must always prompt an intensive search for an infectious origin.
References ¨ [1] Syrjanen J, Valtonen VV, Iivanainen M, Kaste M, Huttunen JK. Preceding infection as an important risk factor for ischaemic brain infarction in young and middle aged patients. Br Med J 1988;296:1156–60. [2] Grau A, Buggle F, Heindl S, Steichen-Wiehn C, Banerjee T, Maiwald M, Rohlfs M, Suhr H, Fiehn W, Becher H, Hacke W. Recent infection as a risk factor for cerebrovascular ischemia. Stroke 1995;26:373–9. [3] Macko RF, Ameriso SF, Barndt R, Clough W, Weiner JM, Fisher M. Precipitants of brain infarction: Roles of preceding infection / inflammation and recent psychological stress. Stroke 1996;27:1999–2004. [4] Bova IY, Bornstein NM, Korczyn AD. Acute infection as a risk factor ischemic stroke. Stroke 1996;27:2204–6. [5] Grau A, Buggle F, Becher H, Zimmermann E, Spiel M, Fent T, Maiwald M, Werle E, Zorn M, Hengel H, Hacke W. Recent bacterial and viral infection is a risk factor for cerebrovascular ischemia. Clinical and biochemical analysis. Neurology 1998;50:196–203. [6] Hindfeldt B. The prognostic significance of subfebrility and fever in ischaemic cerebral infarction. Acta Neurol Scand 1976;53:72–9. ´ [7] Castillo J, Martınez F, Leira R, Prieto JM, Lema M, Noya M. Mortaility and morbidity of acute cerebral infarction related to temperature and basal analytic parameters. Cerebrovasc Dis 1994;4:66–71. [8] Azzimondi G, Bassein L, Nonino F, Fiorani L, Vignatelli L, Re G, ´ D’Alessandro R. Fever in acute stroke worsens prognosis. A prospective study. Stroke 1995;26:2040–3. [9] Reith J, Jørgensen HS, Pedersen PM, Nakayama H, Raaschou HO, Jeppesen LL, Olsen TS. Body temperature in acute stroke: Relation
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A. J. Grau et al. / Journal of the Neurological Sciences 171 (1999) 115 – 120 to stroke severity, infarct size, mortality and outcome. Lancet 1996;347:422–5. ´ Castillo J, Davalos A, Marrugat J, Noya M. Timing for fever-related brain damage in acute ischemic stroke. Stroke 1998;29:2455–60. Brott T, Adams HP, Olinger CP, Marler JR, Barsan WG, Biller J, Spilker J, Holleran R, Eberle R, Hertzberg V, Rorick M, Moomaw CJ, Walker M. Measurements of acute cerebral infarction: A clinical examination scale. Stroke 1989;20:864–70. and the TOAST investigators, Adams HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE. Classification of subtype of acute stroke. Definitions for use in a multicenter clinical trial. Stroke 1993;24:35–41. ¨ B, Schnabel PA, Brandt T, Hacke W. Grau AJ, Eckstein HH, Schafer Stroke from internal carotid artery occlusion during mumps infection. J Neurol Sci 1998;155:215–7.
[14] Przelomski MM, Roth RM, Gleckman RA, Marcus EM. Fever in the wake of a stroke. Neurology 1986;36:427–9. [15] Tarkowski E, Rosengren L, Blomstrand C, Wikkelso¨ C, Jensen C, Ekholm S, Tarkowski A. Early intrathecal production of interleukin6 predicts the size of brain lesion in stroke. Stroke 1995;26:1393–8. [16] Langer M, Cigada M, Mandelli M, Mosconi P, Tognoni G. Early onset pneumonia: a multicenter study in intensive care units. Intensive Care Med 1987;13:342–6. [17] Kennedy GA, Kanter RK, Weiner LB, Tompkins JM. Can early bacterial complications of aspiration with respiratory failure be predicted? Pediatr Emerg Care 1992;8:123–5. [18] Ginsberg MD, Busto R. Combating hyperthermia in acute stroke. A significant clinical concern. Stroke 1998;29:529–34.
Fever and infection early after ischemic stroke a, a b a a Armin J. Grau *, Florian Buggle , Paul Schnitzler , Maike Spiel , Christoph Lichy , Werner Hacke a
b
a Department of Neurology, University of Heidelberg, Heidelberg, Germany Department of Microbiology University of Heidelberg, Heidelberg, Germany
Received 31 May 1999; received in revised form 5 August 1999; accepted 21 September 1999
Abstract Previous studies showed that elevated body temperature early after ischemic stroke is associated with severe neurological deficit and a poor outcome. The aim of this study was to analyse the prevalence and putative etiology of febrile body temperature ($38.08C) early after stroke and to investigate the association between body temperature, stroke severity and outcome. We investigated 119 consecutive patients who were admitted within 24 h after ischemic stroke. Patients were examined for infection before ischemia using a standardized questionnaire and received daily clinical examination after stroke. In case of fever, standardized radiological and microbiological examinations were performed. Fever within 48 h after stroke was observed in 30 (25.2%) patients. The probable cause of fever was infective or chemical aspiration pneumonia (n512), other respiratory tract infection (n57), urinary tract infection (n54), viral infections (n53) or insufficiently defined (n55). (One patient had two potential causes of fever.) In thirteen of these patients, infection was most probably acquired before stroke. Fever newly developed more often during day 1 to 2 than day 3 to 7 after stroke (P50.016). Fever was associated with a more severe deficit on admission independent from age, vascular diseases and risk factors (odds ratio 9.6; 95% confidence interval 3.1–29). Fever is a frequent complication early after stroke and in the majority of cases, it can be explained by infection or chemical aspiration pneumonia. In about half of the infected patients, infection was most probably acquired before stroke. Fever was associated with a more severe neurological deficit on admission. 1999 Elsevier Science B.V. All rights reserved. Keywords: Ischemic stroke; Infection; Fever
1. Introduction Previous studies showed that infection shortly before ischemia is an important risk factor for ischemic stroke [1–5]. Furthermore, fever and infection are frequent complications after stroke which are associated with increased mortality and a worse outcome [6–10]. Fever after stroke can be attributed to infection acquired past ischemia. Infection may be caused by aspiration and later *Corresponding author. Tel.: 149-6221-567-559; fax: 149-6221-565348. E-mail address: armin [email protected] (A.J. Grau) ]
by immobilization and use of indwelling catheters. Alternatively, fever may be the sequel of infection acquired before ischemia. Thirdly, other diseases and mechanisms, particularly the ischemic cerebral tissue damage itself may cause increased body temperature [9]. Previous studies on fever after stroke have not intensively studied the etiology of fever and in particular, they did not differentiate between infection acquired before and after ictus. The aim of this study was to analyse the prevalence and putative etiology of fever early after stroke and to investigate the association between early fever and stroke severity and outcome. This analysis is based on the patients’ group of a recently performed case-control study in which bacterial
0022-510X / 99 / $ – see front matter 1999 Elsevier Science B.V. All rights reserved. PII: S0022-510X( 99 )00261-0
116
A. J. Grau et al. / Journal of the Neurological Sciences 171 (1999) 115 – 120
and viral infection within the preceding week were shown to be an important and independent risk factor for acute cerebral ischemia [5].
2. Subjects and methods We included consecutive patients who were admitted within 24 h after ischemic stroke. In patients who awoke with stroke the last time point when patients were awake and without symptoms was considered. Patients with transient ischemic attack (TIA) were excluded. All patients received cranial computed tomography in order to exclude cerebral hemorrhage. We took a detailed history from all patients using a standardized questionnaire that focuses on signs and symptoms of infection during the last four weeks. If information could not be obtained from the patient, a next-of-kin was interviewed. Criteria for the diagnosis of infection before ischemia were detailed previously [2,5]. Briefly, diagnosis of preceding infection required the report of $1 typical symptom in combination with fever ($38.08C), subfebrile temperature (37.6– 37.98C), or a corresponding serological or cultural finding that indicated an acute infection, or the combination of $2 symptoms typical of a local infection. Combinations of signs and symptoms that may have been caused by diseases other than infection (e.g., by an allergy) were not accepted. The patients received daily physical examinations and oral measurements of body temperature on admission and $2 times per day during hospitalization (Temp Plus II, Ivac, Giessen, Germany). Fever was diagnosed when $1 measurement was $38.08C (subfebrile temperature: 37.6– 37.98C). We assessed the neurological deficit daily using the NIH stroke scale (NIH-SS) [11]. Follow-up examination was done $3 months after stroke and outcome was rated using Barthel-index and NIH-SS. We defined a severe neurological deficit as NIH-SS score values .6 and poor outcome as death or Barthel index ,70. Etiologic subtypes of ischemic stroke were based on the TOAST criteria [12]. In case of fever ($388C), a chest X-ray and an investigation of a urine specimen were performed. If related symptoms were present, additional cultures of sputum, transtracheal aspirate, stools or local swabs were done. Fever .38.58C and fever of unknown origin prompted repeated blood cultures. In case of suspected respiratory tract infection or in case of fever of unknown origin we performed tests for the detection of specific antibodies against adeno virus [enzyme linked immunosorbent assay (ELISA) for Ig M and complement fixation assay (CFA)], influenza virus A and B [immunofluorescence assay (IFA) for Ig G and Ig A and CFA], parainfluenza virus (CFA), picorna virus (CFA), respiratory syncytial virus (ELISA for IgM and CFA), echo virus (CFA), Mycoplasma pneumoniae (ELISA for IgM and CFA) and Chlamydia pneumoniae. (CFA). If possible a second serum sample was
analysed $10 days later. Presence of IgM (or IgA) type antibodies or changes of antibody titers of two or more steps were taken as diagnostic. In case only one sample was available for analysis infection was supposed if titers were above cut-off values according to both data from the manufacturer and values established by the Institute of Virology, Heidelberg. In patients with fever or subfebrile temperature criteria for the diagnosis of infection were as follows: Diagnosis of pneumonia (either infectious or chemical aspiration pneumonitis) required an infiltrate, consolidation, or pleural effusion on chest X-ray or rales or dullness to percussion. In case of cough and purulent sputum in the absence of signs indicative of pneumonia, we diagnosed purulent bronchitis. Upper respiratory infection was diagnosed when cough, sneezing or hoarseness were present in addition to fever and criteria for pneumonia or purulent bronchitis were not met. Diagnosis of urinary tract infection required either typical symptoms (urgency, dysuria or suprapubic tenderness) and a urine culture of $10 5 colonies / ml urine or a dip stick test positive for leukocyte esterase and / or nitrate. Non-infectious sources of increased temperature, mainly venous thrombosis or pulmonary embolism, myocardial infarction, severe dehydration, hyperthyroidism, a history of metastasizing carcinoma or systemic vasculitis were considered in febrile patients and special investigations were performed when indicated clinically. Leukocyte count, C-reactive protein and erythrocyte sedimentation rate were not considered for the differential diagnosis of fever as ischemic stroke itself may lead to an acute phase reaction with an increase of these parameters. During the study period, it was part of the standard treatment of stroke in our hospital to rapidly administer antipyretics in case of fever (.388C) and when an infectious origin was suspected antibiotics were given without delay. To compare sample proportions, we applied the Chisquare test and Fisher’s exact test as appropriate. NIH score values were compared using the Mann–Whitney U-test. We used multivariate analyses to simultaneously assess the influence of various factors on NIH score values. The statistical software package SAS (SAS Institute Inc., Cary, NC) was used for the analyses.
3. Results Among 130 consecutive patients with ischemic stroke, 119 (40 women, 79 men, age 61614 years, mean6S.D.) were admitted within 24 h and were eligible for the present study. In 30 out of 119 patients (25.2%), fever was measured within 48 h after stroke, in nine patients within 24 h and in 21 patients between 24 and 48 h after ischemia. Eight out of these 30 patients (26.7%) had a history of infection during the week before stroke with
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Table 1 Probable cause of fever ($38.08C) within 48 h after ischemic stroke Probable cause of fever
History of infection before stroke a
No history of infection before stroke
Total a
Pneumonia / aspiration pneumonitis b Bronchitis or upper respiratory infection c Urinary tract infection d Viral infection e Fever of unknown origin Total
n52 n54 n52 n51 – n58 a
n510 n53 n52 n52 n55 n522
n512 n57 n54 n53 n55 n530
a
One patient had both bronchitis and urinary tract infection. Probably causative bacteria (pneumococci) were detected in one patient. c Probably causative bacteria (streptococci) were detected in two patients. d Probably causative bacteria [E. coli (n52), enterococci] were detected in three patients. e This group includes one patient with Parainfluenza (complement fixation titers: day 2: 1:20; day 5: 1:160; 6 months: 1:10), Mumps (parotitis and orchitis in the first week, anti Mumps IgM positive on day 7; for more detailed report on this patient see Ref. [13]) and Influenza A infection (Ig A positive on day 2; IgG 1:320 on day 17), respectively. b
signs or symptoms of infection persisting until ischemia (Table 1). Pneumonia was the most common origin of fever (n5 12), (Table 1). Ten of the patients with pneumonia had reduced consciousness on or early after admission, six received ICU treatment and three were artificially ventilated. In eight patients with pneumonia fever developed during the second and in four patients within the first day after stroke; three of these four patients were somnolent and two vomited on admission. Three patients without history of preceding infection had fever and cough without evidence of pneumonia and were diagnosed to have bronchitis or upper respiratory tract infection. Two of these patients were alert and without reason for silent aspiration and one of them had a borderline IgA titer against Influenza A or B virus (1:160; cut-off value: 1:160) on the third day after ischemia, however, a second serum sample was not available. Two patients developed urinary tract infections within 48 h; in one of them the diagnosis was established within less than 24 h after stroke and before the use of a urinary catheter. Three patients had evidence of viral infections caused by parainfluenza, influenza and mumps virus, infections that were acquired before stroke (Table 1). In five patients, four of whom had fever above 398C, a definite cause of fever could not be certified; in two of these patients borderline Ig A titers against Influenza virus (1:160) were detected. In one patient with high fever (39.98C), hyperthyroidism [triiodothyronine (T3) 2.73 (normal range 0.6–1.7) ng / ml; thyroxine (T4)
175 (normal range 45–126) ng / ml] may have contributed to the pathogenesis of fever. She also had a borderline IgM titer against respiratory syncytial virus. Between day 3 and 7 after stroke fever developed in six of 65 patients (9.1%) who were afebrile within the first 48 h and could be followed for >7 days on our wards. Therefore, fever was newly diagnosed more often during the first two days after stroke (30 / 119; 25.2%) than during the longer period between day 3 and 7 (P50.016). However, 24 patients without initial fever could not be followed until the end of the first week and this may limit our analysis. In six additional patients, the maximum body temperature within the first 48 h was between 37.6 and 37.98C. Two patients had symptoms of upper respiratory infection (cough and sneezing), one patient had a urinary tract infection with significant bacteriuria and one patient had serologic evidence of acute picorna virus infection (CF titer of 1:160; cut-off value 1:160), however a second serum sample was not available. In the other two patients, there was no evidence of infection or any other source of increased body temperature. Patients with fever within 48 h were older and had a more severe deficit on admission and after $3 months and a higher mortality than patients without fever (Table 2). Fifty percent of the patients with fever within 48 h (15 out of 30) but only 20.2% of the afebrile patients (18 out of 89) required ICU treatment during the first week (P5 0.002). The prevalence of vertebrobasilar artery territory
Table 2 Univariate analysis of demographic data, risk factors, stroke severity and outcome in patients with and without fever within 48 h after stroke
Age (years) NIH-SS on admission a NIH-SS after $3 months Barthel-Index $3 months Mortality after $3 months a
Patients without fever within 48 h
Patients with fever within 48 h
P-value
n589 59615 n587; 4; 2–10 n575; 1; 0–3 n574; 100; 85–100 9 / 89 (10.1%)
n530 67613 n529; 19; 10–25 n523; 12; 2–42 n522; 60; 0–95 10 / 30 (33.3%)
P50.02 P#0.0001 P50.002 P#0.0001 P50.003
NIH-SS5NIH Stroke Scale. Data on NIH stroke scale and Barthel Index are given as median and 25–75% quartile.
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Table 3 Multiple logistic regression analysis of severe deficit on admission and poor outcome Parameter
Fever (48 h) Age .60 years Diabetes mellitus Hypertension Current smoking CHD and / or PAD a a
Poor outcome after $3 months (Barthel Index ,70)
Severe deficit on admission (NIH-SS .6) Odds ratio (95% c.i.)
P-value
Odds ratio (95% c.i.)
P-value
9.6 1.0 0.9 0.7 0.7 1.3
#0.0001 0.94 0.79 0.37 0.56 0.57
3.9 3.6 2.4 1.1 0.8 2.5
0.024 0.062 0.15 0.91 0.77 0.12
(3.1–29) (0.37–2.5) (0.31–2.4) (0.27–1.6) (0.26–2.1) (0.50–3.5)
(1.20–13) (0.94–14) (0.73–7.8) (0.31–3.8) (0.16–3.8) (0.79–7.9)
CHD5Coronary heart disease; PAD5peripheral arterial disease
stroke was not different between patients with (8 / 30; 26.7%) and without early fever (31 / 83; 37.4%). Fever within 48 h after stroke was associated with a more severe deficit on admission independent from age, stroke risk factors and concomitant vascular diseases (Table 3). Early fever was also correlated with poor outcome after $3 months (Table 3). However, when stroke severity on admission was included in the multivariate analysis, severe deficit on admission (NIH-SS .6) was a predictor for poor outcome [odds ratio (OR) 11.8; 95% confidence interval (ci) 2.7–52] but early fever (OR 2.0; 95% ci 0.53–7.4) and the other covariates of Table 3 were not significant. Patients with cardioembolic stroke had more often fever within 48 h (16 out of 42; 38.1%) than the other patients (14 out of 77; 18.2%; P50.018). Cardioembolic stroke was also associated with a trend to a more severe deficit on admission (NIH-SS, 10; 3–21 versus 4.5; 2–12.5 [median; 25–75% quartile; P50.082]. Other stroke etiologies were not associated with a high prevalence of fever or a more severe deficit.
4. Discussion In our study approximately 25% of the patients had fever and 32% had a body temperature $37.58C within 48 h after ischemic stroke. Previous studies reported fever ($38.38C) in 22% of patients within five days after stroke [14] and elevated body temperature (.37.28C on axilar measurement) in 43% of patients within one week after stroke [8]. In contrast, a recent study found increased body temperature ($37.58C on axilar measurement) in as much as 61% of patients within 72 h after stroke [10]. Due to less frequent temperature monitoring, mild (,38.08C) and short-lasting elevation of temperature may have been missed in some of our patients. However, it is unlikely that we underestimated the prevalence of febrile temperature. Similar to previous studies, fever occurred most often within the first two days after stroke [8,14]. Thus, febrile temperature is a frequent complication in the early stages after stroke. In the majority of febrile patients (83%), early fever can
be explained by infection (or by aspiration chemical pneumonitis) in our study. This result justifies the use of the word ‘fever’ which points to a shift in the hypothalamic setpoint of temperature regulation instead of the term ‘hyperthermia’ which denominates increased body temperature from excessive heat production or inability to lose heat. Previous studies found an association between increased body temperature and infection in 65% [14] and 58% [10] of patients, however, screening for antimicrobial antibodies and a search for pre-stroke infection was not performed in these investigations. Our study was still limited with respect to microbiological techniques, e.g. we did not perform viral antigen detection assays. Due to the present evidence that fever after stroke is harmful for the patient, antibiotics are administered early if an infectious origin is suspected and cultural tests are not repeated several times before antibiotic treatment. This practice limits the probability of cultural detection of bacteria and may explain the low detection rate of bacteria in our study. During the study period, antipyretics were not given to patients with subfebrile temperature (,38.08C). Thus, the prevalence of fever was not influenced by antipyretic treatment. However, antipyretics may have altered the course of fever after temperature of more than 38.08C had been measured. Therefore, we did not include parameters such as duration of fever and maximum temperature in our analyses. Our data indicate that in most cases, infection can explain fever after stroke. In principle, there is a multitude of non-infectious sources of febrile temperature, including drug fever, neoplastic, endocrinological, inflammatory and immunologically mediated disorders. In only one of our patients with fever, was there evidence that any of these alternative conditions (hyperthyroidism) may have contributed to elevated body temperature. Presently it is discussed whether cerebral ischemia and tissue necrosis itself may cause increased body temperature [9]. Interleukin (IL)-1b and IL-6, both important contributors to the induction of fever, are increased in the cerebrospinal fluid after stroke. This intrathecal production showed a timerelated variation with a peak two to three days after stroke; on the day of ischemia and the first day thereafter no
A. J. Grau et al. / Journal of the Neurological Sciences 171 (1999) 115 – 120
(IL-1b) or only a minor (IL-6) increase over chronic levels could be found [15]. Thus, intrathecal production of these major pyrogens may not be an important contributor to fever early after stroke. However, a role of these endogenous pyrogens cannot be completely excluded and other pyrogenic factors (e.g. interferons or tumor necrosis factora) could also contribute to fever. In our study five patients had early fever without definite identification of an infectious cause. Four of these patients had high fever (.39.08C), one had evidence of hyperthyroidism and in three patients borderline antiviral antibody titers were present. Infection is the most likely cause of fever in these patients with hyperthyroidism also contributing in one patient. As the diagnosis of infection could not be proven, other etiologies such as a reaction to brain infarction can not be excluded, however. The frequent use of indwelling catheters and the immobility after stroke increase the risk of infection. Therefore, infection after stroke is often regarded as a consequence of cerebral ischemia and its treatment. Most of the patients with pneumonia required artificial ventilation or had reduced consciousness or both. In the majority of these patients, silent aspiration or aspiration after vomiting may have caused pneumonia. Pneumonitis after aspiration can cause fever and is frequently followed by early bacterial infection even within the first 48 h [16,17]. In the patients with pneumonia, fever is most likely a sequel of stroke. In contrast, 27% of the patients with early fever had a history of infection which started before ischemia. These infections are not a sequel of stroke. In addition, two patients with viral infections, one of the patients with urinary tract infection and at least two of the patients with bronchitis or upper respiratory tract infection had certainly or most likely acquired their infection before ischemia although related symptoms were not present or reported for the period before stroke. Therefore, 13 out of 30 patients (43%) with early fever had probably acquired infection before ischemia. To the best of our knowledge, this is the first study showing that fever early after stroke is frequently caused by community acquired infection. This result indicates that the role of infection as a stroke risk factor may be even more important than estimated in previous analyses where only patients with signs and symptoms of infection before ischemia were considered. In parallel with previous studies [6–10], we found that early fever was independently associated with a severe deficit in the acute stage after stroke. It was also a predictor for poor outcome but this association was not independent from initial stroke severity. High fever can itself lead to confusion, reduced alertness and disturbed orientation and can therefore worsen the neurological score independent from any interaction with cerebral ischemia. This may have an influence on the particularly strong association between fever and deficit on admission. However, it does certainly not explain the whole association between stroke severity and fever. Several studies showed
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that even a mild elevation of body temperature causes larger infarcts and more severe deficits in experimental stroke (for review see [18]). This and results from clinical studies [10] clearly indicate that high temperature is a negative predictor independent from its etiology. Hyperthermia worsens cerebral ischemia by enhanced release of neurotransmitters, increased oxygen free radical production, worsening of blood–brain barrier break-down and cytoskeletal proteolysis and other mechanisms [18]. As shown in our study, fever in the clinical setting can be both cause and sequel of severe stroke. Febrile infection is often acquired before ictus, but severe stroke also predisposes to early aspiration causing febrile infection that in turn may worsen the neurological deficit. In summary, fever is a frequent early complication after stroke and is most common within the first two days after ischemia. In the majority of cases, early fever can be explained by infection or by chemical aspiration pneumonia. Pneumonia, the most common cause of fever early after stroke, is mostly caused by early aspiration. In few cases it is community acquired. More than 40% of patients with early fever had an infection acquired before stroke. In accordance with previous reports we found that increased body temperature early after stroke is associated with a more severe neurological deficit in the acute stage. Based on these findings we conclude that fever in a patient with acute stroke must always prompt an intensive search for an infectious origin.
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