Journal of Internal Medicine 1999; 246: 203209

Aetiology of fever in patients with acute stroke*

1 1 2 3 1
K. GEORGILIS , A. PLOMARITOGLOU , U. DAFNI , Y. BASSIAKOS & K. VEMMOS
1 2
From the Department of Clinical Therapeutics, University of Athens School of Medicine, `Alexandra' Hospital, Athens, Greece; the Department of
3
Biostatistics, Harvard School of Public Health, Boston, Massachusetts; and the National School of Public Health, Athens, Greece

Abstract. Georgilis K, Plomaritoglou A, Dafni U, herniation (P , 0.001), intraventricular blood

Bassiakos Y, Vemmos K (University of Athens School (P , 0.001), and larger size of ischaemic infarct
of Medicine, `Alexandra' Hospital, Athens, Greece; (P = 0.0001) and of haemorrhage (P = 0.0002).
Harvard School of Public Health, Boston, Massachu- Patients with fever had lower scores on admission
setts; and the National School of Public Health, on the Glasgow Coma Scale (P = 0.0001) and the
Athens, Greece). Aetiology of fever in patients with Scandinavian Stroke Scale (P = 0.0001). The devel-
acute stroke. J Intern Med 1999; 246: 203209. opment of fever was associated with prior use of an
invasive technique (P , 0.001) and more specifi-
Objective. Fever in patients with acute stroke is
cally with urinary catheterization (P , 0.001), but
usually related to infectious complications. In some
not with the presence of risk factors for infection.
cases, a focus of infection cannot be identified, fever
Patients with fever had a worse outcome assessed by
does not respond to empirical antibiotic treatment
the Modified Rankin Scale (P = 0.0001) and the
and is thought to be due to the central nervous
Barthel Index (P = 0.0001). In multivariate analy-
system lesion. The aim of this study was to
sis, age, Scandinavian Stroke Scale score and mass
determine the frequency and origin of fever in
effect were found to be significantly associated with
patients with acute stroke and the characteristics
fever (P = 0.035, P = 0.0001 and P = 0.0004,
associated with the presence of fever.
respectively). Patients with fever without documen-
Design. A retrospective study of 36 months' dura-
ted infection had an earlier onset of fever than those
tion.
with infection (P = 0.0061). In a logistic regression
Setting. The study was carried out at `Alexandra'
analysis, the only factor predictive of fever without
Hospital, a tertiary care teaching centre in Athens,
documented infection versus infection was earlier
Greece.
onset of fever (P = 0.029).
Subjects. A total of 330 patients hospitalized for
Conclusion. Patients with acute stroke who develop
acute stroke from June 1992 until July 1994.
fever are older, suffer severe stroke, their fever is
Results. In 37.6% of 330 patients, fever was noted;
associated with the use of invasive techniques, and
22.7% had a documented infection and 14.8% had
they have a poor outcome. In patients with fever
fever without a documented infection. In univariate
without a focus of infection, the only characteristic
analysis, older age was associated with the presence
that is different from patients with known infection
of fever (P = 0.001). The development of fever was
is earlier onset of fever.
associated with intracerebral haemorrhage versus
ischaemic infarct (P , 0.001) and with the pre- Keywords: fever, infection, intracerebral haemor-
sence of mass effect (P , 0.001), transtentorial rhage, ischaemic infarct, stroke.

ment, which increases their risk for adverse reac-

Introduction
Fever is common in patients with acute stroke and
most of the time is due to infectious complications.
In some patients with acute stroke and fever, a focus
of infection cannot be identified. These patients often
receive empirical broad-spectrum antibiotic treat-
tions and the cost of their medical care. In some of
these cases of fever without an obvious focus of
*Presented in part at the 33rd Annual Meeting of the Infectious
Diseases Society of America, San Francisco, California, USA, 16
18 September 1995.

# 1999 Blackwell Science Ltd 203

204 K . G E O R G I L I S et al.
infection, fever does not respond to empirical
antibiotic treatment and is thought to be due to
the central nervous system lesion. The presence of
fever, in general, in patients with acute stroke has
been associated with a poor outcome [1, 2]. How-
ever, characteristics of patients with acute stroke
who develop fever have not been defined.
In a retrospective study, we attempted to define
the types of infection that develop in patients
hospitalized for acute stroke; the relation between
type and severity of stroke and development of fever
with or without apparent infection; the relation
between infection and factors predisposing to its
development; and differences between patients who
develop a documented infectious complication and
those who develop fever with no apparent focus of
infection.
Methods
Data collection and analysis
`Alexandra' Hospital is a 344-bed tertiary care
hospital, with clinical units of medicine and
obstetrics/gynaecology, which are teaching depart-
ments for the University of Athens School of
Medicine. The medical units include an acute stroke
unit (ASU), which is a five-bed less intensive care
unit. Bed availability determines whether a patient
admitted for acute stroke will be hospitalized in the
ASU or in the medical wards.
This retrospective study included all patients
hospitalized in the ASU or in the medical units for
acute stroke between June 1992 and July 1994. All
patients admitted within 48 h of the onset of stroke
were included, whether they had ischaemic infarct
or intracerebral haemorrhage, except for patients
with subarachnoid haemorrhage, who are always
transferred to a neurosurgical unit and were there-
fore not included. Exclusion criteria were hospitali-
zation for less than 1 day because of transfer to
another hospital; transfer from another hospital;
development of stroke during hospitalization for
another illness; presence of fever and/or infection
before the onset of stroke; presence of primary or
metastatic brain tumour.
All data on clinical evaluation and neurological
imaging studies of patients with acute stroke were
retrieved from The Athens Stroke Registry, which is
a prospective hospital-based stroke study on aetio-
# 1999 Blackwell Science Ltd Journal of Internal Medicine 246: 203209
pathogenic mechanisms of stroke [3]. Patients are
evaluated using a standard protocol. On admission
they are examined by an internist experienced in the
care of patients with stroke and on the following day
by a neurologist. Glasgow Coma Scale (GCS) and
Scandinavian Stroke Scale (SSS) are used for clinical
evaluation on admission [4, 5]. A head computed
tomography (CT) scan is obtained on the first day
and a second head CT scan and/or a brain magnetic
resonance imaging (MRI) scan is obtained between
the 7th and the 10th day of hospitalization. The size
(volume) of the brain lesion is calculated from the
second head CT scan using a published method [6].
Patients undergo extracranial colour-coded duplex
ultrasonography, digital subtraction angiography,
Holter monitoring and transthoracic or transoeso-
phageal echocardiography when needed. Stroke
classification follows National Institute of Neurolo-
gical and Communicative Disorders and Stroke
(USA) criteria [7]. Modified Rankin Scale and
Barthel Index are used for assessment of outcome
[8, 9].
In the present analysis, determination of the
aetiology of fever was based on data derived from
the patients' medical records. A patient was
considered febrile, if his/her temperature exceeded
37.58C on more than two occasions on two
consecutive days. On a routine basis, an axillary
temperature measurement is taken every 3 h in all
patients with acute stroke. When analysing the
data, in cases where rectal temperatures were noted,
0.58C was subtracted from the recorded measure-
ments. We used clinical data from physicians' notes,
as well as laboratory and radiographic data derived
from the patients' medical records, to determine the
cause of fever. In cases where a focus of infection
could not be identified, the fever was characterized
as fever without documented infection. A documen-
ted infection was characterized as nosocomial if
fever or other signs of infection started more than
48 h after admission.
Statistical analysis
Categorical variables were compared using Fisher's
exact test, whereas continuous variables were
compared using KruskalWallis test. Stepwise logis-
tic regression was used to assess the ability of
independent variables to predict the presence of
fever without documented infection versus fever
 FEVER IN ACUTE STROKE 205

with documented infection. The variables were
removed from the model in a stepwise manner
according to a removing criterion (P . 0.20). All P-
values reported are two-sided [10, 11].
Results
The medical records of 330 evaluable patients were
examined. Fever developed in 37.6% of the patients.
One or more infections developed in 22.7% of the
patients during their hospitalization and 40.0% of
all infections were hospital-acquired. In 14.8% of
the patients fever was noted, but an infection could
not be documented.
The frequency of types of infection in patients
hospitalized for acute stroke is shown in Table 1.
The most common type was community-acquired
respiratory tract infection followed by hospital-
acquired urinary tract infection.
Table 2 shows the comparison between patients
who developed fever (with or without documented
infection) and those who did not (univariate
analysis). Men remained afebrile significantly more
often than women (P = 0.012). Older age was
strongly associated with the presence of fever
(P = 0.001). In a logistic regression analysis, gender
was not significantly different between the two
groups when adjusting for age. The development of
fever was very significantly associated with intra-
cerebral haemorrhage rather than with ischaemic
infarct (P , 0.001) and with the presence on CT
scan of mass effect (P , 0.001), transtentorial
herniation (P , 0.001) and intraventricular blood
in cases of intracerebral haemorrhage (P , 0.001).
Also, the development of fever was associated with a
larger size of ischaemic infarct (P = 0.0001) or of
haemorrhage (P = 0.0002). Patients with fever
(with or without documented infection) had lower
scores on admission on the Glasgow Coma Scale
(P = 0.0001) and the Scandinavian Stroke Scale
(P = 0.0001) than patients without fever. Patients
without fever had lower serum CPK values
(P = 0.0011). The development of fever was un-
related to the presence of risk factors for infection
(risk factors considered are shown in Table 2).
However, it was strongly associated with prior use
of an invasive technique (P , 0.001), and more
specifically with prior urinary catheter (P , 0.001)
or central line (P = 0.05) insertion. Patients with
fever (with or without documented infection) had
significantly worse outcome of their illness as
assessed by the Modified Rankin Scale
(P = 0.0001) and the Barthel Index (P = 0.0001).
Multivariate logistic regression analysis was used to
explore the association of fever with intracerebral
haemorrhage versus ischaemic infarct and their
pathophysiological consequences, as well as age,
gender, severity of illness and outcome. Using the
stepwise elimination procedure, age, SSS score and
mass effect were found to be significantly associated
with fever (P = 0.035, P = 0.0001 and
P = 0.0004, respectively).
Table 3 shows the comparison between patients
with documented infection and those with fever
without a documented infection (univariate analy-
sis). Patients with fever without a documented
infection had earlier onset of fever (P = 0.0061).
All other variables were not significantly different.
Moreover, the outcome of illness in these two
categories of febrile patients was not significantly
different (Table 3). Age, sex, type of stroke, mass
effect, transtentorial herniation, serum CPK levels

Table 1 Frequency and origin of fever in 330 patients with acute stroke

Origin of infection
(% of infections)

Number of With secondary

patients bacteraemia
Origin of fever (% of patients) (% of infections) Community Hospital

Documented infections 75 (22.7) 2 (2.7) 45 (60.0) 30 (40.0)

Urinary tract 38 (11.5) 2 (5.3) 15 (39.5) 23 (60.5)
Respiratory tract 33 (10.0) 0 (0.0) 29 (87.9) 4 (12.1)
Primary bacteraemia 3 (0.9) 1 (33.3) 2 (66.7)
Cholecystitis/cholangitis 1 (0.3) 0 (0.0) 0 (0.0) 1 (100)
Fever without focus of infection 49 (14.8)

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206 K . G E O R G I L I S et al.

Table 2 Comparison of variables between patients without fever or infection and those with fever with or without documented infection

Number of patients (%)

No fever Fever with

or infection or without infection
Variable (n = 206) (n = 124) P

Sex
Male 126 (61) 58 (47) 0.012
Female 80 (39) 66 (53)
Age (years; mean SE) 71.2 0.8 75.4 0.9 0.001
Type of stroke (CT scan findings)
Ischaemic infarct 193 (94) 89 (72) <0.001
Intracerebral haemorrhage 13 (6) 35 (28)
Other CT scan findings
Mass effect 30 (15) 74 (61) <0.001
Transtentorial herniation 13 (6) 46 (38) <0.001
Intraventricular blood 0 (0) 18 (15) <0.001
Haemorrhagic transformation 14 (7) 15 (12) 0.11
Infarct size (cm3; mean SE) 13.9 2.1 48.9 5.5 0.0001
Haemorrhage size (cm3; mean SE) 7.3 2.3 37.5 4.8 0.0002
Clinical assessment on admission
Glasgow Coma Scale (315) (mean SE) 14.0 0.2 9.9 0.4 0.0001
Severe stroke (GCS < 9) 10 (5) 49 (40) <0.001
Scandinavian Stroke Scale (058) (mean SE) 40.6 1.2 15.4 1.5 0.0001
Severe stroke (SSS < 29) 52 (25) 96 (77) <0.001
Serum enzymes (second hospital day)
LDH (U L21; mean SE) 263.2 8.4 277.7 16.6 0.18
CPK (U L21; mean SE) 124.4 11.7 208.1 26.7 0.0011
Risk factor for infection 77 (38) 48 (39) 0.82
COPD 7 (3) 6 (5) 0.56
CRF 10 (5) 7 (6) 0.80
Diabetes mellitus 59 (29) 31 (25) 0.52
Immunosuppression 3 (1) 0 (0) 0.29
Other 12 (6) 15 (12) 0.061
Invasive procedure preceding fever 25 (12) 80 (66) <0.001
Urinary catheter 25 (12) 80 (66) <0.001
Endotracheal tube 0 (0) 1 (1) 0.37
Central line 0 (0) 3 (2) 0.05
Other 2 (1) 6 (5) 0.056
Outcome of illness
Modified Rankin Scale (06) (mean SE) 2.4 0.1 4.9 0.1 0.0001
Severe handicap or death (MRS > 3) 61 (35) 109 (92) <0.001
Barthel Index (0100) (mean SE) 69.4 2.5 26.0 3.6 0.0001
Severe disability (BI < 40) 47 (24) 60 (76) <0.001

SE, standard error; GCS, Glasgow Coma Scale; SSS, Scandinavian Stroke Scale; COPD, chronic obstructive pulmonary disease; CRF, chronic
renal failure; MRS, Modified Rankin Scale; BI, Barthel Index.

and time of fever from onset of stroke were the
independent variables examined in a stepwise
regression analysis comparing these two categories
of febrile patients. In addition, intraventricular blood
and haemorrhage size were examined for the cases
of intracerebral haemorrhage, whilst the presence of
haemorrhagic transformation and the infarct size
were examined in the cases of ischaemic infarct. The
only factor predictive of fever without documented
infection versus fever with documented infection
was earlier onset of fever (P = 0.029).
Discussion
In this retrospective analysis, 22.7% of patients with
acute stroke developed a documented infection, a

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 FEVER IN ACUTE STROKE 207

Table 3 Comparison of variables between patients with documented infection and those with fever without documented infection

Number of patients (%)

Documented Fever without

infection documented infection
Variable (n = 75) (n = 49) P

Sex
Male 34 (45) 24 (49) 0.72
Female 41 (13) 25 (8)
Age (years; mean SE) 75.8 1.1 74.7 1.4 0.57
Type of stroke (CT scan findings)
Ischaemic infarct 58 (77) 31 (63) 0.11
Intracerebral haemorrhage 17 (23) 18 (37)
Other CT scan findings
Mass effect 43 (57) 31 (66) 0.45
Transtentorial herniation 25 (33) 21 (45) 0.25
Intraventricular blood 8 (11) 10 (21) 0.12
Haemorrhagic transformation 8 (11) 7 (15) 0.57
Infarct size (cm3; mean SE) 44.3 6.4 57.7 10.6 0.24
Haemorrhage size (cm3; mean SE) 33.6 6.6 41.5 6.9 0.28
Clinical assessment on admission
Glasgow Coma Scale (315) (mean SE) 10.5 0.5 9.1 0.6 0.11
Severe stroke (GCS < 9) 25 (33) 24 (49) 0.093
Scandinavian Stroke Scale (058) (mean SE) 15.8 1.8 14.8 2.7 0.15
Severe stroke (SSS < 29) 59 (79) 37 (76) 0.83
Serum enzymes (second hospital day)
LDH (U L21; mean SE) 275.6 22.2 304.9 24.8 0.056
CPK (U L21; mean SE) 172.4 27.7 260.5 50.8 0.076
Risk factor for infection 34 (45) 14 (29) 0.089
COPD 5 (7) 1 (2) 0.40
CRF 4 (5) 3 (6) 1.00
Diabetes mellitus 20 (27) 11 (23) 0.68
Immunosuppression 0 (0) 0 (0) 1.00
Other 11 (15) 4 (8) 0.40
Invasive procedure preceding fever 53 (72) 27 (57) 0.12
Urinary catheter 53 (72) 27 (57) 0.12
Endotracheal tube 1 (1) 0 (0) 1.00
Central line 1 (1) 2 (4) 0.56
Other 2 (3) 4 (9) 0.21
Peak of fever (8C; mean SE) 38.6 0.1 38.7 0.1 0.95
Time of fever from onset 98.3 15.9 47.7 8.6 0.0061
of stroke (h; mean SE)
Outcome of illness
Modified Rankin Scale (06) (mean SE) 4.9 0.2 4.9 0.2 0.43
Severe handicap or death (MRS > 3) 67 (93) 42 (89) 0.51
Barthel Index (0100) (mean SE) 23.6 4.1 30.2 6.9 0.74
Severe disability (BI < 40) 39 (78) 21 (72) 0.60

SE, standard error; GCS, Glasgow Coma Scale; SSS, Scandinavian Stroke Scale; COPD, chronic obstructive pulmonary disease; CRF, chronic
renal failure; MRS, Modified Rankin Scale; BI, Barthel Index.

slightly higher percentage than that found in
previous studies [1, 12]. Half of those patients had
a urinary tract infection. Most of the urinary tract
infections were hospital-acquired and were strongly
associated with prior insertion of an indwelling
urinary catheter. In general, prior use of an invasive
technique was strongly associated with development
of infection, as expected. The high prevalence of
urinary tract infections in patients with more severe
stroke is related to their impaired ability to empty
the bladder, resulting in stasis of urine, which, in
addition, often negates the use of a urinary catheter

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208 K . G E O R G I L I S et al.
[13, 14]. Our data show that insertion of a urinary
catheter significantly increased the risk for urinary
tract infection and suggest caution in the use of this
common (and sometimes unnecessary) invasive
technique. Most of the respiratory tract infections
were community-acquired. This finding probably
results from inclusion of aspiration pneumonia,
which often occurs early in the course of a stroke
[12, 15], in the category of respiratory tract
infections. We did not find an association between
known risk factors for infection and development of
infection. This could be explained by the fact that
the occurrence of infections was strongly related to
the severity of stroke, which probably affected
negatively the significance of risk factors. Also, our
analysis relied on patients' medical records and
therefore it is not known whether the search for
possible infectious foci was sufficient. Patients with
less severe stroke had significantly fewer documen-
ted infections. Severe stroke with immobilization is
associated with atelectasis in the dependent lung,
and pooling of mucus in dependent bronchi is also
associated with atelectasis, frequently resulting in
pneumonia [12, 13]. In addition, patients with more
severe stroke are at great risk for aspiration [15].
Patients with fever, whether or not they had a
documented infection, had a poorer outcome than
those without fever. This corroborates findings from
previous studies [1, 2] and was expected, since we
showed that fever develops more often in patients
with severe stroke, for whom a poor outcome is
predicted. On the other hand, it has been shown that
increase in body temperature itself may increase
ischaemic damage in the brain and therefore control
of fever is important for the outcome of these
patients [1, 2].
In our study, approximately 14.8% of all patients
had fever without a documented infection (39.5% of
febrile patients). Most of these patients received
antibiotics, which did not affect the outcome of their
illness as compared with febrile patients with a
documented infection (data not shown). Previous
studies in patients with acute stroke have dealt with
the relationship of fever with the severity of stroke
and with the outcome [1, 2], but this is the first
study that attempted to define characteristics of
patients with acute stroke who develop fever with no
apparent focus of infection. The pathogenesis of
fever implies the production and release of endogen-
ous pyrogens, such as interleukin-1 (IL-1), tumour
# 1999 Blackwell Science Ltd Journal of Internal Medicine 246: 203209
necrosis factor-a (TNF-a) and interleukin-6 (IL-6),
into the circulation after the onset of certain diseases
[1619]. In patients with central nervous system
disease, these pyrogens are thought to reach the
thermoregulatory centre by a direct route and
induce fever, a hypothesis that provides a possible
pathogenetic explanation for the fever of central
origin [16, 17, 20, 21].
In prospective studies, the value of markers of
infection could be assessed in the differential
diagnosis of fever from infection versus fever of
central origin. C-reactive protein (CRP) has not been
evaluated in patients with acute stroke. Serum CRP
levels may prove useful in determining the aetiology
of fever in acute stroke, as they have been previously
shown to be only slightly elevated in inflammation,
but significantly more elevated in infection [22].
Also, serum levels of procalcitonin have been shown
to increase in patients with infection [23]. Secretion
of procalcitonin is stimulated, for as yet unknown
reasons, by the presence of bacterial endotoxin [24].
In our attempt to separate patients with fever due
to infection from those with fever and no infection
(fever of central origin), using a logistic regression
model, we found that the only factor predictive of
fever of central origin was earlier onset of fever. If all
cases of fever without a focus of infection were due
to `fever of central origin', then earlier onset of fever
would make sense, since an incubation period for an
infection to develop would not be needed. Although
a retrospective analysis has the advantage of the
absence of bias from the observer, our analysis has,
on the other hand, the disadvantage that it relied on
patients' medical records to classify the cause of
fever. Therefore, it is not known to what extent
efforts had been made to determine the cause of
fever in each individual case. As a result, some
overlap between the two groups is expected, since,
as we have shown, patients with severe stroke are
more prone to develop not only infections, but fever
in general. Another confounding factor is the
possible existence of undiagnosed subclinical infec-
tions, especially in patients with severe stroke.
Finally, although we excluded patients with infec-
tions that occurred prior to the stroke, in some cases
the value of this information may not have been
definitively known.
In conclusion, this retrospective analysis has
shown that, of patients with acute stroke, approxi-
mately 20% develop fever due to an infection, most

commonly of the urinary or respiratory tract; that
approximately 15% develop fever without a focus of
infection; that patients with fever have a worse
outcome; and that fever starts earlier in cases where
a focus of infection is not identified.
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Received 7 August 1998; accepted 9 March 1999.
Correspondence: Kostis Georgilis MD, Department of Clinical
Therapeutics, University of Athens School of Medicine, `Alexan-
dra' Hospital, 80 Vas. Sofias Avenue, Athens 11528, Greece
(fax: + 301 7770473; e-mail: athena@otenet.gr).