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European Journal of Neurology 2009, 16: 498–505 doi:10.1111/j.1468-1331.2008.02512.

A decrease of human leucocyte antigen-DR expression on


monocytes in peripheral blood predicts stroke-associated infection
in critically-ill patients with acute stroke
D. P. Zhanga,b, F. L. Yanc, H. Q. Xuc, Y. X. Zhuc, Y. Yind and H. Q. Lud
a
Department of Neurology, Zhong-da Hospital, Southeast University, Nanjing, China; bDepartment of Neurology, PeopleÕs Hospital of
Zhengzhou, Zhengzhou, China; cDepartment of Neurology, Zhong-da Hospital, Southeast University, Nanjing, China; and dDetermination
Center of Flow Cytometry, Southeast University; Nanjing, China

Keywords: Background and purpose: To investigate changes in human leucocyte antigen (HLA)-DR
human leucocyte antigen- expression on peripheral monocytes, determine the value of predicting the development of
DR, neurological intensive stroke-associated infection (SAI), and determine the correlation with other conditions in crit-
care unit, predictive value, ically-ill patients in the neurological intensive care unit (NICU) who suffered an acute stroke.
stroke, stroke-associated Methods: All patients were enrolled consecutively and admitted to NICU within 24 h
infection after the onset of symptoms. Patients were followed in order to identify whether
infection developed and determine survival status within 2 weeks after the stroke.
Received 6 August 2008 Patients were divided into stroke or control group by study design, infection or non-
Accepted 28 November 2008 infection group by whether or not they had an infection, survival or death group by
prognosis and cerebral infarction or cerebral haemorrhage group by stroke type. Pa-
tients in which acute stroke was excluded by head CT or MRI were admitted to general
ward and were used as a control group. Blood samples were collected serially on days 1,
2, 4, 6 and 14 after stroke, then monocyte human leucocyte antigen-DR (HLA-DR)
expression was determined by flow cytometry. The National Institute of Health Stroke
Scale (NIHSS), Acute Physiology and Chronic Health Evaluation II (APACHEII) and
Glasgow Coma Scale (GCS) scores were recorded over the course of observation.
Results: Fifty-three subjects and 39 controls were enrolled in the study. On days 1, 2, 4, 6
and 14, there was a significant difference in monocyte HLA-DR expression between stroke
group and control group (all P < 0.001), but no difference was found between ischaemic
stroke group and haemorrhagic stroke group (all P > 0.05). The infection group compared
with non-infection group did not exhibit a significant difference in HLA-DR expression on
days 1 and 2 (all P > 0.05), but significant differences emerged on days 4, 6 and 14 (all
P < 0.01). On days 1 and 2 the HLA-DR expression in the survival group compared with
death group, was not significantly different (all P > 0.05), but differences became signifi-
cant on days 4 and 6 (P < 0.01). On day 1, HLA-DR expression <62.80% had the
predictive value to SAI (sensitivity 83.3%, specificity 55.2%, AUC = 0.661, P = 0.031)
and on day 2, HLA-DR expression <57.83% had the predictive value to SAI (sensitivity
95.8%, specificity 79.3%, AUC = 0.907, P = 0.000) in acute stroke patients. A statisti-
cally significant inverse correlation was found between NIHSS and HLA-DR on days 2 and
4 during the observation period (all P < 0.01), but there was no statistically significant
negative correlation on days 1, 6 or 14 (all P > 0.05). HLA-DR expression did not correlate
with APACHEII (all P > 0.05) or GCS (all P > 0.05) during the measurement period.
Conclusions: Human leucocyte antigen-DR (HLA-DR) expression decreases and sustains
a dynamic change and it also relates to the severity of patientÕs condition in the critically-ill
patients with stroke. Progressively persistent low monocyte HLA-DR expression is asso-
ciated with a poor prognosis. The decline in HLA-DR expression contributes to infection in
critically-acute stroke patients. Monitoring of monocyte HLA-DR expression may be
useful for identifying patients suffering from acute stroke who are at high risk for infection.

Correspondence: Yan Fu-ling, Department of Neurology, Southeast University, Nanjing 210009, P.R. China (tel.: +86 25 83272357; fax: +86 25
83272011; e-mail: yanfuling218@163.com).

 2009 The Author(s)


498 Journal compilation  2009 EFNS
A decrease of human leucocyte antigen-DR expression predicts stroke-associated infection 499

better understanding of the complex interaction be-


Introduction
tween the central nervous system and the immune sys-
Stroke-associated infection (SAI), predominantly chest tem might lead to more effective stroke therapies.
and urinary-tract infections occur in 23–65% of all Therefore, the present study analyses immunological
stroke patients within the first few days after the stroke changes caused by stroke in humans and identifies the
[1–5]. Although early mortality is due to direct com- relationship between HLA-DR expression on periph-
plications from large strokes, pneumonia is the leading eral monocytes and NIHSS, APACHEII and GCS.
cause of death in the post-acute phase of stroke,
regardless of hospitalization [6–8]. The high incidence
Materials and methods
of infections in these patients is probably the result of
an impaired immune function. Recently, stroke-induced
Patients and control subjects
immunodeficiency in a mouse model of cerebral
ischaemia has been described, which results in sponta- We prospectively screened patients admitted to the
neous bacterial infections resulting from impaired Zhong-da Hospital [affiliated with Southeast University
cell-mediated immune responses [9]. Infection after neurological intensive care unit (NICU)] between
experimental focal ischaemia may result from brain- October 2006 and January 2007. The patients not only
induced immunodepression, but it is undetermined met one of the criteria for NICU admission, including
whether a similar syndrome occurs in human stroke haemodynamic instability, acute respiratory failure or
[10]. Recent studies have analysed immunological intubation for airway protection, unstable neurological
changes caused by stroke in humans and identified a status and/or the GCS <10, but also had at least one
persistent loss of CD4+ T-lymphocytes in patients NIHSS ‡6 after stroke onset during the observation
developing an infection, suggesting that defects of T period or stroke symptoms onset <24 h before
helper-cell functions contribute to immunosuppression admission to the NICU. Patients with clinical signs of
in stroke patients [11,12]. These results give additional infection or with compromised immune function upon
support to the notion that stroke induces immunosup- admission were not recruited.
pression in humans. However, the clinical significance Sixty-seven acute stroke patients were admitted to
of monocytes has not been determined in stroke-in- the NICU from October 2006 to January 2007, 62 pa-
duced immunosuppression in humans [13,14]. Mea- tients were recruited into the study and 53 patients were
surement of human leucocyte antigen-DR (HLA-DR) included in the study. These patients were compared
expression on peripheral monocytes is also a good with 39 age-matched non-stroke control subjects in the
marker of global immune function since HLA-DR general neurological ward (Tables 1 and 2). Stroke
expression reflects the net effect of multiple mediators neurologists, infectious disease specialists and research
acting in concert [15]. The existence of a stroke-induced nurses worked in close collaboration to warrant a
immunodepression syndrome might be an adaptive harmonized application of diagnostic and therapeutic
mechanism to brain ischaemia, although further re- measures. Patients had a brain CT scan or brain MRI
search is required to unravel the clinical consequences before admission, as well as the diagnostic workup
of these immunological changes [16]. In clinical prac- aimed to identify the cause of ischaemic or haemor-
tice, the National Institute of Health Stroke Scale rhagic strokes. Blood was obtained from the patients
(NIHSS), Acute Physiology and Chronic Health Eval- immediately at admission and between 5:30 AM and
uation II (APACHEII) and the Glasgow Coma Scale 7:00 AM on days 1, 2, 4, 6 and 14 thereafter. The blood
(GCS) are normally applied to evaluate the patientÕs samples were sent to the determination centre for flow
condition, especially in patients with severe stroke. A cytometry analysis within 3 h. The NIHSS scores were

Table 1 Clinical data for stroke subjects


compared with controls Stroke Control
Variables (n = 53) (n = 39) t/x2 P-value

Age (years, mean ± SD) 67.8 ± 11.6 69.6 ± 8.8 1.295 0.399
Sex (male, n, %) 26 (49.1) 18 (46.2) 0.076 0.783
Hypertension (n, %) 34 (64.2) 24 (61.5) 0.066 0.798
Diabetes mellitus (n, %) 8 (15.1) 3 (17.9) 0.134 0.714
Heart disease (n, %) 19 (35.8) 16 (41.0) 0.146 0.613
COPD (n, %) 3 (5.7) 4 (10.3) 0.675 0.411
Smoking (n, %) 19 (35.8) 11 (28.2) 0.597 0.440
Drinking (n, %) 17 (32.1) 11 (28.2) 0.159 0.690

COPD, chronic obstructive pulmonary disease.

 2009 The Author(s)


Journal compilation  2009 EFNS European Journal of Neurology 16, 498–505
500 D. P. Zhang et al.

Table 2 Patient characteristics


Total no. Age (years) Male Ischaemic Haemorrhage Death (mean ± SD)
Non-stroke control subjects 39 69.6 ± 8.8 18 0 0 0
Total patients included 62 68.1 ± 7.9 30 34 28 8
Cohort included 53 67.8 ± 11.6 26 29 24 7
Infected cohort 24 72.4 ± 10.8 12 13 11 6
Non-infected cohort 29 65.4 ± 11.3 14 16 13 1

recorded on days 1, 2, 4, 6 and 14, whereas the The study protocol was approved by the Research
APACHEII and GCS scores were recorded on days 1, 2 Ethics Committee of Affiliated ZhongDa Hospital,
and 3 (Table 3). Southeast University. All patients gave fully informed
For the purpose of this study, we defined the fol- consent directly or through a surrogate when appropri-
lowing criteria of infection: (i) presence of clinical signs ate. Routine cerebral CT images were acquired on a
of infection. Pneumonia was described as pulmonary 64-row multislice CT scanner (Somatom 64; SIEMENS
infiltrates in a chest radiograph, fever, respiratory Medical Systems, Erlangen, Germany). Cerebral MR
symptoms (cough, dyspnea, or pleuritic pain) and blood images were acquired on Eclipse 1.5T MR scanner
leucocyte count >11 000 cell/ml or <4000 cell/ml. (SIEMENS Medical Systems). Cell types were defined by
Urinary-tract infection was defined as low urinary tract surface marker expression determined in a fluorescence-
symptoms with a positive urine culture for an activated cell sorter analysis performed on a FACScali-
uropathogen (>105 colony-forming units [CFU]/mm3) bur (Beckton Dickinson, Heidelberg, Germany) using
or fever with a positive urine culture for an uropatho- Tru-Count tubes, Simulset IMK Plus-reagents (Becton
gen in absence of other infectious source. Fever of Dickinson, Germany). Monocytes were identified by
unknown origin was described as none of the above direct immunofluorescence staining by a combination of
criteria identified or idiopathic fever; (ii) serum the fluorescein isothiocyanate (FITC)-labelled mono-
concentrations of C-reactive protein >50 mg/ml; and clonal anti-CD14 IgG1. The expression of HLA-DR was
(iii) procalcitonin serum concentrations >0.5 ng/ml. determined with use of phycoerythrin (PE)-labelled
To compare patients who developed infection after monoclonal anti-HLA-DR IgG1 (Becton Dickinson).
stroke with those who did not, two cohorts were FITC-labelled mouse IgG1, PE-labelled mouse IgG1
formed. In the infected cohort, all three criteria for (Becton Dickinson) were used as controls.
infection had to be fulfilled on days 2, 4, 6 or 14. In the In brief, 2-ml blood samples were collected in EDTA-
non-infected cohort, none of the criteria were attained coated tubes. The anticoagulated peripheral blood
throughout the study period. Patients who had some samples were processed using the whole lysis procedure
criteria but not all were not assigned to either cohort, according to the manufacturerÕs protocol. An appro-
involved in 9 patients. priate volume of whole blood was added to the mixture
of a selected panel of monoclonal antibodies. The
Table 3 Scores of infection compared with non-infection
samples were incubated for 30 min at 4C, washed in
Infected or non-infected phosphate-buffered saline and then lyzed with a com-
mercial lyzing reagent (Becton Dickinson). Thereafter,
Infected Non-infected
Scales (n = 24) (n = 29) t/u P-value the samples were analysed on a FACSCallibur flow
cytometer equipped with a 15-mW air-cooled 488-nm
NIHSS(mean ± SD)
argon–ion laser for the excitation of FITC and PE. The
day1 18.8 ± 6.0 7.6 ± 3.9 5.942 0.012
day2 20.0 ± 6.4 8.8 ± 4.2 7.032 0.000
fluorescence of FITC was measured by a 530/30-nm
day4 20.4 ± 7.4 8.5 ± 4.3 7.599 0.000 band pass filter. The orange emission from PE was
day6 19.5 ± 7.9 7.1 ± 4.1 6.254 0.000 measured by a 582/42-nm band pass filter. The pro-
day14 14.6 ± 5.4 5.7 ± 3.6 4.424 0.023 portion of HLA-DR positive cells in the monocyte
APACHEII (mean ± SD)
population was determined. Final analysis was per-
day1 16.6 ± 5.4 10.3 ± 3.9 4.752 0.001
day2 17.6 ± 7.1 10.2 ± 3.7 4.650 0.000
formed using Quanticalc software (all from Becton
day3 18.8 ± 7.4 10.1 ± 3.7 5.226 0.000 Dickinson) to obtain the molecules HLA-DR per cell
GCS (M, IQR) from the measured geometric means.
day1 9.5 (8–13) 15 (13.5–15) )4.271 0.000 Procalcitonin serum concentration was measured on
day2 10.0 (7.3–13.8) 15 (14–15) )4.171 0.000
a Liaison analyzer (DiaSorin, Dietzenbach, Germany;
day3 10.0 (8.3–13.8) 15 (14–15) )4.275 0.000
reagents: Brahms, Hennigsdorf, Germany); C-reactive
M, median; IQR, interquartile range. protein on a Dimension RxL (Dade Behring, Eschborn,

 2009 The Author(s)


Journal compilation  2009 EFNS European Journal of Neurology 16, 498–505
A decrease of human leucocyte antigen-DR expression predicts stroke-associated infection 501

Germany). It was first determined whether the studied Ischaemia and haemorrhage
variables had normality. The differences in proportions Monocyte HLA-DR expression was slightly degraded
were then compared using the Pearson x2 test and in cerebral haemorrhage patients compared with the
normally distributed continuous variables were com- cerebral infarction patients. On days 1, 2, 4, 6 and 14,
pared using StudentÕs two-tailed t-test or one-way monocyte HLA-DR expression in the ischaemic stroke
ANOVA. Statistical analyses were performed using SPSS group was 64.73 ± 15.32%, 57.56 ± 17.84%,
13.0 for Windows (SPSS Inc, Chicago, IL, USA). 57.43 ± 13.53%, 62.81 ± 15.75% and 69.89 ±
Correlations between two variances were applied to 19.23%, respectively. In the haemorrhagic stroke
GraphPad Prism 4.0 (GraphPad Software, San Diego, group, these values were 57.95 ± 18.08%, 51.66 ±
CA, USA), Pearson correlation analysis was used for 14.73%, 53.25 ± 17.40%, 61.48 ± 20.84% and
normally distributed variables and Spearman non- 72.88 ± 12.45%, respectively. There were no signifi-
parametric correlation analysis was employed for non- cant differences between groups (P = 0.146, 0.201,
normally distributed variables. The Receiver Operating 0.329, 0.797 and 0.555, respectively; Fig. 2).
Characteristic (ROC) curve was performed using MED-
CALC 9.2 (MedCalc Software, Broekstraat, Mariakerke, Infection and non-infection
Belgium) in order to evaluate the predictive value of Monocyte HLA-DR expression decreased more rapidly
HLA-DR on stroke-associated infection. All the prob- and recovered more slowly in patients who were
ability values were two-tailed and the level of statistical assigned to the infected cohort in comparison with the
significance was set at P < 0.05. patients who remained uninfected. On days 1, 2, 4, 6
and 14, the monocyte HLA-DR expression in the
infection group was 59.74 ± 16.70%, 51.44 ± 16.34%,
Results
48.86 ± 16.10%, 51.78 ± 21.15% and 60.26 ±
20.89%, respectively. In the non-infection group,
Stroke induces rapid immunological changes in
these values were 63.25 ± 17.03%, 57.74 ± 16.58%,
peripheral blood
61.07 ± 12.54%, 70.12 ± 9.77% and 77.49 ± 9.14%,
Stroke and control respectively. In the infection group compared with non-
Monocyte HLA-DR expression in individuals with infection group, there were no significant differences in
stroke was below the control individuals and further HLA-DR expression on days 1 and 2 (P = 0.445 and
decreased reaching its nadir on days 2 and 4, then 0.172), but significant differences emerged on days 4, 6
recovered gradually over the follow-up period. On days and 14 (P = 0.003, 0.001 and 0.004, respectively;
1, 2, 4, 6 and 14, the monocyte HLA-DR expression in Fig. 3).
the stroke group was 61.66 ± 16.81%, 54.89 ±
16.61%, 55.54 ± 15.39%, 62.21 ± 18.04% and Survival and death
71.12 ± 16.67%, respectively. In the control group, the Monocyte HLA-DR expression decreased over time in
values were 78.14 ± 7.87%, 79.92 ± 10.48%, 82.67 ± the death patients, whilst it gradually normalized over
8.69%, 80.09 ± 9.45% and 80.54 ± 8.23%, respec- the follow-up period in the survival patients. On days 1,
tively. There were statistically significant differences at
these time points (all P = 0.000; Fig. 1). 100 Ischaemic stroke Hemorrhagic stroke

Control Stroke 80
100
90
HLA-DR (%)

80 60
70
HLA-DR (%)

60 40

50
20
40
30
0
20 Day 1 Day 2 Day 4 Day 6 Day 14
10 Time
0
Day 1 Day 2 Day 4 Day 6 Day 14 Figure 2 Expression of HLA-DR in ischaemic and haemorrhagic
stroke. Ischaemic stroke: n (day1) = 29, n (day2) = 29, n
Figure 1 Expression of HLA-DR in control and stroke. Control: (day4) = 28, n (day6) = 26, n (14) = 26. Haemorrhage stroke: n
n = 39; Stroke: n (day1) = 53, n (day2) = 53, n (day4) = 52, n (day1) = 24, n (day2) = 24, n (day3) = 24, n (day6) = 23, n
(day6) = 49, n (day14) = 46. *P < 0.05; Data: mean ± SD. (day14) = 20. Data: mean ± SD.

 2009 The Author(s)


Journal compilation  2009 EFNS European Journal of Neurology 16, 498–505
502 D. P. Zhang et al.

100 Non-infection Infection Correlations between NIHSS, APACHEII, GCS and HLA-
90 DR
80
A statistically significant inverse correlation was found
70
HLA-DR (%)

60
between the NIHSS and HLA-DR expression on days 2
50 and 4 (day 2: r = )0.447, P = 0.001; day 4: r =
40 )0.626, P = 0.000), but there was no statistically sig-
30 nificant correlation on days 1, 6 or 14(day 1:
20 r = )0.105, P = 0.571; day 6: r = )0.293, P = 0.104;
10 day 14: r = )0.167, P = 0.268). HLA-DR expression
0 did not statistically correlate with the APACHEII score
Day 1 Day 2 Day 4 Day 6 Day 14
(day 1: r = )0.112, P = 0.424; day 2: r = )0.159,
Time
P = 0.255) or GCS (day 1: r = 0.135, P = 0.337; day
Figure 3 Expression of HLA-DR in infection and non-infection 2: r = 0.105, P = 0.454; Fig. 5).
groups. Non-infection: n (day1) = 29, n (day2) = 29, n
(day4) = 28, n (day6) = 28, n (day14) = 27; Infection: n
(day1) = 24, n (day2) = 24, n (day4) = 24, n (day6) = 21, Predictive value to SAI
n (day14) = 19. *P < 0.05; Data: mean ± SD.
Receiver operating characteristic curve indicated that a
HLA-DR expression <62.80% had predictive value for
SAI (sensitivity 83.3%, specificity 55.2%, AUC =
2, 4, 6 and 14, monocyte HLA-DR expression in the
0.661, P = 0.031, 95% CI 0.518–0.785, positive likeli-
survival group was 62.59 ± 15.98%, 55.43 ± 15.82%,
hood ratio 1.73, negative likelihood ratio 0.32, positive
57.95 ± 13.63%, 65.82 ± 14.41% and 71.12 ±
predictive value 60.6%, negative predictive value
16.67%, respectively, whereas on days 1, 2, 4 and 6 the
80.8%) on day 1. On day 2, HLA-DR expression
monocyte HLA-DR expression in the death group was
55.51 ± 21.96%, 51.32 ± 22.33%, 39.66 ± 17.91%
and 28.93 ± 14.06%, respectively (all patients died
within 8 days after the stroke). There were no signifi- Day 2
(a) 40
cant differences between groups on days 1 and 2
(P = 0.303 and 0.548), but differences became signifi-
cant on days 4 and 6 (P = 0.003 and 0.000; Fig. 4). In 30
logistic regression (admission NIHSS and age
NIHSS2

adjusted), there was a statistical significance in the 20


association between poor outcome and decreased
expression of HLA-DR at day 4 (OR 5.72, 95% CI
1.63–45.18, P = 0.020), and at day 6 (OR 7.44, 95% CI 10
2.85–84.71, P = 0.009).
0
0 10 20 30 40 50 60 70 80 90 100
Survival Death HLA-DR2
100
90
80 (b) 40 Day 4
70
HLA-DR (%)

60
50 30
40
NIHSS4

30
20 20
10
0
Day 1 Day 2 Day 4 Day 6 Day 14 10
Time

Figure 4 Expression of HLA-DR in survival and death groups. 0


Survival: n (day1) = 46, n (day2) = 46, n (day4) = 46, n 0 10 20 30 40 50 60 70 80 90 100
(day6) = 46, n (day14) = 46. Death: n (day1) = 7, n (day2) = 7, HLA-DR4
n (day4) = 5, n (day6) = 3, n (day14) = 0. *P < 0.05; Data:
mean ± SD. Figure 5 Correlation between NIHSS and HLA-DR (%).

 2009 The Author(s)


Journal compilation  2009 EFNS European Journal of Neurology 16, 498–505
A decrease of human leucocyte antigen-DR expression predicts stroke-associated infection 503

100 multiple mediators acting in concert [15]. In the present


study, earlier differences of HLA-DR expression had
been detected, remarkably indicating the studied infec-
80 tions occurring in early time-points was focused on,
however, HLA-DR was not different in the infection
group in the first days, different only occurring by days
60
4, 6 or 14 in the infection group compared to non-
Sensitivity

infection group.
Our results suggest that stroke induces long-lasting
dramatic depression of monocyte immunity function
40 Day 1 (HLA-DR expression decrease) associated with SAI
Day 2 and monocyte immunity function showed a remarkably
dynamic change. The expression of HLA-DR in the
20 infection group was lower than in the non-infection
group and the recovery in infection group was slower
than in the non-infection group, suggesting that
0 monocyte deactivation was more serious in the infec-
0 20 40 60 80 100 tion group. Stroke type has no influence on the
100-Specificity expression of HLA-DR. ROC indicated that on day 2,
HLA-DR expression <57.83% had predictive value for
Figure 6 Value of HLA-DR (%) predicted SAI.
SAI (sensitivity 95.8%, specificity 79.3%, AUC =
0.907, P = 0.000, 95% CI 0.794–0.969, positive likeli-
<57.83% had predictive value for SAI (sensitivity hood ratio 4.63, negative likelihood ratio 0.053, positive
95.8%, specificity 79.3%, AUC = 0.907, P = 0.000, predictive value 79.3%, negative predictive value
95% CI 0.794–0.969, positive likelihood ratio 4.63, 95.8%) in acute stroke patients. A reduced HLA-DR
negative likelihood ratio 0.053, positive predictive value expression predicted subsequent stroke associated
79.3%, negative predictive value 95.8%) in acute stroke infections was also observed recently by Harms et al.
patients (Fig. 6). [21]. However, our study included different patients
(ischaemic and haemorrhagic stroke) and used different
analysis methods (ROC) confirmed the predictive value
Discussion
of HLA-DR for post-stroke infections. These facts
Observations in mouse models suggest that stroke-in- further reveal that decreased HLA-DR expression was
duced immunodepression is a cause of infection fol- close linked to the SAI.
lowing cerebral stroke [9,17]. However, attempts to Expression of HLA-DR <30% predicted infection in
transfer these findings into clinical practice have yielded trauma patients [22], which implies that stroke patients
contradictory results [18–20]. Most recently, there have are more liable to suffer from infection due to immun-
been two clinical studies supporting the notion that odepression because stroke patients have more risk
stroke induces immunosuppression in humans. One factors for infection than the trauma patients. For
study [11] analysed lymphocyte subsets after stroke and example, stroke patients are more prone to incur
demonstrated that low CD4+ T cell counts as well as a impaired consciousness and aspiration for various rea-
low percentage of lymphocytes on day 1 may pre-dis- sons. These results support to the notion that stroke
pose patients to infection after cerebral ischaemia. The induces monocyte immunosuppression in humans,
other study [12] also found cellular immunodepression which contributes to developing an infection after
preceding infectious complications after acute ischae- stroke.
mic stroke in humans. A diminished monocytic HLA- On days 2 and 4, HLA-DR expression correlated
DR expression early after stroke onset has also been inversely with NIHSS, but this effect was not seen on
described simply by the above mentioned two studies days 1, 6 and 14. The fact that HLA-DR expression is
[11,12]. However, these outcomes mainly observed the inversely correlated with NIHSS suggests that the brain
lymphocyte subsets after stroke and monocytes proba- lesion promotes the down-regulation of HLA-DR.
bly played more important role in defending microor- These findings also indicate the recovery of HLA-DR
ganism which close linked to SAI. Measurement of and NIHSS are partly asynchronous; the former
HLA-DR expression on peripheral monocytes also recovered more rapidly than the latter. To observe
seems to be a good marker of global immune function stroke-induced immunodepression, the level of HLA-
since HLA-DR expression reflects the net effect of DR after stroke should be determined. HLA-DR did

 2009 The Author(s)


Journal compilation  2009 EFNS European Journal of Neurology 16, 498–505
504 D. P. Zhang et al.

not correlate with APACHEII or GCS at the observa- mechanisms by which the adaptive and innate immune
tional points in the present study. This may be because systems react to brain tissue damage and to unravel the
APACHEII is mainly associated with peripheral consequences that this has for the patient.
inflammatory conditions (i.e., a chronic health state).
Stroke-induced immunodepression results from a local
Acknowledgements
increase in proinflammatory cytokines in damaged
brain tissue, which triggers a systemic immunoinhibi- We wish to express our gratitude to the healthcare
tory response via sympathoadrenal activation [9]. workers at the Neurological Intensive Care Unit at
Whether or not this is involved in the peripheral Zhong-da Hospital affiliated with Southeast University
inflammatory reaction is debated based on differing for their helpful cooperation. This study was supported
results in humans and laboratory animals [12,23]. The by the Natural Science Foundation of Jiang-su Prov-
GCS normally evaluates the severity of brain insult, but ince (BK2008299).
stroke location, lateralization and mental status
together affected stroke-induced immunodepression
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research is needed to understand the signals and

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 2009 The Author(s)


Journal compilation  2009 EFNS European Journal of Neurology 16, 498–505