1. Pediatr Allergy Immunol 2009: 20: 266–272 Ó 2008 The Authors
DOI: 10.1111/j.1399-3038.2008.00779.x Journal compilation Ó 2008 Blackwell Munksgaard
PEDIATRIC ALLERGY AND
IMMUNOLOGY
Association of lower eosinophil-related T
helper 2 (Th2) cytokines with coronary artery
lesions in Kawasaki disease
Kuo H-C, Wang C-L, Liang C-D, Yu H-R, Huang C-F, Wang L, Ho-Chang Kuo1,2, Chih-Lu Wang3, Chi-
Hwang K-P, Yang KD. Association of lower eosinophil-related T Di Liang4, Hong-Ren Yu1,2, Chien-Fu
helper 2 (Th2) cytokines with coronary artery lesions in Kawasaki Huang4, Lin Wang1,2, Kao-Pin Hwang5
disease. and Kuender D. Yang1,2
1
Pediatr Allergy Immunol 2009: 20: 266–272. Division of Allergy, Immunology and Rheumatology;
Ó 2008 The Authors Department of Pediatrics, Chang Gung Memorial
Journal compilation Ó 2008 Blackwell Munksgaard Hospital-Kaohsiung Medical Center; 2Graduate
Institute of Clinical Medical Sciences, Chang Gung
University College of Medicine; 3Department of
Kawasaki disease (KD) is a systemic febrile vasculitis particular coro- Pediatrics, Po-Jen Hospital; Divisions of 4Cardiology
nary artery involvement. Eosinophilia has been found in our and other and 5Infectious Disease, Department of Pediatrics,
studies in KD. This study further investigates whether eosinophil- Chang Gung Memorial Hospital-Kaohsiung Medical
related T helper 2 (Th2) cytokines or the activation marker (eosinophil Center, Kaohsiung, Taiwan
cationic protein – ECP) is involved in KD with coronary artery lesions
(CAL). A total of 95 KD patients were enrolled for this study. Plasma
samples were subjected to the measurement of interleukin (IL)-4, IL-5, Key words: Kawasaki disease; coronary artery
and eotaxin by Luminex-Bedalyte multiplex beadmates system and to lesions; eosinophils; T helper 2; interleukin-5;
the measurement of ECP by fluoroimmunoassay. Patients with KD had eosinophil cationic protein
higher eosinophils than controls. Eosinophil-related mediators: IL-4,
IL-5, eotaxin, and ECP levels were also higher in KD patients than Kuender D. Yang, Department of Medical Research
controls before intravenous immunoglobulin (IVIG) treatment. After and Pediatric Allergy, Immunology and Rheumatology,
IVIG treatment, ECP decreased but IL-4, IL-5, and eotaxin increased Chang Gung Memorial Hospital-Kaohsiung Medical
significantly. The higher the IL-5 and eosinophil levels after IVIG Center, 123 Ta-Pei Road, Niaosung Hsiang,
Kaohsiung, Taiwan
treatment, the lower rate of CAL was found. Changes of eosinophils
Tel.: +886-7-7317123
after IVIG treatment were positively correlated to changes of IL-5 levels Fax: +886-7-7312867
but not ECP levels. An increase of eosinophils and IL-5, but not ECP E-mail: yangkd@adm.cgmh.org.tw
levels after IVIG treatment, was inversely correlated with CAL for-
mation in KD. Accepted 28 May 2008
Kawasaki disease (KD) is an acute febrile multi- A complication of coronary artery aneurysm
systemic vasculitis of unknown etiology, which develops in 20% of untreated KD affected
was first reported by Kawasaki et al. (1) from children (3). A single high-dose (2 g/kg) of
Japan in 1974 in the English language literature. intravenous immunoglobulin (IVIG) plus aspirin
It occurs worldwide and mainly affects children can diminish the incidence of aneurysm from
less than 5 yr old. The clinical characteristics of 20% to 3–5% (6). The IVIG treatment can also
KD include prolonged fever, bilateral non-puru- shorten the fever duration when given within
lent conjunctivitis, diffuse mucosal inflammation, 10 days after the disease onset (6, 7). As CAL
polymorphous skin rashes, indurative angioe- occurs at a mean of 9.5 days after the onset of
dema of the hands and feet, and non-suppurative KD, it is important to treat and prevent pro-
cervical lymphadenopathy (1–4). The most seri- gression of coronary artery injury within 10 days
ous complication of KD is coronary artery (2, 3). Kawasaki et al. (1) were the first to
lesions (CAL) including myocardial infarction, describe eosinophilia in the peripheral blood of
coronary artery dilatation, or coronary artery KD patients. Later, eosinophils were also found
aneurysm (2, 3). In the developed countries, KD in coronary artery autopsies (8). We have
is the leading cause of acquired heart diseases in recently shown that eosinophilia was positively
children (2–5). correlated to IVIG treatment success (9), and
266

2. Role of eosinophil-related Th2 mediators in KD
patientsÕ characteristics as well as IVIG prepara- Cytokine Beadmates system (Upstate Group,
tions might affect eosinophilia (10). Inc., Billerica, MA, USA) for the 95 KD patients
To explore the mechanism of eosinophilia in and 30 control samples. The study method was
KD, this study was conducted to investigate modified from a previous report (13). In brief,
whether eosinophil-related T helper 2 (Th2) 50 ll samples were mixed with multiplexed
cytokines (IL-4, IL-5, and eotaxin) or the eosin- antibody-conjugated beads before being sub-
ophil activation mediator (eosinophil cationic jected to multi-channel detection of the bead-
protein – ECP) were associated with CAL array. Acquired fluorescence data were assessed
formation in KD patients. by the MasterPlexTM QT software (Ver. 1.2;
MiraiBio, Inc., South San Francisco, CA, USA).
Calibration of cytokine concentrations was
Patients and methods determined by interpolation of a series of well-
known standard samples following the manufac-
Patients studied
turerÕs recommendation. In order to make sure
All subjects studied were children who fulfilled that the effect seen is not an IVIG effect itself, we
the criteria for KD (4) and were admitted for also measured the levels of IL-4, IL-5, and
IVIG treatment at Chang Gung Memorial Hos- eotaxin in IVIG production (Gamimune N
pital-Kaohsiung Medical Center from 2001 to 10%, Bayer Corporation, Elkhart, IN, USA)
2006. All patients were initially treated with a from eight different bottles of four different
single dose of IVIG (2 g/kg) during a 12-h batches based on the normalization to average
period. Aspirin (3–5 mg/kg/day) was given until blood immunoglobulin (Ig) G concentration
all signs of inflammation were resolved or (2000 mg/dl) (14). The assay sensitivities of these
regression of CAL under two-dimensional (2D) cytokines were 1.8 pg/ml of IL-4, 0.2 pg/ml of
echocardiography was seen. This study was IL-5, and 1.4 pg/ml of eotaxin, respectively. To
approved by the Institutional Review Board of avoid inter-assay bias of immunoassays, the
Chang Gung Memorial Hospital. Blood samples cytokines in paired samples before and after
were collected after informed consent was IVIG therapy were measured at the same time.
obtained from the parents or guardians. Blood
samples collected both before (within 24 h before
IVIG treatment, pre-IVIG) and after IVIG Measurement of eosinophil activation mediator – ECP
treatment (within 3 days after IVIG treatment, Concentrations of ECP were measured by
post-IVIG) were subjected to this study. Patients Pharmacia CAP system fluoroimmunoassay
whose symptoms did not fit the KD criteria, had (Pharmacia and Upjohn Diagnostics AB,
an acute fever for less than 5 days, or incomplete Uppsala, Sweden) according to the instructions
collection of pre- and post-IVIG blood samples of the manufacturer. In brief, 40 ll plasma
were excluded. CAL was defined as the internal samples from the 95 KD patients and 30
diameter being at least 3 mm of the coronary controls as well as the eight different IVIG
artery (4 mm if the subject was over the age of products were subjected to the automatic pro-
5 yr) or the internal diameter of a segment at cedure of analysis.
least 1.5 times as large as that of an adjacent
segment by echocardiogram (11, 12). We ana-
lyzed the complete blood counts (CBC)/differen- Statistical analysis
tial counts (DC) and C-reactive protein (CRP)
from 95 KD patients and 30 age-matched febrile Data of CBC/DC and CRP levels between the KD
controls (male/female = 16/14). Blood samples patients and controls were assessed by the
from the febrile control patients who were StudentÕs t-test. Changes of IL-4, IL-5, eotaxin,
admitted for upper and/or lower respiratory and ECP levels before and after IVIG treatment
tract infections (including acute bronchiolitis, were tested by the paired sample t-test. Levels of
acute pharyngitis, acute bronchitis, croup, and IL-4, IL-5, eotaxin, and ECP between KD patients
acute tonsillitis) without a past history of allergic with and without CAL were tested by the Mann–
disease were also included for comparison. Whitney U-test. Correlations between groups
were tested by the PearsonÕs correlation.
A p-value <0.05 was considered as statistically
Measurement of eosinophil-related Th2 chemokines and
significant. Data are presented as mean and
cytokines by the Luminex-100 system
standard error. All statistical tests were performed
Plasma concentrations of IL-4, IL-5, and eotaxin using SPSS 12.0 for Windows XP (SPSS, Inc.,
were assessed by the Upstate Beadlyte Human Chicago, IL, USA).
267

3. Kuo et al.
Results (12.07 ± 1.36 pg/ml vs. 28.55 ± 3.84 pg/ml,
p < 0.001, Fig. 2a), IL-5 (5.17 ± 0.56 pg/ml
Clinical features of the KD patients with and without CAL
vs. 10.33 ± 0.92 pg/ml, p < 0.001, Fig. 2b),
A total of 165 KD patients were admitted from and eotaxin (129.1 ± 14.3 pg/ml vs. 296.5 ±
2001 to 2006. Ninety-five of the KD patients 31.5 pg/ml, p < 0.001, Fig. 2c) were signifi-
whose blood samples were collected both before cantly increased after IVIG treatment. In con-
and after the IVIG treatment were enrolled in trast, the eosinophil activation mediator (ECP)
this study. There were 31 girls (32.6%) and 64 levels were greatly decreased after IVIG treat-
boys (67.4%). There were 20 patients (21.05%) ment (11.57 ± 1.98 pg/ml vs. 7.49 ± 1.22 pg/
with CAL formation. There were no significant ml, p = 0.03, Fig. 2d).
difference of the rates of CAL formation between
the study group (20/95) and the remainder KD
Eosinophil and IL-5 but not CRP levels associated with KD with
patients (13/70, p = 0.7). The age distribution of
CAL after IVIG treatment
KD patients with and without CAL was 18.36 ±
2.32 (median: 15.0 months) and 22.47 ± 1.55 After IVIG treatment, CRP levels decreased and
(median: 17.0 months), respectively. The major revealed no significant difference between the KD
clinical features including conjunctivitis, fissured patients with and without CAL (63.7 ± 8.4 mg/l
lips, polymorphous skin rashes, indurative an- vs. 51.4 ± 4.3 mg/l, p = 0.15). In contrast, we
gioedema of hands and feet, cervical lymphade- found that eosinophils were significantly higher
nopathy, and Bacillus Calmette-Guerin (BCG) in the KD patients without CAL (5.09 ± 0.43%
vaccination scar reaction between KD patients vs. 3.33 ± 0.54%; p = 0.03, Fig. 3a) than those
with and without CAL showed no significant with CAL after IVIG treatment. The eosinophil-
difference. There were also no difference between related Th2 cytokine (IL-5) was also significantly
age distribution and total admission days higher in the KD patients without CAL than
between the KD patients with and without CAL. those with CAL (11.4 ± 1.2 pg/ml vs. 5.5 ±
1.6 pg/ml; p = 0.02, Fig. 3b). The plasma levels
of IL-4, eotaxin, and ECP between KD patients
Peripheral leukocytes and eosinophil in the KD patients and
with and without CAL showed no significant
controls
difference. Changes of eosinophils after IVIG
The KD patients had higher leukocyte counts treatment had a positive correlation with changes
and platelet counts than controls. There was a of IL-5 levels (p = 0.007, R2 = 0.19, Fig. 3c),
significantly higher eosinophil percentage but had no significant correlation with changes
(2.5 ± 0.2% vs. 0.4 ± 0.1%; p < 0.01) in KD of ECP levels (p = 0.29, Fig. 3d).
patients than controls, but no statistical differ-
ence in neutrophil, lymphocyte, monocyte, and
Levels of cytokines: IL-4, IL-5, eotaxin, and ECP in the IVIG
basophil percentages between the KD patients
products
and the controls (Table 1). The KD patients had
lower hemoglobin levels than the controls. After In consideration of cytokines in the IVIG prod-
IVIG treatment, eosinophils were greatly ucts, which may contribute to the elevation of
increased (2.5 ± 0.2% vs. 4.7 ± 0.3%; p < 0.0-
01, Fig. 1), while the inflammatory marker CRP Table 1. Analysis of complete blood counts/differential counts in KD and age-
levels were significantly decreased (105.7 ± 5.8 matched controls
mg/L vs. 55.4 ± 4.1 mg/L; p < 0.001). Hence,
experiments were next performed to assess eosin- KD (n = 95) Control (n = 30) p Values
ophil-related Th2 cytokines and the eosinophil Total leukocyte/mm3 13792 € 733 9412 € 551 <0.01
activation mediator between the KD patients and Hemoglobin (g/dl) 10.8 € 0.1 12.2 € 0.1 <0.01
the controls as described below. Platelet (·104/mm3) 37.6 € 1.4 26.4 € 1.1 <0.01
Neutrophil (%) 65.9 € 1.4 62.4 € 2.7 0.23
Lymphocyte (%) 24.6 € 1.2 27.5 € 2.5 0.31
Eosinophil-related Th2 cytokines/eosinophils activation Monocyte (%) 5.7 € 0.3 6.8 € 0.7 0.20
mediator between the KD patients and controls Eosinophil (%) 2.5 € 0.2 0.4 € 0.1 <0.01
Basophil (%) 0.17 € 0.03 0.21 € 0.05 0.61
As shown in Table 2, we found that IL-4 (p <
0.001), IL-5 (p < 0.001), eotaxin (p = 0.004), Data in KD were measured before IVIG treatment (5.97 € 1.96 days after
ECP (p < 0.001), and CRP (p = 0.003) were disease onset). Data in the control group were also collected in the acute
stage of upper or lower respiratory tract infection (including acute bronchio-
significantly higher in the KD patients before litis, acute pharyngitis, acute bronchitis, croup, and acute tonsillitis without
IVIG treatment than the controls. Further past history of allergic disease). Values presented as mean € SE. p Values
analysis found that the plasma levels of IL-4 were assessed by the StudentÕs t-test.
268

4. Role of eosinophil-related Th2 mediators in KD
different studies (15–21), while the underlying
mechanism of CAL remains unclear. Kawasaki
et al. (22) first observed that 11 of 50 KD
patients (22%) had eosinophilia in the peri-
pheral blood. Terai et al. (8) found accumula-
tion of eosinophils in the coronary micro-vessel
lesions and eosinophilia in peripheral blood
(PB) and postulated the involvement of eosin-
ophils in the pathogenesis of KD vasculitis. We
have recently shown that eosinophils were
significantly elevated in KD both before and
after IVIG treatment, and eosinophilia after
IVIG treatment had an inverse correlation to
the KD patients with IVIG-resistance (9). In
this study, we have further shown that eosino-
Fig. 1. Eosinophils were greatly increased after IVIG treat-
phil-related Th2 mediators (IL-4, IL-5, and
ment. Bars represent mean and standard error of mean eotaxin) increased, but ECP and CRP levels
(n = 95, paired sample t test). IVIG, intravenous immuno- decreased after IVIG treatment in KD.
globulin. Further analysis found that changes of eosin-
ophil percentage after IVIG treatment were
higher in KD patients without CAL than with
Table 2. Comparison of eosinophil-related Th2 cytokines/eosinophil mediator CAL. The absolute cell counts of eosinophil were
and CRP between the KD patients and age-matched controls not significantly different between the KD
patients with and without CAL (367.1 ± 75.1
KD (n = 95) Control (n = 30) p value
vs. 444.3 ± 48.5/mm3, p = 0.23, respectively).
IL-4 (pg/ml) 12.07 € 1.36 5.96 € 0.54 <0.001 The higher eosinphil percentage in the KD
IL-5 (pg/ml) 5.17 € 0.56 2.65 € 0.55 <0.001 patients without CAL may result from increased
Eotaxin (pg/ml) 129.1 € 14.3 74.5 € 7.4 0.004 recruitment of eosinophils from the bone marrow
ECP (pg/ml) 11.57 € 1.98 2.98 € 0.23 <0.001
CRP (mg/l) 105.7 € 5.8 39.5 € 14.8 0.003
or from the decrease of other leukocyte subpop-
ulations. The changes of eosinophil percentage
IL, interleukin; ECP, eosinophil cationic protein; CRP, C-reactive protein. Values were correlated to changes of IL-5 levels but not
presented as mean € SE. p Values were assessed by the StudentÕs t-test. correlated to changes of ECP levels suggesting a
Th2 reaction associated with an increase of
eosinophil chemotactic factors but not eosinophil
IL-4 and IL-5 levels after IVIG treatment, we activation factors associated with the decrease of
measured IL-4, IL-5, eotaxin, and ECP levels in CAL in KD patients. The changes of absolute
eight different bottles of four different batches of eosinophil counts did not positively correlate with
IVIG products. Using a basis of the blood IgG changes of IL-5 levels (p = 0.12, R2 = 0.051).
concentration at 2000 mg/dl, the ECP levels from This may be the reason that higher Th2 reaction
eight different bottles of IVIG had a concentra- in KD could induce disproposrtion of eosinophils
tion less than 2.0 pg/ml. The levels of IL-5, IL-4, but not eosinophil activation or absolute eosino-
and eotaxin from eight different bottles of IVIG phil counts. This is compatible to our recent
shown a median fluorescence intensity less than report that although a decline of total leukocyte
basal fluorescence intensity detected by Luminex. count after IVIG treatment was found in both
This suggests that exogenous cytokines in the KD patients with and without CAL, total leuko-
IVIG preparation may not affect the levels of cyte count after IVIG treatment remained signif-
blood cytokines that are measured 48–72 h after icant higher in KD patient with CAL (23). Taken
IVIG treatment. together, a higher total leukocyte with lower
eosinophil percentage after IVIG treatment is
associated with CAL formation in KD patients.
Discussion
We have also measured the levels of IL-4, IL-5,
A number of factors including prolonged fever, eotaxin, and ECP in IVIG products from eight
young age, male gender, initially high CRP, different bottles. All cytokines were lower than
higher neutrophil, and band form counts in KD those in plasma levels based on the normalization
patients have been implicated in prediction of to average blood IgG concentration (2000 mg/
CAL (15–17). These predictors, however, dl). In consideration of the short half-life of
revealed inconsistent correlation to CAL in cytokines of about 20 min in blood, the
269

5. Kuo et al.
(a) (b)
(c) (d)
Fig. 2. Levels of eosinophil chemotactic factors and activation factor before and after IVIG treatment. Eosinophil-related
Th2 mediators (IL-4, IL-5, and eotaxin) significantly increased after IVIG treatment (n = 95, p < 0.001) (a–c). Eosinophil
activation mediator (ECP) significantly decreased after IVIG treatment (n = 95, p = 0.03) (d). Bars represent mean and
standard error of mean. Values were tested by paired samples t-test. IVIG, intravenous immunoglobulin.
exogenous cytokines in IVIG preparation may that release different cytokine profiles in response
not affect the blood cytokines levels that are to different stimuli. They reciprocally constitute
measured 48–72 h after IVIG treatment. There an immunoregulatory loop between Th1 and Th2
were four out of the 95 study KD patients had cytokines from Th1 cells inhibiting Th2 cells and
allergy history before the diagnosis of KD. The vice versa (28). Th2 cells produce IL-4, IL-5, and
Th2 cytokines measured in this study showed no other cytokines, which promote humeral immu-
significant difference between KD patients with nity, allergic inflammation, and stimulate B cells
and without allergic disease history (p > 0.1). to produce IgE as well as other Igs (29). In
Therefore, the higher Th2 cytokines found in KD contrast, Th1 cells secrete IFN-c and IL-2, which
patients may be the natural course of KD. initiate the killing of intracellular organisms and
There are several lines of evidence pointing out viruses through activating cytotoxic T cells and
an abnormal Th1/Th2 balance in KD patients. macrophages. In this study, we found that Th2
Brosius et al. (24) reported that the incidence of cytokines (IL-4, IL-5, and eotaxin) significantly
atopic dermatitis among children with KD was increased in KD patients before and after IVIG
nine times greater than that of controls. Serum treatment. It is controversial whether Th1 cyto-
IgE and IL-4 levels were also significantly higher kines such as IFN-c increase or decrease in KD
in KD patients than age-matched children (24– patients (30–32). It remains unclear why Th2
26). Matsubara et al. (27) found a decrease of mediators are increased but Th1 mediators do
IFN-c expression in KD patients. These results not decrease in KD. We are the first to demon-
suggest a skewed imbalance toward Th2 reaction strate that IL-5 and eosinophil levels were
in KD. There are certain subpopulations of Th2s associated with the CAL in KD. Further studies
270

6. Role of eosinophil-related Th2 mediators in KD
(a) (b)
(c)
(d)
Fig. 3. Correlation of eosinophilia with IL-5 but not eosinophil cationic protein (ECP) levels in the KD patients before and
after IVIG treatment. Eosinophils (p = 0.03) and IL-5 (p = 0.02) levels after IVIG treatment were significantly higher in the
KD patients without CAL than with CAL (a, b) (Mann–Whitney U-test). Changes of eosinophils after IVIG treatment had a
significant correlation with changes of IL-5 levels (p = 0.007, PearsonÕs correlation test, R2 = 0.19) but not significantly
correlated with changes of ECP levels (p = 0.29) (c, d). Bars represent mean and standard error of mean. IVIG, intravenous
immunoglobulin; CAL, coronary artery lesions; ECP, eosinophil cationic protein.
to clarify whether genetic variants of Th2 genes this study, we found an increase in the Th2
are responsible for the susceptibility and mor- mediators (IL-4 and IL-5), but a decrease of
bidity of KD are needed. ECP, was associated with eosinophilia and less
Certain studies have shown that atheroscle- CAL formation in KD, suggesting eosinophilia
rosis is related to a skewed Th1-like response in KD is a bystander of Th2 response, but not
(33), and autoimmune disease such as BehcetÕs an effector of KD.
disease is related to Th1 cytokine and pro-
inflammatory cytokine (34, 35). We postulate Acknowledgment
that the prominent Th2 reaction may be devel- This study was in part supported by a grant CCF07-01 from
oped to combat the Th1-mediated vasculitis in the Foundation of Taiwanese Childhood Heart Diseases.
KD after IVIG treatment. Th2-related cytokines
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