Predicting IVIG resistance in UK Kawasaki Disease
Sarah Davies*1, Natalina Sutton*1, Sarah Blackstock1, Stuart Gormley1,2, Clive J Hoggart3,
Michael Levin1,2, Jethro A Herberg1,2
*Equal contribution
Paediatric Infectious Diseases, St Mary’s Hospital, Imperial College Healthcare NHS Trust,
1
Praed St, London W2 1NY, UK; 2Section of Paediatrics and 3Department of Genomics of
Common Disease, Imperial College London, Norfolk Place, London W2 1PG, UK
Running title: IVIG-resistant Kawasaki disease
Corresponding author:
Name:
Dr Jethro A Herberg
Address:
Section of Paediatrics, Imperial College, Norfolk Place, London W2 1PG, UK
Email:
j.herberg@imperial.ac.uk
Tel:
+44 (0) 207 594 3915
Keywords: Kobayashi Score, Kawasaki Disease, prediction, IVIG-resistant
Word count, excluding title page, abstract, references, figures and tables: 1,358
Number of figures: 1
Number of tables: 1
Number of references: 5
Number of supplementary files for online only publication: 1
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IVIG-resistant Kawasaki disease
Contributorship statement
All authors contributed to writing, and approved, the final manuscript. SD, NS, SB and SG
compiled and analysed data; SD and NS wrote the first draft; CH analysed data; ML
conceived and supervised the project; JH supervised the project and developed the
manuscript.
What is known about this topic
 Early switch-off of the inflammatory response in Kawasaki Disease, using antiinflammatory medications, reduces the incidence of coronary artery abnormalities
(CAA)
 The Kobayashi score (derived from clinical and lab values) has been validated to
predict treatment failure (resistance to intravenous immunoglobulin (IVIG)) in Japan
 Japanese children with a high Kobayashi score given early adjunctive steroid
treatment alongside IVIG were less likely to develop CAA
What this study adds
 This is the first study of the utility of the Kobayashi score in a UK cohort. We found
that the Kobayashi score did not predict IVIG resistance or CAA
 Previously described biomarkers of severe Kawasaki disease (haemoglobin,
albumin, CRP) were poor discriminators of IVIG resistance or CAA
 This study does not provide evidence to support the use of the Kobayashi Score in
assessment of UK children with KD: alternative biomarkers are needed
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IVIG-resistant Kawasaki disease
ABSTRACT
The Kobayashi Score (KS) predicts intravenous immunoglobulin (IVIG) resistance in
Japanese children with Kawasaki Disease (KD) and has been used to select patients for
early corticosteroid treatment. We tested the ability of the KS to predict IVIG resistance and
coronary artery abnormalities (CAA) in 78 children treated for KD in our UK centre.
19/59 children were IVIG non-responsive. This was not predicted by a high KS (11/19 IVIG
non-responders, compared with 26/40 responders had a score ≥4; P=0.77). CAA were not
predicted by KS (12/20 children with CAA vs. 25/39 with normal echo had a score ≥4;
p=0.78). Low albumin and haemoglobin, and high CRP were significantly associated with
CAA.
The KS does not predict IVIG resistance, or CA abnormalities in our population. This
highlights the need for biomarkers to identify children at increased risk of CAA, and to select
patients for anti-inflammatory treatment in addition to IVIG.
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IVIG-resistant Kawasaki disease
INTRODUCTION
Kawasaki Disease (KD) is an acute inflammatory disorder of unknown origin associated with
vasculitis affecting medium size vessels. Coronary artery abnormalities (CAA) – aneurysms
or dilatations - are the most serious complication of KD, which is the commonest cause of
acquired heart disease in children in developed countries. Up to 20% of children with KD fail
to respond to the initial standard treatment with intravenous immunoglobulin (IVIG) and
aspirin, and have persisting fever and inflammation (see (1) for a recent guideline including
source references). The vasculitis leading to CAA begins early in the illness, leaving little
time for additional therapies in IVIG non-responders before vascular damage occurs. CAA
occur most frequently in IVIG-non responders (1), suggesting that there is a critical window
for switching off the inflammatory process and preventing long term coronary artery damage.
Early administration of steroids together with IVIG improved coronary artery outcomes in
Japanese children predicted to be at risk of IVIG non-response (2, 3), and meta-analysis of
published trials suggests a reduction in CAA in patients receiving steroids. However there is
on-going debate about the optimal steroid regimen and which patients with KD should
receive steroids. The Kobayashi Score (KS), based on clinical and laboratory data, has been
reported to identify patients with KD at high risk of IVIG resistance. In a Japanese
population, KS of ≥4 has been validated as predictive of IVIG resistance, and increased risk
of CAA (4). However the KS failed to predict IVIG resistance in the US, where it had low
sensitivity but moderate specificity for high-risk disease (5). As the KS has not been tested in
a UK population, we performed a retrospective analysis to investigate the predictive value of
the KS and other proposed prognostic markers (hypoalbuminaemia, deranged liver function,
jaundice and anaemia) for IVIG resistance and coronary artery aneurysms in a UK cohort.
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METHODS
Children treated for KD at a London tertiary referral infectious diseases centre during an 8year period (2005 – 2013), were identified from hospital clinical coding data. Of 78 children,
70 had case notes available. Data were extracted from case records on a standard proforma
including, as part of an approved audit at Imperial College Healthcare NHS Trust: clinical
features of KD; laboratory data for each day until IVIG was received (full blood count, CRP,
AST/ALT, albumin, bilirubin and sodium); details of all treatments; echocardiography results;
and demographic data. The KS was calculated based on the worst pre-IVIG results. We
defined IVIG resistance as lack of defervescence within 24 hours of administration, to match
Kobayashi (4). Data were analysed using Mann-Whitney and Fishers Exact test for
categorical variables, and logistic regression for multivariate analyses. We aimed to
determine if the KS was a useful predictor of IVIG resistance in our cohort.
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RESULTS
69 of 70 children received IVIG and aspirin during the acute illness (there was one
retrospective diagnosis). There were no cases of recrudescent fever amongst our patient
group. Ten cases had inadequate data recorded to calculate the KS (Figure 1): these were
not significantly different in sex, age or referral method; 7 were IVIG-resistant and 3
developed CAA. Of the 59 remaining cases 41/59 were male (69.5%), the mean age was 33
months (range 2-113 months). Black children were over-represented and white children
under-represented compared to London population norms (20 and 22% in the study, and 13
and 60% in the 2011 census (P=0.04 and P=<0.001 for black and white groups respectively)
(Office for National Statistics: December 2012).
KS and IVIG Resistance
Of the 59 cases with full data, 37 patients (63%) were identified as having a high risk KS
(score ≥4) (Fig 1). Nineteen of 59 had IVIG resistance, and required second line treatment
for persisting fever, including a second dose of IVIG (n=13), steroids (n=11), infliximab (n=4)
and ciclosporin (n=1). KS ≥4 was not a sensitive predictor of IVIG resistance (11 of 19
resistant cases, sensitivity 58%). Specificity of the KS score was low (14 of 40 IVIG sensitive
cases had KS<4 – specificity 35%) (Table 1). The proportion of children with KS≥4 in the
IVIG-resistant and sensitive groups (11 of 19 vs. 26 of 40) was not different (P=0.77).
Children referred for tertiary management from other hospitals included those referred for
refractory disease. Fourteen of 25 referred patients had received IVIG before transfer, and in
consequence, a higher proportion of the referred group required second-line treatment than
‘walk-in’ children admitted directly from our emergency department (11/25 vs. 8/34; Fishers
exact, P=0.16). We compared the predictive value of the KS in each group (Table 1). A
KS≥4 had poor sensitivity and specificity for referred patients (55% and 29% respectively),
and for walk-in patients (63% and 38%).
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Table 1
Kobayashi score in children with and without IVIG resistance and coronary artery
abnormalities.
Table 1
Cohort used
KS category
Response to IVIG
Development of CAA - echo
Walk-ins
KS≥4
KS<4
Resistant
5
3
Sensitive
16
10
Abnormal
5
4
Normal
16
9
Referred
KS≥4
KS<4
6
5
10
4
7
4
9
5
Walk-ins &
referred
KS≥4
KS<4
11
8
26
14
12
8
25
14
Walk-ins &
referred
PPV
NPV
IVIG Resistance
0.24
0.73
Development of CAA
0.32
0.64
Abbreviations: KS – Kobayashi Score; IVIG – intravenous immunoglobulin; CAA –
Coronary Artery Abnormalities; PPV – positive predictive value; NPV – negative predictive
value
The Kobayashi Score (KS) was calculated for each patient, and patients were assigned to
a ‘high risk’ cohort (KS≥4) or a ‘low risk’ cohort (KS<4). The table shows the number of
patients in the high and low risk categories, in relation to the IVIG response and the
development of CAA. The top panel refers to ‘walk-in’ patients who were admitted via the
emergency department. The middle panel refers to children referred for specialist
management, who had a higher burden of complex KD. The lower panel refers to the entire
cohort taken together. PPV and the NPV of the KS is shown for prediction of IVIG
resistance and CAA development in the combined cohort.
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KS and coronary abnormalities
We considered whether the KS was able to predict development of CAA. Twenty of 59
patients developed CAA (including aneurysm or dilatation but not prominent or bright
coronaries). Of these, 9/20 patients with CAA were IVIG non-responsive. Ten of 39 without
CAA were also IVIG non-responsive (p=0.15). CAA were not predicted by KS≥4 (12/20,
sensitivity 60%). Fourteen of 39 cases without CAA had KS<4 (specificity 36%). The
proportion of KS<4 or ≥4 did not vary significantly between groups with and without CAA
(P=0.78).
There was a higher incidence of CAA in referred than the walk-in cases (11/25 vs. 9/34,
Fishers exact P=0.17) but the predictive value of the KS for aneurysms was poor for both
groups (sensitivity 57% and 64% for walk-ins and referred patients respectively; specificity
36% for both).
Incomplete KD
Eighteen patients were classed as having incomplete KD (5 days of fever with 2 or 3 typical
features). When they were excluded, the KS failed to predict IVIG resistance (KS ≥ 4 in
22/33 IVIG sensitive and 7/10 IVIG non-responsive cases - p=1.0) or CAA (KS≥4 in 10/16
with CAA and 19/27 without CAA; p=0.74).
Laboratory Data
We correlated laboratory data for 9 parameters previously associated with severe disease
with the presence of IVIG resistance and the development of CAA (supplementary Table 1).
No laboratory markers were associated with IVIG resistance. Three laboratory markers
correlated with development of CAA: haemoglobin (P=0.025), albumin (P=0.035) and CRP
(P=0.005). However, there was considerable overlap between the results in both groups.
CRP had the greatest difference (median 195mg/l (CAA) vs. 135mg/l (no CAA)), but
remained a poor discriminator (supplementary Fig 1). We used logistic regression to
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IVIG-resistant Kawasaki disease
compare prediction of CAA status by CRP and by the 3 significant laboratory parameters
combined in a multivariate model. The combination of CRP, albumin and haemoglobin
offered little advantage over CRP alone (supplementary Fig 2).
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IVIG-resistant Kawasaki disease
DISCUSSION
We have demonstrated that in our patient group with Kawasaki disease, the KS is a poor
predictor of IVIG resistance and an unhelpful test for identification of children who may
benefit from early adjunctive treatment with steroids. Our findings are consistent with a US
study, in which KS failed to predict IVIG resistance (5). Although a high proportion of
children had a high KS (63%), this correlated poorly with IVIG resistance. Our study was
limited by a small sample size. However, the cohort was enriched with referred, severe KD
cases facilitating the assessment of relatively more children with CAA. The KS was not
found to be predictive of IVIG resistance or CAA in either the ‘walk-in’ patients or the
referred patients. The findings were unchanged when incomplete KD cases were excluded
from the overall analysis.
In Japan, the KS has been validated as a predictor of IVIG resistance and CAA
development. In our study, the KS failed to predict either. Furthermore, although we
identified laboratory markers that were associated with CAA, there was considerable overlap
and none of the laboratory markers reliably identified patients in any group.
Our results indicate that neither the KS nor proposed laboratory markers including CRP,
albumin and haemoglobin can reliably identify UK patients at risk of IVIG non-response and
CAA, who require additional anti-inflammatory treatment (1). In view of this, we suggest that
the findings of the RAISE trial, in which steroids are advocated for treatment of children with
a high KS (3), should not be assumed to be directly applicable to children in the UK without
substantiation in further trials. Development of biomarkers that predict CAA rather than IVIG
resistance might result in administration of additional anti-inflammatory agents to some
children whose disease would respond to IVIG alone, but potentially would reduce the
numbers developing CAA.
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COMPETING INTERESTS
There are no competing interests to declare
FUNDING
The research was supported by the National Institute for Health Research (NIHR) Imperial
Biomedical Research Centre. The views expressed are those of the authors and not
necessarily those of the NHS, the NIHR or the Department of Health.
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IVIG-resistant Kawasaki disease
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IVIG-resistant Kawasaki disease
FIGURE LEGENDS
Figure 1 - Sample selection flowchart
After excluding patients with incomplete information, and one patient who did not receive
IVIG, 59 patients were eligible for study. The KS was calculated as follows: a score of 2
points is given for fever for ≤4 days at diagnosis; ALT≥ 100iu/ml; ≥80% neutrophils. One
point is given for age < 1 year; CRP≥ 100mg/L; platelets ≤300 x 109/L. A score of 4 or more
indicates ‘High Risk’ disease.
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