EUROPEAN CONSENSUS-BASED RECOMMENDATIONS FOR THE DIAGNOSIS AND

TREATMENT OF KAWASAKI DISEASE – THE SHARE INITIATIVE

*Nienke de Graeff1, *Noortje Groot1,2,3, Seza Ozen4, Despina Eleftheriou5, Tadej Avcin6, Brigitte
Bader-Meunier7, Pavla Dolezalova8, Brian M. Feldman9, Isabelle Kone-Paut10, Pekka
Lahdenne11, Liza McCann3, Clarissa Pilkington5, Angelo Ravelli12, Annet van Royen-Kerkhof1,
Yosef Uziel13, Bas Vastert1, Nico Wulffraat1, Sylvia Kamphuis2, **Paul Brogan5, **Michael W.
Beresford3,14

1 2
Wilhelmina Children's Hospital, Utrecht, The Netherlands; Sophia Children's Hospital,
Erasmus University Medical Centre, Rotterdam, The Netherlands; 3 Alder Hey Children's NHS
Foundation Trust, Liverpool, United Kingdom; 4Dept. of Paediatric Rheumatology, Hacettepe
University, Ankara, Turkey; 5Great Ormond Street Hospital for Children, London, United
Kingdom; 6University Children's Hospital Ljubljana, Ljubljana, Slovenia; 7Necker Hospital,
Assistance Publique-Hôpitaux de Paris, Paris, France; 8First Faculty of Medicine, Charles
University and General University Hospital, Prague, Czech Republic; 9The Hospital for Sick
Children, University of Toronto, Toronto, Canada; 10Bicêtre Hospital, APHP, university of Paris
SUD, France; 11Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland;
12
Gaslini Children's Hospital, Genoa, Italy; 13Meir Medical Centre, Sackler Faculty of Medicine,
Tel Aviv University, Tel Aviv, Israel; 14Institute of Translational Medicine, University of Liverpool,
Liverpool, United Kingdom

NB: * Joint first authors

** Joint senior authors

Corresponding author:
Professor Michael W Beresford
Institute in the Park, University of Liverpool
Alder Hey Children’s NHS Foundation Trust, Liverpool L14 5AB, United Kingdom
[email protected]
+44 151 282 4536

Key messages
1. In children with Kawasaki disease, coronary artery aneurysms may be prevented by
early institution of adequate anti-inflammatory therapy, typically intravenous
immunoglobulin (IVIG).
2. Coronary artery outcomes associated with Kawasaki disease are currently worse
than historically described, with diagnostic delay contributing to this.

1
 3. Patients resistant to IVIG are at highest risk of coronary artery aneurysms. However,
there are no reliable biomarkers to identify such patients outside of Japan and thus
stratify for adjunctive anti-inflammatory treatment
4. Meta analyses indicate a role for corticosteroids as adjunctive treatment to IVIG to
prevent coronary artery aneurysms for high risk patients
5. We provide evidence-based recommendations for the diagnosis and treatment of
Kawasaki disease in the light of these advances

Key words
Childhood / paediatric; Kawasaki disease; Systemic vasculitis; SHARE recommendations;
Treatment

Disclosure Statement
None declared

Funding Statement
This work was supported by the European Agency for Health and Consumers (EAHC; grant
number 2011 1202)

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ABSTRACT
Background
The European SHARE initiative (Single Hub and Access point for paediatric Rheumatology in
Europe) aimed to optimize care for children with rheumatic diseases. Kawasaki disease (KD)
is the most common cause of acquired heart disease in children and an important cause of
long-term cardiac disease into adulthood. Prompt diagnosis and treatment of KD is difficult due
to the heterogeneity of the disease but is crucial for improving outcome. To date, there are no
European internationally agreed, evidence-based guidelines concerning the diagnosis and
treatment of KD in children. Accordingly, treatment regimens differ widely.
Objectives
To provide consensus based, European-wide evidence-informed recommendations for
diagnosis and treatment of children with KD.
Methods
Recommendations were developed using the European League Against Rheumatism’s
standard operating procedures. An extensive systematic literature search was performed, and
evidence-based recommendations were extrapolated from the included papers. These were
evaluated by a panel of international experts via online surveys and subsequently discussed in
three consensus meetings, using nominal group technique. Recommendations were accepted
when ≥80% agreed.
Results
In total, 17 recommendations for diagnosis and 14 for treatment of KD in children were
accepted. Diagnostic recommendations included laboratory and imaging workup for complete
as well as incomplete KD. Treatment recommendations included the importance of early
treatment in both complete and incomplete KD, use of intravenous immunoglobulin, aspirin,
corticosteroids for high-risk cases, and other treatment options for those with resistant disease.
Conclusions
The SHARE initiative provides international evidence-based recommendations for diagnosing
and treating KD in children, facilitating improvement and uniformity of care.

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INTRODUCTION
Kawasaki disease (KD) is the second most common systemic vasculitic illness of childhood
after IgA vasculitis (IgAV, previously known as Henoch-Schönlein purpura)[1]. KD is more
prevalent in Japanese children (308/100,000) under the age of five years[2], a risk which is
independent of geography.[3] In the UK, an indirect 2016 epidemiological survey indicated an
incidence of 9.2/100,000 children under five years, with over-representation of Chinese and
Japanese cases[4], but a recent direct British Paediatric Surveillance Unit (BPSU)
epidemiological survey suggests an incidence of 4.55/100,000 children under 5 years (Tulloh
and Brogan et al, manuscript submitted). In the USA, the incidence of KD is approximately
25/100,000 children under the age of five.[3]

Importantly, KD is the most common cause of acquired heart disease in children in developed
countries, causing coronary artery aneurysms (CAA) in up to 25% of untreated patients due to
coronary vasculitis. This declines to approximately 4% with intravenous immunoglobulin (IVIG)
treatment.[3, 5] Mortality varies by population: 0.015% in Japan[3]; 0.17% in the USA[3] and
0.36% in the UK.[4] KD remains an important cause of long-term cardiac disease into
adulthood.[3, 6, 7] The complexity and heterogeneity of presentation of KD, broad differential
diagnosis, and lack of a diagnostic test can be important barriers for making a prompt diagnosis.

In 2012, the European initiative SHARE (Single Hub and Access point for paediatric
Rheumatology in Europe) was launched to optimize care for children and young adults with
Paediatric Rheumatic Diseases (PRD).[8] To date, SHARE-recommendations for paediatric
antiphospholipid syndrome, juvenile dermatomyositis, familial Mediterranean fever/auto-
inflammatory diseases and childhood-onset lupus have been published.[9-13] Although the
American Heart Association (AHA) provided updated and detailed guidelines for KD in 2017[3],
there are no internationally-agreed, evidence-based recommendations for KD in children.
Treatment regimens still differ widely between centres, and internationally.[5, 14] Thus, the
SHARE recommendations aim to fulfil this important unmet need to provide a practical tool for
optimal care of children with KD.

METHODS
A panel of 17 experts in paediatric rheumatology and systemic vasculitides from across Europe
was established to develop evidence-based recommendations for diagnosing and treating
childhood KD. Experts needed to be senior consultants with at least 10 years’ experience
working in a major tertiary paediatric rheumatology referral centre routinely looking after
children with KD and as part of a multi-disciplinary team. As SHARE was a European Union
(EU)-funded project, only experts from across Europe were able to be selected, representing a
balance between experience and geography, although the panel carefully considered literature
and other published recommendations from experts from across the globe. The panel were
informed by expert recommendations from paediatric cardiology and infectious diseases and

4
other specialists, but due to the specific scope of the SHARE initiative, the panel did not include
directly experts from these specialties in the process. The panel used the previously
described[12] SHARE methods and following the European League Against Rheumatism
(EULAR) standardised operating procedure for developing best practice recommendations.[15]

Systematic literature review and study selection

Based on specific research questions, the PubMed/MEDLINE, EMBASE and Cochrane
databases were systematically searched on 20th June 2013 resulting in a set of articles that
were then assessed (Supplementary Figure S1). All systemic vasculitides synonyms were
searched using MeSH/Emtree terms, title and abstract, using a validated filter pertaining to
children and adolescents only[16] (Supplementary Table S1). Articles were assessed using
pre-specified inclusion/exclusion criteria (Supplementary Table S2). The comprehensive
literature review was undertaken inclusive of these other forms of systemic vasculitis to ensure
no manuscripts including data on KD along with any of these other forms were missed. All
articles were screened independently by two reviewers (NdG, NG) and full text assessed when
necessary to determine eligibility. Disagreement was resolved by a third reviewer (MWB);
agreement was reached in all cases. This literature review was cross-referenced with key
articles that had informed a contemporaneous UK national guideline for KD[5].

Additional key KD articles identified between the initial literature search and the final manuscript
drafting (May 2018) were identified using the same search strategy. Whilst these latter did not
directly inform the recommendations, they were included in the manuscript commentary to
provide up-to-date face validity and contextualisation, particularly to incorporate updated AHA
2017 guidance.[3]

Validity assessment
Papers pertaining to KD were analysed using standardized data extraction and scoring forms
by two experts (PB and DE); any discrepancies were resolved by a third expert (MWB). Data
were extracted using predefined scoring forms for demographics, diagnostic[17] and
therapeutic[18] studies. Adapted classification tables for diagnostic[19] and therapeutic[20]
studies were used to determine the level of evidence and strength of each recommendation
(Supplementary Tables S3, S4).

Establishment of recommendations
Provisional statements regarding diagnosis and treatment were developed using data from
included articles (NdG, NG, SO, SK, PB and MWB). These statements were presented to the
expert committee (n=14/17 of the experts) in an online survey (100% response rate).
Recommendations were revised according to responses and discussed at three face-to-face
consensus meetings in March 2014 (Genoa, n=14/17 expert participants); January 2015
(Utrecht, n=10/17 experts) and March 2015 (Barcelona, n=16/17 experts). Nominal group

5
technique was used to reach consensus[21], with final recommendations accepted with ≥80%
agreement.

RESULTS
Literature search and formulation of recommendations
The literature search yielded 826 articles relating to KD (Figure S1). References concerning
rare paediatric systemic vasculitides and IgA vasculitis informed additional recommendations
described in separate manuscripts (Figure S1). A total of 31 recommendations were accepted
with 100% agreement: 17 relating to diagnosis and 14 concerning treatment of KD.

Diagnosis of Kawasaki Disease

Table 1 summarises the SHARE recommendations for diagnosing KD and incomplete KD.

6
Table 1: SHARE Recommendations for the diagnosis and assessment of KD

KD Recommendations – Diagnosis LoE SoR

1. There are different diagnostic criteria for KD. The AHA diagnostic criteria should be used to diagnose complete KD (see Table 2). 4 D
2. The diagnosis of KD should be considered in any child with a febrile exanthematous illness and evidence of inflammation, particularly if it 4 D
persists longer than 4 days.
3. KD diagnosis and treatment should not be delayed if: 4 D
- 5/6 diagnostic criteria of KD are present before day 5 of fever.
- Coronary Artery Aneurysms (CAA) or coronary dilatation are present.
- There is evidence of persistent (≥5 days) elevation of inflammatory markers and/or persistent fever, especially in infants or younger
children without other explanation.
4. In a patient in whom KD is suspected, but all criteria have not yet been fulfilled, the following clinical signs strengthen the suspicion of KD: 4 D
- Irritability
- New erythema and/or induration at the site of previous BCG immunisation.
5. It is recognized that there are incomplete cases of KD (who do not fulfil the AHA-criteria); however, these patients may still be at risk of CAA, 4 D
particularly infants.
6. Criteria should be designed and validated to help diagnose incomplete KD*. 4 D
7. In children presenting with less than 5 out of 6 criteria for KD ('incomplete KD'), with evidence of unexplained systemic inflammation (e.g. 3 D
elevated CRP, ESR or WBC), an echocardiogram should be considered.
8. The following laboratory values should be determined: ESR, CRP, full blood count and liver function (bilirubin, AST/ALT), albumin, natremia, 3 C
renal function and urinalysis. Ferritin and fibrinogen should be considered if there is a concern for macrophage activation syndrome.
9. Cerebrospinal fluid analysis may be important to rule out infectious meningitis. 4 D
10. The following laboratory values can be important in assessing risk stratification for IVIG resistance: Low sodium, raised bilirubin, raised ALT, 3 C
low platelet count, high CRP, low albumin**.
11. The following laboratory values can be important in monitoring inflammation: ESR (prior to IVIG), CRP and full blood count. 2B C
12. All patients with suspected KD should undergo echocardiography and ECG at baseline, as soon as the diagnosis is suspected. 1A B
13. An intermediate echocardiogram, 2 weeks after the first IVIG, should be performed in all patients with KD whose initial echo was normal and 1A B
in whom disease activity has been arrested.
14. All patients with KD should undergo echocardiography at 6-8 weeks after disease onset. 2A C
15. In those with ongoing active inflammation (increasing or persistently elevated CRP and/or persisting signs and symptoms), ECG and 2A C
echocardiography should be performed at least weekly to monitor the possible development of cardiac sequelae.
16. In those with coronary abnormalities detected on initial echocardiography, echocardiography should then be performed at least weekly to 2A C
monitor progression until there is clinical stabilization.
17. In children with CAA, ECG and echocardiography should be performed 3 to 6-monthly, depending on the severity of the CAA*** 4 D

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Footnotes:
*These SHARE recommendations were formulated prior to publication of the American Heart Association (AHA) 2017 recommendations3, which describe an algorithm for the diagnosis and
treatment of incomplete KD cases. Although the AHA algorithm is not evidence-based, it provides a useful diagnostic framework (see main text).
** See also Supplementary Table S5 which provides details of the 3 main scoring systems used to determine risk of IVIG resistance.
*** Or as otherwise recommended by an expert paediatric cardiologist.

Abbreviations:
AHA, American Heart Association; ALT, alanine transaminase; AST, aspartate transaminase; CAA, coronary artery aneurysm; CRP, C-reactive protein; ECG, electrocardiogram; ESR, erythrocyte
sedimentation rate; IVIG, intravenous immunoglobulin; KD, Kawasaki disease; WBC, white blood cell count

LoE, level of evidence: 1A, meta-analysis of cohort studies; 1B, meta-analysis of case control studies; 2A, cohort studies; 2B, case control studies; 3, non-comparative descriptive study; 4 expert
opinion. SoR, strength of recommendation; A, based on level 1 evidence; B, based on level 2 or extrapolated from level 1; C, based on level 3 or extrapolated from level 1 or 2; D, based on level 4
or extrapolated from level 3 or 4 expert opinion.

Table 2: Kawasaki disease: Diagnostic criteria (AHA 20173)

Criteria Description
Fever Duration of 5 days or more PLUS 4 of 5 of the following:
1. Conjunctivitis Bilateral, bulbar, conjunctival injection without exudate
2. Lymphadenopathy Cervical, often >1.5 cm usually unilateral
3. Rash Rash: Maculopapular, diffuse erythroderma or erythema multiforme
4. Changes of lips or oral mucosa Red cracked lips; "strawberry" tongue; or diffuse erythema of oropharynx
5. Changes to extremities Erythema and oedema of palms and soles in acute phase and periungal
desquamation in subacute phase

NB. KD may be diagnosed with fewer than 4 of these features if coronary artery abnormalities are detected (Figure 1).

8
Diagnostic criteria for KD
There is no diagnostic test for KD; thus, diagnosis rests on clinical criteria and laboratory
findings. To establish the diagnosis according to the Diagnostic Guidelines of the Japan KD
Research Committee, any five of the six criteria in Table 2 must be present.[5] The AHA (2004)
diagnostic criteria are similar, except that fever is mandatory, and four of the remaining five
criteria are required.[14] The expert panel assessed the merits and strengths of each, and
recommended that the AHA diagnostic criteria should be used for complete KD. Subsequently,
the AHA revised their diagnostic criteria, as summarised in Table 2. These are broadly similar
to the 2004 criteria, but now acknowledge that diagnosis may be made earlier than day 5 of
fever, if fever plus ≥4 principle clinical features are present, in line with the SHARE
recommendations. However, many patients have some but not all of the clinical features of KD
and may still be at risk of CAA (see below). Clinical features may present sequentially, such
that an ‘incomplete’ case can evolve into a ‘complete’ case.[14] Thus, the diagnosis of KD must
be considered in any child with a febrile exanthematous illness and evidence of inflammation,
particularly if it persists longer than 4 days.[5, 14, 22]

Diagnosing KD before day 5 of fever

The SHARE experts acknowledged that the requirement for fever ≥5 days may lead to delayed
treatment. While fever duration has historically been of importance for the standardisation of
case definitions, clinicians should not delay diagnosing KD and instituting treatment if 5 out of
6 diagnostic criteria of KD are present before day 5 of fever, or if CAA (Z-score ≥2.5) or coronary
dilatation (Z-score>2, but <2.5) are present.[5, 14, 22]

Diagnosing Incomplete Kawasaki disease

Whilst the diagnosis of KD is generally straightforward in patients fulfilling all the criteria for KD
(‘complete’ KD), many patients have only some of the clinical features.[3, 5, 14, 22] However,
they may still be at risk of CAA, especially infants who may have prolonged fever alone or
fleeting clinical signs. The panel acknowledged that diagnosing KD in patients with incomplete
clinical criteria relies on a high index of suspicion, in agreement with other current guidelines.[3,
5, 14] In these situations, early echocardiography is recommended. This may reveal evidence
of coronary vasculitis, confirming the diagnosis of KD. Notably, however, a negative
echocardiogram does not exclude the diagnosis of KD.
The definition of ‘incomplete KD’ can cause confusion. As is the case for complete KD, the
requirement of fever ≥5 days to fulfill current diagnostic criteria may delay treatment
unnecessarily. The expert panel recommended that an important research priority is to design
and prospectively validate criteria to help diagnose incomplete KD in children. The AHA 2017
recommendations provide some guidance in this respect, defining incomplete KD as children
with fever ≥5 days and 2 or 3 clinical criteria, or infants with fever for ≥7 days without other
explanation.[3] Thereafter, treatment decisions are determined by laboratory tests including
inflammatory markers (Figure 1). These AHA recommendations offer a practical solution for the

9
diagnosis and treatment of incomplete KD cases, but are not evidence-based, as
acknowledged by McCrindle et al.[3]

Figure 1

Figure 1: Management of suspected incomplete Kawasaki disease KD (adapted from AHA

2017[3]). CRP=C-reactive protein; ESR=erythrocyte sedimentation rate; WCC=white cell
count; ALT=alanine transaminase; hpf=high power field.

10
Laboratory work-up of suspected Kawasaki Disease
The diagnosis of KD is unlikely in the absence of significant systemic inflammation. Certain
laboratory parameters may help stratify the severity of KD and thus help inform therapeutic
decisions. Therefore, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), full blood
count, electrolytes, renal and liver function (including bilirubin, AST or ALT, and albumin) should
be monitored in all patients.[3, 5, 14] Notably, ESR is only useful prior to IVIG therapy, since
this may be elevated post-IVIG as a consequence of binding to red blood cells.[23, 24] It is
equally important to rule out severe infections (such as meningitis), and/or identify other
systemic inflammatory diseases or complications of KD including macrophage activation
syndrome (also referred to as secondary haemophagocytic lymphohistiocytosis, HLH).[3, 5]
Thus, consideration of a full septic screen (including consideration of lumbar puncture) and
serum ferritin are recommended. Evidence of infection might occur in patients with KD, and
should not deter clinicians from treating both entities[25].

Scoring systems to predict high-risk cases

Several scoring systems have been developed to identify children at highest risk of IVIG
resistance and hence highest risk of developing CAA[26-28]. Kobayashi et al. developed a
model to predict unresponsiveness to IVIG in Japanese children with KD based on a cut-off
point ≥4 calculated as per below: sodium ≤ 133 mmol/L (2 points); days of illness at initial
treatment ≤4 (2 points); aspartate aminotransferase ≥100 IU/L (2 points); percentage of
neutrophils ≥ 80% (2 points); C-reactive protein ≥ 100mg/L (1 point); age ≤ 12 months (1 point);
platelet count ≤ 300 × 10 9/L (1 point)[27] (see Supplementary Table S5). This model was used
to define severe cases in a pivotal clinical trial of corticosteroids, because IVIG resistance is
known to be a strong risk factor for the development of CAA[27]. The Kobayashi, Egami, and
Sano scores (see Supplementary Table S5), when tested in North American patients,
demonstrated comparably high specificity for predicting IVIG non-response, but with relatively
low sensitivity[29]. These data suggested that in non-Japanese children, a positive Kobayashi
score might identify a patient at high risk of IVIG resistance, but a negative score may not
reliably exclude a high-risk case. More recently, studies from the UK and Germany also
demonstrated suboptimal performance of the Kobayashi score for predicting high-risk
cases[30, 31]. Therefore, clinicians must adopt a pragmatic approach and synthesise an overall
picture of disease severity based on clinical features and laboratory parameters. Factors that
increase risk include young age (i.e. <12 months), low serum sodium, high ALT, low albumin,
high bilirubin, high CRP, low platelet count, falling haemoglobin, features of HLH and shock,
and are all important features to consider when assessing risk and hence choice of primary KD
treatment modality.

Echocardiography and monitoring systemic inflammation

As up to 25% of untreated KD cases develop CAA, and a significant proportion have other
cardiac manifestations, including pericardial effusion, pericarditis, myocarditis, valvular

11
incompetence, cardiac failure and even myocardial infarction, all patients with suspected KD
should undergo echocardiography at baseline, as soon as it is suspected.[3, 5, 14, 22]
Treatment should not be delayed whilst awaiting echocardiography.[3, 5, 14, 22] In view of the
potential rapidly evolving nature of this critical complication, all patients with KD should have
an intermediate echocardiogram, two weeks after administration of the first IVIG, including
those whose initial echo was normal and in whom disease activity has been arrested.[3, 5, 14,
22, 32-35] All patients should undergo echocardiography at 6-8 weeks after disease onset.[3,
5] Although not noted as a specific recommendation, it was acknowledged that all patients
should have echocardiography undertaken by a paediatric cardiologist or by
echocardiographers trained specifically in paediatric cardiology working directly within a
paediatric cardiology team.

Historically, resolution of fever has been used as a metric of therapeutic outcome success in
KD. However, some patients may become afebrile but still have significant ongoing systemic
inflammation as indicated by elevation of acute phase reactants, including CRP. Indeed, recent
clinical trials have employed resolution of fever and normalisation of CRP in their therapeutic
design[36], emphasising that temperature alone should not be used to gauge the degree of
systemic inflammation, as reflected in recent clinical guidelines.[3, 5] Close monitoring of
patients with increasing or persistently elevated CRP and/or persisting signs of systemic
inflammation is therefore critical, combined with regular cardiology reviews including at least
fortnightly ECG and echocardiography to assess cardiac sequelae.[3, 5] Erythrocyte
sedimentation rate should not be taken into account after IVIG (as an elevation of proteinemia
leads to an elevation of ESR). In those with coronary abnormalities including CAA, at least
weekly echocardiography should be considered to monitor progression until clinical
stabilization. Among those with CAA, ECG and echocardiography should be performed every
3 to 6 months (or as specified by a paediatric cardiologist for individual cases), depending on
CAA severity.[3, 5] A final important caveat in relation to echocardiography for young children
who present with systemic inflammation, is that other inflammatory diseases might be
associated with transient coronary artery dilatation, particularly systemic-onset juvenile
idiopathic arthritis.[37]

Treating Kawasaki Disease

Table 3 summarises the SHARE recommendations for treating KD in childhood.

IVIG
Randomized controlled trials and meta-analyses have demonstrated unequivocally, that early
recognition and treatment of KD with IVIG and aspirin reduces the occurrence of CAA.[38, 39]
Therefore, the panel recommended strongly that IVIG and aspirin should be started as soon as
a patient is diagnosed with complete or incomplete KD. In keeping with previous guidance[3,
5], treatment should include a dose of 2g/kg IVIG as a single infusion, in view of greater

12
therapeutic effect in preventing CAA when compared to a lower, divided dose regimen.[40] As
the Kobayashi criteria in non-Japanese patients may not reliably exclude IVIG resistance even
if ‘negative’ [29], close monitoring of patients is critical, taking into account temperature, acute
phase reactants (particularly CRP post-IVIG), clinical symptoms and signs of systemic
inflammation.

13
Table 3: SHARE Recommendations for the treatment of KD

KD Recommendations – Treatment LoE SoR

1. As soon as a patient is diagnosed with KD, treatment should be initiated*. This applies to both complete and incomplete KD. 1A A
2. Treatment of KD should include IVIG at a dose of 2g/kg as a single infusion. 1A A
3. In non-Japanese patients, the Kobayashi criteria may indicate risk of IVIG resistance if 'positive' (score ≥4) but may not reliably exclude IVIG 2A C
resistance if ‘negative’ (score<4).
4. All patients diagnosed with KD who are treated with IVIG should be treated with aspirin at a dose of 30-50mg/kg/day until fever has settled 2A C
for 48 hrs; clinical features are improving; and CRP levels are falling.
5. The dose of aspirin should subsequently be reduced to an antiplatelet dose of 3-5mg/kg once daily when fever and inflammation have 3 D
subsided.
6. If aneurysms persist in the convalescent phase of KD, antiplatelet therapy in the form of low-dose aspirin (3–5mg/kg) should be continued 3 D
long-term, at least until the aneurysms resolve.
7. In patients with CAA that resolve, long term aspirin (3-5mg/kg/day) should be considered, taking into account the risk-benefit ratio for 4 D
individual patients.
8. Corticosteroid treatment should be given to patients with severe KD*: **1A A
a. Who are IVIG resistant, that is, with ongoing fever and/or persistent inflammation or clinical signs ≥48 h after receiving IVIG as a single
dose of 2g/kg. A second dose of IVIG is at the discretion of the treating physician. 1A C
b. Kobayashi score ≥5 (see Supplementary Table S5) 3 C
c. With features of haemophagocytic lymphohistiocytosis (HLH) 4 D
d. With features of shock 4 D
e. Who are under the age of 1 year 4 D
f. Who present with coronary and/or peripheral aneurysms 4 D
9. If corticosteroids are indicated, the following regimens would be reasonable: 2A B
- Regimen 1: methylprednisolone 0.8 mg/kg BD IV for 5-7 days or until CRP normalizes; then convert to oral
prednisone/prednisolone 2 mg/kg/day and wean off over next 2-3 weeks.
- Regimen 2: methylprednisolone 10-30 mg/kg (up to maximum of 1g/day) once daily for 3 days followed by oral
prednisone/prednisolone 2 mg/kg per day until day 7 or until CRP normalizes; then wean over next 2-3 weeks.
10. TNF-alpha blockade (e.g. infliximab) should be considered in KD patients with persistent inflammation despite IVIG, aspirin and corticosteroid 2A C
treatment, after consultation with a specialist unit.
11. The use of DMARDs such as ciclosporin, cyclophosphamide, and methotrexate, along with anakinra and plasma exchange, cannot be 4 D
recommended, except on an individual basis after consultation with a specialist unit.
12. In the presence of giant aneurysms (internal diameter ≥8 mm; or Z-score ≥10; and/or coronary artery stenosis) warfarin should be 2B C
administered (in addition to aspirin), after initial heparinisation; heparin can be stopped when a stable INR between 2-3 is reached.

14
 13. If symptoms of ischaemia or obstruction occur in a patient with KD, a paediatric cardiologist/cardiac surgeon/interventional radiologist 4 D
(depending on local expertise available) should be consulted immediately
14. Immunisation with all vaccines should be deferred for at least 6 months following an episode of KD treated with IVIG. 4 D
Abbreviations and footnotes:
* Treatment should not be delayed whilst awaiting echocardiography.
** Level of evidence 1A and strength of recommendation A for this overall statement in relation to severe KD.

Abbreviations: C-Reactive Protein (CRP); Coronary Artery Aneurysms (CAA); Disease Modifying Anti-Rheumatic drugs (DMARDs); haemophagocytic lymphohistiocytosis (HLH); Intravenous
Immunoglobulin (IVIG); Kawasaki disease (KD);

LoE, level of evidence: 1A, meta-analysis of randomised controlled trials; 1B, randomised controlled study; 2A, controlled study without randomisation; 2B, quasi-experimental study; 3, descriptive
study; 4 expert opinion; SoR, strength of recommendation: A, based on level 1 evidence; B, based on level 2 or extrapolated from level 1; C, based on level 3 or extrapolated from level 1 or 2; D,
based on level 4 or extrapolated from level 3 or 4 expert opinion.

15
Aspirin
All patients should initially receive aspirin at a dose of 30-50mg/kg/day, in 3-4 divided doses.
Meta-analysis comparing the 30-50mg/kg/day dose with high-dose (80–120mg/kg/day), both
combined with IVIG, demonstrated no significant difference in the incidence of CAA.[41] Aspirin
should be reduced to an antiplatelet dose of 3–5 mg/kg/day, but only after the fever has settled
for 48 hours, clinical features are improving, and CRP levels are falling.[3, 5] Aspirin can be
stopped if the echocardiogram at 6-8 weeks remains normal. If CAA persist in the convalescent
phase, continuation of low-dose aspirin (3-5mg/kg/day) is recommended long-term, at least
until the aneurysms resolve.[3, 5] In patients with resolved CAA, long term aspirin (3-5
mg/kg/day) should still be considered, taking into account the risk-benefit ratio for individual
patients. It is increasingly recognized that patients with regressed aneurysms may demonstrate
coronary artery endothelial function abnormalities comparable to those with persistent CAA.[6]
The adverse effects of late KD vasculopathy, even in those with resolved CAA, is increasingly
recognized.[3, 5] It should be remembered that ibuprofen and other nonsteroidal anti-
inflammatory drugs interfere with the antiplatelet effect of aspirin and thus should be avoided if
possible; a point emphasized in the recent AHA guidelines.[3] It is possible that future guidance
may recommend low dose aspirin (3-5 mg/kg/day) at all stages of KD, as suggested by data
from a retrospective cohort[42]; whilst the SHARE group acknowledged this recent
development, there has never been a prospective controlled clinical trial to support this
approach.

Treatment with Corticosteroids

Up to 20-40% of patients are IVIG resistant, and are at increased risk of developing CAA.[36,
43-45] In the UK, CAA rates remain significantly higher (19-29%) despite IVIG, a worrisome
complication rate that has remained stable over 25 years of surveillance.[4, 46] Similarly poor
outcomes are now recognized in Sweden, and Russia.[47, 48] Although therapeutic delay is a
major contributing factor to these poor outcomes, some authors speculate that IVIG response
may vary across populations[46], perhaps due to genetic differences such as Fc gamma-
receptor polymorphisms[3], emphasizing the need for adjunctive primary treatment in some
patients.

Whilst significant equipoise remains regarding the use of corticosteroids for unselected KD
patients, the use of corticosteroids as primary adjunctive treatment of patients with severe
KD[49], has an increasingly compelling evidence-base.[36, 43, 44, 50-53] Meta-analysis of 16
comparative studies involving 2746 KD patients demonstrated that early addition of
corticosteroids to conventional IVIG therapy is associated with reduced risk of CAA compared
with IVIG therapy alone (odds ratio 0.424; 95%CI, 0.270-0.665).[44] This beneficial effect was
only observed when corticosteroids were used as primary therapy rather than rescue therapy
for IVIG resistance. It was most beneficial for patients who were determined at baseline to have
high-risk for IVIG resistance. The authors highlighted the importance of prompt diagnosis and

16
treatment: meta-regression analyses demonstrated that the overall efficacy of corticosteroids
was negatively correlated with illness duration before corticosteroid therapy.[44] Thus, the need
for more robust clinical risk scoring systems to identify high-risk patients is underlined.

Notwithstanding the ongoing debate regarding the definition of KD severity in non-Japanese

patients, it is unclear whether corticosteroids benefit patients with less severe KD[3, 5], and the
optimal corticosteroid dosing regimen to use is uncertain.[5, 49] Thus, preventing potentially
life-long cardiac sequelae needs to be balanced against careful vigilance for corticosteroid-
related complications. In view of this, the expert panel recommended that adjunctive primary
corticosteroid treatment should be given to patients: a) who are IVIG resistant, with ongoing
fever and/or persistent inflammation or clinical signs ≥48 hours after receiving a single dose of
IVIG[5] (a second dose of IVIG alongside corticosteroids is at the discretion of the treating
physician[5]); b) have a Kobayashi score ≥4[29]; c) have features of HLH[54]; and/or d) have
features of shock.[55, 56] The panel defined additional ‘high-risk groups’ who are also likely to
benefit from primary adjunctive corticosteroids, namely: infants <1 year of age[5], and in
patients who present with coronary and/or peripheral aneurysms at diagnosis[5], although this
may impact on damage limitation only.[44] As the meta-analysis of corticosteroid treatment in
KD does not provide definite evidence for optimal treatment regimens[43, 44, 49], treating
clinicians will need to determine the corticosteroid regimen for individual patients. If
corticosteroids are indicated, the panel noted two treatment regimens that in their consensus
opinion would be reasonable (Table 3).

TNF-alpha blockade and other treatments

An increasing number of studies have explored the potential use of TNF-alpha blockade in
children with IVIG-resistant KD.[57-61] Although these studies have demonstrated no
significant differences in cardiac-related outcomes, such as reduction in CAA, they generally
demonstrate a significant impact on reducing the acute-phase response, fever, and potentially
length of hospital stay. Therefore, use of anti-TNF-alpha medication (e.g. infliximab) was
recommended for consideration in KD patients with persistent inflammation despite IVIG,
aspirin and corticosteroid treatment; albeit after consultation with a specialist unit. The panel
did not make specify dosing or need for additional doses of anti-TNF-alpha medication, which
were felt to be beyond the scope of these recommendations. Evidence supporting the use of
other treatments such as ciclosporin, cyclophosphamide, methotrexate, along with anakinra or
plasma exchange, was less robust and therefore could not be routinely recommended, apart
from on a case-by-case basis after consultation with a specialist unit.

Anti-coagulation and anti-aggregation

Those with medium sized aneurysms (Z score 5-10) should also take aspirin at 3-5mg/kg/day,
and consider addition of an antagonist of ADP-mediated activation platelet aggregation such
as Clopidogrel, at a dose of 0.5-1 mg/kg/daily.[3] Managing patients with giant aneurysms

17
(internal diameter ≥8 mm; or Z-score≥10; and/or coronary artery stenoses) includes anti-
coagulation as well as antiplatelet therapy with aspirin.[62] Warfarin should be administered in
addition to aspirin after initial heparinisation, and heparin can be stopped when a stable INR of
2-3 is reached.[22, 62, 63] If symptoms of ischaemia or vascular occlusion occur in a patient
with KD, a paediatric cardiologist/cardiac surgeon/interventional radiologist (depending on local
expertise available) should be consulted, if not already closely involved in management.[3, 5]
Detailed advice on the use of low molecular weight heparin, clopidogrel and other
thienopyridines, thrombolysis and other acute revascularisation procedures was not considered
in the SHARE process, but these issues have been addressed in the recent AHA guidance,
albeit with limited evidence to inform guidance.[3]

Immunisation
Immunisation with all live vaccines should be deferred for at least 6 months following an episode
of KD treated with IVIG, mainly due to the potential lack of effectiveness following IVIG[64, 65].
Thereafter, all vaccines should be administered as recommended by national schedules. As
IVIG particularly supresses the response to measles vaccine, and in line with recent AHA
guidance, we also suggest that MMR vaccine (and VZV vaccine, albeit with less supporting
evidence) might be deferred for at least 11 months after IVIG administration[3]. We however
acknowledge that children at high-risk of exposure to measles should be vaccinated earlier
than this 11-month window, with the possibility of re-vaccination if serological response is
suboptimal.

Management of other KD scenarios

A wide range of other complex management scenarios arising in the care of children with KD,
spanning acute scenarios (such as emergency thrombolysis, calculation of coronary Z scores,
long-term follow-up strategies and transition to adult care) were beyond the scope of the
SHARE process but are covered elsewhere.[3, 5]

Conclusions
The SHARE recommendations provide international, evidence-based consensus
recommendations for the diagnosis and treatment of KD in children, facilitating improvement
and uniformity of care. A total of 17 recommendations for diagnosis, and 14 for treatment were
accepted with 100% agreement. In developing these recommendations, the importance of on-
going and future clinical trials/studies in KD was recognised to further improve the diagnosis,
treatment, and monitoring into adulthood of these patients.

18
Acknowledgements
We would like to thank all those who contributed to the SHARE initiative, and especially their
suggestions, advice and expertise to the paediatric systemic vasculitis workstream.

Contributors
NW and BV designed the SHARE initiative. NdG and NG performed the systematic literature
review, supervised by MWB and SK. Validity assessment of selected papers was done by SO,
PB, LM, AvR, DE and MT. Recommendations were formulated by NdG, NG, SK, PB, and MWB.
The expert committee consisted of PB, SO, TA, BB-M, PD, IK-P, PL, SDM, LM, CP, AvR, YU,
NW, SK and MWB; they completed the online surveys and/or participated in the subsequent
consensus meetings. NdG, NG, SK and MWB prepared, and NdG and NG chaired the
consensus meetings and took minutes. AR and BF facilitated the consensus procedure using
nominal group technique. NdG, DE, SK, PB and MWB wrote the manuscript, with contribution
and approval of all co-authors. PB supported and MWB oversaw all aspects as senior authors.

19
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