645391

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Hindawi Publishing CorporationInternational Journal o PediatricsVolume 983090983088983089983091 Article ID 983094983092983093983091983097983089 983095 pageshttpdxdoiorg983089983088983089983089983093983093983090983088983089983091983094983092983093983091983097983089

Review ArticleKawasaki Disease A Clinicianrsquos Update

Nathan Jamieson1 and Davinder Singh-Grewal2

983089 School of Womenrsquos and Childrenrsquos Health University of New South Wales Sydney NSW 983090983088983093983090 Australia983090 Te Sydney Childrenrsquos Hospitals Network Randwick and Westmead Campuses Sydney NSW Australia

Correspondence should be addressed to Nathan Jamieson z983091983091983095983093983096983089983096zmailunsweduau

Received 983092 August 983090983088983089983091 Accepted 983092 September 983090983088983089983091

Academic Editor Joel R Rosh

Copyright copy 983090983088983089983091 N Jamieson and D Singh-Grewal Tis is an open access article distributed under the Creative CommonsAttribution License which permits unrestricted use distribution and reproduction in any medium provided the original work isproperly cited

Aims Kawasaki disease is an acute systemic vasculitis and is the most common cause o acquired heart disease in children inthe developed world Tis review aims to synthesise recent insights into the disease and provide an update or clinicians ondiagnostic and treatment practices Methods We conducted a review o the literature exploring epidemiology aetiology diagnosisandmanagement o Kawasaki disease We searched MEDLINE Medline In-Process Embase Google Scholar and reerence lists o relevant articles Conclusions Kawasaki disease is a ebrile vasculitis which progresses to coronary artery abnormalities in 983090983093 o untreated patients Te disease is believed to result rom a genetically susceptible individualrsquos exposure to an environmental triggerIncidence is rising worldwide and varies widely across countries and within different ethnic groups Diagnosis is based on thepresence o ever in addition to our out o 1047297ve other clinical criteria but it is complicated by the quarter o the Kawasaki diseasepatients with ldquoincompleterdquo presentation reatment with intravenous immunoglobulin within ten days o ever onset improvesclinical outcomes and reduces the incidence o coronary artery dilation to less than 983093 Given its severe morbidity and potentialmortality Kawasaki disease should be considered as a potential diagnosis in cases o prolonged paediatric ever

1 Introduction

Kawasaki disease (KD) is an acute systemic vasculitis whichprogresses to cause coronary artery abnormalities in 983090983093o untreated patients [983089] It has surpassed rheumatic heart

disease as the leading cause o acquired cardiovasculardisease in children in the developed world [983090] Tough over983092983088 years have passed since its initial identi1047297cation in patientsby Kawasaki [983091] its aetiology remains largely unknown anda speci1047297c diagnostic test eludes researchers and cliniciansDiagnosis is based primarily on clinical criteria however thepresentation is incomplete in approximately 983090983093 o patientsandthis patient subset appears to be at a comparatively higherrisk o serious complications [983092] Coronary artery dilationand aneurysms can be prevented by timely administration o intravenous immunoglobulin a limited and costly resourceplacing an onus on practitioners to diagnose the diseasepromptly and accurately

2 Epidemiology

Kawasaki disease was shown to account or 983090983091 o allpaediatric vasculitides in a United States rheumatology clinicpopulation study and is the second most common multi-system vasculitis o inancy and childhood behind Henoch-

Schonlein purpura [983093ndash983095] Tough signi1047297cant differences inepidemiological distribution have been observed worldwide[983096] a number o actors appear relatively constant Teseinclude a male predominance with a male-to-emale ratioo between 983089983093983089 and 983090983089 [983097ndash983089983089] marked seasonality withheightened incidence in winter and early spring in temperateclimates [983089983090] and summer peaks in some Asian countries [983089983091]approximately 983095983093 o cases occurring in children under 983093years o age [983089983088 983089983092] and a heightened incidence in people o Asian descent both inside and outside Asia [983089983093ndash983089983095] A risingincidence has been observed worldwide over time perhapsdue to heightened awareness and recognition o the disease[983096 983089983088 983089983092 983089983096]

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983090 International Journal o Pediatrics

3 Aetiology

Determining the exact nature o the causative mechanismbehind KD remains an area o controversy unresolvedsince Kawasaki 1047297rst described the condition in 983089983097983094983095 [983091]It is hypothesised that KD results rom the exposure o agenetically predisposed individual to an as-yet unidenti1047297edpossibly inectious environmental trigger [983094] As such thediscussion o potential genetic and environmental aetiologiesshould be viewed as complementary rather than con1047298ictingtheories

983091983089 Genetic Aspect of Aetiology Te epidemiology o thecondition suggests that Mendelian inheritance is not at play in determining KD susceptibility Epidemiological data isstrongly suggestive o a genetic component to aetiology withstudies worldwide reporting ocal heightened incidence inchildren o East Asian origin While the highest incidence o KD is observed in Japan this incidence is matched in NorthAmerica by Japanese-American children with an incidence

o 983090983089983088983093983089983088983088983088983088983088 Tis trend is also present in children o Paci1047297c Islander native Hawaiian and Korean descent [983089983093 983089983097983090983088] A genetic predisposition is also supported by the higherrelative risk o KD within amilies whereby siblings o a KDpatient are at a 983089983088-old higher risk o KD compared to thegeneral population [983089983094 983090983089]

Linkage analysis and genome-wide association studieshave identi1047297ed several single nucleotide polymorphisms thatshow an association with genetic susceptibility to KD woprominent discoveries include unctional polymorphismso the FC gamma RIIa locus and the IPKC gene whichhave been shown to predispose individuals in Japan andNorth America to KD and the subsequent development o

coronary artery aneurysms [983089983094 983090983090 983090983091] Te IPKC geneis a -cell activity modulator and its identi1047297cation as asusceptibility gene suggests that -cell activity regulation may be an underlying mechanism in determining predispositionto and severity o the disease course [983090983092]

983091983090 Environmental Aspect of Aetiology It is widely postulatedthat ollowing exposure to one or multiple environmentaltriggers in childhood the immune response in a smallgenetically susceptible patient subset maniests as systemic

vasculitis [983089983096] Tis hypothesis is supported by the abruptsymptomatic onset o KD the seasonal and temporal clus-tering o cases the spontaneous resolution o the disease

even without treatment in the majority o cases and thepredomination o IgA plasma cells at mucosal suraces in theimmune response common characteristics o the inectiousdiseases o childhood [983089983091 983090983090 983090983093 983090983094] Additionally KDoccurs principally between the ages o three months and 1047297veyears when susceptibility to ubiquitous inectious agents isat its highest Tis epidemiological clustering suggests thatmost adults have immunity to the causative agent ollowingexposure and transplacental antibodies protect newborninants [983089983095 983089983096 983090983095 983090983096]

It is possible that bacterial or viral inections super-antigens humoral actors or a combined superantigen-conventional peptide antigen response may underlie the

onset o the disease [983090983097 983091983088] though to date no aetiologicalagents have been con1047297rmed in studies [983094] Up to 983091983091 o KD patients have at least one concurrent inection at thetime o diagnosis but no correlation between a speci1047297c agentand the severity o the disease course has been identi1047297ed[983091983089] Tough the clinical and biochemical similarities seen

in KD and staphylococcal and streptococcal toxin-mediatedillnesses are suggestive o the involvement o a bacterial toxinin the disease aetiology Rowley et al [983091983090] have isolatedintracytoplasmic inclusion bodies in the ciliated bronchialepithelium o acute-stage KD sufferers suggesting insteadthat an intracellular viral pathogen is likely to be at workAn intrinsic autoimmune cause seems unlikely based oncurrent evidence given patientsrsquo lack o autoantibodies andthe spontaneous resolution and absence o recurrence seenin the condition [983090983092]

4 Diagnosis

983092983089 Clinical Course Te clinical course o KD consists o ourphases (983089) acute the period lasting 983089-983090 weeks i untreatedwhen the child has a spiking ofen remittent 983092983088∘ Celsius everand principal symptomatic eatures and may present withcardiac maniestations including valvitis pericarditis andmyocarditis (983090) subacute the approximately 983090 week periodollowing the abatement o ever when the child is at thegreatest risk o sudden death due to myocardial inarction(983091) convalescent the clinically invisible period ollowingthe cessation o symptoms and continuing until acute-phasereactants return to normal serum levels and (983092) chronicwhich describes patients who require ollow-up managementdue to coronary artery involvement [983089983089 983089983096 983091983091ndash983091983093] Diagnosis

should occur in the acute stage so that prompt treatment canbe administered to abate in1047298ammation and reduce the risk o coronary artery involvement in the later disease phases [983090]

983092983090 Diagnosis of Acute KD Tere is no speci1047297c diagnostictest available or KD to date [983091983094] Diagnosis is currently basedon clinical criteria as established by the Japanese Ministry o Health and adopted by the American Heart Association[983090] and is presented in able 983089 alongside the nonspeci1047297claboratory tests used to support the diagnosis Neither theclinical criteria nor laboratory eatures have been systemati-cally validatedas diagnostic tools [983091983095] andthe clinical criteriarely on the recognition o nonspeci1047297c symptoms that may not

be present in KD but can be present in a number o other vasculitides toxin-mediated illnesses viral exanthema andin1047298ammatory conditions [983090983097] Differential diagnoses or KDinclude Epstein-Barr virus adenovirus echovirus measlestoxic shock syndrome scarlet ever idiopathic juvenilearthritis polyarteritis nodosa Rocky Mountain spotted everleptospirosis juvenile mercury poisoning and adverse drugreactions including Stevens-Johnson syndrome [983090983097 983091983096 983091983097]

Tis dependence on clinical criteria is problematic giventhat the eatures o KD may maniest sequentially ratherthan simultaneously [983092983088] Te principal clinical 1047297ndings canbe accompanied by the multitude o symptoms that accom-pany ebrile vasculitides including arthritis gastrointestinal

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International Journal o Pediatrics 983091

983137983138983148983141 983089 Clinical diagnosiscriteria as determined by theAmericanHeart Association and laboratory criteria that may be used to help establishthe diagnosis

American Heart Association diagnostic clinical criteria [983090] Supplementary laboratory criteria

[983090 983091983092 983091983094 983092983089 983092983091]

Fever persisting gt983093 days plus at least our out o 1047297ve o the ollowing principaleatureslowast

(i) Changes in extremities including indurative angioedema and desquamation(ii) Polymorphous exanthema(iii) Bilateral bulbar conjunctival injection without exudate(iv) Changes to the lips and oral cavity including pharyngeal injection dry 1047297ssuredlips andor strawberry tongue(v) Acute nonpurulent cervical lymphadenopathy (gt983089983093 cm diameter)

(i) Albumin lt983091 gdL

(ii) C-reactive proteingt

983091 mg(iii) Erythrocyte sedimentation rate gt983092983088 mmh(iv) Elevated alanine aminotranserase(v) Leukocytosis white cell count gt983089983093983088983088983088mm(vi) Normochromic normocytic anaemia or age(vii) Sterile pyuria gt983089983088 white blood cellmm983091

lowastI less than our o the principal eatures are present but two-dimensional echocardiography detects coronary artery abnormalities patients are diagnosedwith incomplete KD [983090]

upset rhinorrhoea weakness extreme irritability hydropso the gallbladder and mild anterior uveitis all o whichmay contribute to misdiagnosis and treatment delay [983090 983092983089]Additional occasionally seen eatures such as pyuria andpleocytosis o the cerebrospinal 1047298uid can suggest that otherinectious processes underlie the presenting complaint anddelay diagnosis [983092983090] Tis variability in patient presentationplaces pressure on clinicians to consider KD in any case o prolonged and otherwise unexplained ever

Clinical diagnosis is hindered urther by the signi1047297cantsubset o patients who present with incomplete KD charac-terised as KD wherein less than our o the principal eaturesare present but laboratory results or echocardiography sug-gests the diagnosis o KD Patients less than 983089983090 months oldand children older than 1047297ve are more likely to present withincomplete KD [983091983095 983092983094] Tese patientswho make up approx-imately 983090983093 o the KD cohort [983092] are at a heightened risk

o experiencing coronary artery complications because theassociated higherrates o misdiagnosis may delay appropriatetreatment an issue compounded by their placement outsidethe typical KD age cohort [983092983088 983092983095 983092983096]

983092983091 Diagnostic Procedure for Cardiovascular Sequelae wo-dimensional echocardiography is undamental in the assess-ment o the coronary arteries ollowing the diagnosis o KDbased on the presence o the principal clinical eatures or i KD is suspected in a patient that otherwise does not ul1047297llthe diagnostic criteria Echocardiography is a sensitive andspeci1047297c means o detecting dilation ectasia or aneurysms inchildren [983092983095] though the use o mild sedative agents may be

required in younger children to ensure that the quality o theechocardiographic imaging is not compromised by excessivemovement Abnormal echocardiographs may show ectasiade1047297ned by a body-adjusted score o the dilation o the lefanterior descending or right coronary artery o 983090983093 or greateror by the presence o a segmental aneurysm [983090]

Aneurysms in children are classi1047297ed by the Ameri-can Heart Association as small (983093 mm internal diameter)medium (983093ndash983096 mm internal diameter) or giant (983096 mm internaldiameter) Te Japanese Ministry o Health criteria orassessing the coronary arteries are age dependent and statethat coronary arteries should be considered abnormal i theinternal lumen diameter measures greater than 983091 mm in

children under 983093 years or greater than 983092 mm in children o 983093 years i the internal diameter o a segment is 983089983093 timesthe diameter o an adjacent segment or i obvious lumenirregularities are present [983090] Giant coronary aneurysms arethe least likely to regress and have the highest associationwith progression to stenosis and myocardial inarction [983092983097]Regression is acilitated by smaller aneurysm size usiormmorphology and location in a distal coronary segment [983089983089]

5 Acute Phase Management

Te aim o acute phase management in KD is to reducein1047298ammation particularly coronary arteritis and myocardi-tis [983093983088] Tough the mechanisms underlying KD are notcompletely understood and the efficacy o intravenousimmunoglobulin (IVIG) as a 1047297rst-line treatment in acute-phase KD has been validated in a number o prospectivemulticentre treatment trials [983093983089 983093983090] Te American HeartAssociation recommends that patients be treated with asingle inusion o IVIG over twelve hours at a dosage o 983090 gkg within ten days o ever onset along with an anti-in1047298ammatory 983089983088983088 mgkgday dose o aspirin (acetylsalicylicacid) spread out over 983092 doses until the child is aebrile [983090]A recent Japanese randomised control trial ound that theaddition o 983090 mgkgday prednisolone to the standard IVIGregimen signi1047297cantly reduced adverse coronary outcomesthough these results have yet to be replicated in non-Japanesepopulations [983093983091]

While aspirin is a standard component o the treatmentregime worldwide evidence as to its bene1047297t is sparing o

date no sufficiently-powered randomised control trials haveproven the bene1047297t o aspirin versus placebo though it isbelieved to be o bene1047297t given its antiplatelet and anti-in1047298ammatory effects at high doses [983096 983093983092] However concernsabout the risks o high-dose aspirin administration includingaspirin toxicity Reyersquos syndrome and sensorineural hearingloss have led to adjustments to dosing practices in somecountries including Japan where the recommended acute-phase dose has been lowered to 983091983088ndash983093983088 mgkgday [983093983093]

imely administration o treatment is critical in pre- venting adverse coronary artery outcomes IVIG adminis-tered geten days afer ever onset acilitates a reduction inin1047298ammation but is ineffective in preventing coronary artery

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983092 International Journal o Pediatrics

983137983138983148983141 983090 Risk strati1047297cation based on degree o coronary artery involvement

Risk strati1047297cation in Kawasaki disease [983090 983090983095 983091983093 983092983092 983092983093]

Description Recommended action

Level 983089 No coronary artery changes detected at any stage No intervention required beyond 983096 weeks afer illness onset

Level 983090 Patient exhibits transient coronary dilation that

regresses within 983096 weeks No intervention required beyond 983096 weeks afer illness onset

Level 983091 Echocardiography locates an isolated small

aneurysm in 983089 coronary artery

(i) Long-term antiplatelet therapy with low-dose aspirin until regression(ii) Annual electrocardiogram (ECG) and echocardiograph(iii) Biennial stress test with myocardial perusion imaging i child gt983089983088years old(iv) Angiography i ischaemia is implicated

Level 983092 Echocardiography locates at least one large

coronary artery aneurysm

(i) Long-term antiplatelet therapy with low-dose aspirin(ii) Adjunctive wararin or heparin therapy (iii) Biennial echocardiograph and ECG(iv) Annual stress test(v) Cardiac catheterisation with coronary angiography within 983094ndash983089983090months and repeated i ischaemia is implicated

Level 983093

Coronary artery involvement has progressed to

coronary artery obstruction

(i) Long-term antiplatelet therapy with aspirin(ii) Adjunctive wararin or heparin therapy

(iii) Beta blockers to reduce myocardial oxygen consumption(iv) Biannual echocardiograph and ECG(v) Annual stress test

lesions [983093983094] Studies have also reported a higher rate o IVIGresistance i patients are treated beore the 1047297fh day o everthough it is unclear whether early treatment leads to pooreroutcomes or i patients that present with KD beore the 1047297fhday have a more severe orm o the disease [983091983094]

983093983089 IVIG Resistance Between 983089983089 and 983090983091 o patients may present with IVIG resistance diagnosed i a patient exhibits

persistent or recurrent ever at least 983091983094 hours afer the 1047297rstIVIG dose has been inused [983093983095 983093983096] IVIG resistance isproblematic because recalcitrant everis indicative o ongoingarteritis which places patients at a higher risk o developingcoronary artery aneurysms [983091983097] It is recommended thatreractory disease is 1047297rst treated with a second dose o IVIG983090 gkg though the efficacy o a number o other therapeuticoptions including intravenous corticosteroid pulse therapyanti-NF-alpha antibodies and cytotoxic agents is an ongo-ing area o research [983096 983089983089 983093983097]

983093983090 Aneurysm Management Aneurysm management in theacute phase o KD is an area o uncertainty and it is

recommended that a paediatric cardiologist be involvedin patient care and the development o an individualisedaction plan i echocardiography shows dilation or aneurysmo the coronary arteries afer diagnosis Te presence o coronary artery dilation necessitates the early involvemento a paediatric cardiologist requent echocardiography tomonitor the coronary arteries and long-term regular stressand perusion tests o the heart [983090983095 983094983088]

Percutaneous coronary intervention procedures are indi-cated in patients at high risk o ischaemia Tese proceduresinclude intracoronary thrombolysis balloon angioplastystent implantation and rotational ablation and should beperormed on patients presenting with either symptomatic

ischaemia laboratory 1047297ndings that suggest ischaemia orseverely stenotic lesions that appear likely to progress tocoronary artery ischaemia [983092983091 983094983088] Coronary artery bypasssurgery is indicated i angiography detects severely occlusivelesions or jeopardised collateral blood supply [983094983088 983094983089]

6 Chronic Phase Management

Te aim o chronic phase management is to prevent coronary artery occlusion and myocardial inarction through reducingplatelet aggregation and inhibiting thrombogenesis [983093983088 983094983088]Long-term treatment consists o antiplatelet aspirin doses o 983091ndash983093 mgkgday until a normal echocardiograph is seen at 983094ndash983096weeks [983089983096] I coronary artery abnormalities ail to regress by this time long-term pharmacological therapy and diagnosticollowup are implicated (able 983090)

Patients with coronary artery involvement require long-term antiplatelet doses o aspirin In addition to this systemicanticoagulation therapy with wararin or low molecularweightheparin (LMWH) is indicatedin patients with giant ormultiple large aneurysmsLMHW is more likely to contributeto a statistically signi1047297cation reduction in the coronary artery

score and is less likely to result in severe bleeding making ita viable option or young patients with severe coronary artery involvement [983094983090] Children who have experienced Kawasakidisease and acute phase coronary artery involvement shouldreduce exposure to atherosclerosis risk actors includingobesity hyperlipidaemia and smoking [983094983088]

It is important that immunisations be delayed in childrenwho have received treatment with IVIG as this treatmentblocks the acquisition o active immunity by preventing thereplication o live viral vaccines Official recommendationsstate that immunisations should be delayed by 983089983089 months[983090] Inactive immunisations are unaffected by serum IVIG[983094983091 983094983092]

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International Journal o Pediatrics 983093

7 Clinical Outcomes

Possible outcomes or KD include (983089) resolution withoutcardiac sequelae (983090) the development o coronary artery abnormalities o which approximately 983094983088 regress in a year(983091) cardiac involvement including myocarditis aneurysmthrombosis cardiac dysrhythmia or myocardial inarctionand (983092) KD recurrence in 983091 o patients [983089 983094983093 983094983094]

Prior to the discovery o IVIG as a sae and efficacioustreatment 983090983088ndash983091983088 o cases progressed to coronary artery dilation with a 983090 mortality rate [983094983095 983094983096] I treated withIVIG within ten days o ever onset transient coronary artery dilation only develops in 983091ndash983093 o children and giantaneurysms develop in 983089 [983094983096] Factors that predispose KDpatients to cardiovascular sequelae include a longer durationo ever prior to treatment low serum albumin upon hospitaladmission (lt983091gL) [983097 983094983097] age under 983089 year or over 983093 years[983090983097 983095983088 983095983089] and presentation with IVIG resistance [983095983089] orincomplete KD [983095983090]

A conceivable long-term implication or otherwise

healthy KD survivors is the potential or acceleratedatherosclerosis development Only a small number o post-mortem cadavers have been available or study though itappears that endothelial dysunction and coronary artery scarring are present in patients with coronary artery involve-ment Despite the presence o histopathological abnormali-ties upon biopsy o the myocardium long-term contractility appears normal in patients affected by transient myocarditisduring KD [983090] However increased arterial stiffness sec-ondary to 1047297brotic changes within the arterial wallis indicativeo an increased risk o developing atherosclerosis which willlikely become apparent as the 1047297rst cohort o identi1047297ed KDpatients approaches middle age [983093983090 983095983091]

8 Conclusion

KD is a disease associated with signi1047297cant morbidity andpotential mortality yet no speci1047297c diagnostic test is availableIncreased physician awareness o the principal eatures o KD and appropriate use o echocardiography have togetherimproved patient outcomes through acilitating timely treat-ment but incomplete presentations complicate diagnosis andare associated with signi1047297cantly worse coronary outcomesGiven the severe consequences o late diagnosis the imme-diate bene1047297ts offered by available therapies including IVIGandthe rising incidence o KD worldwide it is important thatneonatal and paediatric clinicians consider KD as a diagnosisin cases o prolonged paediatric ever

References

[983089] H Kato Sugimura Akagi et al ldquoLong-term consequenceso Kawasaki disease a 983089983088- to 983090983089-year ollow-up study o 983093983097983092patientsrdquo Circulation vol 983097983092 no 983094 pp 983089983091983095983097ndash983089983091983096983093 983089983097983097983094

[983090] J W Newburger M akahashi M A Gerber et al ldquoDiagnosistreatment and long-term management o Kawasaki diseasea statement or health proessionals rom the committee onrheumaticever endocarditis and Kawasaki disease council on

cardiovascular disease in the young american heart associa-tionrdquo Pediatrics vol 983089983089983092 no 983094 pp 983089983095983088983096ndash983089983095983091983091 983090983088983088983092

[983091] Kawasaki ldquoAcute ebrile mucocutaneous syndrome with lym-phoid involvement with speci1047297c desquamation o the 1047297ngersand toes in childrenrdquo Arerug ı vol 983089983094 no 983091 pp 983089983095983096ndash983090983090983090 983089983097983094983095

[983092] C Manlhiot E Christie B W McCrindle H RosenbergN Chahal and R S M Yeung ldquoComplete and incompleteKawasaki disease twosides o the same coinrdquo European Journal of Pediatrics vol 983089983095983089 no 983092 pp 983094983093983095ndash983094983094983090 983090983088983089983090

[983093] K ullus and S D Marks ldquoVasculitis in children and adoles-cents clinical presentation etiopathogenesis and treatmentrdquoPediatric Drugs vol 983089983089 no 983094 pp 983091983095983093ndash983091983096983088 983090983088983088983097

[983094] C Galeotti J Bayry I Kone-Paut and S V Kaveri ldquoKawasakidisease aetiopathogenesisand therapeutic utility o intravenousimmunoglobulinrdquo Autoimmunity Reviews vol 983097 no 983094 pp 983092983092983089ndash983092983092983096 983090983088983089983088

[983095] S Bowyer and P Roettcher ldquoPediatric rheumatology clinicpopulations in the United States a 983091 year surveyrdquo Journal of Rheumatology vol 983090983091 no 983089983089 pp 983089983097983094983096ndash983089983097983095983092 983089983097983097983094

[983096] N J Luca and R S Yeung ldquoEpidemiology and management o

Kawasaki diseaserdquo Drugs vol 983095983090 no 983096 pp 983089983088983090983097ndash983089983088983091983096 983090983088983089983090[983097] D Singh-Grewal M Wong and D Isaacs ldquoDiagnosis treat-

ment and outcome o Kawasaki disease in an Australian tertiary setting a reviewo three years experiencerdquo Journalof Paediatricsand Child Health vol 983092983089 no 983097-983089983088 pp 983092983097983093ndash983092983097983097 983090983088983088983093

[983089983088] Y Lin C Manlhiot J C Y Ching et al ldquoRepeated systematicsurveillance o Kawasaki disease in Ontario rom 983089983097983097983093 to 983090983088983088983094rdquoPediatrics International vol 983093983090 no 983093 pp 983094983097983097ndash983095983088983094 983090983088983089983088

[983089983089] R Gerding ldquoKawasaki disease a reviewrdquo Journal of PediatricHealth Care vol 983090983093 no 983094 pp 983091983095983097ndash983091983096983095 983090983088983089983089

[983089983090] R-K R Chang ldquoHospitalizations or Kawasaki disease amongchildren in the United States 983089983097983096983096ndash983089983097983097983095rdquo Pediatrics vol 983089983088983097 no983094 p e983096983095 983090983088983088983090

[983089983091] D Burgner and A Harnden ldquoKawasaki disease what is the

epidemiology telling us about the etiologyrdquo International Journal of Infectious Diseases vol 983097 no 983092 pp 983089983096983093ndash983089983097983092 983090983088983088983093

[983089983092] R Uehara and E D Belay ldquoEpidemiology o Kawasaki diseasein Asia Europe and the United Statesrdquo Journal of Epidemiology vol 983090983090 no 983090 pp 983095983097ndash983096983093 983090983088983089983090

[983089983093] Y Nakamura M Yashiro R Uehara et al ldquoEpidemiologiceatures o Kawasaki disease in Japan results o the 983090983088983088983097-983090983088983089983088nationwide surveyrdquo Journal of Epidemiology vol 983090983090 no 983091 pp983090983089983094ndash983090983090983089 983090983088983089983090

[983089983094] J C Burns and J W Newburger ldquoGenetics insights into thepathogenesis o Kawasaki diseaserdquo Circulation Cardiovascular Genetics vol 983093 no 983091 pp 983090983095983095ndash983090983095983096 983090983088983089983090

[983089983095] J C Burns and M P Glode ldquoKawasaki syndromerdquo Te Lancet

vol 983091983094983092 no 983097983092983091983091 pp 983093983091983091ndash983093983092983092 983090983088983088983092[983089983096] A Harnden M akahashi and D Burgner ldquoKawasaki diseaserdquoBMJ vol 983091983091983096 p b983089983093983089983092 983090983088983088983097

[983089983097] R P Sundel and R E Petty ldquoKawasaki diseaserdquo in extbookof Pediatric Rheumatology J Cassidy R E Petty R MLaxer and C B Lindsley Eds pp 983093983088983093ndash983093983090983088 Elsevier SaundersPhiladelphia Pa USA 983094th edition 983090983088983089983089

[983090983088] R C Holman K Y Christensen E D Belay et al ldquoRacialethnic differences in the incidence o Kawasaki syndromeamong children in Hawaiirdquo Hawaii Medical Journal vol 983094983097 no983096 pp 983089983097983092ndash983089983097983095 983090983088983089983088

[983090983089] Y Onouchi ldquoGenetics o Kawasaki disease what we know anddonrsquot knowrdquo Circulation Journal vol 983095983094 no 983095 pp 983089983093983096983089ndash983089983093983096983094983090983088983089983090

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983094 International Journal o Pediatrics

[983090983090] A H Rowley ldquoKawasaki disease novel insights into etiology and genetic susceptibilityrdquo Annual Review of Medicine vol 983094983090pp 983094983097ndash983095983095 983090983088983089983089

[983090983091] Y Onouchi Gunji J C Burns et al ldquoIPKC unctionalpolymorphism associated with Kawasaki disease susceptibility and ormation o coronary artery aneurysmsrdquo Nature Genetics vol 983092983088 no 983089 pp 983091983093ndash983092983090 983090983088983088983096

[983090983092] R S Yeung ldquoKawasaki disease update on pathogenesisrdquo Cur-rent Opinion in Rheumatology vol 983090983090 no 983093 pp 983093983093983089ndash983093983094983088 983090983088983089983088

[983090983093] A H Rowley and S Shulman ldquoPathogenesis and man-agement o Kawasaki diseaserdquo Expert Review of Anti-InfectiveTerapy vol 983096 no 983090 pp 983089983097983095ndash983090983088983091 983090983088983089983088

[983090983094] A H Rowley ldquoCan a systems biology approach unlock themysterieso Kawasakidiseaserdquo Wiley Interdisciplinary ReviewsSystems Biology and Medicine vol 983093 no 983090 pp 983090983090983089ndash983090983090983097 983090983088983089983091

[983090983095] G S Pinna D A Kaetzis O I selkas and C L SkevakildquoKawasaki disease an overviewrdquo Current Opinion in InfectiousDiseases vol 983090983089 no 983091 pp 983090983094983091ndash983090983095983088 983090983088983088983096

[983090983096] J C Burns D R Cayan G ong et al ldquoSeasonality andtemporal clustering o Kawasaki syndromerdquo Epidemiology vol

983089983094 no 983090 pp 983090983090983088ndash983090983090983093 983090983088983088983093[983090983097] P F Weiss ldquoPediatric vasculitisrdquo Pediatric Clinics of North

America vol 983093983097 no 983090 pp 983092983088983095ndash983092983090983091 983090983088983089983090

[983091983088] R S M Yeung ldquoTe etiology o Kawasaki disease a superanti-gen-mediated processrdquo Progress in Pediatric Cardiology vol 983089983097no 983090 pp 983089983089983093ndash983089983090983090 983090983088983088983092

[983091983089] S M Benseler B W McCrindle E D Silverman P N yrrellJ Wong and R S M Yeung ldquoInections and Kawasaki diseaseimplications or coronary artery outcomerdquo Pediatrics vol 983089983089983094no 983094 pp e983095983094983088ndashe983095983094983094 983090983088983088983093

[983091983090] A H Rowley S C Baker S Shulman et al ldquoRNA-containingcytoplasmic inclusion bodies in ciliated bronchial epitheliummonths to years afer acute Kawasaki diseaserdquo PLoS ONE vol983091 no 983090 Article ID e983089983093983096983090 983090983088983088983096

[983091983091] L Wood and R ulloh ldquoKawasaki disease diagnosis manage-ment and cardiac sequelaerdquo Expert Review of Cardiovascular Terapy vol 983093 no 983091 pp 983093983093983091ndash983093983094983089 983090983088983088983095

[983091983092] Endocarditis Council on Cardiovascular Disease in theYoung Committee on Rheumatic Fever and Endocarditis andKawasaki Disease American Heart Association ldquoDiagnosticguidelines or Kawasaki diseaserdquo Circulation vol 983089983088983091 no 983090 pp983091983091983093ndash983091983091983094 983090983088983088983089

[983091983093] J B Gordon A M Kahn and J C Burns ldquoWhen childrenwith Kawasaki disease grow up Myocardial and vascularcomplications in adulthoodrdquo Journal of the American College of Cardiology vol 983093983092 no 983090983089 pp 983089983097983089983089ndash983089983097983090983088 983090983088983088983097

[983091983094] H-C Kuo K D Yang W-C Chang L-P Ger and K-S Hsieh

ldquoKawasaki disease an update on diagnosis and treatmentrdquoPediatrics and Neonatology vol 983093983091 no 983089 pp 983092ndash983089983089 983090983088983089983090

[983091983095] S R JohnsonO N Goek DSingh-Grewal et al ldquoClassi1047297cationcriteria in rheumatic diseases a review o methodologic prop-ertiesrdquo Arthritis and Rheumatism vol 983093983095 no 983095 pp 983089983089983089983097ndash983089983089983091983091983090983088983088983095

[983091983096] R Scuccimarri ldquoKawasaki diseaserdquo Pediatric Clinics of North America vol 983093983097 no 983090 pp 983092983090983093ndash983092983092983093 983090983088983089983090

[983091983097] J Newburger ldquoKawasaki diseaserdquo in Pediatric Cardiology chap-ter 983090983093 pp 983089983088983094983095ndash983089983088983095983096 983090983088983089983088

[983092983088] R Sittiwangkul Y Pongprot S Silvilairat and C PhornphutkulldquoDelayed diagnosis o Kawasaki disease risk actors and out-come o treatmentrdquo Annals of ropical Paediatrics vol 983091983089 no 983090pp 983089983088983097ndash983089983089983092 983090983088983089983089

[983092983089] A L Baker M Lu L L Minich et al ldquoAssociated symptomsin the ten days beore diagnosis o Kawasaki diseaserdquo Journal of Pediatrics vol 983089983093983092 no 983092 pp 983093983097983090ndash983093983097983093 983090983088983088983097

[983092983090] M Ayusawa Sonobe S Uemura et al ldquoRevision odiagnosticguidelines or Kawasaki disease (the 983093th revised edition)rdquoPediatrics International vol 983092983095 no 983090 pp 983090983091983090ndash983090983091983092 983090983088983088983093

[983092983091] G M Satou J Giamelli and M H Gewitz ldquoKawasaki diseasediagnosis management and long-term implicationsrdquo Cardiol-ogy in Review vol 983089983093 no 983092 pp 983089983094983091ndash983089983094983097 983090983088983088983095

[983092983092] M H Wu H C Chen S J Yeh M Lin S C Huang andS K Huang ldquoPrevalence and the long-term coronary riskso patients with Kawasaki disease in a general population iexcl983092983088years a national database studyrdquo Circulation Cardiovascular Quality and Outcomes vol 983093 no 983092 pp 983093983094983094ndash983093983095983088 983090983088983089983090

[983092983093] L E Wood and R M R ulloh ldquoKawasaki disease in childrenrdquoHeart vol 983097983093 no 983089983088 pp 983095983096983095ndash983095983097983090 983090983088983088983097

[983092983094] A Kentsis A Shulman S Ahmed et al ldquoUrine proteomics ordiscovery o improved diagnostic markers o Kawasaki diseaserdquoEMBO Molecular Medicine vol 983093 no 983090 pp 983090983089983088ndash983090983090983088 983090983088983089983091

[983092983095] J J Yu ldquoDiagnosis o incomplete Kawasaki diseaserdquo Korean

Journal of Pediatrics vol 983093983093 no 983091 pp 983096983091ndash983096983095 983090983088983089983090[983092983096] M S Wilder L A Palinkas A S Kao JF Bastian C L urnerand J C Burns ldquoDelayed diagnosis by physicians contributesto the development o coronary artery aneurysms in childrenwith Kawasaki syndromerdquo Pediatric Infectious Disease Journal vol 983090983094 no 983091 pp 983090983093983094ndash983090983094983088 983090983088983088983095

[983092983097] N E Manghat G J Morgan-Hughes I D Cox and C ARoobottom ldquoGiant coronary artery aneurysm secondary toKawasaki disease diagnosis in an adult by multi-detector row C coronary angiographyrdquo Te British Journal of Radiology vol983095983097 no 983097983092983094 pp e983089983091983091ndashe983089983091983094 983090983088983088983094

[983093983088] N Paredes Mondal L R Brandao and A K C Chan ldquoMan-agement o myocardial inarction in children with Kawasakidiseaserdquo Blood Coagulation and Fibrinolysis vol 983090983089 no 983095 pp

983094983090983088ndash983094983091983089 983090983088983089983088[983093983089] H Muta M Ishii K Egami et al ldquoEarly intravenous gamma-

globulin treatment or Kawasaki disease the nationwide sur- veys in Japanrdquo Journal of Pediatrics vol 983089983092983092 no 983092 pp 983092983097983094ndash983092983097983097983090983088983088983092

[983093983090] R M Oates-Whitehead J H Baumer L Haines et al ldquoIntra- venous immunoglobulin or the treatment o Kawasaki diseasein childrenrdquo Te Cochrane Database of Systematic Reviews no983092 Article ID CD983088983088983092983088983088983088 983090983088983088983091

[983093983091] Kobayashi Saji Otani et al ldquoEfficacy o immunoglob-ulin plus prednisolone or prevention o coronary artery abnormalities in severe Kawasaki disease (RAISE study) arandomised open-label blinded-endpoints trialrdquo Te Lancet vol 983091983095983097 no 983097983096983090983094 pp 983089983094983089983091ndash983089983094983090983088 983090983088983089983090

[983093983092] J H Baumer S J Love A Gupta L C Haines I Maconochieand J S Dua ldquoSalicylate or the treatment o Kawasaki diseasein childrenrdquo Cochrane Database of Systematic Reviews no 983092Article ID CD983088983088983092983089983095983093 983090983088983088983094

[983093983093] K-S Hsieh K-P Weng C-C Lin -C Huang C-L Lee andS-M Huang ldquoreatment o acute Kawasaki disease aspirinrsquosrole in the ebrile stage revisitedrdquo Pediatrics vol 983089983089983092 no 983094 ppe983094983096983097ndashe983094983097983091 983090983088983088983092

[983093983094] H Muta M Ishii M Yashiro R Uehara and Y NakamuraldquoLate intravenous immunoglobulin treatment in patients withKawasaki diseaserdquo Pediatrics vol 983089983090983097 no 983090 pp e983090983097983089ndashe983090983097983095 983090983088983089983090

[983093983095] C A Wallace J W French S J Kahn and D D Sherry ldquoIni-tial intravenous gammaglobulin treatment ailure in Kawasakidiseaserdquo Pediatrics vol 983089983088983093 no 983094 p E983095983096 983090983088983088983088

7252019 645391

httpslidepdfcomreaderfull645391 78

International Journal o Pediatrics 983095

[983093983096] K Durongpisitkul J Soongswang D Laohaprasitiporn ANana C Prachuabmoh and C Kangkagate ldquoImmunoglobulinailure and retreatment in Kawasaki diseaserdquo Pediatric Cardiol-ogy vol 983090983092 no 983090 pp 983089983092983093ndash983089983092983096 983090983088983088983091

[983093983097] A Coustasse J Larry and D Lee ldquoCan Kawasaki disease bemanagedrdquo Te Permanente Journal vol 983089983094 no 983090 pp 983095983088ndash983095983090983090983088983089983090

[983094983088] J J W G JCS Joint Working Group ldquoGuidelines or diagnosisand management o cardiovascular sequelae in Kawasaki dis-ease (JCS 983090983088983088983096)mdashdigest versionrdquo Circulation Journal vol 983095983092no 983097 pp 983089983097983096983097ndash983090983088983090983088 983090983088983089983088

[983094983089] R Fukazawa and S Ogawa ldquoLong-term prognosis o patientswith Kawasaki disease at risk or uture atherosclerosisrdquo Journal of Nippon Medical School vol 983095983094 no 983091 pp 983089983090983092ndash983089983091983091983090983088983088983097

[983094983090] C Manlhiot L R Brandao Z Somji et al ldquoLong-term anti-coagulation in Kawasaki disease initial use o low molecularweight heparin is a viable option or patients with severecoronary artery abnormalitiesrdquo Pediatric Cardiology vol 983091983089 no983094 pp 983096983091983092ndash983096983092983090 983090983088983089983088

[983094983091] P A Brogan M J Dillon A Bose et al ldquoKawasaki disease anevidence based approach to diagnosis treatment and proposalsor uture researchrdquo Archives of Disease in Childhood vol983096983094no983092 pp 983090983096983094ndash983090983097983088 983090983088983088983090

[983094983092] K B Dummer and J W Newburger ldquoAcute management o Kawasaki diseaserdquo Progress in Pediatric Cardiology vol 983089983097 no983090 pp 983089983090983097ndash983089983091983093 983090983088983088983092

[983094983093] A M Fimbres andS Shulman ldquoKawasaki diseaserdquo Pediatricsin Review vol 983090983097 no 983097 pp 983091983088983096ndash983091983089983094 983090983088983088983096

[983094983094] M akahashi W Mason and A B Lewis ldquoRegression o coronary aneurysms in patients with Kawasaki syndromerdquoCirculation vol 983095983093 no 983090 pp 983091983096983095ndash983091983097983092 983089983097983096983095

[983094983095] A S Dajani K A aubert M A Gerber et al ldquoDiagnosis andtherapy o Kawasaki disease in childrenrdquo Circulation vol 983096983095 no

983093 pp 983089983095983095983094ndash983089983095983096983088 983089983097983097983091

[983094983096] H Kato Akagi Sugimura et al ldquoKawasaki diseaserdquoCoronary Artery Disease vol 983094 no 983091 pp 983089983097983092ndash983090983088983094 983089983097983097983093

[983094983097] H-C Kuo C-DLiangC-L Wang H-R Yu K-P Hwang andK D Yang ldquoSerum albumin level predicts initial intravenousimmunoglobulin treatment ailure in Kawasaki diseaserdquo ActaPaediatrica vol 983097983097 no 983089983088 pp 983089983093983095983096ndash983089983093983096983091 983090983088983089983088

[983095983088] V E A Honkanen B W McCrindle R M Laxer B MFeldman R Schneider and E D Silverman ldquoClinical relevanceo therisk actors or coronary artery in1047298ammation in Kawasakidiseaserdquo Pediatric Cardiology vol 983090983092 no 983090 pp 983089983090983090ndash983089983090983094 983090983088983088983091

[983095983089] S R Dominguez M S Anderson M El-Adawy and MP Glode ldquoPreventing coronary artery abnormalities a need

or earlier diagnosis and treatment o Kawasaki diseaserdquo TePediatric Infectious Disease Journal vol 983091983089no 983089983090 pp 983089983090983089983095ndash983089983090983090983088983090983088983089983090

[983095983090] E S Yellen K Gauvreau M akahashi et al ldquoPerormanceo 983090983088983088983092 american heart association recommendations or treat-ment o Kawasaki diseaserdquo Pediatrics vol 983089983090983093 no 983090 pp e983090983091983092ndashe983090983092983089 983090983088983089983088

[983095983091] H obayama K akahashi H Fukunaga et al ldquoAnalysis o arterial unction in adults with a history o Kawasaki diseaserdquo Journal of Cardiology vol 983094983089 no 983093 pp 983091983091983088ndash983091983091983093 983090983088983089983091

7252019 645391

httpslidepdfcomreaderfull645391 88

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