Kawasaki DiseaseKawasaki Disease

Androu WaheebAndrou WaheebRCSI-Bahrain Medical StudentRCSI-Bahrain Medical Student

Acknowledgement:Acknowledgement:

Dr. Brian McCrindle at the Hospital for Sick Dr. Brian McCrindle at the Hospital for Sick Children, TorontoChildren, Toronto

HistoryHistory

Tomisaku Kawasaki, Red Cross Hospital, Tomisaku Kawasaki, Red Cross Hospital, Tokyo, Japan (Jan 1961)Tokyo, Japan (Jan 1961)

Alternative NamesAlternative Names lymph node syndromelymph node syndromeMucocutaneous lymph node syndromeMucocutaneous lymph node syndromeKawasaki syndromeKawasaki syndrome

Syndrome ?!Syndrome ?!

DefinitionDefinition

Auto-immune mediated vasculitisAuto-immune mediated vasculitisMedium sized arteriesMedium sized arteriesFavours coronary arteriesFavours coronary arteries

EpidemiologyEpidemiology85% younger than 5 years85% younger than 5 yearsUncommon in 1 year < age < 5 yearsUncommon in 1 year < age < 5 yearsMale:female ratio 1.6:1Male:female ratio 1.6:12-52-5

Increased prevalence in Asian decent Increased prevalence in Asian decent (10x)(10x)Japan highest (2006: 188.1/100k < 4 yo)Japan highest (2006: 188.1/100k < 4 yo)66

Korea 2Korea 2ndnd (2005: 104.6/100k < 5 yo) (2005: 104.6/100k < 5 yo)77

Vs USA (2000:17.1/100k < 5 yo)Vs USA (2000:17.1/100k < 5 yo)88

Epidemiology cont’dEpidemiology cont’d

Average recurrence 3%Average recurrence 3%Average sibling occurrence 1%Average sibling occurrence 1%Average mortality < 1%Average mortality < 1%Racial DemographicRacial Demographic

Asian and Pacific Island descent >Asian and Pacific Island descent >non-Hispanic African-American >non-Hispanic African-American >Hispanics >Hispanics >CaucasianCaucasian

AetiologyAetiology

Unknown: infectious patternUnknown: infectious patternVirusVirusBacterial (superantigenic toxin vs. Bacterial (superantigenic toxin vs.

conventional antigen)conventional antigen)GeneticsGeneticsAuto-immuneAuto-immune

6 cardinal symptoms/signs6 cardinal symptoms/signs

1.1. FeverFever• ≥ ≥ 5 days5 days• ≥ ≥ 4040ooCC• self-remittingself-remitting• onsetonset

2.2. Non-purulent bilateral conjunctivitisNon-purulent bilateral conjunctivitis• Onset after feverOnset after fever

6 cardinal symptoms/signs cont’d6 cardinal symptoms/signs cont’d

3.3. Oromucosal changesOromucosal changes• LipsLips

RedRed CrackedCracked BleedingBleeding SwollenSwollen

• Strawberry tongueStrawberry tongue

4.4. Erythematous rashErythematous rash• TruncalTruncal peripheral extremities peripheral extremities

6 cardinal symptoms/signs cont’d6 cardinal symptoms/signs cont’d

5.5. Changes in extremitiesChanges in extremities• Erythema of hands and feetErythema of hands and feet

a/w paina/w pain a/w brawny oedema dorsum of handa/w brawny oedema dorsum of hand

• Desquamation of fingers and toesDesquamation of fingers and toes

6 cardinal symptoms/signs cont’d6 cardinal symptoms/signs cont’d

6.6. Cervical lymphadenopathyCervical lymphadenopathy• Least commonLeast common• ≥ ≥ 1 lymph node, ≥ 1.5 cm in diameter1 lymph node, ≥ 1.5 cm in diameter• UnilateralUnilateral• Anterior cervical triangleAnterior cervical triangle

Diagnostics Diagnostics

No specific diagnosis or testNo specific diagnosis or testUse clinical presentationUse clinical presentationNot always simultaneousNot always simultaneous

Diagnostic CriteriaDiagnostic Criteria

Japanese MOHJapanese MOHComplete KDComplete KD

Fever + 5/6 cardinal symptomsFever + 5/6 cardinal symptoms

Incomplete KDIncomplete KDFever + 4/6 cardinal symptomsFever + 4/6 cardinal symptoms+ evidence of coronary artery abnormality+ evidence of coronary artery abnormality

Echo:Echo: ≥ ≥ 3mm ≤ 5 yo; ≥ 4mm ≥ 5 yo3mm ≤ 5 yo; ≥ 4mm ≥ 5 yo Internal diameter >1.5 x from adjacent segmentInternal diameter >1.5 x from adjacent segment

More common in younger childrenMore common in younger children

CardiacCardiac Findings Findings Prominent in the acute phaseProminent in the acute phase leading cause of long-term morbidity and leading cause of long-term morbidity and

mortality. mortality.

Involvement ofInvolvement of1.1. PericardiumPericardium2.2. MyocardiumMyocardium3.3. EndocardiumEndocardium4.4. ValvesValves5.5. Coronary arteriesCoronary arteries

CardiacCardiac Findings cont’d Findings cont’d

Cardiac auscultationCardiac auscultation hyperdynamic precordiumhyperdynamic precordium TachycardiaTachycardia a gallop rhythma gallop rhythm innocent flow murmurinnocent flow murmur

AnemiaAnemia FeverFever depressed myocardial contractility (myocarditis)depressed myocardial contractility (myocarditis)

significant MR significant MR pansystolic regurgitation pansystolic regurgitation murmur murmur

low cardiac output syndrome or shock (poor low cardiac output syndrome or shock (poor myocardial function)myocardial function)

Non-Cardiac FindingsNon-Cardiac Findings increased irritability vs. other febrile increased irritability vs. other febrile

diseasesdiseasesArthritis or arthralgia (first week)Arthritis or arthralgia (first week)

multiple jointsmultiple joints favours knees and ankles.favours knees and ankles.

Gastrointestinal complaints (33%)Gastrointestinal complaints (33%)DiarrhoeaDiarrhoeaVomitingVomitingabdominal pain, occur in approximatelyabdominal pain, occur in approximately

Non-Cardiac Findings cont’dNon-Cardiac Findings cont’d

Hepatic enlargement + jaundiceHepatic enlargement + jaundiceAcute acalculous gallbladder distensionAcute acalculous gallbladder distension

first two weeksfirst two weeksCause hydropsCause hydrops identified by abdominal ultrasoundidentified by abdominal ultrasound

Non-Cardiac Findings cont’dNon-Cardiac Findings cont’d

site of previous BCG erythema + site of previous BCG erythema + induration induration CommonCommonYounger than 1 yearYounger than 1 year

perianal erythematous desquamationperianal erythematous desquamation

Characteristic Lab FindingsCharacteristic Lab Findings acute stage (4-6w)acute stage (4-6w)

LeukocytosisLeukocytosis predominance of immature and mature granulocytespredominance of immature and mature granulocytes

Upregulated apoptosisUpregulated apoptosisDepleted peripheral lymphocytes.Depleted peripheral lymphocytes. AnemiaAnemia

RBC indices,RBC indices, particularly with a prolonged duration of active inflammation.particularly with a prolonged duration of active inflammation.

Elevated Acute Phase ReactantsElevated Acute Phase Reactants ESRESR CRPCRP

Platelet count rapidly increases week 2-3, (can be > Platelet count rapidly increases week 2-3, (can be > 1,000,000/mm1,000,000/mm33))

ANA and RF -veANA and RF -ve

Lab Findings cont’dLab Findings cont’d serum transaminases moderately elevatedserum transaminases moderately elevated HypoalbuminemiaHypoalbuminemia

a/w with increased severity + durationa/w with increased severity + duration Intermittent sterile pyuriaIntermittent sterile pyuria

(Urinalysis not suprapubic)(Urinalysis not suprapubic)urethritisurethritis CSF pleocytosis CSF pleocytosis

mononuclear cells predominancemononuclear cells predominance normal glucose and proteinnormal glucose and protein

Inflammatory synovial fluidInflammatory synovial fluid Decreased plasma cholesterol, HDL, Decreased plasma cholesterol, HDL,

apolipoprotein A-Iapolipoprotein A-I

TreatmentTreatment Conventional=IVIG + AspirinConventional=IVIG + Aspirin IVIGIVIG

Reduces the prevalence of coronary artery Reduces the prevalence of coronary artery abnormalitiesabnormalities

MOA unknown (neutralization of antigen or immune MOA unknown (neutralization of antigen or immune inhibition?)inhibition?)

2g/kg infusion 10-12 h2g/kg infusion 10-12 h Higher doseHigher dose Less infusionsLess infusions

Best within 7 days (earlier better)Best within 7 days (earlier better)Live vaccines 11 mo reduced immunogenicityLive vaccines 11 mo reduced immunogenicity

Treatment cont’dTreatment cont’d AspirinAspirin

Anti-platelet and anti-inflammatory; no reduction of Anti-platelet and anti-inflammatory; no reduction of CAA incidenceCAA incidence

80-100 mg/kg/d/4 doses80-100 mg/kg/d/4 doses 3-5 mg/kg/d afebrile 72 hours + ≥ day 14 of illness.3-5 mg/kg/d afebrile 72 hours + ≥ day 14 of illness. D/C no CAA 6 week follow-upD/C no CAA 6 week follow-up Reye syndrome a/w varicella and influenza vaccineReye syndrome a/w varicella and influenza vaccine

SteroidsSteroids ControversialControversial

Combined (30mg/kg steroids + conventional)Combined (30mg/kg steroids + conventional) No significantNo significant

Treatment failureTreatment failure

Retreatment IVIG 2g/kgRetreatment IVIG 2g/kgMethylprednisolone IV pulse 30mg/kg 2-3 Methylprednisolone IV pulse 30mg/kg 2-3

h od 1-3 dh od 1-3 d Infliximab (monoclonal anti-TNF-a Infliximab (monoclonal anti-TNF-a

antibody)antibody)

Treatment Failure cont’dTreatment Failure cont’d

UlinastatinUlinastatinPlasmapheresisPlasmapheresisCytotoxic agentsCytotoxic agents

CyclophosphamideCyclophosphamideCyclosporin ACyclosporin A

MTX: dihydrofolate reductase inhibitor MTX: dihydrofolate reductase inhibitor (anti-inflammatory)(anti-inflammatory)10mg/BSA, once weekly10mg/BSA, once weeklyMOA unclearMOA unclear

ManagementManagement

Serial stress testSerial stress testFollow up 4-6 w, 6m, 1 yFollow up 4-6 w, 6m, 1 y

EchoEcho20% Aneurysm20% AneurysmstenosisstenosisMIMI

Percutaneous Transluminal AngioplastyPercutaneous Transluminal AngioplastyRotational atherectomyRotational atherectomyStentStentBypass graftBypass graft transplanttransplant

ComplicationsComplications CardiacCardiac

Coronary artery dilations and aneurysms (5%)Coronary artery dilations and aneurysms (5%) ThrombosisThrombosis Myointimal proliferation Myointimal proliferation stenosis (20%) stenosis (20%)myocardial ischemiamyocardial ischemia

1% giant aneurysms1% giant aneurysms

Aspirin, clopidogrel, ticlopidineAspirin, clopidogrel, ticlopidine LMW Heparin, Warfarin, anti platelet receptor monoclonal LMW Heparin, Warfarin, anti platelet receptor monoclonal

antibodiesantibodies Pericarditis + effusionPericarditis + effusion MyocarditisMyocarditis Valvulitis (1%. Mitral Valve)Valvulitis (1%. Mitral Valve)

Coronary AneurysmsCoronary Aneurysms Smaller with timeSmaller with time Risk factorsRisk factors

MaleMale 8 year < Age < 1 year8 year < Age < 1 year Fever non-responsive to IVIGFever non-responsive to IVIG DecreasedDecreased

HbHb Serum[albumin]Serum[albumin]

IncreasedIncreased WBCWBC BandBand CRPCRP

Morbidity & MortalityMorbidity & Mortality

Thrombosis principal causeThrombosis principal causeMI highest rate 1 year after onsetMI highest rate 1 year after onset

LMCALMCARCA + LADRCA + LAD

No cardiac sequelae within 1No cardiac sequelae within 1stst mo mo full full recovery + asymptomaticrecovery + asymptomatic

Take Home MessageTake Home Message

Auto-immune mediated vasculitis Auto-immune mediated vasculitis (mucuopurulent lymphadenopathy)(mucuopurulent lymphadenopathy)

6 Cardinal Symptoms, don’t have to occur in 6 Cardinal Symptoms, don’t have to occur in totality (Japanese Diagnostic Criteria)totality (Japanese Diagnostic Criteria)

Etiology unknown: behaves as infectious and Etiology unknown: behaves as infectious and geneticgenetic

Devastating cardiac complicationsDevastating cardiac complicationsMI, anurysms, vasculitisMI, anurysms, vasculitis

Treatment: IVIG + Aspirin + ComplicationsTreatment: IVIG + Aspirin + Complications

ReferencesReferences1.1. Kim, D. S. (2006). "Kawasaki Disease." Kim, D. S. (2006). "Kawasaki Disease." Yonsei Medical JournalYonsei Medical Journal 4747(6): 759-772.(6): 759-772.

2.2. Li, X.-h., X.-j. Li, et al. (2008). "Epidemiological Survey of Kawasaki Disease in Sichuan Province Li, X.-h., X.-j. Li, et al. (2008). "Epidemiological Survey of Kawasaki Disease in Sichuan Province of China." of China." Journal of tropical pediatricsJournal of tropical pediatrics 5454(2): 133-136.(2): 133-136.

3.3. Huang, W.-C., L.-M. Huang, et al. (2009). "Epidemiologic Features of Kawasaki Disease in Huang, W.-C., L.-M. Huang, et al. (2009). "Epidemiologic Features of Kawasaki Disease in Taiwan, 2003-2006." Taiwan, 2003-2006." PediatricsPediatrics 123123(3): e401-405.(3): e401-405.

4.4. Chang, R.-K. R. (2002). "Epidemiologic characteristics of children hospitalized for Kawasaki Chang, R.-K. R. (2002). "Epidemiologic characteristics of children hospitalized for Kawasaki disease in California." disease in California." Pediatric Infectious Disease JournalPediatric Infectious Disease Journal 2121(12): 1150-1155.(12): 1150-1155.

5.5. Morens, D. M., L. J. Anderson, et al. (1980). "National Surveillance of Kawasaki Disease." Morens, D. M., L. J. Anderson, et al. (1980). "National Surveillance of Kawasaki Disease." PediatricsPediatrics 6565(1): 21-25.(1): 21-25.

6.6. Yosikazu Nakamura, M. Y., Ritei Uehara, Izumi Oki, Makoto Watanabe, and Hiroshi Yanagawa Yosikazu Nakamura, M. Y., Ritei Uehara, Izumi Oki, Makoto Watanabe, and Hiroshi Yanagawa (2008). "Epidemiologic Features of Kawasaki Disease in Japan: Results from the Nationwide (2008). "Epidemiologic Features of Kawasaki Disease in Japan: Results from the Nationwide Survey in 2005-2006." Survey in 2005-2006." J EpidemiolJ Epidemiol 1818(4): 167-172.(4): 167-172.

7.7. Park, Y., J. Han, et al. (2007). "Kawasaki Disease in Korea, 2003-2005." Park, Y., J. Han, et al. (2007). "Kawasaki Disease in Korea, 2003-2005." Pediatric Infectious Pediatric Infectious Disease JournalDisease Journal 2626(9): 821-823.(9): 821-823.

8.8. Robert C. Holman, A. T. C., Ermias D. Belay, Claudia A. Steiner and Lawrence B. (2003). Robert C. Holman, A. T. C., Ermias D. Belay, Claudia A. Steiner and Lawrence B. (2003). "Kawasaki Syndrome Hospitalizations in the United States, 1997 and 2000." "Kawasaki Syndrome Hospitalizations in the United States, 1997 and 2000." PediatricsPediatrics 112112(3): (3): 495-501.495-501.