Update on Kawasaki Update on Kawasaki DiseaseDisease

June 7June 7thth, 2010, 2010Aaron S. Miller, MD, MSPHAaron S. Miller, MD, MSPH

Division of Hospitalist MedicineDivision of Hospitalist MedicineSt. Louis Children’s HospitalSt. Louis Children’s Hospital

Update on Kawasaki DiseaseUpdate on Kawasaki Disease

Definition / pathologyDefinition / pathology HistoryHistory Epidemiology and search for etiologyEpidemiology and search for etiology Differential diagnosis Differential diagnosis Clinical findingsClinical findings EvaluationEvaluation TreatmentTreatment Follow-upFollow-up

Kawasaki Disease (KD):Kawasaki Disease (KD):

An acute, self-limited disease that An acute, self-limited disease that manifests as a multisystemic medium manifests as a multisystemic medium vessel vasculitis that is largely seen in vessel vasculitis that is largely seen in

children under 5 years of age children under 5 years of age

PathologyPathology

Systemic vasculitis affecting Systemic vasculitis affecting any medium sized vessels any medium sized vessels (e.g. coronary, celiac, (e.g. coronary, celiac, mesenteric)mesenteric)

Vessel walls infiltrated with Vessel walls infiltrated with neutrophils, mononuclear neutrophils, mononuclear cells and lymphocytescells and lymphocytes

Endothelial cell swellingEndothelial cell swelling Destruction of internal elastic Destruction of internal elastic

lamina gives way to vessel lamina gives way to vessel dilatation and aneurysm dilatation and aneurysm formationformation

HistoryHistory Dr. Tomisaku Kawasaki first described Dr. Tomisaku Kawasaki first described

the clinical features in children in Japan the clinical features in children in Japan in late 1960’s and called it in late 1960’s and called it mucocutaneous lymph node syndromemucocutaneous lymph node syndrome

1970’s coronary sequelae became 1970’s coronary sequelae became apparent when children who had the apparent when children who had the disease had sudden death and were disease had sudden death and were found to have coronary artery found to have coronary artery aneurysms with thrombosis and aneurysms with thrombosis and myocardial infarctionmyocardial infarction

Burns JC et al. Kawasaki Disease: A Brief History. Pediatrics. Burns JC et al. Kawasaki Disease: A Brief History. Pediatrics.

2000;106(2): E27.2000;106(2): E27.

Dr. Kawasaki’s original notes on Dr. Kawasaki’s original notes on first KD patientfirst KD patient

Etiology of KDEtiology of KD Streptococcal superantigensStreptococcal superantigens Scald injuriesScald injuries Mycoplasma pneumoniaeMycoplasma pneumoniae Varicella zosterVaricella zoster PollenPollen Neisseria meningitidisNeisseria meningitidis Chlamydia pneumoniaeChlamydia pneumoniae MeaslesMeasles Staphylococcal toxinStaphylococcal toxin Parvovirus B19Parvovirus B19 HHV-6HHV-6

Rug shampooingRug shampooing Proprionibacterium acnesProprionibacterium acnes House dust mitesHouse dust mites Living near bodies of waterLiving near bodies of water Humidifier useHumidifier use Coxiella burnetiiCoxiella burnetii AdenovirusAdenovirus RetrovirusRetrovirus Pseudomonas aeruginosaPseudomonas aeruginosa Parainfluenza virusParainfluenza virus Ehrlichia canisEhrlichia canis ““New Haven” CoronavirusNew Haven” Coronavirus

EpidemiologyEpidemiology

Most common in Japan and in children of Most common in Japan and in children of Japanese descentJapanese descent

Asian > African American > Hispanic > Asian > African American > Hispanic > CaucasianCaucasian

Median age = 2 years (>80% of patients < 5 Median age = 2 years (>80% of patients < 5 years)years)

Most common cause of acquired childhood heart Most common cause of acquired childhood heart disease in the developed worlddisease in the developed world

Holman RC et al. Kawasaki syndrome hospitalizations in the United States, 1997-2000. Holman RC et al. Kawasaki syndrome hospitalizations in the United States, 1997-2000. Pediatrics. 2003;112:495–501.Pediatrics. 2003;112:495–501.

Genetic componentGenetic component

Individuals of Japanese origin, no matter Individuals of Japanese origin, no matter which country they live in, are more likely which country they live in, are more likely to acquire Kawasaki diseaseto acquire Kawasaki disease

Siblings of children with Kawasaki’s Siblings of children with Kawasaki’s disease are more likely than other disease are more likely than other neighborhood children to develop the neighborhood children to develop the illness illness

Epidemiological data suggests Epidemiological data suggests an infectious etiologyan infectious etiology

Seasonal peak in winter and spring monthsSeasonal peak in winter and spring months Epidemics often with a clear epicenterEpidemics often with a clear epicenter Peak incidence in toddlers with rare cases less than Peak incidence in toddlers with rare cases less than

3 months and in adults 3 months and in adults Similar clinical presentation to adenovirus and Similar clinical presentation to adenovirus and

scarlet feverscarlet fever Self limited nature of the illnessSelf limited nature of the illness

Classic Clinical CriteriaClassic Clinical Criteria

Fever for Fever for >> 5 days 5 days >> 4 of the 5 principle features 4 of the 5 principle features Exclusion of diseases with similar findingsExclusion of diseases with similar findings

Rules that have expanded the Rules that have expanded the clinical criteriaclinical criteria

Kawasaki’s Disease may be diagnosed if:Kawasaki’s Disease may be diagnosed if: If fever and If fever and >> 4 principle features are present, 4 principle features are present,

the diagnosis of KD can be made on day 4 of the diagnosis of KD can be made on day 4 of illnessillness

If fever If fever >> 5 days, < 4 principle features are 5 days, < 4 principle features are present AND ECHO evidence of coronary artery present AND ECHO evidence of coronary artery diseasedisease

KD should be considered in any infant < 6 KD should be considered in any infant < 6 months of age with prolonged fever, even if no months of age with prolonged fever, even if no principle features are presentprinciple features are present

Differential DiagnosisDifferential Diagnosis Viral infection (adenovirus, enterovirus, EBV, HHV-6, Viral infection (adenovirus, enterovirus, EBV, HHV-6,

measles)measles) Drug hypersensitivity reactionDrug hypersensitivity reaction Stevens-Johnson syndrome / Toxic epidermal necrolysisStevens-Johnson syndrome / Toxic epidermal necrolysis Scarlet feverScarlet fever Ehrlichiosis / Rocky Mountain Spotted FeverEhrlichiosis / Rocky Mountain Spotted Fever Staphylococcal scalded skin syndromeStaphylococcal scalded skin syndrome Toxic shock syndromeToxic shock syndrome Juvenile rheumatoid arthritisJuvenile rheumatoid arthritis LeptospirosisLeptospirosis Mercury hypersensitivity reaction (acrodynia)Mercury hypersensitivity reaction (acrodynia)

FeverFever

Most common manifestation of KDMost common manifestation of KD High-spiking High-spiking Peak temperatures >39Peak temperatures >39°° Without therapy, fever lasts a mean of 11 days Without therapy, fever lasts a mean of 11 days

but up to 4 weeksbut up to 4 weeks Usually resolves within 2 days of appropriate Usually resolves within 2 days of appropriate

therapytherapy

Bulbar ConjunctivitisBulbar Conjunctivitis

Appears shortly after the Appears shortly after the onset of fever and is seen onset of fever and is seen in 90% of patientsin 90% of patients

Typically spares the Typically spares the limbus limbus

Painless and non-Painless and non-exudativeexudative

Mild acute iridocyclitis or Mild acute iridocyclitis or anterior uveitis may be anterior uveitis may be seen on slit lamp examseen on slit lamp exam

http://www.rch.org.au/clinicalguide

http://www.mars.dti.ne.jp/~maachan/Kawasaki.html

Polymorphous ExanthemPolymorphous Exanthem

Rash usually appears Rash usually appears within 5 days of feverwithin 5 days of fever

Rash most commonly a Rash most commonly a diffuse maculopapular diffuse maculopapular eruption, but may be eruption, but may be urticarial, scarlatiniform, urticarial, scarlatiniform, erythroderma, erythema-erythroderma, erythema-multiforme-like, or multiforme-like, or micropustularmicropustular

Rash usually involves the Rash usually involves the trunk and extremities and trunk and extremities and is accentuated in the is accentuated in the perineal regionperineal region

www.chennaionline.com/.../ kawasaki-disease.jpghttp://www.emedicine.com/MED/topic1223.htm

Changes in the Lips and Oral CavityChanges in the Lips and Oral Cavity

Erythema, dryness, Erythema, dryness, fissuring, peeling, fissuring, peeling, cracking and bleeding cracking and bleeding of the lipsof the lips

““Strawberry tongue” Strawberry tongue” with erythema and with erythema and prominent papillaeprominent papillae

Diffuse erythema of Diffuse erythema of the oral mucosathe oral mucosa

http://www.healthcentral.com/mhc/top/003097.cfm

Cervical LymphadenopathyCervical Lymphadenopathy

Unilateral and Unilateral and confined to the confined to the anterior cervical anterior cervical triangletriangle

>> 1.5 cm in diameter 1.5 cm in diameter Firm and non-Firm and non-

fluctuantfluctuant

Council on Cardiovascular Disease in the Young. Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease. American Heart Association. Diagnostic guidelines for Kawasaki disease. Circulation. 2001;103(2):335-6.

Extremity ChangesExtremity Changes

Acute:Acute: Erythema of the palms Erythema of the palms

and soles and/or and soles and/or edema of the hands edema of the hands and feetand feet

Subacute (2-3 Subacute (2-3 weeks):weeks): Desquamation of the Desquamation of the

fingers and toes (70-fingers and toes (70-98% of children)98% of children)

CNS: Extreme irritability, aseptic meningitis,

GU: Urethritis

Hepatic: Hepatic dysfunction, hydrops of the gallbladder

GI: Vomiting, diarrhea, abdominal pain

CVS: Myocarditis, pericarditis, valvular dysfunction, CHF, coronary artery abnormalities

PERIPHERAL VASCULAR: Raynaud’s phenomenon, peripheral gangrene

SKIN: Desquamating rash in the groin

MUSCULOSKELETAL: Arthritis/arthralgia

EYE: Anterior uveitis

Additional Clinical FindingsAdditional Clinical Findings

PULMONARY: Dyspnea, tachypnea, hypoxia, cough, pulmonary infiltrate on CXR

Laboratory Findings in KDLaboratory Findings in KD

↑↑ WBC WBC ↑↑ CRPCRP ↑↑ ESRESR ↑↑ Platelets Platelets (after week one)(after week one)

↑↑ AST, ALT, GGTAST, ALT, GGT ↓ ↓ Hgb/HctHgb/Hct ↓↓ AlbuminAlbumin ↓↓ NaNa

Sterile pyuriaSterile pyuria CSF pleocytosisCSF pleocytosis Leukocytosis in the Leukocytosis in the

synovial fluidsynovial fluid elevated plasma lipidselevated plasma lipids

Coronary Artery Disease in KDCoronary Artery Disease in KD

~15% to 25% of untreated patients develop ~15% to 25% of untreated patients develop coronary artery abnormalitiescoronary artery abnormalities

~5% of children treated with IVIG within 10 days ~5% of children treated with IVIG within 10 days develop coronary artery abnormalitiesdevelop coronary artery abnormalities

1% of children treated with IVIG within 10 days 1% of children treated with IVIG within 10 days develop giant aneurysmsdevelop giant aneurysms

Coronary artery aneurysms may lead to ischemic Coronary artery aneurysms may lead to ischemic heart disease, myocardial infarction, or sudden heart disease, myocardial infarction, or sudden deathdeath

Kato H et al. Long-term consequences of Kawasaki disease. A 10- to 21-year follow-up study of Kato H et al. Long-term consequences of Kawasaki disease. A 10- to 21-year follow-up study of 594 patients. Circulation. 1996; 94: 1379–1385.594 patients. Circulation. 1996; 94: 1379–1385.

Z-scoresZ-scoresof coronary artery diametersof coronary artery diameters

Pediatrics. 2004;114:1708-1733.

What is a positive ECHO?What is a positive ECHO?

Z-score of LAD or RCA of >2.5Z-score of LAD or RCA of >2.5 Coronary aneurysm Coronary aneurysm OR ≥ 3 of the following featuresOR ≥ 3 of the following features

z-score ≥ 2-2.5z-score ≥ 2-2.5 PV brightnessPV brightness lack of taperinglack of tapering low LV functionlow LV function mitral regurgitationmitral regurgitation pericardial effusionpericardial effusion

Evaluation of Suspected Incomplete KD

Supplemental Laboratory Criteria•Albumin < 3 g/dL•Anemia for age•Elevated ALT•Platelets > 450,000 after 7 days of illness•WBC > 15,000/mm3

•UA with > 10 WBC/hpf

Treatment of KDTreatment of KDAspirin Aspirin

Mechanism of action of aspirin:Mechanism of action of aspirin: Anti-inflammatory at high dose (80-100 Anti-inflammatory at high dose (80-100

mg/kg/day divided in 4 doses)mg/kg/day divided in 4 doses) Antiplatelet at low dose (3-5 mg/kg/day)Antiplatelet at low dose (3-5 mg/kg/day)

Aspirin dosingAspirin dosing High dose aspirin should be given acutelyHigh dose aspirin should be given acutely

• Until day 14 of illnessUntil day 14 of illness• AND/ORAND/OR until afebrile for 48-72 hours until afebrile for 48-72 hours

Low dose aspirin is continued as indicated by Low dose aspirin is continued as indicated by risk levelrisk level

Newburger, JW et al. Pediatrics. 2004;114:1708-1733.

Treatment of KDTreatment of KDIntravenous Immune Globulin (IVIG)Intravenous Immune Globulin (IVIG)

First reports of use 1983First reports of use 1983 Dosing: 2 g/kg in a single infusion over 8-12H Dosing: 2 g/kg in a single infusion over 8-12H Timing: Timing:

Should be given within the first 10 days of illnessShould be given within the first 10 days of illness IVIG should be given after day 10 of illness in children IVIG should be given after day 10 of illness in children

with persistent fever or aneurysms and ongoing with persistent fever or aneurysms and ongoing systemic inflammation as manifested by elevated ESR systemic inflammation as manifested by elevated ESR and CRPand CRP

Adverse reactions: chills, rash, aseptic meningitis, Adverse reactions: chills, rash, aseptic meningitis, anaphylaxis, heart failure secondary to fluid overloadanaphylaxis, heart failure secondary to fluid overload

Vaccines: Live virus vaccines should be deferred for 11 Vaccines: Live virus vaccines should be deferred for 11 months after administration of IVIGmonths after administration of IVIG

Newburger, JW et al. Pediatrics. 2004;114:1708-1733.

Corticosteroids plus IVIG as initial Corticosteroids plus IVIG as initial treatment of KDtreatment of KD

The addition of corticosteroids to IVIG and aspirin has shown mixed The addition of corticosteroids to IVIG and aspirin has shown mixed results has from RCTresults has from RCT

2006 Japan study: 178 patients, RCT 2006 Japan study: 178 patients, RCT Prednisolone 2mg/kg/day x 15 days plus IVIG (1g/kg QD x 2 days) plus Prednisolone 2mg/kg/day x 15 days plus IVIG (1g/kg QD x 2 days) plus

aspirin VERSUS IVIG + aspirin aspirin VERSUS IVIG + aspirin Prednisolone group had fewer CA aneurysms (2.2% vs. 11.4%), quicker Prednisolone group had fewer CA aneurysms (2.2% vs. 11.4%), quicker

resolution of fever and were less likely to require IVIG retreatment resolution of fever and were less likely to require IVIG retreatment 2007 US study: 199 patients, RCT 2007 US study: 199 patients, RCT

Methylprednisolone (30mg/kg/day) x 1 plus IVIG (2g/kg x 1) plus aspirin Methylprednisolone (30mg/kg/day) x 1 plus IVIG (2g/kg x 1) plus aspirin VERSUS IVIG and aspirin alone. VERSUS IVIG and aspirin alone.

There were no differences in CA, duration of fever or need for retreatmentThere were no differences in CA, duration of fever or need for retreatment

Inoue Y et al. A multicenter prospective randomized trial of corticosteroids in primary therapy for Kawasaki disease: clinical course and coronary artery outcome. J Pediatr. 2006;149(3):336-341.

Newburger JW et al. Randomized trial of pulsed corticosteroid therapy for primary treatment of Kawasaki disease. N Engl J Med. 2007;356(7):663-75.

Treatment of Refractory KDTreatment of Refractory KD 10 % of patients with KD fail to respond to initial 10 % of patients with KD fail to respond to initial

IVIG (persistent or recurrent for IVIG (persistent or recurrent for >> 36 hours after 36 hours after initial IVIG)initial IVIG)

Retreatment with IVIG (2 g/kg) is recommended Retreatment with IVIG (2 g/kg) is recommended for patients with refractory KDfor patients with refractory KD

Treatment with steroids (methylprednisolone 30 Treatment with steroids (methylprednisolone 30 mg/kg daily for 3 days) should be restricted to mg/kg daily for 3 days) should be restricted to patients who fail to respond to patients who fail to respond to >> 2 doses of IVIG 2 doses of IVIG

Multiple case reports of successful use of Multiple case reports of successful use of infliximab, cyclophosphamide, plasmapheresisinfliximab, cyclophosphamide, plasmapheresis

Burns JC et al. Infliximab treatment of intravenous immunoglobulin-resistant Kawasaki disease. J Pediatr. 2008;153(6):833-8.

Slide 40Slide 40

Follow-up Cardiac Evaluation in Follow-up Cardiac Evaluation in Patients Diagnosed with KDPatients Diagnosed with KD

Follow-up with consulting services (ID and Follow-up with consulting services (ID and cardiology if consulted originally) should cardiology if consulted originally) should be arranged for 2 weeks and 6-8 weeks be arranged for 2 weeks and 6-8 weeks after initial diagnosis.after initial diagnosis.

ECHO should be performed at these visits.ECHO should be performed at these visits. ECHO evaluation may be limited to the ECHO evaluation may be limited to the

coronary arteries.coronary arteries.

PrognosisPrognosis

Rate of recurrence: 3% (in Japan)Rate of recurrence: 3% (in Japan) In hospital mortality: 0.17% (in US)In hospital mortality: 0.17% (in US) Peak mortality: 15-45 days after onset of Peak mortality: 15-45 days after onset of

feverfever Older children with KD may have a higher Older children with KD may have a higher

rate of cardiovascular complications rate of cardiovascular complications related to delayed diagnosisrelated to delayed diagnosis

Natural History of Coronary Artery Natural History of Coronary Artery Lesions in KDLesions in KD

~50% to 67% of coronary artery ~50% to 67% of coronary artery aneurysms resolve within 1-2 yearsaneurysms resolve within 1-2 years

Factors associated with resolution:Factors associated with resolution: Initial size of lesion smallInitial size of lesion small Age < 1 yearAge < 1 year Fusiform rather than saccular aneurysmFusiform rather than saccular aneurysm Aneurysm location in the distal Aneurysm location in the distal

coronary segmentcoronary segment

Thank you to Rachel Orscheln, MD and Thank you to Rachel Orscheln, MD and Jeffery McKinney, MD, PhD for providing Jeffery McKinney, MD, PhD for providing me with the slides I used as a starting me with the slides I used as a starting point for my talkpoint for my talk

Thanks to the SLCH Hospitalist group for Thanks to the SLCH Hospitalist group for providing feedback for this talkproviding feedback for this talk

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