1. Update on Kawasaki Disease June 7 th, 2010 Aaron S. Miller, MD, MSPH Division of Hospitalist Medicine St. Louis Children’s Hospital

2. Update on Kawasaki Disease  Definition / pathology  History  Epidemiology and search for etiology  Differential diagnosis  Clinical findings  Evaluation  Treatment  Follow-up

3. Kawasaki Disease (KD): An acute, self-limited disease that manifests as a multisystemic medium vessel vasculitis that is largely seen in children under 5 years of age

4. Pathology  Systemic vasculitis affecting any medium sized vessels (e.g. coronary, celiac, mesenteric)  Vessel walls infiltrated with neutrophils, mononuclear cells and lymphocytes  Endothelial cell swelling  Destruction of internal elastic lamina gives way to vessel dilatation and aneurysm formation

5. History  Dr. Tomisaku Kawasaki first described the clinical features in children in Japan in late 1960’s and called it mucocutaneous lymph node syndrome  1970’s coronary sequelae became apparent when children who had the disease had sudden death and were found to have coronary artery aneurysms with thrombosis and myocardial infarction Burns JC et al. Kawasaki Disease: A Brief History. Pediatrics. 2000;106(2): E27.

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

7. Etiology of KD  Streptococcal superantigens  Scald injuries  Mycoplasma pneumoniae  Varicella zoster  Pollen  Neisseria meningitidis  Chlamydia pneumoniae  Measles  Staphylococcal toxin  Parvovirus B19  HHV-6  Rug shampooing  Proprionibacterium acnes  House dust mites  Living near bodies of water  Humidifier use  Coxiella burnetii  Adenovirus  Retrovirus  Pseudomonas aeruginosa  Parainfluenza virus  Ehrlichia canis  “New Haven” Coronavirus

8. Epidemiology  Most common in Japan and in children of Japanese descent  Asian > African American > Hispanic > Caucasian  Median age = 2 years (>80% of patients 80% of patients < 5 years)  Most common cause of acquired childhood heart disease in the developed world Holman RC et al. Kawasaki syndrome hospitalizations in the United States, 1997-2000. Pediatrics. 2003;112:495–501.

9. Genetic component  Individuals of Japanese origin, no matter which country they live in, are more likely to acquire Kawasaki disease  Siblings of children with Kawasaki’s disease are more likely than other neighborhood children to develop the illness

10. Epidemiological data suggests an infectious etiology  Seasonal peak in winter and spring months  Epidemics often with a clear epicenter  Peak incidence in toddlers with rare cases less than 3 months and in adults  Similar clinical presentation to adenovirus and scarlet fever  Self limited nature of the illness

11. Classic Clinical Criteria  Fever for > 5 days  > 4 of the 5 principle features  Exclusion of diseases with similar findings

12. Rules that have expanded the clinical criteria Kawasaki’s Disease may be diagnosed if:  If fever and > 4 principle features are present, the diagnosis of KD can be made on day 4 of illness  If fever > 5 days, 5 days, < 4 principle features are present AND ECHO evidence of coronary artery disease  KD should be considered in any infant < 6 months of age with prolonged fever, even if no principle features are present

13. Differential Diagnosis  Viral infection (adenovirus, enterovirus, EBV, HHV-6, measles)  Drug hypersensitivity reaction  Stevens-Johnson syndrome / Toxic epidermal necrolysis  Scarlet fever  Ehrlichiosis / Rocky Mountain Spotted Fever  Staphylococcal scalded skin syndrome  Toxic shock syndrome  Juvenile rheumatoid arthritis  Leptospirosis  Mercury hypersensitivity reaction (acrodynia)

14. Fever  Most common manifestation of KD  High-spiking  Peak temperatures >39°  Without therapy, fever lasts a mean of 11 days but up to 4 weeks  Usually resolves within 2 days of appropriate therapy

15. Bulbar Conjunctivitis  Appears shortly after the onset of fever and is seen in 90% of patients  Typically spares the limbus  Painless and non- exudative  Mild acute iridocyclitis or anterior uveitis may be seen on slit lamp exam http://www.rch.org.au/clinicalguide

16. http://www.mars.dti.ne.jp/~maachan/Kawasaki.html Polymorphous Exanthem Polymorphous Exanthem  Rash usually appears within 5 days of fever  Rash most commonly a diffuse maculopapular eruption, but may be urticarial, scarlatiniform, erythroderma, erythema- multiforme-like, or micropustular  Rash usually involves the trunk and extremities and is accentuated in the perineal region

17. www.chennaionline.com/.../ kawasaki-disease.jpg http://www.emedicine.com/MED/topic1223.htm Changes in the Lips and Oral Cavity  Erythema, dryness, fissuring, peeling, cracking and bleeding of the lips  “Strawberry tongue” with erythema and prominent papillae  Diffuse erythema of the oral mucosa

18. http://www.healthcentral.com/mhc/top/003097.cfm Cervical Lymphadenopathy  Unilateral and confined to the anterior cervical triangle  > 1.5 cm in diameter  Firm and non- fluctuant

19. 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 Changes  Acute: Erythema of the palms and soles and/or edema of the hands and feet Erythema of the palms and soles and/or edema of the hands and feet  Subacute (2-3 weeks): Desquamation of the fingers and toes (70- 98% of children) Desquamation of the fingers and toes (70- 98% of children)

20. 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 Findings PULMONARY: Dyspnea, tachypnea, hypoxia, cough, pulmonary infiltrate on CXR

21. Laboratory Findings in KD  ↑ WBC  ↑ CRP  ↑ ESR  ↑ Platelets (after week one)  ↑ AST, ALT, GGT  ↓ Hgb/Hct  ↓ Albumin  ↓ Na  Sterile pyuria  CSF pleocytosis  Leukocytosis in the synovial fluid  elevated plasma lipids

22. Coronary Artery Disease in KD  ~15% to 25% of untreated patients develop coronary artery abnormalities  ~5% of children treated with IVIG within 10 days develop coronary artery abnormalities  1% of children treated with IVIG within 10 days develop giant aneurysms  Coronary artery aneurysms may lead to ischemic heart disease, myocardial infarction, or sudden death 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.

24. Z-scores of coronary artery diameters Pediatrics. 2004;114:1708-1733.

25. What is a positive ECHO?  Z-score of LAD or RCA of >2.5  Coronary aneurysm  OR ≥ 3 of the following features z-score ≥ 2-2.5 z-score ≥ 2-2.5 PV brightness PV brightness lack of tapering lack of tapering low LV function low LV function mitral regurgitation mitral regurgitation pericardial effusion pericardial effusion

26. 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/mm 3 UA with > 10 WBC/hpf

27. Treatment of KD Aspirin  Mechanism of action of aspirin: Anti-inflammatory at high dose (80-100 mg/kg/day divided in 4 doses) Anti-inflammatory at high dose (80-100 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 dosing High dose aspirin should be given acutely High dose aspirin should be given acutely Until day 14 of illnessUntil day 14 of illness AND/OR until afebrile for 48-72 hoursAND/OR until afebrile for 48-72 hours Low dose aspirin is continued as indicated by risk level Low dose aspirin is continued as indicated by risk level Newburger, JW et al. Pediatrics. 2004;114:1708-1733.

28. Treatment of KD Intravenous Immune Globulin (IVIG)  First reports of use 1983  Dosing: 2 g/kg in a single infusion over 8-12H  Timing: Should be given within the first 10 days of illness Should be given within the first 10 days of illness IVIG should be given after day 10 of illness in children with persistent fever or aneurysms and ongoing systemic inflammation as manifested by elevated ESR and CRP IVIG should be given after day 10 of illness in children with persistent fever or aneurysms and ongoing systemic inflammation as manifested by elevated ESR and CRP  Adverse reactions: chills, rash, aseptic meningitis, anaphylaxis, heart failure secondary to fluid overload  Vaccines: Live virus vaccines should be deferred for 11 months after administration of IVIG Newburger, JW et al. Pediatrics. 2004;114:1708-1733.

29. Corticosteroids plus IVIG as initial treatment of KD  The addition of corticosteroids to IVIG and aspirin has shown mixed results has from RCT  2006 Japan study: 178 patients, RCT Prednisolone 2mg/kg/day x 15 days plus IVIG (1g/kg QD x 2 days) plus aspirin VERSUS IVIG + aspirin Prednisolone 2mg/kg/day x 15 days plus IVIG (1g/kg QD x 2 days) plus aspirin VERSUS IVIG + aspirin Prednisolone group had fewer CA aneurysms (2.2% vs. 11.4%), quicker resolution of fever and were less likely to require IVIG retreatment Prednisolone group had fewer CA aneurysms (2.2% vs. 11.4%), quicker resolution of fever and were less likely to require IVIG retreatment  2007 US study: 199 patients, RCT Methylprednisolone (30mg/kg/day) x 1 plus IVIG (2g/kg x 1) plus aspirin VERSUS IVIG and aspirin alone. Methylprednisolone (30mg/kg/day) x 1 plus IVIG (2g/kg x 1) plus aspirin VERSUS IVIG and aspirin alone. There were no differences in CA, duration of fever or need for retreatment There 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.

30. Treatment of Refractory KD  10 % of patients with KD fail to respond to initial IVIG (persistent or recurrent for > 36 hours after initial IVIG)  Retreatment with IVIG (2 g/kg) is recommended for patients with refractory KD  Treatment with steroids (methylprednisolone 30 mg/kg daily for 3 days) should be restricted to patients who fail to respond to > 2 doses of IVIG  Multiple case reports of successful use of infliximab, cyclophosphamide, plasmapheresis Burns JC et al. Infliximab treatment of intravenous immunoglobulin-resistant Kawasaki disease. J Pediatr. 2008;153(6):833-8.

31. Slide 40

33. Follow-up Cardiac Evaluation in Patients Diagnosed with KD  Follow-up with consulting services (ID and cardiology if consulted originally) should be arranged for 2 weeks and 6-8 weeks after initial diagnosis.  ECHO should be performed at these visits.  ECHO evaluation may be limited to the coronary arteries.

34. Prognosis  Rate of recurrence: 3% (in Japan)  In hospital mortality: 0.17% (in US)  Peak mortality: 15-45 days after onset of fever  Older children with KD may have a higher rate of cardiovascular complications related to delayed diagnosis

35. Natural History of Coronary Artery Lesions in KD  ~50% to 67% of coronary artery aneurysms resolve within 1-2 years  Factors associated with resolution: Initial size of lesion small Initial size of lesion small Age < 1 year Age < 1 year Fusiform rather than saccular aneurysm Fusiform rather than saccular aneurysm Aneurysm location in the distal Aneurysm location in the distal coronary segment coronary segment

36.  Thank you to Rachel Orscheln, MD and Jeffery McKinney, MD, PhD for providing me with the slides I used as a starting point for my talk  Thanks to the SLCH Hospitalist group for providing feedback for this talk

37. End