Kawasaki disease: Difficult case scenario and guidelines Dr Neeraj Aggarwal Pediatric Cardiologist Department of Pediatric cardiac sciences Sir Ganga Ram Hospital

•At least 4/5 days of daily fever –Temp >102 F and Diagnostic criteria •At least 4/5 days of daily fever –Temp >102 F and 4 of 5 of the following (need not all be present at time of your examination): Polymorphic Rash-usually within 5 days of fever onset Bilateral, non purulent ,Bulbar Conjunctivitis, without exudate , sparing limbus Changes in extremities –acute phase -Swelling of hands/feet ---later in subacute phase (1-3 weeks from onset) periungual desquamation Mucous membrane changes-strawberry tongue, cracked/peeling lips, oral erythema Cervical Lymphadenopathy- least common ,unilateral cervical, at-least one node >1.5 cm, without inflammation

Kawasaki disease - AHA diagnostic criteria Fever of  5 days duration + four of five criteria Strawberry tongue (90%+ of cases) 1. Bilateral non-purulent conjunctival injection (90%+ of cases) 3. 2. Polymorphous rash (95%+ of cases) 4. Changes in peripheral extremities (90%+ of cases) Cervical lymphadenopathy (~75% of cases) 5.

Acta Paediatr. 2012

Laboratory Findings Leukocytosis with neutrophilia Elevated ESR and CRP Anemia , Hypoalbuminemia Hyponatremia Thrombocytosis after week 1 Sterile pyuria Elevated serum transaminases,Gamma glutamyl transpeptidase (GGTP) CSF Pleocytosis Leukocytosis in synovial fluid

ESR Elevation of ESR (but not of CRP) can be caused by IVIG therapy per se. Therefore, ESR should not be used as the sole determinant of the degree of inflammatory activity in IVIG–treated patients

Other clinical and laboratory findings Cardiovascular findings -Congestive heart failure, myocarditis, pericarditis, valvular regurgitation ,Coronary artery abnormalities ,Aneurysms of medium-size non coronary arteries ,Raynaud’s phenomenon ,Peripheral gangrene Musculoskeletal system -Arthritis, arthralgia Gastrointestinal tract -Diarrhea, vomiting, abdominal pain Hepatic dysfunction -Hydrops of gallbladder

Other clinical and laboratory findings Central nervous system -Extreme irritability, Aseptic meningitis ,Sensorineural hearing loss Genitourinary system -Urethritis/meatitis Other findings -Erythema, induration at BCG inoculation site ,Anterior uveitis ,Desquamating rash in groin

Kawasaki disease is unlikely if platelet counts and acute-phase inflammatory reactants (ie, ESR and CRP) are normal after 7 days of illness. 2. low WBC count, lymphocyte predominance ,and low platelets in the absence of disseminated intravascular coagulation suggest a viral etiology

Kawasaki disease is unlikely Exudative conjuctivitis Exudative pharyngitis Discrete intra oral lesions Bullous or vesicular rash Generalized adenopathy

How Frequent - ECHOs – Classic kawasaki disease ‐At time of diagnosis or suspected ‐At 2 weeks ‐6-8 weeks after symptom onset Repeat more frequently if higher risk (Persistently febrile or who exhibit coronary abnormalities, ventricular dysfunction, pericardial effusion, or valvular regurgitation). Classic kawasaki disease

Echocardiogram Positive if any of 3 conditions are met: z score of LAD or RCA >2.5 coronary arteries meet Japanese ministry of Health criteria for aneurysms 3 other suggestive features exist, including perivascular brightness, lack of tapering, decreased LV function, mitral regurgitation, pericardial effusion, or z scores in LAD or RCA of 2–2.5.

Echocardiogram Measure from inner edge to inner edge and should exclude points of branching Aneurysm –clearly irregular lumen or size 1.5 times that of the surrounding segment Aneurysms are classified (AHA) Small ( <5 mm internal diameter), Medium (5 to 8 mm internal diameter), Giant ( >8 mm internal diameter)

Echocardiogram common sites of coronary aneurysms include the proximal LAD and proximal RCA, followed by the LMCA, then LCX and finally the distal RCA

ECHO –Additional notes The aortic root dilatation Pericardial effusion Ejection fraction and LV dimensions MR /TR or AR

Treatment Treatment should be given to children within 10 d of fever onset and Beyond day 10 with fever and laboratory signs (CRP, ESR) of ongoing inflammation

Treatment IVIG 2g/kg over 12 hours (anti-inflammatory effects) ,single large dose is better than divided doses and Aspirin 80-100 mg/kg/day (4 divided doses, antiinflammatory ) Then 3-5 mg/kg/day, 48 hours after fever subsides Aspirin continued till 6-8 weeks (if echo normal )

IVIG Efficacy if untreated Treatment given Rate of coronary aneurysms If IVIG given within 10d of fever onset 5 % (1 % have giant aneurysms) if untreated 15-25 %

No response to IVIG Fever recrudescence/IVIG resistance (seen in 10 % pts)- no response in 36 hrs Repeat IVIG OR corticosteroids OR Infliximab Additional newer regimens

IVIG resistance Repeat 2 nd dose of IVIG -2g/kg over 12 hrs

Corticosteroids as adjunctive first line Rx? Randomized Trial of pulsed corticosteroid therapy for primary treatment of Kawasaki disease. - No effect on Coronary aneurysm Newburger JW et al. NEJM 2007; 356: 663-675

IVIG resistance-steroids Hashino et al – Compared additional IVIG therapy Vs pulse steroid. IVIG 2gm/kg+ Aspirin no response Then 2 groups either IVIG or pulse steroid therapy No differences in coronary outcomes , but shorter hospital stay in steroid group

Corticosteroids as adjunctive first line Rx? Inoue Y et al. A multicenter prospective randomized trial of corticosteroids in primary therapy for Kawasaki disease: clinical course and coronary artery outcome. 2006; J Pediatr; 149: 336-341 Prospective RCT of 178 patients Fewer aneurysms at 1 month in those receiving IVIG AND prednisolone (11.2% versus 2.4%) But Metanalysis (Eur J Pediatr (2012) – no significant differences in coronary outcomes ,but shorter hospital stay –IVIG +aspirin+ steroids Vs IVIG +aspirin ,

Guidelines (AHA) for steroids usage If 2 infusions of IVIG ineffective(evidence level C). I.V. pulse methyl-prednisolone, 30 mg/kg for 2 to 3 hours, OD for 1 to 3 days

Rationale for blocking TNF-α –promising Murine model of KD: Production of TNF- α in the peripheral immune system Response site directed, migration to the coronary arteries Mice treated with etanercept and TNFRI knockout mice resistant to development of both coronary arteritis and coronary aneurysm formation. Our results suggest that blocking TNF- or its downstream functions, such as leukocyte recruitment or matrix degradation, may be exciting new options in the battle against coronary artery damage in children with Kawasaki disease. Kawasaki disease is the most common cause of multisystem vasculitis in childhood. The resultant coronary artery lesions make Kawasaki disease the leading cause of acquired heart disease in children in the developed world. TNF- is a pleiotropic inflammatory cytokine elevated during the acute phase of Kawasaki disease. In this study, we report rapid production of TNF- in the peripheral immune system after disease induction in a murine model of Kawasaki disease. This immune response becomes site directed, with migration to the coronary arteries dependent on TNF--mediated events. Production of TNF- in the heart is coincident with the presence of inflammatory infiltrate at the coronary arteries, which persists during development of aneurysms. More importantly, inflammation and elastin breakdown in the coronary vessels are completely eliminated in the absence of TNF- effector functions. Mice treated with the TNF--blocking agent etanercept, as well as TNFRI knockout mice, are resistant to development of both coronary arteritis and coronary aneurysm formation. Taken together, TNF- is necessary for the development of coronary artery lesions in an animal model of Kawasaki disease. These findings have important implications for potential new therapeutic interventions in children with Kawasaki disease. Hui-Yuen JS et al J Immunol. 2006;176:6294-301

Infliximab (Remicade) Monoclonal antibody against TNF-α Dose 5 mg/kg IV

Evidence for infliximab Burns JC et al 2005 J Pediatr 2005; 146:662–667. 13 patients with IVIG resistant KD, good response Burns JC et al 2008 J Pediatr 2008; 153:833–838 24 patients 2nd IVIG vs infliximab (non inferior) Case reports: O‘Connor MJ, Saulsbury FT. Incomplete and atypical Kawasaki disease in a young infant: severe, recalcitrant disease responsive to infliximab. Clin Pediatr 2007; 46:345-8 Zulian F et al. Efficacy of infliximab in long-lasting refractory Kawasaki disease. Clin Exp Rheumatol. 2006; 24: 453 TNF-a blocking agents ? part of the therapeutic arsenal combating life-threatenig primary vascular inflammation

Role for infliximab Resistant to IVIG and steroids infliximab or other agents directed at TNF- might be considered (evidence level C)

Cytotoxic agents Exceptional patients with particularly refractory acute Kawasaki disease Cyclophosphamide with oral steroids

Plasma exchange Mori et al . Resistance to 2 doses of IVIG 46 children --received exchange compare to 59 children -- third dose of IVIG therapy No complications with exchange Aneurysms in exchange group = 17.3% Aneurysm in 3rd IVIG group- 40.7% (p < 0.001). Mori M, Imagawa T, Katakura S, et al. Efficacy of plasma exchange therapy for Kawasaki disease intractable to intravenous gamma-globulin. Mod Rheumatol 2004;14:43e7

Follow up Stop aspirin if echo at 6 weeks normal Continue aspirin if coronary aneurysm present Giant aneurysms (>8mm) never resolve: Aspirin and warfarin (heparin until INR 2-3) Long term follow up

Risk stratification Risk Level I,2 —Patients with no coronary artery changes/transient coronary ectasia resolving In 6-8 weeks – Aspirin for 6-8 weeks Risk level 3 –small to medium coronary aneurysm (3-5 mm or Z score 3-7 )- long term antiplatelets till aneurysms disappear and Annual ECHO

Risk level 4 –Aneurysm >6 mm/giant aneurysm /multiple aneurysms –long term antiplatelet therapy (single/dual with clopidogrel ) Add warfarin or low molecular wt heparin for giant aneurysms

KD outcome 25 % CAA if untreated 4-9% CAA with IVIG and aspirin IVIG resistance 10 % Very high risk of CAA in IVIG resistance cases: 20-30% The acute mortality rate due to myocardial infarction <1%

Prognosis for those with giant CAA (>8mm) 76 patients from 1972 Median observational period 19 years 61% required surgical coronary intervention At one month to 21 years Mode time of intervention: one month Survival rate: 10 yrs: 95% 20 yrs: 88% 30 years: 88% Suda et al 2011 Circulation

Take home messages If a child has fever approaching 5 days, look for other KD symptoms Limited window of opportunity to influence outcome: switch off the inflammation As soon as possible Newer modalities may improve coronary outcomes

Thanks Dr Neeraj Aggarwal