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

2. •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

3. 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.

4. Acta Paediatr. 2012

5. 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

6. 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

7. 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

8. 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

9. 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

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

11. 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

12. 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.

15. 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)

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

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

20. 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

21. Treatment
IVIG 2g/kg over 12 hours (anti-inflammatory effects) ,single large dose is better than divided doses
and
Aspirin 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 )

22. 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 %

23. 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

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

25. 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:

26. 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

27. 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:
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 ,

28. 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

29. 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:

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

31. Evidence for infliximab
Burns JC et al 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

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

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

34. 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

35. 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

36. 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

37. 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

38. 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%

39. 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

41. 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

42. Thanks
Dr Neeraj Aggarwal