1. Kawasaki Disease Dr Paul A Brogan Senior Lecturer in vasculitis
Department of Rheumatology ICH/GOSH

2. Overview History and Epidemiology Clinical features Pathogenesis
Treatment
Outcome
Research at GOSH: Long term KD follow up study

3. NEW GENERAL CLASSIFICATION OF CHILDHOOD VASCULITIS
1 Predominantly large vessel vasculitis
Takayasu arteritis
2 Predominantly medium-sized vessel vasculitis
Childhood polyarteritis nodosa
Cutaneous polyarteritis
Kawasaki disease

4. NEW GENERAL CLASSIFICATION OF CHILDHOOD VASCULITIS
3 Predominantly small vessel vasculitis
(A) GRANULOMATOUS
Wegener granulomatosis
Churg-Strauss syndrome
(B) NON GRANULOMATOUS
Microscopic polyangiitis
HSP
Isolated cutaneous leukocytoclastic vasculitis
Hypocomplementemic urticarial vasculitis

5. What time is dinner?

6. The first case of Kawasaki disease: London 1870B
                   C

7. Epidemiology

8. KD epidemiology World wide distribution Male preponderance
Commoner in oriental children
Some seasonality and occasional epidemics
The incidence of KD is rising world-wide, including the UK.
Incidence in the UK is 8.1 / children aged less than 5 years old

9. Epidemiology
Japan:
Incidence 220 per hundred thousand children under the age of five
peak age onset 9-11 months
70% of all cases younger than 3 years
cases in Japan
Increased cases in winter
Epidemics moving from adjoining region
Risk higher in siblings of index cases

10. Hawaii Mean 40 per 100 000 360 for Japanese 95 for Chinese
77 for Hawaiians
56 for Filipino
7 for Caucasians

11. Race-specific incidence of Kawasaki disease
Davis RL , Waller PL , Mueller BA , et al. Kawasaki syndrome in Washington State. Race-specific incidence rates and residential proximity to water. Arch Pediatr Adolesc Med 1995; 149:66-69

13. Rising incidence of Kawasaki disease in the UK
Harnden A et al. BMJ 2002; 324:

14. Clinical features

15. Kawasaki disease - AHA diagnostic criteria
Fever of  5 days duration + four of five criteria
Oropharyngeal changes
(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.

16. KD differential diagnosis
Toxic shock syndrome (streptococcal and staphylococcal)
Staphylococcal scalded skin syndrome
Scarlet fever
Infection with viruses
enterovirus, adenovirus, measles, parvovirus, Epstein–Barr virus, cytomegalovirus
Mycoplasma pneumoniae
Rickettsiae
Leptospirosis
The differential diagnosis of IVIG (intravenous immunoglobulin) resistant KD includes polyarteritis nodosa, systemic onset juvenile idiopathic arthritis, and malignancy (particularly lymphoma).

17. The cause of KD is…

18. … nature & nurture

19. Genetics

20. Genetics of KD

21. KD is polygenic Mannose binding lectin: ambiguous role ACE MMP
TNF alpha (IVIG resistance)
IL-10 promoter
Chemokines (CCR5)
IL-18 promoter (Taiwanese)
IL 1 beta- no association
eNOS/iNOS not associated with CAA in Japanese
Fc gamma so far not associated

22. No infectious cause yet found

23. For and against Superantigens in KD
Studies for
Studies against
Seroconvert (IgG and IgM) for SAgs (Matsubara et al 2006, CEI)
T cell activation consistent with SAg mediated disease (Brogan et al 2008, CEI)

24. A new RNA virus? Rowley et al PIDJ 2011

25. Treatment

26. Treatment IVIG 2g/kg over 12 hours
Aspirin mg/kg/day (4 divided doses)
Then 2-5 mg/kg/od 48 hours after fever settles
Fever recrudescence/IVIG resistance:
Repeat IVIG
OR corticosteroids
OR Infliximab

27. Recent developments in KD Rx

28. 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 CAA at 1 month in those receiving IVIG AND prednisolone (11.2% versus 2.4%)

29. Corticosteroids as adjunctive first line Rx?
Newburger JW et al. Randomized trial of pulsed corticosteroid therapy for primary treatment of Kawasaki disease. NEJM 2007; 356:
No effect on CAA

30. Rationale for blocking TNF-α in KD
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:

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
Brogan RJ et al Pediatr Rheumatol Online J Jan 21;7:3.
TNF-a blocking agents
? part of the therapeutic arsenal combating life-threatenig primary vascular inflammation

32. Infliximab Chimeric monoclonal antibody against TNFα Dose 6mg/kg IV
?repeat after 2 weeks if ongoing inflammation (consider differential diagnosis)

33. KD outcome 25 % CAA untreated 4-9% CAA with IVIG and aspirin
IVIG resistance 15-20%
V high risk of CAA: 20-30%
The acute mortality rate due to myocardial infarction <1%

34. Follow up Stop aspirin if echo at 6/52 normal Continue if CAA present
Giant aneurysms (>8mm) never resolve:
Aspirin and warfarin (heparin until INR 2-3)
Long term follow up

35. 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

36. Does KD cause premature atherosclerosis?

38. GOSH KD follow up study

39. Hypothesis: KD predisposes to premature atherosclerosis (or vasculopathy) in UK patients
We are studying:
Subclinical endothelial injury
Sub-clinical inflammation
Arterial stiffness (vicorder PWV)
Carotid intimal medial thickness
Years after KD

40. Take home messages
HSP and KD are the commonest paediatric vasculitides
KD still kills children- limited window of opportunity to influence outcome: switch off the inflammation ASAP
Earlier use of steroids and infliximab ie after 1 dose of IVIG
Polygenic and no infectious cause yet found
Does KD predispose to premature atherosclerosis?