1. 1st Philippine Kawasaki Disease Summit
Philippine Heart Center
February 9-10, 2015

2. Course
Red flags in the diagnosis and interpretation of its five diagnostics criteria
Definition and presentation of incomplete and atypical Kawasaki Disease
Presentation of management based on medical evidence and recent studies on its etiology and pathogenesis
Establish clinical pathways in diagnosis and follow-up
Develop a Philippine Registry for Kawasaki Disease

3. KAWASAKI DISEASE Acute febrile illness of infants and childhood
Primary systemic vasculitis of medium sized blood vessels predilection for coronary arteries

4. EPIDEMIOLOGY Top 3 Country with increased incidence rates of KD:
Japan
Korea
Taiwan
PPS Registry
Total Admission from Jan 2007 to Dec 2014 is 2,171,491
Peak Incidence of KD is 1-5 years old with male preponderance

5. ETIOLOGY Remains an area of controversy
Immunulogic Response/Infectious/Genetics
Infectious agent in genetically susceptible individuals

6. PRINCIPAL DIAGNOSTIC FEATURES
Fever
Eye Changes
Erythematous Rash
Hand and Foot Changes
Indurative edema
Palm and sole erythema
Convalescent desquamtion
Mouth Changes
Red cracked lips
Strawberry tongue
Oral-pahryngeal erythema
Cervical Lymph Node Enlargement >1.5cm

7. 1. Fever High spiking and remittent (>39.9) for at least 5 days
May be intermittent
Persists 1-2 weeks without treatment but may continue for 3-4 weeks
May not respond to anti-pyretics
Resolves 1-2 days after treatment with IVIg

8. 2. Eye Changes >75% of patients
Few days after the onset of fever and lasts 1-3 weeks
Bilateral nonexudative bulbar conjunctival injection with relative sparing around the limbus
Slit lamp examination: mild iridocyctitis or anterior uveitis
Rarely associated with eye pain or photophobia

9. 3. Rash
>90% of patients
Polymorphic exanthem within 3-5 days of the onset of fever
Nonspecific erythema of the palms, soles, and perineal regions, which gradually and diffusely involves the trunk and extremities
Pruritic, macular, papular, morbiliform, scarlatiniform, urticarial, erythrodermatous, targetoid or fine micropustules
Fine desquamation few days after onset
Never vesicular or bullous
Crust formation at BCG site

10. 4. Extremity Changes 50 – 85% of cases
Initial erythema, palms and soles gradually become indurated and painful, which may limit mobility
Last manifestation of appear
Desquamation occur during the subacute phase of the illness (14 days after the onset of fever)
Glovelike fashion: periungual region of the fingers  week later similar desquamation of the toes

11. 5. Mucositis First few days after the onset of fever
Erythema of the oral and pharyngeal mucosa
Dry, erythematous, fissured lips that bleed easily (75-90%)
Strawberry tongue with prominent papillae and erythema (50-77%)
No oral exudates or ulcerations

12. 6. Cervical Lymphadenopathy
Least common
70% of cases in Japan, 50-86% of cases in the US
Unilateral, nontender, nonsuppurative anterior cervical lymphadenopathy
Single node larger than 1.5cm in diameter

13. Cardiovascular Findings
Not part of the diagnostic criteria
Support the diagnosis
Most conditions that mimic KD do not involve the heart
Acute phase: tachycardia out of proportion of the degree of fever, gallop sounds, and muffled heart tones

14. Arthritis Not included in the diagnosis 7.5-25% of patients with KD
More likely to have increased levels of inflammatory markers
No differences in clinical feature, response to therapy, or clinical outcome between patients with or without arthritis

15. Associated Features: Acute Disease
Brain-irritable behavior, Sleep distrubances, Lethargy, Semi-coma
90%
Urethritis & Pyuria, Meatal ulcer
60%
Liver
Elevated liver enzymes, Jaundice
Gall bladder hydrops
40%
10%
Arthritis
33%
Abdominal Pain, Vomiting, Diarrhea
20%
Cardiac Dysfunction (acute Symptoms
>10%
Aseptic Meningitis
Self-limited, episodic; features are additive not always present at the same time

16. ACUTE PHASE
SUBACUTE PHASE
CONVALESCENT PHASE
CHRONIC PHASE
Days 0-11
Days 11-21
Days 21-60
?Years
Fever, Conjunctival Changes, Changes in Lips and Pharynx, Rash, Changes in Extremities, Irritability
Periungual
Desquamation
Beau’s Lines
Platelet Count Normal
Markedly elevated
May still be elevated
Complications:
Early Arthritis, Myocarditis, Pericarditis, Mitral Insufficiency, Uveitis, Meningitis
Arthritis, Coronary Aneurysm, Coronary Thrombosis, Mitral Insufficiency
Arthritis, Coronary may persist, Coronary and Peripheral Aneurysms
Angina Pectoris, and/or Myocardial Infarction
Cause of Death:
Myocarditis
Myocardial Infarction, Myocarditis, Rupture of Aneurysm
Myocardial Infarction, Ischemic Heart Disease

18. LABORATORY FINDINGS HEMATOLOGIC
Leukocytosis with granulocyte predominance
Appears during the acute stage
50% have WBC >15,000/mm3
Leukopenia is rare
Normocytic and normochromic anemia
Severe Hemolytic Anemia is rare but may occur as reaction to IVIG
No laboratory findings are included in the diagnostic criteria for typical KD

19. LABORATORY FINDINGS Hematologic Thrombocytosis Thrombocytopenia
500,000 to >1,000,000/mm3
Appears on the second week of illness
Peaks in the third week of illness
Returns to normal by the 4th to 8th week of illness
Thrombocytopenia
rarely in acute stage
Sign of DIC
Risk factor for coronary aneurysm
No laboratory findings are included in the diagnostic criteria for typical KD

20. LABORATORY FINDINGS Inflammatory markers
Returns to normal by 6-10 weeks after onset
ESR: Elevated (≥40mm/hr)
CRP: Elevatec (≥30mg/dl)
No laboratory findings are included in the diagnostic criteria for typical KD

21. LABORATORY FINDINGS Blood Chemistry
Mild to moderate elevation of serum transaminases in ≤ 40%
Mild hyperbilirubinemia in 10%
Plasma gammaglutamyl transpeptidase elevation in 67%
Hypoalbuminemia
Common
Associated with more severe and more prolonged acute disease (<3.5g/dl)
Elevation of triglycerides and LDL, and decreased HDL  returns to normal within weeks or months following IVIg therapy
Hyponatremia (<135mEq/L) may be seen and is associated with an increased risk of CA aneurysms
No laboratory findings are included in the diagnostic criteria for typical KD

22. LABORATORY FINDINGS Urinalysis Lumbar puncture Cardiac Troponin I
Intermittent mild to moderate sterile pyuria in 33%
Lumbar puncture
Aseptic Meningitis in 50%
Cardiac Troponin I
Specific for myocardial damage
Does play a role in the routine management of KD
Arthrocentesis of involved joints typically demonstrate pleocytosis, 125,00 to 300,00 WBC/mm3, primarily neutrophils
No laboratory findings are included in the diagnostic criteria for typical KD

23. Stages of Microvascular Pathology
Stage 1 (0-9 days)
Microvascular angitis
Acute endoarteritis and perivasculitis of major coronary arteries
Pericarditis, valvulitis and andocarditis
Myocarditis including arterioventricular conduction system
Causes of death: heart failure and dysrhythmia

24. Stages of Microvascular Pathology
Stage 2 (12-25 days)
Panvasculitis of major coronary arteries with aneurysms and thromobus formation
Intimal proliferation of coronary arteries
Myocarditis, endocarditis and pericarditis
Causes of death: heart failure, dysrhythmia, myocardial infarction, aneurysm rupture

25. Stages of Microvascular Pathology
Stage 3 (28-31 days)
Granulation of coronary arteries
Marked intimal thickening
Disappearance of microvascular angitis
Causes of death: myocardial infarction

26. Stages of Microvascular Pathology
Stage 4 (40 days – 4 years)
Scaring, stenosis, calcification and recanalization of major coronary arteries
Fibrosis of myocardium and endocardium
Causes of death: myocardial infarction

27. IMMUNOLOGY
KD is characterized by an acute systemic inflammatory process with possible sequelae of chronic inflammatory vascular damage
Cascade of complex immune reaction
Immunogenetics do have a role in the susceptibility, pathogenesis, response to treatment and sequelae
Genetic polymorphisms exist among KD patients but vary depending on race and ethnicities

28. INCOMPLETE KAWASAKI DISEASE
Patients who do not fulfill the Clinical Criteria for Classic KD
Atypical KD
Reserved for patients who presents with other problems such as renal impairment that is not generally seen in KD
Diagnosis that is often based on echocardiographic findings of coronary abnormalities
Most common manifestation is fever and rash
Least common manifestation is lymphadenopathy

29. Guidelines for Diagnosis of Incomplete KD (AHA)
Children <6 months of age with incomplete presentation might have:
Unexplained fever for >5 days
Associated with 2 or 3 principal clinical features in the acute phase
Supplemental Laboratory & Echo
Criteria recommended by AHA with more than 3 laboratory criteria to support diagnosis

30. Supplemental Laboratory Criteria
Serum albumin <3.0g/dl
Anemia for age
Elevation of ALT
Platelets after 7 days >450,000/mm3
WBC >15,000/mm3
Urine WBC >10/hpf

31. Algorithm for Incomplete KD

32. 2D ECHO INDICATIONS Establish a baseline
Increase suspicion of KD when clinical criteria for KD are incomplete
Helpful in guiding appropriate therapy
Surveillance for coronary artery changes and its complication

33. Echocardiography & Incomplete KD
Echo should be considered in:
Any infant aged < 6 months with fever >7days duration
Laboratory evidence of systemic inflammation
No other explanation for the febrile illness

34. Cardiovascular Changes Acute and Subacute Phase
PANCARDITIS
MR, TR, AR
Mycordial dysfunction
Pericardial effusion
CORONARY ARTERY ABNORMALITIES
Perivascular inflammation
Ectasia
Aneurysm

35. Cardiovascular Changes Chronic Phase
CORONARY ARTERY ABNORMALITIES/SEQUELAE
Coronary artery insufficiency
Regional and global dysfunction
Ischemia related AV valve dysfunction
Coronary artery stenosis
Chronic fibrosis and thickening
Thrombus formation

36. Characteristics of Coronary Artery Abnormalities
Perivascular brightness
Coronary ectasia
Coronary artery enlargement without aneurysm
Coronary artery aneurysm
Saccular-axial and longitudinal dimensions are almost equal
Fusiform-axial dimension is less than longitudinal dimension

37. Characteristics of Coronary Artery Abnormalities

38. Quantitative Assessment
Internal Vessel Diameter (AHA)
Z Score
Small to Medium
>3mm - <6mm
+3 to + 7
Large
≥ 6mm
Giant
> 8mm
≥ +10
Japanese Ministry of Health Definition of Coronary Artery Dilatation
Internal Diameter
Age
>3mm
<5 y/o
>4mm
≥5 y/o
Internal Diameter is at least 1.5 times the diameter of a adjacent coronary segment
Coronary artery lumen is clearly irregular

39. Echocardiogram Positive
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:
Perivascular brightness of CA
Lack of tapering of coronary arteries
Decreased LV Contractility
Mild Valvular Regurgitation
Pericardial Effusion
Z score in LAD or RCA of 2 to 2.5

40. Coronary Artery Complications
Coronary artery DILATATION
Arterial dilatation greater than
2mm in children younger than 2y/o
2.5mm in children older than 2 y/o
Coronary artery ANEURYSM
Presence of arterial dilatation >4mm
Giant aneurysm: arterial dilatation of >8mm

41. CORONARY ARTERY IMAGING
Selective Coronary Angiography/Conventional Angiogram
Gold standard in the evaluation of coronary lesion
Invasive nature, radiation exposure, contrast
Not generally accepted as a routine follow-up
Low level of acceptance by parents
Computed Tomography/Coronary CT Angiography
Able to evaluate both cardiac and extracardiac structures of the chest
Identify plaque even without stenosis
High detection rate for calcifications
Less invasive, reduced risks and complications, fast, lower cost

42. THERAPY
Single dose of IVIG at 2g/kg initiated within 10 days of fever if possible
Children who present after 10 days of fever still should be treated if fever or other signs of persistent inflammation are present (elevated ESR and CRP)
High dose Aspirin at mkday is divided into four doses, administered initially for its anti-inflammatory effect the Low dose Aspirin at 3-5mkday orally after deverfescence for its anti-thrombotic effect

43. THERAPY Researches on Infliximab
chimeric monoclonal antibody that specifically binds TNF α
Suppress the inflammation but not the coronary artery abnormality

44. Prevention of Thrombosis in Patient with Coronary Disease
Anti-platelet therapy – plays a critical role in managing patients at every stage
Aspirin ± dipyridamole or clopidogrel
Anti-coagulant therapy – warfarin or LMWH
Cases of rapid expansion of aneurysm
Prevention of thrombosis and modification of the evolution of the derangement of the coronary shape and size
Or combination usually of warfarin + ASA

45. Treatment of Coronary Thrombosis
Goals of therapy: reestablishing the coronary patency, salvaging the myocardium, and improving survival
Target multiple steps in the coagulation cascade
Streptokinase, urokinase, and tissue plasminogen activator (tPA): adults
Glycoprotein Iib/IIIa Inhibitor (Abciximab)
Great potential for improving outcomes when administered with ASA and heparin with/without thrombolytics in adults

46. Treatment of Coronary Thrombosis Surgical Management
Primarily: Coronary Artery Bypass Grafts for obstructive lesions
Indications (not been established)
Reversible ischemia present on stress-imaging test results
Myocardium to be perfused still viable
No appreciable lesions present in the artery distal to the planned graft site
Indicated after recurrent MI due to unfavorable prognosis

47. Treatment of Coronary Thrombosis Interventional Cardiac Catheterization
Balloon Angioplasty, Rotational Ablation, Stent Placement
Indications
Ischemic symptoms
Without ischemic symptoms but with reversible ischemia on stress test
Without ischemia but with ≥ 75% stenosis in LAD
Contraindication
Vessels with multiple, ostial or long segment lesions

48. Treatment of Coronary Thrombosis Cardiac Transplantation
Only for severe, irreversible myocardial dysfunction and coronary lesions for which interventional catheterization or bypass are not feasible

49. REFRACTORY KD IVIG resistant KD
Persistent or Recrudescent fever (T38) ≥ 36 hours after completion of the initial IVIG infusion
Corticosteroids
Most common regimen: IV pulse methylprednisolone, 30mg/kg for 2-3 hours, once daily for 1-3 days

50. Predictors of Non-responsive to IVIG
SCORE
Age ≤ 6 months 1
Days of illness at initial IVIG ≤ 4 days
Platelet count ≤ 300,000
ALT ≥ 80 IU/L 2
CRP ≥ 8mg/dl
Score ≤ 3 predicts responsive to IVIG
Score > 3 predicts resistance to IVIG
Sensitivity 78%, specificity 76%

51. KOBAYASHI 2006 Predict IVIG Resistance (112 Resistant, 434 Responsive)
AST ≥ 100 IU/L 2
Serum Na ≤ 133mmol/L
KD diagnosis ≤ 4 days
% PMNs ≥ 80
CRP ≥ 10mg/dl 1
Age ≤ 1 y/o
Platelet ≤ 300,000
Low Risk 0-3 points
High Risk ≥ 4 points
Sensitivity 76%, Specificity 80%

52. RISK SCORES FOR PREDICTING ANEURYSM
Duration of Fever
Reflects severity of ongoing vasculitis
Persistent of recrudescent fever is the single strongest risk factor for the development of coronary artery aneurysms

53. HARADA SCORE
Determine the risk of coronary artery aneurysm and the subsequent need for IVIG
At least 4 of the following criteria within 9 days of onset:
WBC >12,000/mm3
Platelets <350,000/mm3
CRP >3+
Hct <35%
Albumin <3.5g/dl
Age <12 months
Male sex

54. ASAI Higher Risk for Death Prior to Echocardiography
Male Sex
Age < 1 y/o
Fever ≥ 14 days or Relapse
Hgb < 10
WBC > 30, 000
ESR >101
Cardiomegaly
Arrythmias, increased QR ratio in II, III and AVF

55. Recommendations for Follow-up Imaging
Coronary artery changes followed up at 2-3 weeks, one month, 3-4 months, and 1-4 years after and every 5 years
2 weeks
Appearance of cardiac abnormalities
6-8 weeks after diagnosis
Transient changes in coronary dilatation and ectasia are often resolve
In Complex cases
Imaging is performed as indicated by clinical abnormalities
Annual follow-up
For chronic coronary artery abnormalities

56. Complex Cases
Giant Coronary Artery Aneurysm for Surveillance of Thrombus Formation
At least twice per week
Once weekly on the 1st 45 days of illness
Monthly until the 3rd month of the disease
Once every 3 months until the end of the 1st year of illness

57. Long Term Follow up Regression and Evolution of Coronary Lesions
Lesions change dynamically with time
50% to 67% resolved 1 to 2 years after onset
Positive Association
Initial size
Age at onset < 1 y/o
Fusiform morphology
Aneurysm located in a distal coronary segment
Rupture can occur – exceddingly rare

58. Hyperlipidemia Screening
Birth – 2 years: no lipid screening
2 – 8 years: screened high risk children (FHx of diabetes, HPN or Obesity and Kawasaki with CA)
9 – 11 years: Universal Screening
12 – 16 years: no routine screening
17 – 21 years: Universal Screening should be repeated once

59. I. No Coronary Changes at any Stage of Illness
Pharmacologic Therapy
none beyond 6-8 weeks
Physcial Activity
No restrictions beyond 6-8 weeks
Follow-up and Diagnostic testing
CV risk assessment, counselling at 5 year intervals
Invasive Testing
None recommended

60. II. Transient CA Ectasia resolved within 6-8 weeks
Pharmacologic Therapy
none beyond 6-8 weeks
Physcial Activity
No restrictions beyond 6-8 weeks
Follow-up and Diagnostic testing
CV risk assessment, counselling at 3-5 year intervals
Invasive Testing
None recommended

61. III. Single Small or Medium Size Aneurysm in One Major Artery
Pharmacologic Therapy
Low dose ASA until regression documented
Physcial Activity
No restrictions beyond 1st 6-8 weeks in < 11y/o
11-20 y/o: restrictions based on stress test/myocardial perfusioon scan
Contact/high impact discouraged if taking anti-ply drugs
Follow-up and Diagnostic testing
Annual exam, Echo, EKG
CV risk assessment, counselling
Invasive Testing
Angiography (suggestion of ischemia)

62. IV. Aneurysm without Stenosis
Pharmacologic Therapy
Long term antiplatelet tx and warfarin or LMWH
Physcial Activity
Restrictions based on stress test/myocardial perfusioon scan
Contact/high impact avoided due to risk of bleeding
Follow-up and Diagnostic testing
Biannual exam, Echo, EKG (twice a year)
Annual stress test/myocardial perfusioon scan
Invasive Testing
months, sooner/repeated if cllinically indicated
Elective repeat in certain circumstances

63. V. Obstruction Pharmacologic Therapy
Long term low dose ASA ± warfarin or LMWH if giant aneurysm persists
Consider β blockade to reduce myocardial O2 comsumption
Physcial Activity
No contact/high impact sports
Other activities guided by stress test/myocardial perfusion scan
Follow-up and Diagnostic testing
Biannual exam, Echo, EKG
Annual stress test/myocardial perfusioon scan
Invasive Testing
Angiography indicated to assess lesions and guide therapy
Repeat angiography with change in symptoms

64. Diagnostic Pitfalls
Rash and mucosal changes mistaken for Antibiotic reaction for bacterial lymphadenitis
Sterile pyuria mistaken for partially treated urinary tract infection
CSF pleocytosis mistaken for viral meningitis