Understand Kawasaki Disease and learn proper treatment algorithm and agents.

1. KAWASAKI DISEASE
PPE III/IV
PHAR 660/665
ZEINAB NOORMONAVAR
4/17/2021
1
1

2. TOMISAKU KAWASAKI
 Tomisaku Kawasaki was a Japanese pediatrician who first described the condition now known as
Kawasaki disease in the 1960s.
2 https://en.wikipedia.org/wiki/Tomisaku_Kawasaki

3. OUTLINE
At the end of the presentation we’ll be able to:
Recall the pathophysiology, diagnosis, symptoms, epidemiology of
Kawasaki Disease.
Identify the classification and pharmacological treatment modalities
Learn the different drugs used
3

4. DEFINITION OF KAWASAKI DISEASE
• Kawasaki disease (KD), formerly known as Mucocutaneous Lymph Node
Syndrome and Infantile Polyarteritis Nodosa
• It’s an acute febrile illness characterized by inflammation of blood vessels
(Vasculitis) throughout the body that primarily affects young children and
infants.
• It’s considered to be the leading cause of acquired heart disease in children
worldwide.
4 https://pubmed.ncbi.nlm.nih.gov/28356445/

5. EPIDEMIOLOGY
80% of cases in children < 4 years
Male : Female = 2:1
Highest incidence occurring in East
Asian (Japan, Taiwan, Korea) children.
Positive family history in 1% but 13%
risk of occurrence in twins.
Infants <6 months and children >5
years are at the highest risk of CAA.
One-fourth of adult KD cases have
occurred in patients with human
immunodeficiency virus (HIV)
infection.
Seasonal variation- More cases in
winter and spring but occurs
throughout the year.
5 https://www.cdc.gov/kawasaki/about.html#

6. https://www.e-cep.org/m/journal/view.php?number=20125553556

7. RISK FACTORS
ETHNICITY
SEX
AGE
7 https://www.mayoclinic.org/diseases-conditions/kawasaki-disease/symptoms-causes/syc-20354598
Less than 5 years

8. PATHOPHYSIOLOGY
• The etiology of KD remains unknown. A variety of theories have been
proposed based upon pathologic, epidemiologic, and demographic data.
• Theories:
8
Immunologic
response
Infectious
etiology
Genetic
factors
Multisystem
inflammatory
syndrome
https://emedicine.medscape.com

9. PATHOPHYSIOLOGY
Immunologic Response:
 affects medium-sized arteries, especially the coronary arteries.
 The unknown stimulus cause the inflammatory cell infiltration into vascular tissues 
vascular damage.
 The destruction of elastin and collagen fibers and loss of structural integrity of the
arterial wall lead to dilatation and aneurysm formation.
 Inflammatory cells are:
• Neutrophils
• T cells = CD 8
• Eosinophil
• Plasma cell = Ig A
9 https://www.nature.com.

10. PATHOPHYSIOLOGY
Infectious etiology:
 KD is caused or triggered by a transmissible agent or agents.
 Similar clinical presentation to Adenovirus, Measles and Scarlet fever.
 No studies have convincingly identified a specific virus, bacteria or bacterial toxin, or
other pathogen associated with KD.
10 https://www.nature.com.

11. PATHOPHYSIOLOGY
Multisystem inflammatory syndrome:
 Coronavirus disease 2019 (COVID-19) is associated with hyper inflammatory syndromes.
 Children may develop organ failure involving the gastrointestinal tract, heart, central
nervous system, kidneys, and other systems.
 The severe inflammation, cytopenias, coagulopathy, and hyper ferritinemia are similar to
macrophage activation syndrome or toxic shock in some children.
11 https://www.nature.com.

12. PATHOPHYSIOLOGY
Genetic factors:
 Increase frequency of the disease in Asian and Asian-American populations and among
family members.
 Variants or polymorphisms that are associated with an increased susceptibility to KD:
• Inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene on chromosome 19q13.2. ITPKC acts as a
negative regulator of T cell activation which act more vigorously than normal.
• Upregulation of Angiopoietin 1 (ANGPT1)
• Downregulation of Vascular endothelial growth factor A (VEGFA) genes
• The genes encoding the chemokine receptor CCR5 and its major ligand CCL3L1
• ATP binding cassette, subfamily C, member 4 (ABCC4) gene
12 https://www.nature.com.

13. CLINICAL MANIFISTASTIONS
Fever
• Most consistence manifestation
• Above 38.5 ºC during most of the illness
Conjunctivitis
• Bilateral non-exudative conjunctivitis is present in more than 90
percent of patients.
Lymphadenopathy
• Primarily involve the anterior cervical nodes overlying the
sternocleidomastoid muscles
• >1.5 cm in diameter
13

14. CLINICAL MANIFISTASTIONS
MUCOSITIS
 Often becomes evident as KD progresses.
 Cracked, red lips and a "strawberry
tongue"
RASH
 Polymorphous
 Begins during the first few days of illness.
 Perineal erythema and desquamation,
followed by macular, morbilliform, or targetoid
skin lesions of the trunk and extremities.
EXTREMITIES CHANGES
 Last manifestation to appear
 Indurated edema of the dorsum of their
hands and feet
 Desquamation that begins in the
periungual region of the hands and feet
CARDIOVASCULAR
 First week to 10 days of illness
 Tachycardia, Muffle sound, Fusiform
aneurysms
 Infants may have cold, pale, or cyanotic
digits of the hands and feet due to reduced
perfusion
14 https://www.mayoclinic.org/diseases-conditions/kawasaki-disease/diagnosis-treatment/drc-20354603

15. Liver
Enzyme
• ALT
• AST
Albumin
Laboratory
Tests
15 https://www.utmb.edu/pedi_ed/CoreV2/Cardiology/cardiologyV2/cardiologyV218.html

16. DIAGNOSIS
• Presence of Fever lasting for at least 5 days + 4 or 5 of below criteria:
16
+
Fever
Bilateral bulbar
conjunctiva
Oral mucus membrane
changes
Peripheral
extremity
changes
Polymorphous rash
Cervical
lymphadenopathy
Kawasaki Disease
https://onlinelibrary.wiley.com

17. https://www.uptodate.com
17

18. TREATMENT
18
Primary
• IV Immune Globulin
+
• Aspirin (ASA)
Adjunctive
• Corticosteroid
• Infliximab
• Etanercept
Alternative
• Cyclosporine
• Anakinra
• Cyclophosphamide
https://www.ahajournals.org

19. 19
Patient diagnosed with Kawasaki Disease
Asses patient’s risk for IVIG risk
https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000484
For Japanese patient: use the KOBAYASHI criteria (≥5 consider high risk)
 Sodium ≤ 133 mmol/L (2 POINTS)
 Aspartate aminotransferase ≥ 100 IU/L (2POINTS)
 CRP ≥ 10 mg/dL (1 POINT)
 Neutrophils ≥ 80% of the WBC-D (2 POINTS)
 Platelet count ≤ 300,000/mm3 (1 POINT)
 Days of illness at initial treatment ≤ 4 (2 POINTS)
 Age ≤ 12 months (1 POINT)
For non-Japanese patient: (≥3 considered high risk)
 Enlarged CAs on echocardiogram with maximum Z-score at baseline ≥2.00 (2 POINTS)
 Age at fever onset < 6 months (1 POINT)
 Any Asian race reported (1 POINT)
 CRP > 13 mg/Dl (1 point)

20. Patient diagnosed with Kawasaki Disease
Asses patient’s risk for IVIG risk
Low Risk High Risk
Standard initial therapy: Combination
• IVIG: 2g/kg × 1 dose over 8-12 hours
• Aspirin: initially 30-50 mg/kg/day OR 80-100
mg/kg/day orally in 4 divided dose.
 Maximum: 4 g/day
 Decrease dose to 3-5 mg/kg/day 48 hours after
resolution of fever
 Stop after normalize of ESR unless CA
abnormalities detected
Adjunctive initial therapy: all of 3 agents
• IVIG: 2g/kg × 1 dose over 8-12 hours
• Aspirin: initially 30-50 mg/kg/day orally in 4 divided
dose.
 Maximum dose: 4 g/day
• Prednisone/ Prednisolone: 2mg/kg/day IV/PO in
two divided doses for 10 days (max dose: 60mg), then
1 mg/kg/day for 5 days.
• Etanercept: further studies needed
20 https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000484

21. 21
Agents MOA SE
IVIG (Gammagard®)
Offer passive immunity by
increasing antibody titer and
antigen-antibody reaction potential
Acute renal dysfunction and renal failure
Headache, Fatigue, N/V, Chills
Aspirin
Inhibit synthesis of prostaglandin by
cyclooxygenase, Antiplatelet
Bronchospasm, GI pain, Hearing loss
Reye syndrome
Prednisone
Glucocorticosteroid, anti-
inflammatory
Sodium water retention, Osteoporosis
Skin atrophy, Weight gain
Etanercept (Enbrel®) Bind and inactivates TNF
URTI, Injection site reaction, Diarrhea
and Rash
 All children ≥6 months should receive a seasonal influenza vaccine, as should their family members.
 Only inactivated vaccine should be administered to children on aspirin therapy.
 Concomitant use of ibuprofen antagonizes the irreversible platelet inhibition induced by ASA. thus,
ibuprofen generally should be avoided in children with coronary artery aneurysms taking ASA for its
antiplatelet effects.
https://www.medscape.com
https://www.ahajournals.org

22. 22
IVIG RESISTANCE
Approximately 10% to 20% of patients with KD have
persistent or recurrent fever at least for 36 hours after end
of primary therapy with IVIG plus ASA.
Many studies have shown that patients who are resistant
to initial IVIG are at increased risk of developing Coronary
Artery Abnormalities.
It is likely that host genetic factors, such as polymorphisms
in the Fc gamma receptors, play a role in both the
response and resistance to IVIG.
https://www.nhlbi.nih.gov

23. 23 https://www.ahajournals.org

24. 24
Agents MOA SE
Infliximab (Remicade®)
Recombinant humanized
monoclonal anti-TNF-a antibody
Development of antinuclear
antibodies, Infection, URTI,
Abdominal pain
Cyclosporine (Sandimmune®)
Calcinurin inhibitor, suppress
cellular and humoral immunity
(mainly T cells)
Tremor, Nephrotoxicity, HTN,
Headache, infection
Anakinra (Kineret®) IL-1 receptor antagonist
Injection site reaction,
Headache, Arthralgia,
Vomiting
Cyclophosphamide (Endoxan®)
Potent immunosuppressant
activity
Neutropenia, Fever, Vomiting,
Anorexia, Diarrhea
https://www.medscape.com
https://www.ahajournals.org

25. 25
FOLLOW UP
Monitoring
for Fever
Cardiac
Evaluation
Physical
Activity
Vaccination
McCrindle BW, Rowley AH, Newburger JW, et al. Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart
Association. Circulation 2017; 135:e927.

26. 26
• There has been apparent cluster of children
presenting with Kawasaki disease (KD)-like
symptoms in United Kingdom, United States
and Italy.
• Some of these children patients have
confirmed SARS-CoV-2 infections by RT-PCR.
• The relationship of KD to COVID-19 is not
yet defined, there is growing concern of
SARS-CoV-2 infection related inflammatory
syndrome as a possible link between
coronavirus infection and KD affecting
young children.
• SARS-CoV-2 infection and hyper
inflammation in COVID-19 could be acting as
the "priming trigger" that could lead to KD.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247462/

27. • COVID-19 cases of children in the UK, US and
Italy show KD-like symptoms which sparks
concern about a possible link to COVID-19, as
both disease show similar signs of fever. KD
causes vascular inflammation and restricts
blood flow to the heart.
• Patients with KD and tested positive for
COVID-19 have 25% higher risk for Coronary
Artery Aneurysm (CAA).
• Therefore, KD patients should be closely
monitored for potential COVID-19 infection
and quarantined after IVIG infusion and
patient discharge if tested positive for SARS-
CoV-2 infection.
• It is important to administer IVIG within 7
days since disease onset till KD symptoms
gone and COVID-19 test negative.
• Further studies needed to define mechanistic
link between COVID-19 and KD.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247462/
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