kawasaki%20disease
KAWASAKI DISEASE
Kawasaki disease is an acute, febrile illness that is self-limited. It is a systemic vasculitic syndrome that primarily involves the medium- and small-sized muscular arteries of the body.
It is also known as mucocutaneous lymph node syndrome.
It affects primarily children <5 years old with peak incidence in 1-2 year of age.
The cause remains unknown but current research supports an infectious origin.
Epidemiological findings suggest that genetic predisposition and environmental factors play a role in the pathogenesis of the disease.

Principles of Therapy

  • The goals of treatment in the acute phase are to:
    • Rapidly reduce the inflammation in the coronary arteries
    • Minimize the incidence & progression of coronary artery aneurysm
    • Prevent arterial thrombosis
  • Long-term therapy in individuals who develop coronary artery aneurysm is aimed at preventing myocardial ischemia or infarction

Pharmacotherapy

Primary Disease

  • Treatment of intravenous immunoglobulin (IVIG) & Aspirin is given w/in the 7th-10th day of onset of illness
    • The treatment regimen has an overall systemic anti-inflammatory effect in approximately 80% of patients & reduces the formation of aneurysm to<5%
    • Treatment should be initiated once coronary artery aneurysm is detected in a patient prior to fulfilling all the diagnostic criteria

Intravenous Immunoglobulin (IVIG)

  • Efficacy of intravenous immunoglobulin (IVIG) administered in the acute phase in reducing the prevalence of coronary artery abnormalities is well established
  • It also reduces the inflammation of the vessel walls involved by the disease
  • It is recommended that intravenous immunoglobulin (IVIG) be administered in Kawasaki Disease patients before the 10th day of illness, either having persistent fever of unknown origin/cause, or significant elevation of  erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) & serum amyloid-A (SAA)
  • Intravenous immunoglobulin (IVIG) should not be administered in patients in whom the diagnosis of Kawasaki disease has been missed earlier or if it occurred retrospectively w/o persisting lab findings of inflammation

Aspirin

  • Used to reduce inflammation & to inhibit platelet aggregation; however, it does not lower the frequency of the development of coronary abnormalities
  • Recommended dose: 30-100 mg/kg/day, until normalization of inflammatory markers, specifically  C-reactive protein (CRP)
  • After the acute phase, dose can be reduced to a single daily dose of 3-5 mg/kg; continue the dose for at least 6-8 weeks or longer if echocardiography shows coronary changes
  • High-dose Aspirin is aimed at reducing fever & inflammatory signs related to Kawasaki disease
  • Low-dose Aspirin in the subacute phase is aimed at reducing the risk of thrombosis in patients showing coronary artery dilations

Flurbiprofen

  • A potential alternative to Aspirin in patients w/ severe hepatic impairment
  • Further studies are needed to establish its efficacy on acute Kawasaki disease

Clopidogrel

  • May be a potential alternative to patients w/ an allergy to Aspirin or w/ concomitant varicella & influenza infection
  • Efficacy & safety have not been established in children

Corticosteroids

  • Usefulness in the initial treatment of Kawasaki disease is not well established
  • A recent study showed that there is a high regression rate of coronary artery aneurysm, including giant aneurysms, after intravenous immunoglobulin (IVIG) infusion followed by pulse IV Methylprednisolone at a dose of 30 mg/kg for 3 consecutive days

Pentoxifylline

  • Therapeutic adjunct to standard therapy
    • Inhibits tumor necrosis factor-α (TNF-α ) & messenger ribonucleic acid (mRNA) transcription
  • Role as part of initial treatment in Kawasaki Disease is uncertain

Refractory Kawasaki Disease

Intravenous Immunoglobulin (IVIG)

  • Repeat doses of intravenous immunoglobulin (IVIG) are usually given 36 hours after completion of the first dose
  • Retreatment w/ 2 g/kg intravenous immunoglobulin (IVIG) is recommended; doses can be repeated for a total of 3 infusions

Corticosteroids

  • Reduce fever but effects on coronary artery abnormalities are uncertain
    • High incidence of giant aneurysms & coronary artery rupture have been reported
  • Treatment should be restricted in patients in whom ≥2 infusions of have been ineffective in alleviating fever & acute inflammation
  • Most commonly used steroid regimen is IV Methylprednisolone 30 mg/kg 24 hourly for 3 consecutive days

Tumor Necrosis Factor (TNF) Inhibitors

  • Infliximab
    • Has been shown to be successful in patients refractory to intravenous immunoglobulin (IVIG) & corticosteroids
    • Reverses the clinical signs of Kawasaki disease
    • May be used in patients w/ severe coronary artery disease, w/o any substantial side effects
    • Reduces cytokine-mediated inflammation but has no effect in suppressing vascular cellular infiltration
    • Further studies are needed to establish its effect in reducing the prevalence of coronary artery aneurysms
  • Etanercept
    • Therapy has lead to defervescence w/o increase in coronary artery diameter or new coronary artery dilation
    • Further studies are needed to establish its use in the treatment of Kawasaki disease
  • Ulinastatin
    • A human urinary glycoprotein proteolytic enzyme inhibitor that suppresses production & down-regulates various cytokines involved in the inflammatory process
    • Indicated for patients resistant to intravenous immunoglobulin (IVIG) treatment
    • Studies have shown that patients treated w/ intravenous immunoglobulin (IVIG), Ulinastatin & Aspirin combination therapy did not require further treatment & had lower risk of developing coronary artery aneurysm

Immunosuppressants

  • Eg Cyclosporin A, Methotrexate
  • May be used in patients refractory to intravenous immunoglobulin (IVIG) therapy as 3rd-line treatment
  • Studies have shown that treatment w/ Cyclosporin A effectively reduces fever
Prevention of Thrombosis in Patients w/ Coronary Disease
  • Management depends on severity & extent of coronary involvement
  • Platelet activation is a profound component of the acute illness & persists throughout the convalescence & chronic phases
  • Patients including those w/o coronary sequelae, should be treated w/ antiplatelet drugs at low doses for about 3 months
    • Platelet aggregation activity remains high during the 1st 3 months after onset
  • Patients should be carefully monitored for bleeding tendency due to excessive anticoagulant therapy

Aspirin

  • Low-dose Aspirin may be appropriate for asymptomatic patients w/ mild & stable coronary disease
  • As the extent & severity of coronary enlargement increases, combination w/ other antiplatelet agents may be more effective in suppressing platelet aggregation
  • Combination of Aspirin & Dipyridamole is used to treat patients w/ mild-to-moderate coronaryw involvement

Clopidogrel

  • Combination of Clopidogrel & Aspirin has been shown to be more effective than either agent alone in preventing vascular events in both coronary & cerebral arteries in adults

Dipyridamole

  • Effectively potentiates the effects of Aspirin in inhibiting platelet aggregation
  • Not to be given alone; may cause hemorrhage & worsening of angina

Ticlopidine

  • Given in combination w/ Aspirin to prevent coronary ischemia & thrombus formation

Heparin

  • The use of low molecular weight heparin w/ Aspirin has been advocated in rapidly expanding coronary aneurysms since the risk of thrombosis or bleeding is high

Warfarin

  • Combination of Warfarin & Aspirin is used to prevent thromboembolism, myocardial infarction (MI) & potential risk of sudden death in patients w/ giant coronary aneurysms

Treatment of Coronary Thrombosis

  • Goals of therapy include reestablishing coronary patency, myocardial salvaging & improving patient survival
  • Should target multiple steps in the coagulation cascade
  • The following agents may be administered to infants & children w/ coronary thrombosis w/ varying success rates: Alteplase, Monteplase, Streptokinase, Urokinase, tissue plasminogen activator (tPA)

Treatment of Myocardial Ischemia

  • Treatment is aimed at increasing coronary blood flow, preventing or relieving coronary spasm, inhibiting the formation of thrombi & decreasing cardiac work
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