Kawasaki%20disease Treatment

• The goals of treatment in the acute phase are to:
  • Rapidly reduce the inflammation in the coronary arteries
  • Minimize the incidence and 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

Primary Disease

• Treatment of intravenous immunoglobulin (IVIg) and Aspirin is given within the 7th-10th day of onset of illness
  • The treatment regimen has an overall systemic anti-inflammatory effect in approximately 80% of patients and 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)

• 1st-line and currently the most effective treatment for Kawasaki disease
• Efficacy of IVIg administered in the acute phase in reducing the prevalence of coronary artery abnormalities and reducing fever and inflammatory markers is well established
• It also reduces the inflammation of the vessel walls involved by the disease
• It is recommended that 2 g/kg 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) and serum amyloid-A (SAA)
• IVIg should be administered in patients in whom the diagnosis of Kawasaki disease has been missed earlier or if it occurred retrospectively with either persistent fever without any other diagnoses or coronary abnormalities with persisting lab findings of inflammation
• Those in whom fever have resolved and whose laboratory values and echocardiography are normal do not require IVIg treatment especially beyond the 10th day of illness

Aspirin

• Used to reduce inflammation and to inhibit platelet aggregation
  • High-dose Aspirin is aimed at reducing fever and 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
• Does not lower the frequency of the development of coronary abnormalities
• Recommended dose: 30-100 mg/kg/day, until normalization of inflammatory markers, specifically 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
• Caution should be observed in children with or suspected with viral infection (eg varicella, influenza) due to risk of Reye's syndrome especially with high-dose Aspirin

Flurbiprofen

• Potential alternative to Aspirin in patients with severe hepatic impairment
• Further studies are needed to establish its efficacy on acute Kawasaki disease

Clopidogrel

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

Adjunctive Treatment

• Corticosteroids
  • Eg Methylprednisolone, Prednisolone
  • Usefulness in the initial treatment of Kawasaki disease is not well established
  • May be considered as an adjunctive treatment in patients at high risk for IVIg resistance
  • Several studies including Japanese clinical trials (eg RAISE study) suggest that adjunctive corticosteroid plus IVIg and/or Aspirin has been shown to reduce the rate of coronary artery abnormalities
  • A recent study also showed that there is a high regression rate of coronary artery aneurysm, including giant aneurysms, after 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 ) and 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 IVIg are usually given 36 hours after completion of the first dose
• Retreatment with 2 g/kg IVIg is recommended; doses can be repeated for a total of 3 infusions

Corticosteroids

• Treatment should be restricted in patients in whom ≥2 infusions of IVIg have been ineffective in alleviating fever and acute inflammation
• Most commonly used steroid regimen is IV Methylprednisolone 30 mg/kg 24 hourly for 3 consecutive days with or without Prednisolone taper dose
• 2- to 3-week tapering course of Prednisolone along with IVIg and Aspirin may also be considered in patients with recurrent fever after initial IVIg treatment
• Reduce fever but effects on coronary artery abnormalities are uncertain
  • High incidence of giant aneurysms and coronary artery rupture have been reported

Tumor Necrosis Factor (TNF) Inhibitors

• Infliximab
  • Has been shown to be successful in patients refractory to IVIg and corticosteroids
  • Reverses the clinical signs of Kawasaki disease
  • May be used in patients with severe coronary artery disease, without 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 without 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 of various cytokines involved in the inflammatory process
  • Indicated for patients resistant to IVIg treatment
  • Studies have shown that patients treated with IVIg , Ulinastatin and Aspirin combination therapy did not require further treatment and had lower risk of developing coronary artery aneurysm

Anakinra

• Considered safe as adjunct therapy in patients who are at high-risk for IVIg resistance or highly refractory disease
• Further studies are needed to prove the efficacy of Anakinra as a treatment option for Kawasaki disease

Immunosuppressants

• Eg Cyclophosphamide, Cyclosporin A, Methotrexate
• May be used in patients refractory to IVIg, Infliximab, or corticosteroid therapy as 3rd-line treatment
• Studies have shown that treatment with Cyclosporin A effectively reduces fever
• More studies are needed to establish the efficacy of Cyclophosphamide

Prevention of Thrombosis in Patients with Coronary Disease

• Management depends on severity and extent of coronary involvement
• Platelet activation is a profound component of the acute illness and persists throughout the convalescence and chronic phases
• Patients including those without coronary sequelae, should be treated with antiplatelet drugs at low doses for about 2-3 months
  • Platelet aggregation activity remains high during the 1st 2-3 months after onset
• Patients should be carefully monitored for bleeding tendency due to excessive anticoagulant therapy

Antiplatelet Therapy

• Aspirin
  • Low-dose Aspirin may be appropriate for asymptomatic patients with mild and stable coronary disease until 4-6weeks after onset of illness
  • As the extent and severity of coronary enlargement increases, combination with other antiplatelet agents maybe more effective in suppressing platelet aggregation
  • Combination of Aspirin and Dipyridamole is used to treat patients with mild to moderate coronary involvement
• Clopidogrel
  • Combination of Clopidogrel and Aspirin has been shown to be more effective than either agent alone in preventing vascular events in both coronary and cerebral arteries in adults
• Dipyridamole
  • Effectively potentiates the effects of Aspirin in inhibiting platelet aggregation
  • Not to be given alone; may cause hemorrhage and worsening of angina
• Ticlopidine
  • Given in combination with Aspirin to prevent coronary ischemia and thrombus formation 

Anticoagulant Therapy

• Heparin
  
  • Unfractionated Heparin is indicated as bridging therapy in patients undergoing invasive procedures for anticoagulation reversal
  • Use of low-molecular-weight Heparin with Aspirin has been advocated in rapidly expanding coronary aneurysms and giant aneurysms since the risk of thrombosis or bleeding is high
• Warfarin
  • Combination of Warfarin and Aspirin is used to prevent thromboembolism, myocardial infarction (MI), and potential risk of sudden death in patients with giant coronary aneurysms

Treatment of Coronary Thrombosis

• Goals of therapy include reestablishing coronary patency, myocardial salvaging and improving patient survival
• Should target multiple steps in the coagulation cascade

Recombinant Tissue Plasminogen Activator (tPA)

• Eg Alteplase, Monteplase, Streptokinase, Urokinase
• May be administered within 12 hours to infants and children with coronary thrombosis with actual or impending occlusion with varying success rates
• Should be administered with low-dose Aspirin and Heparin with careful monitoring of bleeding parameters

Treatment of Myocardial Ischemia

• Treatment is aimed at increasing coronary blood flow, preventing or relieving coronary spasm, inhibiting the formation of thrombi and decreasing cardiac work
• Drugs that may decrease heart rate and afterload (eg beta blockers, calcium channel blockers, renin-angiotensin system [RAS] inhibitors) may also be given to decrease oxygen demand

Plasma Exchange

• Reserved for intravenous immunoglobulin (IVIg)-resistant patients in whom all medical therapies have failed
• Directly removes chemokines and cytokines from the blood
• Promotes quick recovery from cytokine storm
• During plasma exchange, anticoagulants (eg Heparin) may be given