Guideline sources The following summarized guidelines for the evaluation and management of Kawasaki disease (KD) are prepared by our editorial team based on guidelines from the Italian Society of Pediatrics (ISP 2021), the Single Hub and Access Point for Pediatric Rheumatology in Europe (SHARE initiative 2019), and the American Heart Association (AHA 2017). 1 2 3 Calculator Calculator Calculator American Heart Association dia Egami score for predicting unres Kobayash https://web.pathway.md/diseases/recufcXEeKiqHcXCt 1/11 6/29/23, 5:44 AM Kawasaki disease Pathway Guidelines 1. Screening and diagnosis Diagnostic criteria: As per ISP 2021 guidelines, diagnose typical KD when fever lasting > 5 days is associated with 4 of the following clinical criteria: bilateral non-exudative conjunctivitis changes of lips and oral mucosa changes of the extremities and perineal region polymorphous exanthema cervical lymphadenopathy). E Show 4 more As per SHARE initiative 2019 guidelines, use the AHA criteria for the diagnosis of complete KD. B Show 4 more 2. Classification and risk stratification Risk stratification: consider using echocardiographic coronary artery luminal dimensions converted to BSA-adjusted Z scores for risk stratification of coronary artery abnormalities. C Show 2 more 3. Diagnostic investigations Electrocardiography: obtain ECG at baseline in all patients with suspected KD, as soon as the diagnosis is suspected. B Echocardiography: As per ISP 2021 guidelines, obtain echocardiography for the diagnosis of coronary artery involvement in pediatric patients with KD, and then periodically repeated 2, 4 and 8 weeks after onset of illness in uncomplicated cases. E As per SHARE initiative 2019 guidelines: Obtain echocardiography at baseline in all patients with suspected KD, as soon as the diagnosis is suspected. B Consider obtaining echocardiography in pediatric patients presenting with < 5/6 criteria for KD (incomplete KD) with evidence of unexplained systemic inflammation (such as elevated CRP, ESR or WBC). C As per AHA 2017 guidelines, obtain echocardiography in patients with suspected KD, but not delaying treatment due to unavailability or technical limitations. B Show 2 more https://web.pathway.md/diseases/recufcXEeKiqHcXCt 2/11 6/29/23, 5:44 AM Kawasaki disease Pathway Advanced imaging: consider obtaining stress echocardiography or cardiac MRI, nuclear medicine myocardial perfusion imaging, or positron emission tomography for assessment of inducible myocardial ischemia. Decide on testing modality based on patient and institutional characteristics minimizing the risk of cumulative radiation dose. C Show 3 more Laboratory tests: As per ISP 2021 guidelines, recognize that abnormal laboratory parameters (mostly the elevation of CRP) can only support the diagnosis of KD in febrile patients with evocative clinical features. E As per SHARE initiative 2019 guidelines: Obtain the following laboratory tests in patients with suspected KD: CBC ESR CRP LFTs (bilirubin, AST, ALT) albumin sodium renal function tests urinalysis. B Consider obtaining ferritin and fibrinogen in patients with suspected KD if there is a concern for macrophage activation syndrome. C 4. Diagnostic procedures Cerebrospinal fluid analysis: consider performing CSF analysis to rule out infectious meningitis. C 5. Medical management General principles: as per SHARE initiative 2019 guidelines, initiate treatment as soon as the diagnosis of complete or incomplete KD is made. A Show 2 more Intravenous immunoglobulin: As per ISP 2021 guidelines: Administer IVIG at a dose of 2 g/kg of body weight in patients with KD, preferably given within the 10th day, better if within the 7th day of illness, but as soon as possible after diagnosis. E Regard failure in the response to IVIG revealed by recrudescent fever reoccurring or persisting 36-48 hours after IVIG infusion as resistant KD. E https://web.pathway.md/diseases/recufcXEeKiqHcXCt 3/11 6/29/23, 5:44 AM Kawasaki disease Pathway As per SHARE initiative 2019 guidelines, administer IVIG at a dose of 2 g/kg as a single infusion in patients with KD. A Show 2 more As per AHA 2017 guidelines, administer high-dose IVIG (2 g/kg given as a single IV infusion) within 10 days of illness onset, but as soon as possible after diagnosis, in patients with complete or incomplete KD. A Show 4 more Aspirin: As per ISP 2021 guidelines: Initiate aspirin at a daily dosage of 30-50 mg/kg in the acute phase of KD until 48 hours after the disappearance of fever, then switch to an antiplatelet dose of 3-5 mg/kg once daily. E Continue low-dose aspirin until 6-8 weeks in pediatric patients without coronary artery abnormalities. Continue low-dose aspirin in pediatric patients with coronary artery abnormalities until the resolution of coronary artery lesions. E As per SHARE initiative 2019 guidelines, initiate aspirin at a dose of 30-50 mg/kg/day in all patients with KD treated with IVIG until: fever has settled for 48 hours clinical features are improving CRP levels are falling. B Show 3 more As per AHA 2017 guidelines, consider administering moderate-to-high-dose (30-50 to 80-100 mg/kg/day) dose aspirin until the patient is afebrile, although there is no evidence that it reduces coronary artery aneurysms. C Show 4 more Corticosteroids: As per ISP 2021 guidelines, administer a second infusion of IVIG in non-responder patients with KD, and - in case of failure - pulses of IV methylprednisolone (30 mg/kg/day) for 3 consecutive days, followed by oral prednisone (2 mg/kg/day, then gradually tapered). E Show 2 more As per SHARE initiative 2019 guidelines: Administer corticosteroids in patients with severe KD with any of the following: A IVIG resistance - ongoing fever and/or persistent inflammation or clinical signs 48 hours after receiving IVIG as a single dose of 2 g/kg; decide on administering a second dose at the discretion of the treating physician B kobayashi score 5 B features of hemophagocytic lymphohistiocytosis B features of shock B age < 1 year B coronary and/or peripheral aneurysms. B https://web.pathway.md/diseases/recufcXEeKiqHcXCt 4/11 6/29/23, 5:44 AM Kawasaki disease Pathway Consider using the following regimens for corticosteroid treatment: IV methylprednisolone 0.8 mg/kg BID for 5-7 days or until CRP normalizes, followed by oral prednisone/prednisolone 2 mg/kg/day, then weaned off over next 2-3 weeks IV methylprednisolone 10-30 mg/kg (up to maximum of 1 g/day) once daily for 3 days, followed by oral prednisone/prednisolone 2 mg/kg/day until day 7 or until CRP normalizes, then weaned off over next 2-3 weeks. C As per AHA 2017 guidelines, do not administer single-dose pulse methylprednisolone with IVIG as routine primary therapy in patients with KD. D Show 3 more Monoclonal antibodies: As per SHARE initiative 2019 guidelines, consider administering TNF-alpha inhibitors (such as infliximab) after consultation with a specialist unit in patients with KD with persistent inflammation despite IVIG, aspirin and corticosteroid treatment. C As per AHA 2017 guidelines: Consider administration of infliximab (5 mg/kg) as an alternative to a second infusion of IVIG or corticosteroids in patients resistant to IVIG. C Consider administering immunomodulatory monoclonal antibody therapy (except TNF-alpha inhibitors) in highly refractory patients not responding to a second infusion of IVIG, an extended course of corticosteroids, or infliximab. C Other immunosuppressive agents: As per ISP 2021 guidelines, consider administering infliximab as rescue therapy in IVIG- and methylprednisolone-refractory patients with KD. E As per SHARE initiative 2019 guidelines, do not use DMARDs, such as ciclosporin, cyclophosphamide and methotrexate, as well as anakinra in patients with KD, except on an individual basis after consultation with a specialist unit. D As per AHA 2017 guidelines: Consider administering cyclosporine in patients with refractory KD if a second IVIG infusion, infliximab, or a course of corticosteroids has failed. C Consider administering cytotoxic agents in highly refractory patients not responding to a second infusion of IVIG, an extended course of corticosteroids, or infliximab. C Statins: consider initiating empirical statin therapy for non-lipid-lowering (pleiotropic) effects in patients with current or regressed small, medium, larger or giant aneurysms. C Beta-blockers: consider initiating empirical -blockers in patients with large or giant aneurysms (current or regressed to medium or small). C 6. Therapeutic procedures Plasma exchange: https://web.pathway.md/diseases/recufcXEeKiqHcXCt 5/11 6/29/23, 5:44 AM Kawasaki disease Pathway As per SHARE initiative 2019 guidelines, do not perform plasma exchange in patients with KD, except on an individual basis after consultation with a specialist unit. D As per AHA 2017 guidelines, consider performing plasma exchange (rarely) in highly refractory patients not responding to a second infusion of IVIG, an extended course of corticosteroids, or infliximab. C Indications for revascularization: avoid performing revascularization in patients with KD in the acute/subacute phase of the illness with STEMI attributable to acute thrombotic occlusion of an aneurysm. D Show 4 more Percutaneous coronary intervention: perform PCI in patients with single-vessel or focal multi- vessel disease amenable to PCI. B Show 7 more 7. Surgical interventions Coronary artery bypass graft: prefer CABG to PCI in patients with left main coronary artery disease, multi-vessel coronary artery disease with reduced LV function, multi-vessel coronary artery disease with lesions not amenable to PCI, and multi-vessel coronary artery disease in diabetic patients. B Show 2 more Heart transplantation: consider performing cardiac transplantation in patients with severe, irreversible myocardial dysfunction and coronary artery lesions, if interventional catheterization procedures or CABG are not feasible. C 8. Specific circumstances Patients with coronary artery thrombosis: As per ISP 2021 guidelines, administer recombinant tPA as first-line thrombolytic therapy in pediatric patients with KD complicated by coronary artery thrombosis. E Show 3 more As per AHA 2017 guidelines, initiate thrombolytic therapy in patients with coronary artery thrombosis with actual or impending occlusion of the arterial lumen, or perform mechanical restoration of coronary artery blood flow at cardiac catheterization in patients of sufficient size. B Show 2 more 9. Patient education General counseling: https://web.pathway.md/diseases/recufcXEeKiqHcXCt 6/11 6/29/23, 5:44 AM Kawasaki disease Pathway Consider providing general counseling regarding healthy lifestyle and activity promotion at every visit in all patients with or without coronary artery involvement. C Educate patients and families that having had KD is part of the patient's permanent medical history. B Physical activity counseling: consider providing physical activity counseling at every visit with no restrictions or precautions at any time in patients with C or without coronary artery involvement C Show 2 more Pregnancy and contraception counseling: Consider providing age-appropriate counseling regarding contraception and pregnancy without modification in patients with: no coronary artery involvement dilation only small aneurysms (current or regressed) large or giant aneurysms regressed to normal or dilation only. C Show 2 more 10. Preventative measures Thromboprophylaxis: As per ISP 2021 guidelines, initiate dual anti-platelet prophylaxis with low-dose aspirin (at a single dose of 3-5 mg/kg/day) and clopidogrel (at a single dose of 0.2 mg/kg/day in pediatric patients aged < 24 months and up to 1 mg/kg/day in pediatric patients aged 24 months) in patients with medium-sized coronary artery aneurysms or with multiple and complex aneurysms. E Show 2 more As per SHARE initiative 2019 guidelines: Initiate warfarin, in addition to aspirin, after initial heparinization in patients with giant aneurysms (internal diameter 8 mm, or Z-score 10, and/or coronary artery stenosis). Consider discontinuing heparin when a stable INR of 2-3 is reached. B Consider initiating low molecular heparin as a suitable alternative to warfarin, particularly in young infants where safe warfarinization can be challenging. C As per AHA 2017 guidelines, initiate low-dose (3-5 mg/kg/day) aspirin in patients without evidence of coronary artery changes until 4-6 weeks after onset of illness. B Show 16 more Immunizations: As per ISP 2021 guidelines, recognize that all inactivated vaccines can be safely administered at any time after IVIG treatment in patients with KD. E Show 2 more As per SHARE initiative 2019 guidelines, postpone immunization with all vaccines for at least 6 months following an episode of KD treated with IVIG. B https://web.pathway.md/diseases/recufcXEeKiqHcXCt 7/11 6/29/23, 5:44 AM Kawasaki disease Pathway 11. Follow-up and surveillance Hospital discharge and follow-up: consider discharging patients without coronary artery involvement from cardiology care at 4-6 weeks after disease onset. Consider obtaining ongoing follow-up to 12 months. C Show 5 more Serial clinical assessment: As per ISP 2021 guidelines, obtain cardiologic assessments to classify patients into different risk classes according to the cardiovascular sequelae and establish a personalized follow-up protocol. E As per AHA 2017 guidelines, consider assessing BP, fasting lipid profile, BMI (and plot), waist circumference, diet and activity, and smoking status in patients with coronary artery involvement at according intervals: Situation Guidance At least once and ideally at least 1 year from the episode Without coronary artery involvement At least once and ideally at least 1 year from the episode Dilation only At least once and ideally at least 1 year from the episode Current small or medium aneurysms Every 6-12 months Current large or giant aneurysms Every 1 year Medium aneurysms regressed to small Every 1 year Large or giant aneurysms regressed to medium or small Every 2 years. C Small, medium, large or giant aneurysms regressed to normal or dilation only Laboratory monitoring: As per SHARE initiative 2019 guidelines, consider obtaining ESR (before IVIG), CRP and CBC to monitor inflammation in patients with KD. C As per AHA 2017 guidelines, do not obtain ESR to assess response to IVIG therapy, as it is accelerated by IVIG. Do not interpret a persistently high ESR alone as a sign of IVIG therapy resistance. D Serial electrocardiography: As per SHARE initiative 2019 guidelines: Obtain ECG at least weekly to monitor the possible development of cardiac sequelae in patients with ongoing active inflammation (increasing or persistently elevated CRP and/or https://web.pathway.md/diseases/recufcXEeKiqHcXCt 8/11 6/29/23, 5:44 AM Kawasaki disease Pathway persisting signs and symptoms). B Obtain ECG 3-6 months in patients with coronary artery aneurysm, depending on the severity of the aneurysm. B Serial imaging: As per ISP 2021 guidelines, obtain echocardiography to identify coronary artery involvement in pediatric patients with KD at 2, 4 and 8 weeks after onset of illness in uncomplicated cases. E As per SHARE initiative 2019 guidelines, obtain intermediate echocardiography 2 weeks after the first IVIG in all patients with normal initial echocardiogram and if the disease activity has been arrested. B Show 4 more As per AHA 2017 guidelines, obtain repeated echocardiography both within 1-2 weeks and 4-6 weeks after treatment of uncomplicated patients. B Show 3 more Surveillance angiography: As per ISP 2021 guidelines, obtain cardiovascular CT and MRA, where available, to assess persistent coronary artery aneurysms and monitor remodeling of either coronary or systemic arteries in the whole body in pediatric patients with KD. E As per AHA 2017 guidelines: Obtain invasive coronary angiography in patients with evidence of inducible myocardial ischemia on testing. B Obtain emergent coronary angiography for determination of best means of flow restoration in the culprit artery in adult patients with remote history of KD presenting with STEMI. B Clinical findings Symptoms Past medical history Abdominal pain Myocarditis Arthralgia Urethritis Cracked lips Neurological exam Diarrhea Fever Facial nerve palsy Foot swelling Meningismus Hand swelling Sensorineural hearing loss Irritability Head and neck exam Vomiting Pharyngeal erythema Vital signs Retropharyngeal edema Tachycardia Strawberry tongue Ocular exam Abdominal exam https://web.pathway.md/diseases/recufcXEeKiqHcXCt 9/11 6/29/23, 5:44 AM Kawasaki disease Pathway Anterior uveitis Hepatomegaly Conjunctival injection Lymphatic exam Cardiac exam Cervical lymphadenopathy AR murmur Lab findings Cardiogenic shock MR murmur Hyponatremia Pericarditis ESR serum ALT Genitourinary exam serum AST Desquamation in groin serum CRP Desquamation in perineal region serum TBIL serum gamma- glutamyltransferase Integument exam urine WBCs serum albumin Beau's lines Desquamation of fingers Imaging findings Desquamation of toes Erythema multiforme-like rash Findings of acute pancreatitis Erythema of lips Interstitial infiltrates Erythema of perineal region Peribronchial infiltrates Erythroderma Pulmonary nodules Finger gangrene Foot erythema Hand erythema Jaundice Maculopapular rash Onychomadesis Raynaud's phenomenon Hematological findings Anemia WBC count blood platelet count References 1. 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 Apr 25;135 17):e927-e999. Open 2. Alessandra Marchesi, Donato Rigante, Rolando Cimaz et al. Revised recommendations of the Italian Society of Pediatrics about the general management of Kawasaki disease. Ital J Pediatr. 2021 Jan https://web.pathway.md/diseases/recufcXEeKiqHcXCt 10/11 6/29/23, 5:44 AM Kawasaki disease Pathway 25;47 1 16. Open 3. Nienke de Graeff, Noortje Groot, Seza Ozen et al. European consensus-based recommendations for the diagnosis and treatment of Kawasaki disease - the SHARE initiative. Rheumatology Oxford). 2019 Apr 1;58 4 672 682. Open 4. Burns JC, Mason WH, Glode MP et al. Clinical and epidemiologic characteristics of patients referred for evaluation of possible Kawasaki disease. United States Multicenter Kawasaki Disease Study Group. J Pediatr. 1991 May;118 5 680 6. Open 5. Fukushige J, Takahashi N, Ueda Y et al. Incidence and clinical features of incomplete Kawasaki disease. Acta Paediatr. 1994 Oct;83 10 1057 60. Open 6. Marchesi A, Tarissi de Jacobis I, Rigante D et al. Kawasaki disease: guidelines of the Italian Society of Pediatrics, part I definition, epidemiology, etiopathogenesis, clinical expression and management of the acute phase. Ital J Pediatr. 2018 Aug 30;44 1 102. Open https://web.pathway.md/diseases/recufcXEeKiqHcXCt 11/11