Management of Kawasaki Disease and its Cardiac Sequelae

▪️ The diagnosis of KD should be considered in any child with a febrile illness and evidence of inflammation, particularly if fever persists longer than 4 days                                     (weak)

▪️  There are different diagnostic criteria for KD. The AHA diagnostic criteria should be used to diagnose complete KD                                                                                                            (weak)

▪️ Typical or classic KD is diagnosed if a fever is associated with ≥4 diagnostic criteria, with or without CAA, or if fever lasts at least for 4 days with ≥4 diagnostic criteria and eventual demonstration of CAA on echocardiography.                                                                    (Strong)

▪️ Incomplete KD can be diagnosed when patients present with fever for ≥5 days and lack enough clinical criteria (≤3) to fulfill the diagnosis, with or without CAA.             (Strong)

▪️ Atypical KD is diagnosed if fever, not otherwise explained, lasting for ≥ 5 days is associated with classic diagnostic criteria and non-classic manifestations, with or without CAA.  (Strong)

▪️ In a patient in whom KD is suspected, but all criteria have not yet been fulfilled, the following clinical signs strengthen the suspicion of KD: Irritability and new erythema and/or induration at the site of previous BCG immunization.                                                       (weak)

▪️ MIS-C and KD may share overlapping clinical features, including conjunctival injection, oropharyngeal findings (red and/or cracked lips, strawberry tongue), rash, swollen and/or erythematous hands and feet, and cervical lymphadenopathy                                    (Strong)

▪️ Epidemiologic studies of MIS-C suggest that younger children are more likely to be present with KD-like features, while older children are more likely to develop myocarditis and shock  (Strong)

▪️ The following laboratory values should be determined: ESR, CRP, full blood count and liver function (bilirubin, AST/ALT), albumin, serum Na, renal function test, and urinalysis. Ferritin and fibrinogen should be considered if there is a concern for macrophage activation syndrome. Cerebrospinal fluid analysis may be important to rule out infectious meningitis.   (Weak)

▪️Laboratory data are nonspecific to KD and can only support diagnosis in patients with suggestive clinical features.                                                                                         (Strong)

▪️ All patients with suspected KD should undergo echocardiography and ECG at baseline, as soon as the diagnosis is suspected.   An intermediate echocardiogram, 2 weeks after the first IVIG, should be performed in all patients with KD whose initial echo was normal and in whom disease activity has been arrested                                                                        (Strong)

▪️ In those with ongoing active inflammation (increasing or persistently elevated CRP and/or persisting signs and symptoms), ECG and echocardiography should be performed at least weekly to monitor the possible development of cardiac sequelae. In those with coronary abnormalities detected on initial echocardiography, echocardiography should then be performed at least twice weekly to monitor progression until there is clinical stabilization.              (Strong)

▪️ Persistently febrile non-responders KD patients with CAA, impaired left ventricular function, mild/moderate mitral regurgitation or significant pericardial effusion need a more frequent echocardiogram check-up (at least twice per week).                                                     (Strong)

▪️In children with CAA, ECG and echocardiography should be performed 3- to 6-monthly, depending on the severity of the CAA.                                                                          (weak)

▪️  For coronary artery sequelae, evaluation by Z-score is the standard method, and +2.5 or higher is defined as a long-term significant CAL (sequelae) (Strong ). For those above the age of 5 years, the definition of a giant aneurysm is ≥8mm inside diameter. (weak)                                                                            

▪️ Cardiovascular CT scan and MR angiography, where available, are important to assess persistent CAA in children with KD and monitor the remodeling of either coronary or systemic arteries in the whole body.                                                                               (weak)

▪️  IVIG is the standard treatment in KD. It must be administered at dose 2 g/kg of body weight in a single infusion, as soon as the diagnosis is confirmed or strongly suspected, with best response to IVIG documented when given within the 10th day from onset of fever. Administration should be performed over 12 h if the patient’s cardiac function is normal, or in 16–24 h for patients displaying cardiac failure.                                                           (Strong)

▪️ All patients diagnosed with KD who are treated with IVIG should be treated with anti-inflammatory dose of aspirin (30-50 mg/kg/day) until fever has settled for 48 h, clinical features are improving, and CRP levels are falling. The dose of aspirin should subsequently be reduced to an antiplatelet dose (3-5 mg/kg once daily).                                         (Strong)

▪️  IVIG may not be administered if fever spontaneously disappears and no CAA are shown, and inflammatory markers (ESR and CRP) are within normal limits.  (GPS)

▪️ IVIG should also be administered to children presenting after the 10th day of illness in case of persistent fever or no more fever but aneurysms and ongoing systemic inflammation, as shown by elevation of CRP                                                                                                   (Strong)

▪️ In patients without CAA anti-platelet ASA treatment is to be discontinued 8 weeks after KD onset. In children who develop CAA it may be continued until the resolution of CAA lesions or indefinitely in case of its persistence.                                                                              (Strong)

▪️ High-risk KD patients may receive initial therapy with IVIG + ASA + corticosteroid.  (Strong)

▪️ The following laboratory values can be important in assessing risk stratification for IVIG resistance: Low sodium, raised bilirubin, raised Alanine Transferase, Low platelet count, high CRP, Low albumin.                                                                                                                      (Weak)

▪️  Resistant KD is defined by failure of response to IVIG and is revealed by recrudescent fever reoccurring or persisting 36–48 h after IVIG infusion.                                                        (Strong)

▪️ In case of failure (resistant KD), treatment should be implemented with a further infusion of IVIG + low-dose aspirin (3–5 mg/kg/day) and intravenous methylprednisolone or Infliximab (GPS)

▪️Corticosteroid treatment should be given to patients with severe KD (See recommendation C.7).                                                                                                                                       (Strong)

▪️TNF-alpha blockade (e.g. infliximab) should be considered in KD patients with persistent inflammation despite IVIG, aspirin and corticosteroid treatment, after consultation with a specialist unit                                                                                                                       (Strong)

▪️ The use of Disease Modifying Antirheumatic Drugs (DMARDs) such as cyclosporin, cyclophosphamide and methotrexate, along with anakinra and plasma exchange, cannot be recommended, except on an individual basis after consultation with a specialist unit.  (Weak)

▪️ For patients with acute KD and suspected or diagnosed MAS, treatment with IVIG for KD and additional agents to treat MAS is strongly recommended. For children with unexplained MAS, obtaining an echocardiogram with coronary artery measurements is strongly recommended.                                                                                                                  (Strong)

▪️ KD patients with medium-sized  coronary artery aneurysms (Z-score ≥ 5 to 10 or absolute measurement <8 mm) or those with multiple and complex aneurysms may benefit from dual anti-platelet prophylaxis, based on low-dose ASA (at a single dose of 3–5 mg/kg/day) and clopidogrel (at a single dose of 0.2 mg/kg/day in children aged < 24 months and up to 1 mg/kg/day in children aged ≥ 24 months).                                                                 (Strong)

▪️ Warfarin is used in combination with low-dose aspirin for patients with large CAA , history of MI (myocardial infarction), and thrombosis in the CAA. The dose is adjusted for the international normalized ratio of prothrombin time (PT-INR) target range of 2.0–2.5     (Strong)

▪️ It is imperative to treat KD patients having complex or severe CAA (Z score > 10, diameter >8 mm) with low-dose ASA associated with warfarin (keeping INR targeted at 2.0–3.0) or LMWH (if regular INR checking is difficult). Triple therapy with ASA, warfarin or LMWH and clopidogrel may be considered in KD patients with a relevant risk of thrombosis.       (Strong)

▪️ Recombinant tissue plasminogen activator (rtPA) is the first-choice thrombolytic drug in children with KD complicated by coronary artery thrombosis; the glycoprotein IIb/IIIa inhibitor may be used in case of thrombosis with high risk of occlusion. Both therapies require a concomitant association with low-dose ASA and intravenous heparin.   (Strong)

▪️  All inactivated vaccines can be safely administered at any time after IVIG in KD patients. Attenuated live virus vaccines (MMR, Varicella, and MMRV vaccines) should be administered 10–12 months after the administration of IVIG to avoid a reduced specific immune response of the vaccine in KD patients; influenza vaccination is recommended in KD patients receiving ASA.                                                                                                             (Strong)

▪️ Low-Dose Aspirin is orally administered to patients with persistent CAA                     (Weak)

▪️ Statins may be used to prevent cardiovascular events in patients with CAL (coronary artery lesion).                                                                                                                                           (Weak)

▪️ACEI (Angiotensin Converting Enzyme inhibitor) or ARB (Angiotensin Receptor Blocker) may be used if coronary artery stenosis is at risk in patients with CAL. Beta-blockers, calcium antagonists, or nitrates can be used to prevent Acute coronary syndrome (ACS) in patients with CAL                                                                                                                                       (Strong)

▪️ Preventing the loss of follow-up (the so-called dropouts) is the most important issue in the management of the adolescent and young adult (AYA) generation. A preset plan of transfer for adult care should be available (GPS)                                                                               (Weak).

Guideline development process and methods

After reviewing all the inclusion and exclusion criteria and quality appraisal results, the GDG/ GAG recommended using the following source original clinical practice guidelines (CPGs):

1-  Italian Society of Pediatrics (SIP) CPG on general management of Kawasaki disease (2021) ⁽¹⁾. Some recommendations were adopted from earlier version of this CPG (Italian CPG 2018) ⁽²⁾ as it has the same methodology of development.

2-  JCS/JSCS 2020 CPG on Diagnosis and Management of Cardiovascular Sequelae in Kawasaki Disease (2020) ⁽³⁾

3-  American College of Rheumatology/Vasculitis Foundation (ACR/VF) CPG for the Management of Kawasaki Disease. (2021) ⁽⁴⁾.

4-  European consensus-based recommendations for the diagnosis and treatment of Kawasaki disease - the SHARE initiative (2019) ⁽⁵⁾.

5-  American College of Rheumatology/Vasculitis Foundation (ACR/VF) CPG for Multisystem Inflammatory Syndrome in Children Associated with SARS-CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 2(2022) ⁽⁶⁾

6-  Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals from the American Heart Association. Circulation ⁽⁷⁾, and its updated version “Update on Diagnosis and Management of Kawasaki Disease: A Scientific Statement from the American Heart Association, 2024”. ⁽⁸⁾ 

We conducted Adolopment for these guidelines: (Adoption, Adaptation, and Development)

        -   Adoption for most of the guideline recommendations.

        -      Development of Good Practice Statements

Recommendations and Good Practice Statements (GPS)

➡️This version of the CPG includes recommendations and good practice statements on the following four sub-sections:

A. Diagnosis of Kawasaki Disease in Children

The guideline covers the recommended criteria for diagnosis of classical cases of KD as well as atypical or incomplete cases. Laboratory investigations needed for initial diagnosis are covered in this section too as well as differentiation between KD and MISC.

B. Investigations in Kawasaki disease.

This section covers recommendations for laboratory as well as echocardiographic evaluation of patients with KD. Further details are given also on non-echocardiographic imaging using cardiac CT scans and MRI.

C. Management of Kawasaki disease and its possible complications

This section includes recommendations and good practice statements on management of KD patients, with recommendations on risk stratification, identification of high-risk patients and non-respondents.

D. Long term follow-up of patients with Kawasaki disease

This section deals with long-term follow-up of patients post convalescence with or without chronic coronary affection. Data are provided also on post-KD activity limitations, vaccinations, and long-term cardiovascular care till successful transition of the child to adult care.

➡️We can summarize the guidelines’ recommendations for KD in the following:

• Diagnostic criteria and KD types (complete, incomplete, atypical).
• Key clinical and lab findings supporting diagnosis.
• Differentiation from MIS-C.
• Echocardiography and ECG use, including frequency of monitoring.
• Coronary artery assessment using Z-scores and advanced imaging.
• Primary treatment with IVIG and aspirin.
• Management of IVIG-resistant cases (steroids, infliximab).
• Antithrombotic therapy for CAA (ASA, dual therapy, warfarin/LMWH, thrombolysis).
• Vaccination recommendations after IVIG.
• Long-term cardiovascular management and follow-up transition.

➡️Guideline Registration

PREPARE (Practice guideline REgistration for transPAREncy), WHO Collaborating Center for Guideline Implementation and Knowledge Translation, EBM Center, University of Lanzhou, Lanzhou, China. Registration Number: (submitted and in process)). Link: http://www.guidelines-registry.org/