Table 3 Summary of recommendations

Overarching principle

KD needs a multidisciplinary team consisting of pediatric rheumatologist or rheumatologist with a special interest in pediatric rheumatology, a pediatric cardiologist, a cardiologist who is interested in pediatric rheumatology and may need other specialists such as an ophthalmologist, pediatric, hematology, etc.

The child presented with KD, general pediatricians should consider the diagnosis of KD and early referral to a specialist if the child has persistent fever and 2 or more of KD characteristic symptoms (rash, red eye … ..etc.)

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Who are the targeted population?

The guideline targets the management of children diagnosed with Kawasaki disease either typical or incomplete by American Heart Association diagnostic criteria.

Our target physicians are pediatric rheumatologists, adult rheumatologists who are interested in pediatric rheumatology, pediatric cardiologist, a cardiologist who is interested in pediatric rheumatology, ophthalmologist, regulatory bodies, health-related organizations, and interested patients’ groups/laypersons

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What is the definition of typical KD, incomplete KD, atypical KD, and acute phase of KD?

Typical KD: Fever lasting at least 5 days without any other explanation with at least 4 of the 5 following principal clinical findings: (1) bilateral bulbar conjunctival injection without exudate, (2) erythema and cracking of lips, strawberry tongue, and/or erythema of oral and pharyngeal mucosa, (3) erythema and edema of the hands or feet (acute phase), and/or periungual desquamation (subacute phase), (4) maculopapular, diffuse erythroderma, or erythema multiforme–like rash, or (5) cervical lymphadenopathy (at least 1 lymph node >1.5 cm in diameter), usually unilaterally. The diagnosis may be made with only 4 days of fever if ≥4 principal clinical features are present or if CAA (Z-score >2.5) or coronary dilatation (Z-score >2, but <2.5) is present.

Incomplete KD: unexplained prolonged fever in an infant (≥ 7 days) or child (≥ 5 days) with less than 4 of the principal clinical findings of KD, and compatible laboratory markers (elevated ESR/CRP level, with 3 or more of the following laboratory findings: anemia, thrombocytosis, leucocytosis, hypoalbuminemia, Increased leukocytes in the urine sediment of an infant 10 < white cell count/hpf and elevated transaminase levels) or echocardiographic findings (coronary artery dilatation).

Atypical KD: occurs in patients presenting a typical fever not otherwise explained, lasting for ≥5 days, and signs or symptoms that differ from the main KD clinical characteristics (i.e., meningeal inflammation, seizures, facial paralysis, acute abdomen, acute pancreatitis, cholestatic jaundice, arthritis, renal injury, pneumonia, etc.), with or without coronary artery aneurysm.

Acute KD: Initial febrile phase of KD.

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What are features of high-risk disease/severe disease?

HIGH RISK. At least one of the following: (LOE:5D)

• Age <12 months

• C-reactive protein higher than 200 mg/l

• Albumin ≤ 2.5 g/dL

• Hb at least 2 g/dL below the lower limit of normal for age

• Liver dysfunction: AST or ALT ≥ 2x upper limit of normal and/or direct bilirubin > 1 mg/dL

• overt coronary artery aneurysms

• macrophage activation syndrome or septic shock

• Kobayashi score ≥ 4

Severe disease

• Shock

• Age < 12 months

• Presence of coronary or peripheral aneurysms or other cardiovascular abnormalities.

• haemophagocytic lymphohistiocytosis

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What are the predictors for the development of coronary artery aneurysms and risk factors for IVIG resistance?

Predictors for the development of coronary artery aneurysms: (LOE:4C)

• a Z-score in the left anterior descending or right coronary artery of ≥2

• age <6 months

• Asian race

• a C-reactive protein level of ≥13 mg/dl

• uveitis

Predictors for nonresponse to IVIG: (LOE:3C): there is no widely accepted grading system for predicting IVIG non-responsiveness, and for the Caucasian population, there is no validated risk score yet but Kobayashi score (≥4 points of the following) can be used but may not reliably exclude IVIG resistance if “negative” (score <4)

• Na ≤133mmol/L

• AST ≥100IU/L

• Day of starting treatment or diagnosis: Day 4 of illness or earlier

• Neutrophils ≥80%

• CRP ≥10mg/dL

• Platelets ≤300,000/μL

• Age (months) ≤12 months

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What is the definition of refractory/resistant KD?

Failure to respond to IVIG therapy and consistent with recrudescent fever 36–48 h after IVIG infusion (LOE:1A)

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How should KD patients assess and monitored and what is the frequency of monitoring KD?

• KD should be differentiated from Infectious diseases such as {viral (rubella, adenovirus, enterovirus, cytomegalovirus, Epstein-Barr virus, parvovirus B19, human herpes virus, scarlet fever, Mycoplasma pneumonia infection, toxic shock syndrome, staphylococcal scalded skin syndrome, bartonellosis, Rocky Mountain spotted fever, leptospirosis} and non-infectious diseases such as juvenile idiopathic arthritis, drug hypersensitivity reaction, Stevens-Johnson syndrome, polyarteritis nodosa, autoinflammatory syndromes, Multisystem Inflammatory Syndrome in Children (MIS-C), sarcoidosis and acrodynia.} The identification of viral or bacterial agents cannot exclude KD diagnosis (LOE:3C).

• Laboratory tests are nonspecific for KD, but it can support the diagnosis in combination with classic features especially in patients with suggestive clinical features of KD (LOE:5D).

• Infant aged 6 months or younger with fever for at least 7 days and no obvious cause should have a laboratory evaluation even if no symptoms of Kawasaki disease are evident; if signs of inflammation are seen, echocardiography should be done.

I. Laboratory test should be done

CBC, ESR, CRP, liver function test, serum Na, renal function, ferritin, and urinalysis (LOE: 3C)

Other tests such as cerebrospinal fluid are needed only if the patient presents with signs of meningeal irritation and to rule out infectious meningitis and synovial fluid analysis if the patient presented with active inflammatory synovitis with effusion (LOE: 5D).

II. ECG should be performed at baseline, as soon as the diagnosis is suspected (LOE: 1A).

III. Echocardiography

• Bidimensional and color-Doppler echocardiography and/or associated techniques (tissue Doppler imaging, 3D echocardiography imaging) are crucial for performing cardiac assessment in patients with KD at baseline, as soon as the diagnosis is suspected, as they are non-invasive repeatable investigations, characterized by both high sensitivity and high specificity and should be performed by a pediatric cardiologist or cardiologist with experience in the pediatric age.

• Echo detects the size of the aneurysm (by Z score), its location, and the morphology of the aneurysm, detect the presence/absence of thrombi, and assess myocardial involvement, ventricular systolic, and diastolic function, LV wall motion, valvular regurgitation, and pericardial effusion.

• Timing of echo

a. In the uncomplicated cases: In all patients with a diagnosis of KD echocardiogram must be done, which should also be repeated 2, 6, and 8 weeks following the onset of the disease because CAA can be identified in the weeks that follow the diagnosis (LOE: 1A).

b. Persistently febrile non-responders patients who have coronary artery aneurysm, decreased left ventricular function, mild-to-moderate mitral regurgitation, or severe pericardial effusion need to have echocardiograms more frequently (at least weekly) until resolution of fever, normalization of symptoms and decrease in CPR levels (LOE:2B).

IV. Cardiovascular CT scan: routine use is not indicated, ideally with a dual-source CT (DSCT) scanner, should be used in patients with KD to (LOE:4C)

– confirm CAA

– assess other aneurysms, both central and peripheral, throughout the entire body

– detect middle-distal CAA (not typically seen at routine echocardiograms)

– more precisely define the caliber and morphology of CAA

– detect coronary artery thrombosis, calcification, or occlusions

– detect myocardial ischemia

V. Cardiovascular MR angiography: routine use is not indicated. It should be used in patients over 8 years with KD to (LOE:4C)

-confirm CAA.

- identify other aneurysmal dilations, either central or peripheral, in the vascular system.

- assess ventricular systolic function.

- detect myocardial ischemia

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What is the initial treatment of acute KD?

I. Patients with complete KD criteria should be treated with high-dose IVIG (2 g/kg given as a single intravenous infusion) over 10–12 h (LOE:1A)

• Time of administration of IVIG

1. Within 10 days of illness onset but as soon as possible after diagnosis (LOE:1A).

• If a child presents after the 10th day of illness (i.e., if the diagnosis was missed earlier) and exhibits either a persistent fever without other cause or coronary artery abnormalities along with ongoing systemic inflammation, as shown by an elevated ESR or CRP (CRP >3.0 mg/dL), it is reasonable to administer IVIG (LOE: 4C).

• Patients should be closely monitored for adverse reactions during IVIG infusion, including aseptic meningitis, Coombs-positive hemolytic anemia, and generalized infusion reactions.

• Since IVIG therapy increases the ESR, it shouldn't be used to evaluate the response to IVIG. IVIG resistance should not be determined from a persistently high ESR alone.

II. Moderate dose of aspirin (ASA) (30–50 mg/kg/d) must be administered until 48 h after the disappearance of fever (LOE:1A).

• After the child has become afebrile, aspirin should be reduced to 3–5mg/kg as a single daily dose for its antithrombotic effect (LOE:1A).

• In patients without CAA, low-dose aspirin is continued for approximately 6–8 weeks after KD onset. In children who develop CAA, low–dose aspirin therapy should be continued long-term, at least until the aneurysms resolve and the patient should be referred to a pediatric cardiologist for long-term follow-up (LOE:3C).

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What is the initial treatment for patients with acute KD who are at high risk of IVIG resistance or developing coronary artery aneurysms?

• Patients with acute KD who are at high risk of IVIG resistance or developing coronary artery aneurysms should receive initial therapy with IVIG + low-dose aspirin (3–5 mg/kg/day) + corticosteroid single intravenous pulse of methylprednisolone (10–30 mg/kg/day) (LOE:1A).

• Patients with acute KD who are at high risk of IVIG resistance or developing coronary artery aneurysms and glucocorticoids are contraindicated should receive initial therapy with IVIG and nonglucocorticoid immunomodulatory therapy such as infliximab, anakinra, or cyclosporine (LOE:2B).

• If treatment fails, additional IVIG infusion, low-dose aspirin (3–5 mg/kg/day), and three pulses of intravenous methylprednisolone (30 mg/kg/day) should be administered, followed by prednisone (2 mg/kg/day) (gradually tapered) (LOE:3B).

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What is the treatment for patients with acute KD resistant to treatment (refractory KD)?

A. Additional IVIG infusions, intravenous methylprednisolone pulses, infliximab, cyclosporine A, methotrexate, plasmapheresis, and ulinastatin are second-line treatment options for refractory KD (LOE:2B).

B. A second dose of IVIG (2 g/kg) is conditionally recommended in patients with acute KD resistant to the first IVIG infusion (LOE:3B).

C. Administration of high-dose pulse steroids (usually methylprednisolone 10–30 mg/kg intravenously for 3 days, followed by prednisone: 2 mg/kg/day, then gradually tapered)) may be taken into account as a potential alternative for a second IVIG infusion or for the retreatment of KD patients who have experienced recurrent or recrudescent fever after further IVIG (LOE:3B).

D. Infliximab [a single intravenous dose of 5 mg/kg of body weight] for IVIG- and corticosteroid-resistant KD patients may be considered (LOE:2B).

E. In patients with refractory KD who have not responded to the second IVIG infusion, infliximab, or corticosteroids, cyclosporine (IV 3 mg/kg/day split q12h, PO 4-8 mg/kg/day divided q12h) may be considered. Cyclosporine should be continued until the patient is afebrile and clinically improving with CRP less than 12 mg/dL or after 2 weeks of therapy. The dose should then be reduced by 10% every 3 days until it reaches 1 mg/kg/day (LOE:4C).

F. IL-1 blockade with anakinra (daily dose of 4–8 mg/kg of body weight for an overall period of 15 days) is highly promising in treating severe multi-refractory patients with KD, with potential benefits also on the cardiovascular complications (LOE:4C).

G. Canakinumab can be used off-label as a single subcutaneous injection of 4 mg/kg for a body weight ≤ 40 kg in KD patients who are resistant to IVIG (LOE:4C).

H. In resistant acute KD, plasma exchange and cytotoxic medications like cyclophosphamide have been used. However, usage of these medications should be restricted to patients for whom other treatments have failed due to the limited data and risks associated with them (LOE:4C).

I. Ulinastatin [5000 U/kg for 3–6 times per day (maximum dose: 50,000 U] has been proposed as useful in IVIG–refractory patients (LOE:3C).

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What is the treatment of patient with acute KD who have arthritis resistant after IVIG treatment and who do not have coronary artery aneurysms KD?

• For patients without coronary artery aneurysms who do not need to take aspirin on a long-term basis and who have arthritis that needs additional treatment, aspirin can be temporarily withheld and a brief course of NSAIDs (usually lasting 3–4 weeks) can be taken as needed (LOE:5D).

• Acetaminophen, a short course of glucocorticoids, or nonsystemic NSAID pain management options (e.g., a topical NSAID) can be given if long-term aspirin use is necessary owing to coronary artery aneurysms. If prolonged use of systemic NSAIDs is necessary (i.e., for more than three weeks), a pediatric hematologist or cardiologist should be consulted, especially in a patient with coronary artery aneurysms (LOE:5D).

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What is the management of opthalmological manifestation of KD?

• Involvement of the eye in Kawasaki disease includes conjunctival injection, keratitis, and uveitis, and it can cause blindness if neglected.

• Costicosteroid eye drops are essential for the treatment of acute anterior uveitis in Kawasaki disease (LOE:4C).

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What is the treatment for patients with incomplete KD?

For patients with incomplete KD (who meet the criteria for incomplete KD according to the AHA guidelines).

It is strongly recommended to start IVIG as soon as the diagnosis is made over delaying therapy until day 10 or later (LOE:1A).

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What is the maintenance treatment in patient with KD after acute attack (treatment of cardiac complication)?

• Patients with KD who have medium-sized aneurysms (5 mm and 7 mm or if Z scores 7 and 10) or those who have multiple and complex aneurysms require antiplatelet prophylaxis based on low-dose ASA (3–5 mg/kg/day) combined with clopidogrel (0.2 mg/kg/day in patients aged < 24 months or 1 mg/kg/day if age ≥ 25 months, max 75 mg/day) in a single dose (LOE:4C).

• KD patients with giant aneurysms (≥8 mm), with or without stenosis, require treatment with low-dose ASA combined with warfarin (targeting an INR of 2.0–3.0) or LMWH (if regular INR checking is difficult) (LOE:2C).

• KD patients with a significant risk of thrombosis should be considered for triple therapy with ASA, clopidogrel, and warfarin or LMWH (LOE:5D).

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What is the prevention and treatment of thrombosis in patients with coronary aneurysms?

• In KD patients with a relevant risk of thrombosis, triple therapy with ASA clopidogrel, and warfarin or LMWH should be considered in these patients (LOE:5D).

• Interventional cardiac catheterization or thrombolytic medication should be used to treat coronary artery thrombosis with actual or impending lumen obstruction. Low doses of ASA and low doses of heparin must be used in conjunction with thrombolytic medications, and the risk of bleeding must be carefully monitored (LOE:1A).

• Recombinant tissue plasminogen activator (rtPA) (alteplase) is the first-choice thrombolytic drug in children with KD complicated by coronary artery thrombosis, with a dose of (0.5 mg/kg, 10% infused over 1–2 min, and the remainder over 60 min). It is more commonly used in combination with low-dose ASA and intravenous heparin. Thorough coagulation tests monitoring every 6 to 12 h is necessary to prevent bleeding (LOE:5D).

• Abciximab, a glycoprotein IIb/IIIa inhibitor, may be used in cases of thrombosis with a high risk of occlusion in conjunction with low-dose ASA and intravenous heparin. Abciximab is administered intravenously (as a bolus of 0.25 mg/kg in 30 min, then followed by 0.125 g/kg/min, max: 10 g/min, for 12 h) (LOE:5D).

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What is the treatment for patients with acute KD and complicated macrophage activation syndrome?

• For patients with acute KD and suspected or diagnosed MAS, treatment with IVIG for KD and additional agents to treat MAS is strongly recommended (LOE:4C)

• IVIG should be used as the first-line therapy for KD, and MAS should also be treated with the proper drugs that target cytokine storms or underlying triggers. In contrast to a primary HLH-directed treatment protocol with cytotoxic drugs, anakinra, and glucocorticoids are preferred for treatment in acute KD patients and complicated with MAS syndrome.

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What about vaccinations in a child with KD?

• Since receiving any vaccine does not enhance the risk of KD recurrence, vaccinations are to be given in KD patients. (LOE:3B)

• Inactivated vaccines, Rotavirus, oral typhoid, intranasal anti-flu, BCG vaccinations, and the yellow fever vaccine can all be given to KD patients at any time following IVIG therapy. (LOE:4C)

• Live attenuated vaccines such as mumps, measles, rubella, and varicella should be given 10–12 months after IVIG therapy in order to avert a lowered immune response in KD patients. (LOE:5D)

• Influenza vaccine is strongly recommended for KD patients on ASA because of the increased risk of Reye’s syndrome (LOE:3B)

• Clopidogrel can be used in instead of ASA in KD patients who must receive the varicella or MPRV vaccines because of a potential risk of Reye’s syndrome related to the attenuated varicella-zoster virus in these vaccines. After 48 h of discontinuing ASA, V, or MPRV vaccine can be given, and ASA can be reintroduced following discontinuing clopidogrel 6 weeks after vaccination. (LOE:5D)

• It is recommended that patients with KD on biological treatments receive all inactivated vaccines according to the regular schedule. (LOE:4C)

• Live attenuated vaccines should be given to KD patients one month prior to starting biologic therapy; however, they are not recommended during biologic therapy. (LOE:5D)

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What is the long-term follow-up?

Follow-up of KD patients must continue over time, especially for those who have presented coronary artery aneurysm and it depends on cardiovascular risk classes

1. CLASS I (no abnormality of coronary arteries in the various phases of the disease)

• Cardiologic assessments (ECG, echocardiography, blood pressure monitoring), any blood chemistry investigations, and lipid profile evaluation after 12 months from the onset of the disease.

2. Class II (transient coronary artery ectasia that disappears within 8 weeks)

• Cardiologic assessments (ECG, Echo, blood pressure monitoring), blood chemistry tests, and lipid profile evaluation at 6 and 12 months following the onset of the disease.

3. Class III (single aneurysm of small-medium caliber between + 3 and + 7 SD in one or more arteries)

• Depending on the severity of the lesions, cardiovascular assessments (ECG, echocardiography, blood pressure monitoring, and blood chemistry testing) should be performed every 4–6 months. Cardiologic exams (ECG, echocardiography, blood pressure monitoring) should be performed annually for the first 3 years, thereafter every 3 to 5 years, if there has been a complete regression of aneurysms as shown by two successive negative controls (up to 18 years).

• Assessment of myocardial perfusion every 2 years above the age of 10 (stress-ECG and/or stress echocardiogram) as well as lipid profile evaluation.

• If any myocardial ischemia is detected, a coronary angiography or CT angiography should be performed.

4. Class IV (one or more aneurysms ≥7 SD, including multiple and complex giant aneurysms without any obstruction)

• Cardiologic assessments (ECG, echocardiography, blood pressure monitoring, and blood chemistry tests) every 4 months until a stable decrease in aneurysms is confirmed by two subsequent negative controls. Cardiology evaluations and blood tests along with a stress ECG, stress echocardiography, or stress MRI with contrast to assess myocardial perfusion should be done annually.

• Coronary angiography or coronary CT angiography over the first 6–12 months and after that as indicated.

5. Class V (coronary artery obstruction at the angiography)

• Cardiologic assessments every 3 months, including ECG, echo, and maybe a Holter-ECG; annual evaluations of myocardial perfusion (stress ECG, stress echocardiogram, stress MRI with contrast).

• Coronary angiography or coronary CT angiography to guide treatment decisions and total body angio-CT in the event of myocardial ischemia.

• Coronary angiography or coronary CT angiography during the first 6 to 12 months, and then as needed or indicated by non-invasive investigations.

Subject to the individual patient clinical status, periodic follow-up for the long-term sequelae of the ocular complications.

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