Revised recommendations of the Italian Society of Pediatrics about the general management of Kawasaki disease

Two years after the diffusion of the Italian Guidelines for diagnosis and treatment of Kawasaki disease (KD), we have updated 20 operative recommendations focusing on the general management of this widespread illness of unknown etiology, which mostly occurs in infants and children under 5 years of age with risk of heart implications, especially if the diagnosis is missed or if timely appropriate treatment is overlooked [1, 2]. First described in Japan in l967 by Tomisaku Kawasaki, the disease occurs in children of all ethnicities and is one of the leading cause of acquired cardiovascular disease in the pediatric age [3]. The basic symptom of KD is persistently high and nonresponding fever, despite antipyretic and antibiotic treatments [4]. Japan, Korea and Taiwan are the countries with the highest frequency of KD, reflecting a potential genetic susceptibility among the Asian populations. In addition, the age distribution of KD, higher in children less than 2 years and lower in those less than 6 months, is consistent with a potentially infectious disease, though KD has been even reported in newborns [5, 6].

The identification of the causing mechanisms behind KD would be essential to develop preventive strategies or focused therapies, but the definite etiology remains elusive. A number of theories have linked KD to bacteria, viruses and different environmental factors, but none has been proved. It is discussed if the trigger of KD might be an RNA virus that normally causes an asymptomatic infection in most children and KD in a subset of genetically predisposed children [7]. The most significant complications in KD are cardiovascular and prominently involve coronary arteries, though the overall incidence of coronary artery abnormalities (CAA) has been reduced by treatment with intravenous immunoglobulin (IVIG) given within 7–10 days after disease onset [8]. Diagnosis of KD is clinical, supported by the results of labworks and imaging, but no findings or test can be considered highly specific. Diagnostic difficulties depend also on the different presenting times of signs and symptoms, the gruelling identification of other infectious and non-infectious illnesses mimicking KD, the occurrence of non-typical manifestations and incomplete patterns of the disease [9, 10].

Aim of these synthetically revised recommendations is suggesting the best practice for the management of children with KD, based on the most recent scientific evidence.

KD clinical course can be divided into three phases:

(a) acute (1st-2nd week), in which diagnosis should be established and treatment started,

(b) subacute (3rd-4th week), characterized by defervescence, periungual skin desquamation, thrombocytosis and eventual formation of CAA,

(c) convalescence phase (5th–8th week), in which all KD signs disappear, inflammatory markers subside to normal and nail indentations (Beau’s lines) may appear.

Child’s extreme irritability is characteristic during the acute phase of KD [20].

Diagnosis of KD should be considered in all children displaying fever for 5 days (or more), as prognosis relies on a prompt treatment. Consequently, in case of suspected KD, it is important to recommend patient’s hospitalization. Unfortunately, laboratory tests are nonspecific for KD, though leukocytosis, anemia and elevation of acute-phase reactants, such as CRP, can support the diagnosis in combination with classic features [21, 22]. Hypoalbuminemia is common and associated with more severe and more prolonged acute disease. Urinalysis may show pyuria in up to 80% of children. Additional helpful findings are elevated levels of brain natriuretic peptide (BNP) and N-terminal pro-BNP. Thrombocytosis is characteristic during the subacute phase, peaking in the third week and normalizing 4-to-6 weeks after onset. Thrombocytopenia is rare, but may occur in the first 1–2 weeks of illness: it can be a sign of disseminated intravascular coagulation or macrophage activation syndrome (MAS) and is a risk factor for the development of CAA [23].

Recurrence of KD ranges from 1.4 to 3% of cases, and symptoms are often the same as for the first episode. IVIG resistance, the elevation of liver enzymes and reduced hemoglobin level are risk factors for the recurrence of KD. In addition, recurrent forms of KD can be associated with a higher incidence of CAA [32]. Recurrent KD requires the same treatment as used for the first episode. Hereditary autoinflammatory syndromes need to be considered for a comprehensive differential diagnosis of recurrent KD in childhood [33‐35].

Resistant KD is defined by failure to respond to IVIG therapy and consists in a recrudescent fever 36–48 h after IVIG infusion [36]. It is believed that IVIG-resistant KD reflects severity of the underlying inflammation, explaining the increased incidence of CAA in this subset of patients. Severe anemia at disease onset, early development of CAA, and signs of MAS or septic shock should be considered in predicting the risk of IVIG non-responsiveness [37]. The identification of patients with KD having a higher propensity to be IVIG-refractory is challenging: many efforts have been made to discriminate which patients might not respond to IVIG in order to undertake a more aggressive treatment combined with IVIG, but different scores useful in the Eastern Asiatic populations have been unsuccessful in the Caucasians [21, 38‐40].

Several second-line treatment options are available for resistant KD, which are represented by an additional IVIG infusion, intravenous methylprednisolone pulses, infliximab and other biologic drugs. Randomized controlled trials evaluating the effectiveness of these different options apart from the second infusion of IVIG are poor [41].

The most relevant risk for children with KD is the development of vascular abnormalities, affecting small-to-mid size arteries, but characteristically the coronary arteries. A coronary artery anomaly may start as ectasia, progress to moderate dilatation (5-to-8 mm of diameter) until the formation of large aneurysms (measuring more than 8 mm). A standardized classification to measure coronary arteries and characterize CAA, comparing vessel diameters to the body surface area and measuring the standard deviation from the average in z units, is listed in Table 1 [52]. This classification is recommended for the right coronary, left anterior descending and left main coronary arteries, and z-scores with reference values for pediatric echocardiography are available at the website www.parameterz.com.

Coronary artery involvement is virtually absent if the z-score is < 2 and present if the z-score is beyond 2. Patients with giant aneurysms (having z-scores ≥10) display the highest risk of both coronary thrombosis and stenosis [53]. Other cardiovascular complications include myocarditis, pericarditis, myopericarditis, valvular lesions, arrhythmias, heart failure in addition to coronary thrombosis or stenosis and myocardial infarction [54]. Pneumonia, encephalitis, seizures, paralytic ileus, cholecystitis, liver dysfunction, cholecystitis, anemia, hypoalbuminemia, electrolyte imbalance, diarrhea, vomiting and dehydration might occur in KD, and specific treatments may be required [19]. Other severe non-cardiovascular complications are MAS, largely known to occur in a host of disorders characterized by hypercytokinemia, heralded by non-remitting fever, impaired liver function, hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, pancytopenia and frequently hemophagocytosis [55, 56], and KD-related shock syndrome, associated with hypotension, platelet consumption and increased risk of CAA [57].

KD vasculitis involves a variety of blood vessels and, in particular, small muscular arteries, being caused by diffuse neutrophil infiltration with necrotizing features, which might potentially lead to vessel dilatation mostly occurring during the subacute phase [58]. In general terms, CAA may start as ectasia which might regress within 8 weeks in most cases [59]. The regression of small or medium coronary aneurysms might occur within 1–2 years after onset, but large and giant aneurysms may persist over a long time due to local fibrosis and calcifications, with the risk of acute coronary syndrome [60]. Non-responsiveness to IVIG is a crucial sign to define KD severity, as these children have the highest risk of developing CAA [61]. Additionally, CAA are most prevalent in patients having incomplete KD [62].

Long-term therapy in KD patients with CAA aims at preventing the cardiovascular acute events with reduction of both incidence and severity of acute coronary syndrome. Such therapy depends on the features and extension of CAA. In the absence of “evidence-based” studies, recommendations have been drafted by pediatric retrospective studies. Platelet activation is critical in all KD phases, therefore, in case of persistent CAA, chronic use of anti-platelet low-dose ASA (3–5 mg/kg/day) must be provided, optionally associated with other anti-platelet and/or anticoagulant and/or anti-angina drugs, according to the size of aneurysms, flow characteristics, and presence or absence of myocardial ischemic changes [67].

Patients with giant aneurysms of coronary arteries are at higher risk of presenting thrombosis and developing acute coronary syndrome. The goal of treatment in KD patients who show coronary thrombosis is to restore flow patency, preserve the myocardial tissue and increase patient’s survival [73]. Thrombolytic treatment with tissue-type plasminogen activator is the most commonly administered therapeutic regimen in treating fresh thrombosis within medium/large or giant coronary aneurysms. A multidisciplinary approach is needed to optimize outcome of KD patients receiving thrombolysis, that should be performed by experienced interventional radiologists or cardiologists in intensive care setting to allow rapid intervention in the case of bleeding. The ability to quickly obtain coagulation testing results for ongoing adjustments of therapy is critical for managing patients who require thrombolysis and concomitant anticoagulation. The most relevant thrombolytic drug in young patients with KD complicated by coronary artery thrombosis is the intravenous recombinant tissue plasminogen activator (rtPA), and in recent years “alteplase” has become the most widely used in children. Fresh frozen plasma (10–20 ml/kg) given before using rtPA works as a plasminogen source. Various dosing regimens have been compared, but high doses of alteplase (0.5 mg/kg, 10% infused over 1–2 min and the remainder over 60 min) are more commonly used [74]. A careful monitoring of coagulation testing every 6–12 h is mandatory to prevent bleeding (maintaining the fibrinogen level > 100 mg/dl and platelet count > 50,000/mm³). Low-dose thrombolytic therapy may be also associated with abciximab, a glycoprotein IIb/IIIa inhibitor, given intravenously (as a bolus of 0.25 mg/kg in 30 min, then followed by 0.125 μg/kg/minute, max: 10 μg/min, for 12 h) in the case of thrombosis with high risk of forthcoming vessel occlusion [75, 76]. Both rtPA and abciximab require to be associated with low-dose ASA and intravenous heparin (10 U/kg/hour). Coronary thrombosis should be reassessed with echocardiographic imaging during and after completion of thrombolysis.

Coronary artery reperfusion by both invasive cardiac interventional procedures and cardiac surgery should be considered after unsuccessful pharmacological thrombolysis or when stenotic lesions are eventually present in selected patients. It is important to consult an adult interventional cardiologist and/or an adult cardiothoracic surgeon with experience in revascularization of patients with KD if revascularization is considered.

Cardiac procedures include intracoronary catheter-directed thrombolysis, percutaneous balloon angioplasty with or without coronary stenting and rotational atherectomy with or without coronary stenting [77]. There is no standard protocol or preferred device in pediatrics, and the use of any of these modalities often relies on physician’s experience. In order to determine the most appropriate procedure it is desirable that physicians consider patient’s body size, coronary angiography findings and intravascular ultrasound. Invasive treatment should be considered in patients with or without ischemic symptoms caused by coronary artery stenosis (≥75% of the luminal diameter), but with instrumentally demonstrated ischemia (via stress electrocardiogram or stress perfusion imaging) [78]. Coronary angioplasty procedure has a risk of vessel re-stenosis and occlusion, requiring the use of stenting or alternative procedures, such as coronary artery bypass grafting or percutaneous transluminal rotational ablation [79]. Heart transplantation can be proposed in selected cases with irreversible myocardial dysfunction [80].

Patients with KD must undergo regular cardiologic evaluations with electrocardiogram and echocardiography in the long-term. For patients with large coronary aneurysms diagnosed in the first months after disease onset it is recommended to perform echocardiography weekly [81]. Cardiologic evaluations performed in the convalescence phase allow to subdivide KD patients according to their cardiovascular impairment into different risk classes and establish a personalized follow-up protocol. It is reasonable to consider KD patients worthy of close monitoring for their cardiovascular risk, evaluating and controlling blood pressure, body mass index, blood lipid profile and promoting correct lifestyles [82]. Cardiologic assessment allows to consider 5 different risk classes according to the cardiovascular sequelae and establish a personalized follow-up protocol (Table 2) [1, 2, 13].

Treatment of KD with IVIG does not significantly interfere with inactivated vaccines, oral attenuated live virus vaccines, live virus nasal vaccines, bacillus Calmette-Guérin vaccine or yellow fever vaccine. Subsequently, these vaccines can be safely administered at any time after IVIG administration. Conversely, it is recommended to wait 10–12 months before administration of vaccines against measles, mumps, rubella (MMR), varicella (V) and MMRV, as IVIG administration might result in reduced immunogenicity and interfere specifically with the immune response of these live attenuated vaccines. A seasonal inactivated influenza vaccine is recommended in children with KD receiving ASA [83].

During the 2020 pandemic caused by the novel coronavirus (SARS-CoV-2) infection a number of severely ill patients with a systemic inflammatory syndrome, which has been named “pediatric multisystem inflammatory syndrome temporally associated with coronavirus disease (COVID-19) or PIMS-TS” in the UK and “multisystem inflammatory syndrome associated with COVID-19 or MIS-C” in the USA, have been reported. The pathogenesis of this multisystem syndrome is rather unclear, though some overlapping features suggesting an immune-mediated vasculitis like KD have been described: the inflammatory response in this condition differs from KD with respect to cell subsets involved and biomarkers associated with vascular damage [84]. There has been a huge debate about the substantial risk that first-line providers encountering febrile patients might miss or delay the diagnosis of KD and proper treatment with IVIG. While there are no definite proofs of a relationship between SARS-CoV2 and KD, it is important to remind a high suspicion level for KD in all children with prolonged fever, mostly those younger than 12 months, and to perform echocardiograms to monitor eventual cardiovascular complications in these little patients even after a confirmed infection by SARS-CoV-2 [85].

This list of 20 revised recommendations, drafted 3 years after the American Heart Association Statement and 2 years after the publication of the Italian Guidelines for diagnosis and treatment of KD, summarizes the most relevant clues to manage KD patients, highlighting relevant points for both clinicians and researchers. Their aim is spreading the best practice in general management of children with such a complex disorder, so that long-term morbidity and potential mortality might be prevented across the life span. We have herein refined the definition of cardiovascular and systemic complications of KD, recurrent forms of KD and treatment modalities with corticosteroids or biological agents in refractory patients. Treatment of cardiovascular complications with anti-platelet drugs and/or anticoagulants and treatment of coronary artery thrombosis with both pharmacological and non-pharmacological approaches have been also discussed. Every clinical decision-making should be specifically tailored on the individual patient with KD.