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Kawasaki disease (KD) is an acute vasculitis with a particular tropism for the coronary arteries. KD mainly affects male children between 6 months and 5 years of age. The diagnosis is clinical, based on the international American Heart Association criteria. It should be systematically considered in children with a fever, either of 5 days or more, or of 3 days if all other criteria are present. It is important to note that most children present with marked irritability and may have digestive signs. Although the biological inflammatory response is not specific, it is of great value for the diagnosis. Because of the difficulty of recognising incomplete or atypical forms of KD, and the need for urgent treatment, the child should be referred to a paediatric hospital as soon as the diagnosis is suspected. In the event of signs of heart failure (pallor, tachycardia, polypnea, sweating, hepatomegaly, unstable blood pressure), medical transfer to an intensive care unit (ICU) is essential. The standard treatment is an infusion of IVIG combined with aspirin (before 10 days of fever, and for a minimum of 6 weeks), which reduces the risk of coronary aneurysms. In case of coronary involvement, antiplatelet therapy can be maintained for life. In case of a giant aneurysm, anticoagulant treatment is added to the antiplatelet agent. The prognosis of KD is generally good and most children recover without sequelae. The prognosis in children with initial coronary involvement depends on the progression of the cardiac anomalies, which are monitored during careful specialised cardiological follow-up., (Copyright © 2023. Published by Elsevier Masson SAS.)

Since the coronavirus disease 2019 (COVID-19) outbreak started, children have been considered marginally involved compared to adults, with a quite significant percentage of asymptomatic carriers. Very recently, an overwhelming inflammatory activation, which shares clinical similarities with Kawasaki disease (KD), has been described in children exposed to COVID-19. We report three KD-like cases that occurred during the pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a highly affected area of Northern Italy. The clinical presentation was characterized by the presence of unremitting fever, diarrhea and elevated inflammatory markers. Case #1 and Case #2 occurred one week apart and shared other clinical features: laboratory tests confirmed COVID-19 exposure and high inflammatory activation with myocardial involvement. Case #3 followed a more typical pattern for KD. Interestingly, this patient showed lower levels of procalcitonin, C-reactive protein, D-dimers, and ferritin compared to the other two cases, whereas platelet count was higher. We hypothesize that SARS-CoV-2 might act in children as a trigger, either inducing a classical KD phenotype or causing a systemic inflammatory response leading to a severe KD-like phenotype, eventually characterized by myocardial impairment. We think that bringing these cases and their differences to the attention of the rheumatology community during the COVID-19 pandemic will be beneficial in order to highlight the importance of early diagnosis and to increase awareness of this new phenomenon.

Background: There is mounting evidence on the existence of a Pediatric Inflammatory Multisystem Syndrome-temporally associated to SARS-CoV-2 infection (PIMS-TS), sharing similarities with Kawasaki Disease (KD). The main outcome of the study were to better characterize the clinical features and the treatment response of PIMS-TS and to explore its relationship with KD determining whether KD and PIMS are two distinct entities., Methods: The Rheumatology Study Group of the Italian Pediatric Society launched a survey to enroll patients diagnosed with KD (Kawasaki Disease Group - KDG) or KD-like (Kawacovid Group - KCG) disease between February 1st 2020, and May 31st 2020. Demographic, clinical, laboratory data, treatment information, and patients' outcome were collected in an online anonymized database (RedCAP®). Relationship between clinical presentation and SARS-CoV-2 infection was also taken into account. Moreover, clinical characteristics of KDG during SARS-CoV-2 epidemic (KDG-CoV2) were compared to Kawasaki Disease patients (KDG-Historical) seen in three different Italian tertiary pediatric hospitals (Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste; AOU Meyer, Florence; IRCCS Istituto Giannina Gaslini, Genoa) from January 1st 2000 to December 31st 2019. Chi square test or exact Fisher test and non-parametric Wilcoxon Mann-Whitney test were used to study differences between two groups., Results: One-hundred-forty-nine cases were enrolled, (96 KDG and 53 KCG). KCG children were significantly older and presented more frequently from gastrointestinal and respiratory involvement. Cardiac involvement was more common in KCG, with 60,4% of patients with myocarditis. 37,8% of patients among KCG presented hypotension/non-cardiogenic shock. Coronary artery abnormalities (CAA) were more common in the KDG. The risk of ICU admission were higher in KCG. Lymphopenia, higher CRP levels, elevated ferritin and troponin-T characterized KCG. KDG received more frequently immunoglobulins (IVIG) and acetylsalicylic acid (ASA) (81,3% vs 66%; p = 0.04 and 71,9% vs 43,4%; p = 0.001 respectively) as KCG more often received glucocorticoids (56,6% vs 14,6%; p < 0.0001). SARS-CoV-2 assay more often resulted positive in KCG than in KDG (75,5% vs 20%; p < 0.0001). Short-term follow data showed minor complications. Comparing KDG with a KD-Historical Italian cohort (598 patients), no statistical difference was found in terms of clinical manifestations and laboratory data., Conclusion: Our study suggests that SARS-CoV-2 infection might determine two distinct inflammatory diseases in children: KD and PIMS-TS. Older age at onset and clinical peculiarities like the occurrence of myocarditis characterize this multi-inflammatory syndrome. Our patients had an optimal response to treatments and a good outcome, with few complications and no deaths.

Aim of these revised recommendations for the general management of Kawasaki disease is to encourage its prompter recognition and warrant the most appropriate therapy, based on ascertained scientific data, raising awareness of the complications related to misdiagnosis or delayed treatment. A set of 20 synthetic operative statements is herein provided, including the definition of Kawasaki disease, its protean presentations, clinical course and seminal treatment modalities of all disease phases. The application of these recommendations should improve prognosis of Kawasaki disease and prevent the progression to permanent vascular abnormalities, thereby diminishing morbidity and mortality.

Kawasaki disease (KD) is one of the most common vasculitides of childhood and the main cause of acquired heart disease in developed countries. Intravenous immunoglobulin (IVIG) in association with aspirin represents the main treatment for KD. However, 10-20% of patients fail to respond to standard treatment and have an increased risk of cardiac complications. There is currently no accepted protocol for treatment of resistant cases. Several authors highlighted the role of interleukin-1 (IL-1) as a mediator of inflammation in KD and suggested the possibility of using IL-1 or its receptor as a target of therapy. The use of IL-1 inhibitors in patients with KD has been reported in the scientific literature, but data are largely limited to individual case reports and small case series. We summarized the scientific literature related to the use of anakinra, analyzing preclinical and clinical data. Thirty-eight patients have been described so far, most of them with KD-related complications. Twenty-two were described in case reports and case series, while 16 were patients from the completed KAWAKINRA phase IIa study. Almost all patients received clinical benefit, and no relevant side effects were noted. Based on this evidence, in our opinion, anakinra may be considered as an option after the failure of the first IVIG infusion, especially in patients with coronary involvement.

A few weeks after the peak of the global 2019 novel coronavirus disease pandemic, cases of shock, multisystem inflammation and severe myocarditis have occurred in children and adolescents, generating some concerns and above all many questions. An almost immediate association raised with shock syndrome related to Kawasaki disease (KD). However, in light of bo/th experience and literature have taught us about severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection, and what already known on the epidemiology of KD, we suggest here the hypothesis of a new 'post-viral' systemic inflammatory disease related to excessive adaptive immune response rather than a form of KD caused by SARS-COV-2. We discuss analogies and differences between the two forms., Competing Interests: Competing interests: IK-P has received consulting fees from AbbVie, Pfizer, Roche, CHUGAI, Novartis, SOBI and Novimmune. RC has no competing interests., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

About 10-20% of patients with Kawasaki disease (KD) are unresponsive to intravenous immunoglobulin (IVIg) and are at increased risk of coronary artery abnormalities (CAAs). Early identification is critical to initiate aggressive therapies, but available scoring systems lack sensitivity in non-Japanese populations. We investigated the accuracy of 3 Japanese scoring systems and studied factors associated with IVIg unresponsiveness in a large multiethnic French population of children with KD to build a new scoring system. Children admitted for KD between 2011-2014 in 65 centers were enrolled. Factors associated with second line-treatment; i.e. unresponsiveness to initial IVIg treatment, were analyzed by multivariate regression analysis. The performance of our score and the Kobayashi, Egami and Sano scores were compared in our population and in ethnic subgroups. Overall, 465 children were reported by 84 physicians; 425 were classified with KD (55% European Caucasian, 12% North African/Middle Eastern, 10% African/Afro-Caribbean, 3% Asian and 11% mixed). Eighty patients (23%) needed second-line treatment. Japanese scores had poor performance in our whole population (sensitivity 14-61%). On multivariate regression analysis, predictors of secondary treatment after initial IVIG were hepatomegaly, ALT level ≥30 IU/L, lymphocyte count <2400/mm 3 and time to treatment <5 days. The best sensitivity (77%) and specificity (60%) of this model was with 1 point per variable and cut-off ≥2 points. The sensitivity remained good in our 3 main ethnic subgroups (74-88%). We identified predictors of IVIg resistance and built a new score with good sensitivity and acceptable specificity in a non-Asian population.

Purpose of Review: Kawasaki disease is a childhood vasculitis of unknown origin, whose major complication is the development of coronary artery aneurysms (CAA). The purpose of this review is to provide an overview on the most recent evidence on the pathogenesis, diagnosis and treatment options of Kawasaki disease summarizing the most relevant studies published in the last year., Recent Findings: Several genetic polymorphisms leading to Kawasaki disease susceptibility have been identified, mostly related to immune system regulation; potential external triggers are being investigated by environmental epidemiology studies. A new diagnostic test based on trascriptomics has been tested with promising preliminary results. With regards to first-line treatments, the real effectiveness of high-dose aspirin remains a matter of debate. For refractory cases, the ones at the highest risk for developing CAA, promising results come from the use of biologic agents, especially TNF and IL-1 blockers., Summary: Recent literature has provided interesting insights on the various factors involved in the complex scenario behind the pathogenesis of Kawasaki disease, especially genetic ones. Novel diagnostic tests and new evidence on the use of biologic agents in Kawasaki disease are emerging, but further evidence is needed to permit early diagnosis and effective treatment of this condition.

Background and Aims: Few data are currently available for Kawasaki disease (KD) below 12 months especially in Caucasians. This study aims to analyze clinical and laboratory features of KD among an Italian cohort of infants., Methods: A retrospective chart review of KD children aged less than 1 year at time of disease onset between January 2008-December 2017 was performed. Clinical data, laboratory parameters, instrumental findings, treatment and outcome were collected in a customized database., Results: Among 113 KD patients, 32 (28.3%) were younger than 1 year. Nineteen patients aged below 6 months, and three below 3 months. The median age was 5.7 ± 2.7 months. The mean time to diagnosis was 7 ± 3 days and was longer in the incomplete forms (8 ± 4 vs 6 ± 1 days). Conjunctival injection was present in 26 patients (81.2%); rash in 25 (78.1%); extremity changes in 18 (56.2%); mucosal changes in 13 (40.6%,) and lymphadenopathy only in 7 (21.8%). Mucosal changes were the least common features in incomplete forms (18.2%). Twenty-two patients (68.7%) had incomplete KD. Nineteen (59.4%) had cardiac involvement, of whom 13 (59.0%) had incomplete form. ESR, PCR and platelet values were higher in complete KD; especially, ESR resulted significantly higher in complete forms (80 ± 25.7 mm/h vs 50 ± 28.6 mm/h; p = 0.01). Conversely, AST level was statistically significant higher in patients with incomplete forms (95.4 ± 132.7 UI/L vs 29.8 ± 13.2 UI/L; p = 0.03). All patients received IVIG. Response was reported in 26/32 patients; 6 cases needed a second dose of IVIG and one required a dose of anakinra., Conclusion: In our cohort, incomplete disease was commonly found, resulting in delayed diagnoses and poor cardiac prognosis. Infants with incomplete KD seem to have a more severe disease and a greater predilection for coronary involvement than those with complete KD. AST was significantly higher in incomplete forms, thus AST levels might be a new finding in incomplete forms' diagnosis. Eventually, we highlight a higher resistance to IVIG treatment. To our knowledge this is the first study involving an Italian cohort of patients with KD below 12 months.

Autoimmune diseases affect up to 10% of the world's population and, as a whole, they are far more common in females, although differences exist according to the single disease and also in different age groups. In childhood-onset autoimmune diseases, the sex bias is generally less evident than in adults, probably for the different hormonal milieau, being estrogens strongly implicated in the development of autoimmunity. Still, some rheumatic conditions, such as juvenile idiopathic arthritis (JIA), show a strong predilection for girls (F:M = 3-6.6:1), and differences may coexist between males and females regarding disease outcome. For example, chronic anterior uveitis associated with JIA affects more commonly girls but boys tend to have a more severe course. Systemic lupus erythematosus predominantly affects girls and women (F:M = 3-5:1 in children, F:M = 10-15:1 in adults). Behςet's disease has been reported to be more prevalent in adult males (F:M = 1:1-4); in children, there are no differences. The sex ratio is equal in children and adults for Henoch-Schönlein purpura (F:M = 1:1). A higher male-to-female ratio exists for Kawasaki disease (F:M = 1:1.1-1.6 in children, F:M = 1:1,5 in adults). Juvenile dermatomyositis (F:M = 2-5:1), systemic sclerosis (F:M = 4:1 in children, F:M = 6:1 in adults), and Takayasu arteritis (F:M = 2:1 in children, F:M = 7-9:1 in adults) are more common in girls and women then in boys and men. There is no gender bias for acute rheumatic fever in children, while in adults, the F:M ratio is 2:1. Given that estrogen levels are not different between genders during childhood, pediatric rheumatic diseases could represent good models to study other mechanisms related to the development of autoimmunity. Recently, the levels of miRNA expression, and their variation according to sex chromosomes, have been linked to the development of autoimmune diseases, with different impact among sexes. This review will focus not only on the sex bias reported in the more common rheumatic conditions of childhood, focusing on differences in incidence, but also on outcome and trying to depict the mechanisms underlying those differences.

Autoinflammatory diseases (AIDs) are heterogeneous disorders characterized by dysregulation in the inflammasome, a large intracellular multiprotein platform, leading to overproduction of interleukin-1(IL-1)β that plays a predominant pathogenic role in such diseases. Appropriate treatment is crucial, also considering that AIDs may persist into adulthood with negative consequences on patients' quality of life. IL-1β blockade results in a sustained reduction of disease severity in most AIDs. A growing experience with the human IL-1 receptor antagonist, Anakinra (ANA), and the monoclonal anti IL-1β antibody, Canakinumab (CANA), has also been engendered, highlighting their efficacy upon protean clinical manifestations of AIDs. Safety and tolerability have been confirmed by several clinical trials and observational studies on both large and small cohorts of AID patients. The same treatment has been proposed in refractory Kawasaki disease, an acute inflammatory vasculitis occurring in children before 5 years, which has been postulated to be autoinflammatory for its phenotypical and immunological similarity with systemic juvenile idiopathic arthritis. Nevertheless, minor concerns about IL-1 antagonists have been raised regarding their employment in children, and the development of novel pharmacological formulations is aimed at minimizing side effects that may affect adherence to treatment. The present review summarizes current findings on the efficacy, safety, and tolerability of ANA and CANA for treatment of AIDs and Kawasaki vasculitis with a specific focus on the pediatric setting.

The human Fc-gamma receptors (FcγRs) link adaptive and innate immunity by binding immunoglobulin G (IgG). All human low-affinity FcγRs are encoded by the FCGR2/3 locus containing functional single nucleotide polymorphisms (SNPs) and gene copy number variants. This locus is notoriously difficult to genotype and high-throughput methods commonly used focus on only a few SNPs. We performed multiplex ligation-dependent probe amplification for all relevant genetic variations at the FCGR2/3 locus in >4,000 individuals to define linkage disequilibrium (LD) and allele frequencies in different populations. Strong LD and extensive ethnic variation in allele frequencies was found across the locus. LD was strongest for the FCGR2C -ORF haplotype (rs759550223+rs76277413), which leads to expression of FcγRIIc. In Europeans, the FCGR2C -ORF haplotype showed strong LD with, among others, rs201218628 ( FCGR2A -Q27W, r 2 = 0.63). LD between these two variants was weaker ( r 2 = 0.17) in Africans, whereas the FCGR2C -ORF haplotype was nearly absent in Asians (minor allele frequency <0.005%). The FCGR2C -ORF haplotype and rs1801274 ( FCGR2A -H131R) were in weak LD ( r 2 = 0.08) in Europeans. We evaluated the importance of ethnic variation and LD in Kawasaki Disease (KD), an acute vasculitis in children with increased incidence in Asians. An association of rs1801274 with KD was previously shown in ethnically diverse genome-wide association studies. Now, we show in 1,028 European KD patients that the FCGR2C -ORF haplotype, although nearly absent in Asians, was more strongly associated with susceptibility to KD than rs1801274 in Europeans. Our data illustrate the importance of interpreting findings of association studies concerning the FCGR2/3 locus with knowledge of LD and ethnic variation.

The exact classification of Kawasaki disease (KD) has been debated. Infectious disease specialists have claimed it as an infection with a classic immune responses to an as yet unidentified pathogen that localizes to the coronary arteries. Others have favored an autoreactive hypothesis that KD is triggered by an antigen that shares homology with structures in the vascular wall, and molecular mimicry resulting in an immune response directed to that tissue. Rheumatologists have classified it as a systemic vasculitis, while some immunologists have stressed the robust nature of the innate immune response that causes both systemic inflammation as well as damage to the coronary arterial wall and questioned whether KD falls within the spectrum of autoinflammatory diseases. This review will describe the evidences available up to now regarding these hypotheses.

Objectives: To identify the clinical characteristics, reasons for use and response to treatment with anakinra in a series of patients with Kawasaki Disease (KD)., Study Design: A retrospective chart review of patients treated with anakinra for KD diagnosed according to the AHA criteria. We compared clinical, biological and echocardiographic characteristics of KD before and after anakinra use. We analysed reasons for use of anakinra, and compared treatment regimens used in 7 European KD referral centres., Results: Eight boys and 3 girls with treatment-refractory KD, aged 4 months to 9 years old, received at least 2 different KD treatments prior to anakinra, which was given on mean at 25 days after disease onset (8 to 87 days). The main reasons for use of anakinra were clinical and biological inflammation, progression of coronary dilatations, and severe myocarditis with cardiac failure. Doses of anakinra ranged from 2 to 8 mg/kg and duration varied from 6 to 81 days. Efficacy of anakinra was judged in terms of fever resolution (100%), decrease of CRP (100%), and in terms of its effect on coronary artery dilatation Z scores, which decreased in 10/11 patients and increased in one who died suddenly of pericardial hemorrhage., Conclusion: Anakinra used late in the disease course led to a rapid and sustained improvement in clinical and biological inflammation. Our retrospective analysis did show neither a striking nor a rapid decrease of coronary dilatations and we cannot determine if anakinra itself had an effect on coronary artery dimensions., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Kawasaki disease is a systemic vasculitis with an acute and self-limited course. The incidence of the disease differs widely among ethnic groups and is higher in the Asian populations. In Italy, no recent data are available. We studied the epidemiology of Kawasaki disease in the years 2008-2013 in children 0-14 years old in Italy using hospital ICD-9 discharge codes with a thorough data cleaning for duplicates in order to select the first hospital admission for the disease. The disease peaked in the first 2 years of life, with 85.5% of cases under 5 years. Male/female ratio was 1.4:1. The incidence rate was 5.7 per 100,000 children 0-14 years old and 14.7 for children younger than 5 years. The incidence rose slightly during the study period and had a seasonal distribution, with higher incidence in spring. A coronary artery aneurysm was recorded in 2.2% of the patients younger than 5 years of age., Conclusion: This is the first epidemiologic study on Kawasaki disease incidence in the country of Italy. Figures are in line but slightly higher than those reported for other European countries. What is known: • Kawasaki disease is more common in Asian populations. • European incidence data are scarce. What is new: • Epidemiological data in Italy show similar incidence, albeit slightly higher, than in other European countries. • Incidence data slightly rose in the recent past.

Kawasaki shock syndrome (KSS) is a rare manifestation of Kawasaki disease (KD) characterized by systolic hypotension or clinical signs of poor perfusion. The objectives of the study are to describe the main clinical presentation, echocardiographic, and laboratory findings, as well as the treatment options and clinical outcomes of KSS patients when compared with KD patients. This is a retrospective study. All children referred to two pediatric rheumatology units from January 1, 2012, to December 31, 2014, were enrolled. Patients were divided into patients with or without KSS. We compared the two groups according to the following variables: sex, age, type of KD (classic, with less frequent manifestations, or incomplete), clinical manifestations, cardiac involvement, laboratory findings, therapy administered, response to treatment, and outcome. Eighty-four patients with KD were enrolled. Of these, five (6 %) met the criteria for KSS. Patients with KSS had higher values of C-reactive protein (p = 0.005), lower hemoglobin levels (p = 0.003); more frequent hyponatremia (p = 0.004), hypoalbuminemia (p = 0.004), and coagulopathy (p = 0.003); and increase in cardiac troponins (p = 0.000). Among the KSS patients, three had a coronary artery involvement, but none developed a permanent aneurysm. Intravenous immunoglobulin resistance was more frequent in the KSS group, although not significantly so (3/5, 60 % vs. 23/79, 30 %, P = NS). None of the five cases was fatal, and all recovered without sequelae. KSS patients are more likely to have higher rates of cardiac involvement. However, most cardiovascular abnormalities resolved promptly with therapy.

Background: Kawasaki disease (KD) is an acute pediatric vasculitis in which host genetics influence both susceptibility to KD and the formation of coronary artery aneurysms. Variants discovered by genome-wide association studies and linkage studies only partially explain the influence of genetics on KD susceptibility., Methods and Results: To search for additional functional genetic variation, we performed pathway and gene stability analysis on a genome-wide association study data set. Pathway analysis using European genome-wide association study data identified 100 significantly associated pathways (P<5×10 - 4 ). Gene stability selection identified 116 single nucleotide polymorphisms in 26 genes that were responsible for driving the pathway associations, and gene ontology analysis demonstrated enrichment for calcium transport (P=1.05×10 - 4 ). Three single nucleotide polymorphisms in solute carrier family 8, member 1 (SLC8A1), a sodium/calcium exchanger encoding NCX1, were validated in an independent Japanese genome-wide association study data set (meta-analysis P=0.0001). Patients homozygous for the A (risk) allele of rs13017968 had higher rates of coronary artery abnormalities (P=0.029). NCX1, the protein encoded by SLC8A1, was expressed in spindle-shaped and inflammatory cells in the aneurysm wall. Increased intracellular calcium mobilization was observed in B cell lines from healthy controls carrying the risk allele., Conclusions: Pathway-based association analysis followed by gene stability selection proved to be a valuable tool for identifying risk alleles in a rare disease with complex genetics. The role of SLC8A1 polymorphisms in altering calcium flux in cells that mediate coronary artery damage in KD suggests that this pathway may be a therapeutic target and supports the study of calcineurin inhibitors in acute KD., (© 2016 American Heart Association, Inc.)

Background: Kawasaki disease (KD) is an acute systemic vasculitis of small and middle size arteries; 15-25 % of untreated patients and 5 % of patients treated with intravenous immunoglobulin (IVIG) develop coronary artery lesions (CAL). Many studies tried to find the most effective treatment in the management of resistant KD and to select the risk factors for CAL. Our data are assessed on children from west Sicily, characterized by a genetic heterogeneity., Methods: We studied the clinical data of 70 KD Sicilian children (36 males: 51 %; 34 females: 49 %), analysed retrospectively, including: demographic and laboratory parameters; echocardiographic findings at diagnosis, at 2, 6 and 8 weeks, and at 1 year after the onset of the illness., Results: Forty-seven had Typical KD, three Atypical KD and twenty Incomplete KD. Age at the disease onset ranged from 0.1 to 8.9 years. IVIG were administered 5 ± 2 days after the fever started. Defervescence occurred 39 ± 26 hours after the first IVIG infusion. Fifty-six patients (80 %) received 1 dose of IVIG (responders); 14 patients (20 %) had a resistant KD, with persistent fever after the first IVIG dose (non responders). Ten (14 %) non responders responded to the second dose, 4 (5 %) responded to three doses; one needed treatment with high doses of steroids and Infliximab. Cardiac involvement was documented in twenty-two cases (eighteen with transient dilatation/ectasia, fifteen with aneurysms). Pericardial effusion, documented in eleven, was associated with coronaritis and aneurysms, and was present earlier than coronary involvement in seven. Hypoalbuminemia, D-dimer pre-IVIG, gamma-GT pre-IVIG showed a statistically significant direct correlation with IVIG doses, highlighting the role of these parameters as predictor markers of refractory disease. The persistence of elevated CRP, AST, ALT levels, a persistent hyponatremia and hypoalbuminemia after IVIG therapy, also had a statistical significant correlation with IVIG doses. Non responders showed higher levels of D-dimer and gamma-GT pre-IVIG, persistent high levels of D-dimer, CRP, AST, ALT, hypoalbuminemia and hyponatremia after IVIG., Conclusions: This is the first study on KD in Sicily. We suggest some laboratory parameters as predictive criteria for resistant KD. Patients who show early pericarditis need careful surveillance for coronary lesions.

Kawasaki disease (KD) is an acute febrile childhood inflammatory disease, associated with coronary artery abnormalities. The disease is believed to result from an aberrant inflammatory response to an infectious trigger in a genetically predisposed individual. KD is associated with an endothelial cell injury as a consequence of T cell activation and cytotoxic effects of various proinflammatory cytokines. Intravenous immunoglobulin (IVIG) infusion and aspirin are the standard treatment of acute KD. However, 10-20% of patients show resistance to IVIG therapy and present higher risk of coronary vasculitis. The relative roles of second IVIG infusion, corticosteroids, calcineurin inhibitors, interleukin-1 antagonists and anti-tumor necrosis factor agents remain uncertain. In this review, we highlight the predisposing factors, pathogenesis and therapeutic intervention of KD, particularly new therapeutics for IVIG-resistant patients., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Kawasaki disease (KD) is a systemic vasculitis with an acute and self-limited course. The incidence of KD differs widely among ethnic groups and is higher in the Asian population. In Italy, no recent data are available. Our purpose is to define the epidemiology of Kawasaki disease in the years 2008-2013 in children aged < 14 years in the Italian regions of Tuscany and Emilia Romagna through administrative data., Methods: We studied the epidemiology of KD in the years 2008-2013 in children 0-14 years old resident in Tuscany and in Emilia Romagna regions using hospital ICD-9 discharge codes with a thorough data cleaning for duplicates., Results: The distribution of the KD patients across ages was similar for the two regions with a peak in the second year of life. When considering data of the two regions together, the rate of incidence was 17.6 for 100,000 children under 5 years. For both Regions the incidence rose slightly during the study period and had a seasonal distribution, with higher incidence in spring and winter., Conclusion: This is the first Italian study performed through the use of administrative data. Figures are in line but slightly higher than those published in other European countries.

Objective: To describe the significance of pericardial effusion (PE), mitral regurgitation (MR) and impaired systolic function in predicting coronary artery lesions (CAL) at diagnosis and follow-up in Kawasaki disease (KD)., Design: Echocardiographic records on admission, at 1-3 weeks of illness, and at 6-8 weeks of illness were retrospectively retrieved in children with acute KD treated by intravenous immunoglobulins., Setting, Patients: The study included 194 consecutive children (113 male; median age 2.1 years) in a paediatric cardiology tertiary care centre, from 1988 to 2007., Results: Overall, children with CAL (64/194) were more likely to have PE (OR=3.00, CI 1.34 to 6.72) and MR (OR=2.51, CI 1.22 to 5.16) at diagnosis; PE was the sole echocardiographic abnormality associated with CAL in multivariable analysis. These abnormalities were predictive of the presence of CAL at the first echocardiography in the acute phase of the disease only. MR, systolic dysfunction and PE were not associated with persistence of CAL in the convalescent phase. Male gender, CAL size and resistance to immunoglobulin treatment were independent factors predictive of the persistence of CAL., Conclusions: Children with MR or PE should undergo careful assessment of coronary status at diagnosis. However, PE or MR at diagnosis is not predictive of persistent CAL at follow-up.

In vivo exposure to microorganisms resident in the oral cavity is considered as a possible cause of Kawasaki disease (KD), and some epitopes derived from streptococci display homology with Factor H of Complement. Additionally, calprotectin, a major calcium binding protein released by neutrophils and activated monocytes, could be directly involved in endothelial damage occurring in KD. The aim of our study is to evaluate the percentages of IFN-gamma+ and/or TNF-alpha+ lymphocytes and double positive calprotectin/TNF-alpha monocytes (CD14+) after in vitro stimulation with streptococcal- and/or Factor H-derived peptides, in patients with acute KD. Peripheral Blood Mononuclear Cells (PBMCs) obtained from KD patients and febrile controls were stimulated in vitro with peptides. After culture, cells were collected, stained with fluorochrome-labelled monoclonal antibodies against CD3, CD14, calprotectin, IFN-gamma and TNF-alpha, and cytofluorimetric analyses were performed. Our results showed increased percentages of TNF-alpha+/IFN-gamma+ lymphocytes in KD patients in respect to controls when PBMCs were stimulated with streptococcal or Factor H-derived epitopes. In addition, also calprotectin+/TNF-alpha+ monocytes from KD patients were activated after PBMC in vitro stimulation. These findings lead us to speculate that some peptides, derived from oral streptococci and cross-reactive with the human Factor H of Complement, could induce lymphocyte and monocyte activation potentially involved in the pathogenesis of KD. Our results should be confirmed by further studies enrolling more patients and controls than those analyzed in our study.

Kawasaki disease is a systemic vasculitis of unknown etiology, with clinical observations suggesting a substantial genetic contribution to disease susceptibility. We conducted a genome-wide association study and replication analysis in 2,173 individuals with Kawasaki disease and 9,383 controls from five independent sample collections. Two loci exceeded the formal threshold for genome-wide significance. The first locus is a functional polymorphism in the IgG receptor gene FCGR2A (encoding an H131R substitution) (rs1801274; P = 7.35 × 10(-11), odds ratio (OR) = 1.32), with the A allele (coding for histadine) conferring elevated disease risk. The second locus is at 19q13, (P = 2.51 × 10(-9), OR = 1.42 for the rs2233152 SNP near MIA and RAB4B; P = 1.68 × 10(-12), OR = 1.52 for rs28493229 in ITPKC), which confirms previous findings(1). The involvement of the FCGR2A locus may have implications for understanding immune activation in Kawasaki disease pathogenesis and the mechanism of response to intravenous immunoglobulin, the only proven therapy for this disease.

Objectives: The aims of this study were: 1) to investigate forkhead box P3 (FOXP3) expression in patients with Kawasaki disease (KD), exploring possible differences during the acute phase and after defervescence; 2) to evaluate a possible association of the FOXP3 single nucleotide polymorphism (SNP) 543 (SNP ID: rs2232367) with KD., Methods: FOXP3 expression was evaluated on 8 children with KD and 15 healthy children by flow cytometry and Real-Time polymerase chain reaction (RT-PCR). FOXP3 SNP 543 was genotyped by denaturing high-performance liquid chromatography (DHPLC) and sequencing on DNA samples from 58 additional children with KD and 114 healthy donors., Results: The frequencies of CD4+CD25 +FOXP3+ regulatory T cells were significantly (p=0.0002) lower during the acute phase of KD than in sex- and age-matched healthy donors (median % + SD: 4.8+/-1.3 vs. 7.7+/-1.7) and a similar tendency was revealed for FOXP3 mRNA transcripts (p<0.0001). FOXP3 expression increased significantly, at both protein and mRNA levels, after intravenous immunoglobulin (IVIG) therapy treatment and achieving complete remission of disease (at least 48 hrs; median 9.5 days, range 2-30). Of the 58 patients screened, only one female subject (1.7%) carried the presence of 543 SNP in heterozygosis (C>T; for a total of 1 allele out of 88), with no difference between KD patients and controls (0.0%, 0/203 alleles)., Conclusions: Our data reinforce the notion of an impaired immunoregulation in KD, suggesting also a role of IVIG treatment in modifying the Treg compartment. FOXP3 SNP 543 does not seem to be involved in susceptibility to KD in Italian children.

Objective: To investigate the possible relationship between MIF -173 polymorphism and susceptibility to, and severity of, Kawasaki disease (KD) in a cohort of Italian patients., Methods: Sixty-nine patients (43 F, 26 M, median age 29 months, range 3-135 months) with KD and 60 sex-matched healthy caucasian children were genotyped for MIF-173. Typing of the MIF gene -173 G/C was performed by PCR and restriction fragment length polymorphism., Results: Eight out of 69 (12%) KD children were non-responders: 7 required an additional IVIG infusion, while 1 received 2 IVIG infusions and then steroid administration. 9/69 (13%) KD children developed coronary artery abnormalities (CAA) during the second to fourth week of disease, and 4 of them required an additional IVIG infusion. MIF genotyping did not show significant differences between patients and controls. KD patients carrying a MIF -173*C allele developed CAA more frequently than those without MIF- (7/9 77.8% vs. 16/60 26.7%, OR 9.6, 95% CI 1.80-21.2, p<0.005). Non-responders to a single IVIG infusion carried the MIF -173*C allele more frequently than responders (6/8 = 75% vs. 17/61 = 28%, OR 5.1, 95% CI 1.42-22.31 p<0.014). In multiple regression analysis, KD patients carrying a MIF -173*C allele were found to have an increased risk of coronary involvement (OR 7.7, 95% CI 1.36-16.1, p=0.021)., Conclusions: We showed that children carrying the MIF polymorphism -173*C had a higher percentage of CAA. A potential relationship between a MIF polymorphism and risk of CAA in KD might be considered.

Kawasaki disease (KD) is the most common systemic vasculitis in childhood after Henoch-Schonlein purpura, and the most common cause of acquired heart disease among children living in Western countries. Its diagnosis relies on clinical findings; laboratory tests are useful to rule out other causes of unexplained fever but are not specific for the diagnosis of KD. Numerous efforts to produce a diagnostic algorithm have been made, but without success. Expert opinion is therefore required in doubtful cases, especially those that lack classical criteria (the so-called atypical or incomplete cases). Renal, gastrointestinal, neurologic, pulmonary and ocular involvements have all been described. Infants may be at higher risk of complications since recognising manifestations of the disease might be more difficult in this group. Approaches to treatment and follow-up of KD are changing in parallel with changes in concepts of what constitutes classical and incomplete KD. Guiding this evolution is the probability that the diagnosis is actually KD, the duration of the child's illness and the desired effects of therapy. Until a gold standard for diagnosing KD is available, these therapeutic decisions will continue to be made on an individual basis.

Kawasaki disease (KD) is a febrile systemic vasculitis complicated by coronary and peripheral arterial aneurysms in 20% to 35% of untreated patients. It is reported as the commonest cause of acquired heart disease in children in developed countries, and may be a risk for adult ischaemic heart disease. Although KD has been reported all over the world, it is overexpressed among Asian populations, especially Japanese people. The annual incidence for 100,000 children under five years of age is reported to be 8.1 in the United Kingdom, 17.1 in the United States and 112 in Japan. The principal clinical feature is fever, accompanied by extremity changes, polymorphous rash, conjunctival injection, changes in lips and oral cavity, and cervical lymphadenopathy. The disease pathogenesis is still unknown and several theories have been proposed, including the possibility of an infection by a toxin-secreting microorganism and of a superantigen-driven process. Despite numerous efforts there is still no diagnostic test available for KD, and the diagnosis is based on clinical criteria after the exclusion of other diseases presenting with high persistent fever. Prompt diagnosis is critical, since the early administration of intravenous immunoglobulins and aspirin reduces the rate of coronary abnormalities to less than 5% of patients.

Objective: Emerging evidence from in vitro studies and mouse genetics attributes to osteoprotegerin (OPG), a member of the tumor necrosis factor receptor family, an important role in vascular biology. We evaluated serum levels of OPG in a group of children with Kawasaki disease (KD), before immunoglobulin (IVIG) infusion and at 3-month followup., Methods: Fifty patients (38 boys, 20 girls, median age 3.6 yrs, range 4 mo-7.4 yrs) fulfilling criteria for the diagnosis of KD, 30 febrile controls with infectious diseases, 18 patients with juvenile systemic lupus erythematosus (JSLE), and 40 healthy controls were enrolled. All KD patients received IVIG treatment within the first 10 days of illness, and aspirin. Coronary artery abnormalities (CAA) were reported in 6 out of 58 patients; all were male and younger than 5 years. Serum OPG was measured by ELISA in patients with KD before IVIG and at 3-month followup (median time 3.2 mo, range 3-3.5)., Results: At baseline and at the 3-month followup, KD patients had significantly higher OPG serum levels than febrile controls (p < 0.001 and p < 0.004, respectively), JSLE patients (p < 0.0001), and healthy controls (p < 0.0001). At baseline, KD patients who developed CAA had higher OPG serum levels than those without CAA (p = 0.0001); this difference was not present at 3-month followup. The optimal OPG cutoff value of 123.2 pg/ml was a significant predictor for CAA, with a sensitivity of 100% (6/6), a specificity of 96% (50/52), and a positive predictive value of 75% (6/8)., Conclusion: High OPG levels might be the result of compensatory production during acute and subacute phases of KD. OPG assay might be an additional clinically useful marker to monitor and differentiate patients who develop, from those who do not develop, such coronary artery abnormalities.

Kawasaki disease (KD) is a febrile systemic vasculitis complicated by coronary and peripheral arterial aneurysms in 20-35% of untreated patients. It is reported as the commonest cause of acquired heart disease in children in developed countries, and may be a risk for adult ischaemic heart disease. Although KD has been reported all over the world, it is overexpressed among Asian populations, especially Japanese. The disease pathogenesis is still unknown and several theories have been proposed, including the possibility of an infection by a toxin-secreting microorganism and of a superantigen-driven process. Despite numerous efforts there is still no diagnostic test available for KD, and the diagnosis is based on clinical criteria after the exclusion of other diseases presenting with high persistent fever. Prompt diagnosis is critical, since the early administration of intravenous immunoglobulins and aspirin reduces the rate of coronary abnormalities to less than 5% of patients.

Objective: To evaluate (i) the clinical course and outcome in a cohort of 250 children affected with Kawasaki disease (KD) in northern Italy; (ii) the prevalence of coronary aneurysms and their correlation with treatment; and (iii) the prevalence of incomplete and atypical KD in the series as a whole., Results: The male to female ratio was 1.8 to 1 and the median age at diagnosis 37 months. The majority of cases occurred in children under five years, with the youngest patient aged 51 days. Median duration offever was 8 days; median erythrocyte sedimentation rate (ESR) and C Reactive protein (CRP) values, performed before any treatment, were 77 mm/1st h and 10.4 mg/dl respectively. Median haemoglobin (Hb) levels was 9.2 g/dl and median platelet (PTL) count 408,000/mm3. Out of 250 patients, 209 (83.6%) fulfilled all criteria for the diagnosis of KD whilst 41/250 (16.4%) had an incomplete disease and 11/250 (4.4%) had an atypical onset. Fifty-four children (21.6%) were treated with aspirin alone (50-80 mg/kg/day, during the acute phase), while 196/250 (78.4%) were given aspirin (50-80 mg/kg day, during the acute phase and then 3-5 mg/Kg/day) and high-dose intravenous gammaglobulin (IVIG, 400 mg/Kg/day or 2 g/Kg/day). Coronary artery abnormalities, including aneurysms and dilatation, were reported in 7/54 patients (5 males and 2 females) who had not received IVIG and 53/196 patients (27 males and 26 females) who were treated with the IVIG in addition to aspirin. Other clinical manifestations included abdominal pain/diarrhoea (11), arthritis (10), hydrops of the gallbladder (8), disseminated intravascular coagulation (3), and hemiparesis (1). All patients except one infant are still alive. In most of the patients coronary alterations normalised, while in 20 patients they persisted for more than one year; in 12/20 patients they were permanent., Conclusion: Pediatricians should be aware of the increasing number of children with atypical and incomplete KD, in order to diagnose and treat the disease even in the absence of all typical manifestations and to prevent coronary complications.

To verify if Angiotensin Converting Enzyme (ACE) and von Willebrand factor (vWF) may be used as a laboratory marker for the follow-up of endothelial derangement and therapeutic efficacy in Kawasaki disease (KD), circulating ACE, vWF routine hematological tests and cardiac involvement were assessed in 32 children with established diagnosis of KD before and up to six months after intravenous gamma-globulins (i.v.IG) treatment. I.v.IG treatment normalized progressively all the hematological parameters to levels comparable with healthy controls within 30 days. At baseline, ACE levels resulted significantly lower (1.8 +/- 1.3 pmol/ml/min), and vWF levels significantly increased (210.3 +/- 35.2%) when compared with controls (respectively 7.0 +/- 0.9 pm/ml/min and 99 +/- 17.9%). Seven days after the treatment vWF levels were decreased (188 +/- 18.4%) but still significantly higher than controls, and fully normalized after 15 days (104.8 +/- 14.3%). ACE levels were found progressively increased at 7, 15, and 30 days after the treatment (respectively 2.7 +/- 1.0, 3.7 +/- 0.4, 5.04 +/- 0.9 pm/ml/min) and reached the range of normality only after two months (7.74 +/- 2.46 pm/ml/min). The present study shows that ACE and vWF circulating levels are significantly modified during the acute phase of the disease.

Background: There are reports of the familial occurrence of Kawasaki disease but only a few reports described Kawasaki disease in siblings. However, the familial cases were not simultaneous. In these patients the idea of infective agents as trigger must be considered.Case Presentation: We describe two siblings with atypical presentations of Kawasaki disease; the sister was first diagnosed as having parvovirus infection with anemia and the brother was diagnosed as having myocarditis. The first patient was a 9-month-old Caucasian girl with fever, conjunctivitis, rash, and pharyngitis, and later she had cervical adenopathy, diarrhea and vomiting, leukocytosis, and anemia, which were explained by positive immunoglobulin M against parvovirus. However, coronary artery lesions with aneurysms were documented at day 26 after fever onset. An infusion of intravenous immunoglobulin and high doses of steroids were not efficacious to resolve the coronary lesions. She was treated with anakinra, despite a laboratory test not showing inflammation, with prompt and progressive improvement of coronary lesions. Her 7-year-old Caucasian brother presented vomiting and fever at the same time as she was unwell, which spontaneously resolved after 4 days. Four days later, he again presented with fever with abdominal pain, associated with tachypnea, stasis at the pulmonary bases, tachycardia, gallop rhythm, hypotension, secondary anuria, and hepatomegaly. An echocardiogram revealed a severe hypokinesia, with a severe reduction of the ejection fraction (20%). He had an increase of immunoglobulin M anti-parvovirus, tested for the index case of his sister, confirming the suspicion of viral myocarditis. He received dopamine, dobutamine, furosemide plus steroids, with a progressive increase of the ejection fraction to 50%. However, evaluating his sister's history, the brother showed a myocardial dysfunction secondary to Kawasaki shock syndrome.Conclusions: We report on familial Kawasaki disease in two siblings which had the same infectious trigger (a documented parvovirus infection). The brother was diagnosed as having post-viral myocarditis. However, in view of the two different and simultaneous evolutions, the girl showed Kawasaki disease with late coronary artery lesions and aneurysms, whereas the brother showed Kawasaki shock syndrome with myocardial dysfunction. We stress the effectiveness of anakinra in non-responder Kawasaki disease and the efficacy on coronary aneurysms. [ABSTRACT FROM AUTHOR]

An abstract of the conference paper "Circulating levels of the adipocytokines vaspin and omentin in patients with Kawasaki disease," by L. Cantarini and colleagues is presented.