Kawasaki disease: pathophysiology and insights from mouse models.
ABSTRACT: Kawasaki disease is an acute febrile illness and systemic vasculitis of unknown aetiology that predominantly afflicts young children, causes coronary artery aneurysms and can result in long-term cardiovascular sequelae. Kawasaki disease is the leading cause of acquired heart disease among children in the USA. Coronary artery aneurysms develop in some untreated children with Kawasaki disease, leading to ischaemic heart disease and myocardial infarction. Although intravenous immunoglobulin (IVIG) treatment reduces the risk of development of coronary artery aneurysms, some children have IVIG-resistant Kawasaki disease and are at increased risk of developing coronary artery damage. In addition, the lack of specific diagnostic tests and biomarkers for Kawasaki disease make early diagnosis and treatment challenging. The use of experimental mouse models of Kawasaki disease vasculitis has considerably improved our understanding of the pathology of the disease and helped characterize the cellular and molecular immune mechanisms contributing to cardiovascular complications, in turn leading to the development of innovative therapeutic approaches. Here, we outline the pathophysiology of Kawasaki disease and summarize and discuss the progress gained from experimental mouse models and their potential therapeutic translation to human disease.
Project description:Despite the administration of intravenous immunoglobulin (IVIg) at a dose of 2 g/kg, approximately 3-5% of children with acute Kawasaki disease (KD) may develop coronary artery aneurysms. IVIg-resistance, defined as recrudescence of fever more than 36 h after IVIg completion, is a risk factor for coronary artery abnormalities. Thus, several adjunctive therapies are being evaluated for use in IVIg-resistant KD patients and in patients with coronary artery abnormalities. In this review the role of some of these adjunctive therapies in treatment of children with KD is discussed.
Project description:Kawasaki disease is an acute febrile systemic vasculitis that predominantly occurs in children below five years of age. Its etiopathogenesis is still not clear, but it is thought to be a complex interplay of genetic factors, infections and immunity. Areas covered: This review article discusses in detail Kawasaki disease, with particular emphasis on the recent updates on its pathogenesis and upcoming alternate treatment options. Though self-limiting in many cases, it can lead to severe complications like coronary artery aneurysms and thrombo-embolic occlusions, and hence requires early diagnosis and urgent attention to avoid them. Intravenous immunoglobulin (IVIG) with or without aspirin has remained the sole treatment option for these cases, but 10-15% cases develop resistance to this treatment. Expert commentary: There is a need to develop additional treatment strategies for children with Kawasaki disease. Targeting different steps of pathogenesis could provide us with alternate therapeutic options.
Project description:Kawasaki disease (KD) is a pediatric vasculitis with coronary artery aneurysms (CAA) as its main complication. The diagnosis is based on the presence of persistent fever and clinical features including exanthema, lymphadenopathy, conjunctival injection, and changes to the mucosae and extremities. Although the etiology remains unknown, the current consensus is that it is likely caused by an (infectious) trigger initiating an abnormal immune response in genetically predisposed children. Treatment consists of high dose intravenous immunoglobulin (IVIG) and is directed at preventing the development of CAA. Unfortunately, 10-20% of all patients fail to respond to IVIG and these children need additional anti-inflammatory treatment. Coronary artery lesions are diagnosed by echocardiography in the acute and subacute phases. Both absolute arterial diameters and z-scores, adjusted for height and weight, are used as criteria for CAA. Close monitoring of CAA is important as ischemic symptoms or myocardial infarction due to thrombosis or stenosis can occur. These complications are most likely to arise in the largest, so-called giant CAA. Apart from the presence of CAA, it is unclear whether KD causes an increased cardiovascular risk due to the vasculitis itself.<h4>Conclusion</h4>Many aspects of KD remain unknown, although there is growing knowledge on the etiology, treatment, and development and classification of CAA. Since children with previous KD are entering adulthood, long-term follow-up is increasingly important. What is known: • Kawasaki disease (KD) is a pediatric vasculitis with coronary artery damage as its main complication. • Although KD approaches its 50th birthday since its first description, many aspects of the disease remain poorly understood. What is new: • In recent years, multiple genetic candidate pathways involved in KD have been identified, with recently promising information about the ITPKC pathway. • As increasing numbers of KD patients are reaching adulthood, increasing information is available about the long-term consequences of coronary artery damage and broader cardiovascular risk.
Project description:Kawasaki disease (KD) is a form of systemic vasculitis. Regarding its pathogenesis, HAMP gene encoding hepcidin, which is significant for iron metabolism, has a vital function. In this study, we recruited a total of 381 KD patients for genotyping. Data from 997 subjects (500 subjects from cohort 1; 497 subjects from cohort 2) were used for analysis. Using TaqMan allelic discrimination, we determined five tag SNPs (rs916145, rs10421768, rs3817623, rs7251432, and rs2293689). Treatment outcome data related to such clinical phenotypes as coronary artery lesions (CAL), coronary artery aneurysms (CAA), and intravenous immunoglobulin (IVIG) effects were also collected. Furthermore, we measured plasma hepcidin levels with an enzyme-linked immunosorbent assay. We found that HAMP gene polymorphism (rs7251432, and rs2293689) was significantly correlated with KD risk and that plasma hepcidin levels both before and after IVIG treatment had a significantly positive correlation with length of hospital stays (R = 0.217, p = 0.046 and R = 0.381, p < 0.0001, respectively). In contrast, plasma hepcidin levels has a negative correlation with KD patients' albumin levels (R = -0.27, p < 0.001) prior to IVIG treatment. This study's findings indicate that HAMP might have a role in the disease susceptibility, as well as its expressions correlated length of hospital stays, and albumin levels in Taiwanese children with KD.
Project description:Background: Kawasaki disease (KD) is one of the most common vasculitis in childhood. Intravenous ?-immunoglobulin (IVIG) is recommended to be administrated within 10 days after fever onset. However, some patients didn't have IVIG therapies because of atypical disease presentations or spontaneous defervescence. We aimed to evaluate the coronary outcomes of the KD patients who didn't receive IVIG and had defervescence within 10 days. Methods: We retrospectively reviewed the KD patients in NTUCH between 2008 and 2015. The patients with a diagnosis of KD and had a febrile length between 5 and 10 days were enrolled. Days of fever, clinical symptoms, laboratory data at the acute stage, and series of coronary artery measurements within a minimum of 3 months after disease onset were recorded. Risk factors associated with coronary lesions 1 month after KD onset were also analyzed. Results: Two hundred ninety-three eligible KD patients were enrolled (Male: 55.1%, mean age of onset: 1.8 years old). Thirty-seven patients had spontaneous defervescence without IVIG treatment. The incidence of coronary aneurysms at the 4th week after disease onset was higher in spontaneously defervesced KD patients than those treated with IVIG (18.9% vs. 5.1%, p = 0.002). Interestingly, of the 238 KD patients without coronary lesions at their acute phase, percentages of emerging coronary aneurysms became significantly higher if they didn't have IVIG therapies due to spontaneous defervescence (4/31), compared with those who received IVIG (3/208). Further analysis showed the development of coronary lesions at 1 month after disease onset was associated with younger age (<12 months old, p = 0.024), and leukocytosis (WBC > 17,000/cumm, p = 0.031). Conclusions: 18.9% of KD patients with spontaneous defervescence had coronary aneurysms. Even without initial coronary lesions, such patients were still riskier to develop coronary aneurysms, compared with KD patients who received IVIG therapies. Such findings address the importance of refining the strategy for use of IVIG in the spontaneously defervesced KD patients within 10 days after fever onset, at least in those with age younger than 1 year and those with leukocytosis.
Project description:BACKGROUND:Although Kawasaki disease (KD) is the most common cause of acquired heart disease in children and may result in coronary artery aneurysms (CAA) with an attendant risk of myocardial infarction, there is no recommended therapy to halt progression of arterial wall damage and prevent aneurysm formation in the acute phase of the vasculitis. While intravenous immunoglobulin (IVIG) reduces the risk of CAA, up to 20% of KD patients are IVIG resistant and have a higher risk for developing CAA. The IL-1 pro-inflammatory pathway is upregulated in children with acute KD and plays a critical role in the experimental animal model of KD. Thus, IL-1 is a logical therapeutic target. OBJECTIVES:The goal of this study is to determine the safety, tolerability, pharmacokinetics, and immunomodulatory effects of anakinra, a recombinant human IL-1 receptor antagonist, in acute KD patients with coronary artery abnormalities on the baseline echocardiogram. DESIGN:This is a two-center dose-escalation Phase I/IIa trial in 30 acute KD patients ?8months old with a coronary artery Z score?3.0 in the right coronary artery and/or left anterior descending artery or an aneurysm. Subjects will receive a 2- to 6-week course of anakinra by daily subcutaneous injection and will be assessed for resolution of inflammation and dose limiting toxicities (leukopenia, anaphylactoid reaction, or severe infection). CONCLUSION:The safety and tolerability of blocking both IL-1? and Il-1? by anakinra will be evaluated as a strategy to prevent or attenuate coronary artery damage in infants and children with acute KD. TRIAL REGISTRATION:Clinical Trials.gov # NCT02179853, registered June 28, 2014.
Project description:Kawasaki disease (KD) is a systemic vasculitis of unknown etiology. IFNG gene encoding interferon (IFN)-?, produced by natural killer cells and T cells, has been suggested to play an important role in the immunopathogenesis of Kawasaki disease. The aim of this study was to examin the correlation of gene polymorphisms of the IFNG gene and plasma levels of IFN-? in KD patients and their outcomes.A total of 950 subjects (381 KD and 569 controls) were recruited. Three tagging single-nucleotide polymorphisms (rs2069718, rs1861493, rs2069705) were selected for TaqMan allelic discrimination assay. Clinical phenotypes, coronary artery lesions (CAL), coronary artery aneurysms (CAA) and intravenous immunoglobulin (IVIG) treatment outcomes were collected for analysis. Plasma IFN-? levels were also measured with an enzyme-linked immunosorbent assay.Polymorphisms of the IFNG gene were significantly different between the normal controls and KD patients. The G allele of rs1861493 conferred a better response to IVIG treatment in KD patients. AA allele frequencies of rs1861493 were also associated with a significantly higher risk of CAA in KD patients. Furthermore, the plasma IFN-? level was lower in the AA allele than in the GG allele of rs1861493 both before and after IVIG treatment in KD patients.This study provides the first evidence supporting an association between IFNG gene polymorphisms, susceptibility of KD, IVIG responsiveness, and plasma IFN-? levels in KD patients.
Project description:<h4>Background</h4>Kawasaki disease (KD) is an acute self-limited systemic vasculitis of unknown etiology affecting mainly children less than 5 years of age. Risk factors for cardiac involvement and resistance to treatment are insufficiently studied in non-Japanese children.<h4>Objective</h4>This study aimed to investigate the epidemiology, clinical features and risk factors for resistance to treatment and coronary artery lesions (CAL) in KD in Spain.<h4>Methods</h4>Retrospective study (May 2011-June 2016) of all patients less than 16 years of age diagnosed with KD included in KAWA-RACE network (84 Spanish hospitals).<h4>Results</h4>A total of 625 cases were analyzed, 63% were males, 79% under 5 year-olds and 16.8% younger than 12 months. On echocardiographic examination CAL were the most frequent findings (23%) being ectasia the most common (12%). Coronary aneurysms were diagnosed in 9.6%, reaching 20% in infants under 12 months (p<0.001). A total of 97% of the patients received intravenous immunoglobulin (IVIG) with a median number of days from fever onset to IVIG administration of 7.2. A second dose was given to 15.7% and steroids to 14.5% patients. Only 1.4% patients received infliximab. No deaths were reported. A multivariate analysis identified anemia, hypoalbuminemia, hyponatremia, higher creatinine and procalcitonin as independent risk factors for treatment failure and length under 103 cm, hemoglobin < 10.2 mg/dL, platelets > 900,000 cells/mm3, maximum temperature < 39.5°C, total duration of fever > 10 days and fever before treatment ? 8 days as independent risk factors for developing coronary aneurysms.<h4>Conclusions</h4>In our population, children under 12 months develop coronary aneurysms more frequently and children with KD with anemia and leukocytosis have high risk of cardiac involvement. Adding steroids early should be considered in those patients, especially if the treatment is not started before 8 days of fever. A score applicable to non-Japanese children able to predict the risk of aneurysm development and IVIG resistance is necessary.
Project description:BACKGROUND:Kawasaki disease (KD) is a systemic vasculitis which may be associated with coronary artery aneurysms. A notable risk factor for the development of coronary artery aneurysms is resistance to intravenous immunoglobulin (IVIG) therapy, which comprises standard treatment for the acute phase of KD. The cause of IVIG resistance in KD is largely unknown; however, the contribution of genetic factors, especially variants in immune-related genes, has been suspected. METHODS:To explore genetic variants related to IVIG-unresponsiveness, we designated KD patients who did not respond to both first and second courses of IVIG therapy as IVIG-unresponsive patients. Using genomic DNA from 30 IVIG-unresponsive KD patients, we performed pooled genome sequencing targeting 39 immune-related cytokine receptor genes. RESULTS:The single nucleotide variant (SNV), rs563535954 (located in the IL4R locus), was concentrated in IVIG-unresponsive KD patients. Individual genotyping showed that the minor allele of rs563535954 was present in 4/33 patients with IVIG-unresponsive KD, compared with 20/1063 individuals in the Japanese genome variation database (odds ratio?=?7.19, 95% confidence interval 2.43-21.47). Furthermore, the minor allele of rs563535954 was absent in 42 KD patients who responded to IVIG treatment (P?=?0.0337), indicating that a low-frequency variant, rs563535954, is associated with IVIG-unresponsiveness in KD patients. Although rs563535954 is located in the 3'-untranslated region of IL4R, there was no alternation in IL4R expression associated with the mior allele of rs563535954. However, IVIG-unresponsive patients that exhibited the minor allele of rs563535954 tended to be classified into the low-risk group (based on previously reported risk scores) for prediction of IVIG-resistance. Therefore, IVIG-unresponsiveness associated with the minor allele of rs563535954 might differ from IVIG-unresponsiveness associated with previous risk factors used to evaluate IVIG-unresponsiveness in KD. CONCLUSION:These findings suggest that the SNV rs563535954 could serve as a predictive indicator of IVIG-unresponsiveness, thereby improving the sensitivity of risk scoring systems, and may aid in prevention of coronary artery lesions in KD patients.
Project description:Kawasaki disease is an acute, systemic vasculitis that affects the coronary arteries. However, the relationship between myocardial fibrosis and Kawasaki disease has been completely unknown until now. We aimed to provide quantitative information about myocardial fibrosis using cardiac integrated backscatter in Han race Kawasaki disease patients.Ninety Kawasaki disease patients and 90 healthy control subjects were recruited. Based on Kawasaki disease status, the patients were categorized into 3 groups: acute, subacute, and convalescence phase. Based on coronary artery status, the Kawasaki disease patients were categorized into 3 groups: without coronary artery lesions, with coronary artery dilation, and with coronary artery aneurysms. All subjects underwent two-dimensional and Doppler examinations to measure clinical echocardiographic parameters. Myocardial fibrosis was detected with calibrated integrated backscatter imaging.Left ventricle systolic functions were normal in both the Kawasaki disease and control participants. The myocardial calibrated integrated backscatter values of the left ventricles of the acute (p < 0.001), subacute (p < 0.001) and convalescence phase (p < 0.001) Kawasaki disease patients were significantly greater than those of the healthy controls. The left ventricle myocardial calibrated integrated backscatter values were significantly smaller in the Kawasaki disease patients without coronary artery lesions than in the Kawasaki disease patients with coronary artery dilations and coronary artery aneurysms in different phases. The left ventricle myocardial calibrated integrated backscatter results were positively correlated with coronary artery status in the acute (r = 0.331, p < 0.001), subacute (r = 0.456, p < 0.001) and convalescence phases (r = 0.407, p < 0.001) of Kawasaki disease.Our findings may suggest that myocardial fibrosis occurs during early episodes of Kawasaki disease given uncertainties that exist regarding correlations of calibrated integrated backscatter and myocardial fibrosis.