Methylprednisolone pulse and prednisolone for intensification of primary treatment in Kawasaki disease patients at high risk of treatment resistance: a multicenter prospective cohort study.

The purpose of this study is to determine whether adding intravenous methylprednisolone pulse (IVMP) to primary adjunctive prednisolone with intravenous immunoglobulin (IVIG) improves treatment resistance and coronary artery aneurysms (CAA) in patients with Kawasaki disease (KD) with a high risk of treatment resistance. This multicenter, prospective, observational study was conducted at 28 hospitals in Japan from October 2016 to June 2020. For patients predicted to be resistant to treatment based on a Kobayashi score ≥ 5 and total bilirubin ≥ 1.0 mg/dL, each hospital independently decided to add IVMP followed by prednisolone, prednisolone alone, or nothing to the primary IVIG therapy. In total, 2856 consecutive KD patients were enrolled; of these, 399 (14.0%) were predicted to be treatment resistant. Patients who were resistant to the primary treatment and required additional treatment comprised 59%, 20%, and 26% of the IVIG-alone group, IVIG-plus-prednisolone group, and IVIG-plus-IVMP group, respectively (P < .0001). The CAA incidence (Z score ≥ 2.5) at month 1 was similar among the treatment groups (6.7%, 4.8%, and 7.3%, respectively; P = .66). CAA occurred more frequently in patients who needed third- or later-line therapy.Conclusions: Primary adjunctive corticosteroid therapy improved the treatment response and suppressed inflammation. However, the study found no benefit of adding IVMP to prednisolone therapy. Patients receiving IVIG alone achieved coronary outcomes comparable to those of patients receiving primary adjunctive corticosteroid therapy although they were more likely to require additional rescue treatment. KD inflammation should be resolved no later than the third line of additional treatment to reduce the risk of CAA.Trial registration: University Hospital Medical Information Network Clinical Trials Registry in Japan ( https://www.umin.ac.jp/ctr/index.htm ) under code UMIN000024937.

Pediatric Thromboprophylaxis of Large Coronary Artery Aneurysm Using Rivaroxaban.

Giant or large coronary artery aneurysms (CAA) are rare in children, most often secondary to Kawasaki disease, and anticoagulation is recommended to prevent thromboembolism. There are no published pediatric reports on the use of a direct oral anticoagulant for this indication. We describe the anticoagulation management of an 8-year-old boy with a dilated right CAA secondary to Kawasaki disease that has remained stable on rivaroxaban and aspirin, following bleeding complications on enoxaparin and challenges on warfarin. The use of rivaroxaban appears to be safe and effective in the prevention of thrombosis in a pediatric patient with CAA.

Presence of coronary aneurysms during Kawasaki Disease (KD) correlates with lower levels of autoantibodies to both full form and spliced variant of immune regulator Del-1.

Kawasaki disease (KD), a rare multisystem inflammatory condition that predominantly affects children under six years of age, is the leading cause of childhood-acquired heart disease in developed countries. The pathogenesis is unknown, but studies support that an infectious stimulus triggers an autoimmune reaction in a genetically susceptible child. Recent studies demonstrated an association with autoantibody response to Del-1 (also known as EDIL3) in children with KD. Del-1 is an extracellular matrix protein that is expressed both in macrophages and vascular endothelium. Del-1 has an anti-inflammatory role by preventing leucocyte migration to inflammatory sites. Del-1 has two expression variants and genetic variants of Del-1 have been associated with the risk of intracranial aneurysms. Due to the physiologic plausibility for a role during KD, we chose to assess if autoantibodies against DEL-1 are seen in a larger cohort of children with KD and to assess if responses correlated to aneurysm formation. Contrary to prior findings, in comparison to febrile controls, autoantibodies were not overall higher in children with KD. Elevation in Post-IVIG samples in comparison to pre-IVIG and convalescent samples supports the commonality of anti-Del-1 antibodies. Autoantibodies were notably lower in children with KD who had coronary Z score elevations in comparison to those who did not.

Effect of Beta Blockers on the Hemodynamics and Thrombotic Risk of Coronary Artery Aneurysms in Kawasaki Disease.

This study aims to simulate beta blockers' (BB) effects on coronary artery aneurysms' (CAA) hemodynamics and thrombotic risk in Kawasaki disease (KD). BB are recommended in cases of large aneurysms due to their anti-ischemic effect. Coronary blood flow (CBF) was simulated in KD patient-specific CAA models using computational fluid dynamics. Hemodynamic indices that correlate with thrombotic risk were calculated following two possible responses to BB: (1) preserved coronary flow (third BB generation) and (2) reduction in coronary flow (first and second BB generations) at reduced heart rate. Following CBF reduction scenario, mean TAWSS and HOLMES significantly decreased compared to normal conditions, leading to a potential increase in thrombotic risk. Preserved CBF at lower heart rates, mimicking the response to vasodilating BBs, does not significantly affect local CAA hemodynamics compared with baseline, while achieving the desired anti-ischemic effects. Different BB generations lead to different hemodynamic responses in CAA.

Increased Pentraxin 3 Levels Correlate With IVIG Responsiveness and Coronary Artery Aneurysm Formation in Kawasaki Disease.

Kawasaki disease (KD) is a febrile disease of childhood characterized by systemic vasculitis that can lead to coronary artery lesions (CAL). This was a prospective cohort study to determine the levels of the pentraxin 3 (PTX3), soluble CD24-Subtype (Presepsin) and N-terminal pro-brain natriuretic peptide (NT-pro BNP) in consecutive KD patients. From January 2013 to March 2015, all patients with KD admitted to Aichi Medical University Hospital who provided consent had their plasma saved before IVIG administration. In total, 97 cases were registered. 22 cases of incomplete KD were excluded from the outcome analysis. The total 75 cases were used for statistical analyses. A PTX3 threshold of >7.92 ng/ml provided a specificity of 88.5 %, a sensitivity of 94.4 %, and a likelihood ratio as high as 15.92 for the diagnosis of KD compared with febrile non-KD controls. Although an echocardiographic diagnosis of CAL in the early course of the disease was confirmed in 24 cases, it was not in the remaining 51 cases. Neither NT-proBNP nor Presepsin had statistical significance for the prediction of the echocardiographic CAL diagnosis. Only PTX3 was significantly predictive of the echocardiographic CAL diagnosis (p=0.01). The PTX3 level was significantly higher in the intravenous immunoglobulin (IVIG) non-responders (45.9±7.45) than in the IVIG responders (17.0 ± 1.46 ng/ml) (p< 0.001). The PTX3 level also correlated with the number of IVIG treatment courses needed to resolve fever (R² =0.64). Persistent CAL (pCAL) formation was observed in three cases; one of aneurysm only and two aneurysms with dilatations. The patients with pCAL had significantly higher PTX3 levels (85 ± 8.4 ng/ml) than patients without pCAL (22 ± 2.2 ng/ml) (p< 0.0001). In terms of pCAL prediction, the area under the curve (AUC) of receiver operating characteristic ROC curve of PTX3 was 0.99, and it was significantly greater than that of Presepsin (0.67) or NT-proBNP (0.75). PTX3 is a soluble pattern recognition molecule that acts as a main component of the innate immune system. These data suggest that PTX3 can be utilized as a definitive biomarker for the prediction of IVIG resistance and subsequent CAL formation in patients with KD.

Delayed Development of Coronary Artery Aneurysm in Patients with Kawasaki Disease Who Were Clinically Responsive to Immunoglobulin.

OBJECTIVE: To clarify the frequency and characteristics of discrepant outcomes of intravenous immunoglobulin (IVIG) between fever and coronary artery aneurysms (CAAs) in patients with Kawasaki disease. STUDY DESIGN: This study included 325 patients who responded to oral aspirin and IVIG alone. The main outcome was CAA 4 weeks after disease onset. CAA was defined as ≥2.5 of maximum z score (Zmax) representing the highest value of 4 coronary artery branches. Immunoglobulin dosage and sequential changes in Zmax were reviewed to investigate the effects on fever and timing of CAA development. Logistic regression analyses with receiver operating characteristic curves using clinical and laboratory variables including the initial Zmax were performed to identify predictors of CAA at 4 weeks. RESULTS: CAAs were either persistent or appeared de novo 4 weeks after diagnosis in 13 of 325 patients who responded to a single or repeated IVIG. Four single-dose IVIG-responders developed CAA although they had pretreatment Zmax of <2.0. The 2 single-dose IVIG responders with the greatest pretreatment Zmax (>4.5) developed persistent CAA. Receiver operating characteristic analysis demonstrated Zmax of 2.57 as the cut-off for predicting CAA. Multivariable analyses identified >2.5 Zmax (OR 9.08, 95% CI 1.26-65.3, P = .028, 50% sensitivity, 91% specificity) as the sole risk factor for CAA at 4 weeks in single-dose IVIG responders. CONCLUSIONS: Delayed development and persistence of CAA in single-dose IVIG responders indicate that some factors other than those responsible for systemic inflammation may contribute to vasculitis in CAA. Baseline Zmax 2.5 aids in predicting CAAs.

Effect of different doses of aspirin on the prognosis of Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is the leading cause of acquired heart disease in children, and is steadily increasing in prevalence in East Asia. KD is often complicated by coronary artery damage, including dilatation and/or aneurysms. Aspirin is used with intravenous immunoglobulin (IVIG) to prevent coronary artery abnormalities in KD. However, the role and optimal dose of aspirin remain controversial. Identifying the dose of aspirin in the acute phase will facilitate development of a more appropriate treatment strategy in improving the outcome of KD. METHODS: A total of 2369 patients with KD were retrospectively analyzed and divided into three groups according to the aspirin dose: 510 in group 1 (20-29 mg/kg/day), 1487 in group 2 (30-39 mg/kg/day), and 372 in group 3 (40-50 mg/kg/day). The differences in laboratory data, rate of IVIG resistance and coronary artery damage were compared among the groups. RESULTS: There was no difference in the incidence of coronary artery aneurysms (CAAs) in group 1 compared with groups 2 and 3 (2 weeks of illness: 2.94% vs. 1.90% vs. 3.36%; 3-4 weeks of illness: 1.94% vs. 2.32% vs. 2.65%). The risk for developing CAA was not reduced at 2 weeks of illness onset in groups 2 and 3 compared with group 1 (adjusted OR = 1.05, 95% confidence interval: 0.34-3.18; aOR = 1.81, 95% CI: 0.42-7.83). Furthermore, the risk for developing CAA was not reduced at 3-4 weeks of illness onset in groups 2 and 3 (aOR = 2.63, 95% CI: 0.61-11.28; aOR = 0.52, 95% CI: 0.03-9.54). There was no significant difference in the rate of IVIG resistance among the groups. Platelet levels after IVIG treatment in group 1 were significantly lower than those in groups 2 and 3 (522.29 × 109/L, 544.69 × 109/L, and 557.77 × 109/L, p = 0.013). C reactive protein of the 30-40 mg/kg*day group was slightly higher than the other two groups. (7.76, 8.00, and 7.01 mg/L, p = 0.028). CONCLUSIONS: Aspirin at the dose of 20-29 mg/kg/day dose not increase the risk of coronary artery damage and IVIG resistance compared with the dose of 30-50 mg/kg/day. This low dose may have a lower risk for a potential effect on liver function.

Kawasaki disease: pathophysiology and insights from mouse models.

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.

A Comprehensive Update on Kawasaki Disease Vasculitis and Myocarditis.

PURPOSE OF THE REVIEW: Kawasaki disease (KD) is a childhood systemic vasculitis of unknown etiology that causes coronary artery aneurysms (CAA), and if left undiagnosed can result in long-term cardiovascular complications and adult cardiac disease. Up to 20% of KD children fail to respond to IVIG, the mainstay of therapy, highlighting the need for novel therapeutic strategies. Here we review the latest findings in the field regarding specific etiology, genetic associations, and advancements in treatment strategies to prevent coronary aneurysms. RECENT FINDINGS: Recent discoveries using the Lactobacillus casei cell wall extract (LCWE)-induced KD vasculitis mouse model have accelerated the study of KD pathophysiology and have advanced treatment strategies including clinical trials for IL-1R antagonist, Anakinra. KD remains an elusive pediatric vasculitis syndrome and is the leading cause of acquired heart disease among children in the USA and developed countries. Advancements in combination treatment for refractory KD with further understanding of novel genetic risk factors serve as a solid foundation for future research endeavors in the field.

Japanese Kawasaki Disease Scoring Systems: Are they Applicable to the Iranian Population?

BACKGROUND: Kawasaki disease (KD) is the most frequent cause of coronary artery aneurysm (CAA) in children. This study tried to evaluate the accuracy of different KD scores developed for prediction of CAA, in an Iranian population. METHODS: This is a cross-sectional retrospective investigation on pediatric patients with a diagnosis of KD. Clinical manifestations, laboratory, and echocardiographic data were recorded. Five Kawasaki scores, including Kobayashi, Egami, Sano, Nakano, and Harada, were assessed and analyzed in relation to CAA and intravenous immunoglobulin (IVIG) resistance. RESULTS: During five years, we recruited 121 cases of KD under 13 years of age. The rates of CAA and IVIG resistance were 16.5%, and 13.2% respectively. The IVIG resistance group was significantly younger than responder patients. All five scores had low sensitivity in predicting CAA or IVIG resistant cases; the highest sensitivity pertained to the Harada score with 50% sensitivity and 59% specificity (the area under the curve: 0.545, with a 95% confidence interval: 0.423 to 0.667) in predicting CAA, which is lower than the usual acceptable criteria for a screening test. The specificity of all other scores were more than 85% in predicting CAA or IVIG resistance. Gender, fever before therapy and laboratory data showed no significant difference between the groups. CONCLUSION: The Kobayashi, Egami, Sano, Nakano and Harada scores have limited usefulness in the Iranian population to predict high risk patients for coronary artery involvement or IVIG resistance; in our study, age under one year was a risk factor for IVIG resistance.

Efficacy between low and high dose aspirin for the initial treatment of Kawasaki disease: Current evidence based on a meta-analysis.

BACKGROUND: Kawasaki disease (KD) is now the leading cause of acquired heart disease in children in developed countries. Intravenous immunoglobulin (IVIG) and aspirin were considered as the standard initial treatment of KD for decades. However, the optimal dose of aspirin has remained controversial. In recent years, many studies compared the efficacy of low-dose with high-dose aspirin in the acute phase of KD, but the results have not always been consistent. Therefore, we performed this meta-analysis to evaluate the efficacy of low-dose aspirin compared with high-dose for the initial treatment of KD. METHODS: Studies related to aspirin therapy for KD were selected from PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, and Google scholar through Mar 25th, 2019. Data were analyzed using STATA Version 15.1. Additionally, publication bias and sensitivity analysis were also performed by STATA version 15.1. RESULTS: Six studies were included in our analysis of the rate of coronary artery lesion (CAL), five reports for IVIG-resistant KD (rKD), and four for the duration of fever and hospitalization. However, no significant differences were found between low-dose and high-dose aspirin groups in the incidence of CAL (risk ratio (RR), 0.85; 95%CI (0.63, 1.14); P = 0.28), the risk of rKD (RR, 1.39; 95%CI (1.00, 1.93); P = 0.05), and duration of fever and hospitalization (the mean standard deviation (SMD), 0.03; 95%CI (-0.16, 0.22); P = 0.78). CONCLUSION: Low-dose aspirin (3-5 mg·kg-1·d-1) may be as effective as the use of high-dose aspirin (≥30 mg·kg-1·d-1) for the initial treatment of KD. Further well-designed randomized clinical trials are needed to evaluate the efficacy of low-dose aspirin for the initial treatment of KD.

Kawasaki disease in Turkish children: a single center experience with emphasis on intravenous immunoglobulin resistance and giant coronary aneurysms.

Yilmazer MM, Özdemir R, Mese T, Küçük M, Öner T, Devrim I, Bayram N, Güven B, Tavli V. Kawasaki disease in Turkish children: a single center experience with emphasis on intravenous immunoglobulin resistance and giant coronary aneurysms. Turk J Pediatr 2019; 61: 648-656. Prompt diagnosis and the administration of intravenous immunoglobulin (IVIG) has reduced the incidence of coronary artery abnormalities (CAA) in Kawasaki Disease (KD). The resistance to treatment and development of the coronary sequelae remain the most important problems in KD. We aimed to determine the predicting factors of nonresponse to initial IVIG therapy and to analyze the cases who had giant coronary aneurysms. A total of 120 KD cases, including 61 children fulfilling the criteria for KD and 59 with incomplete KD were enrolled into this study. Demographic, laboratory, clinical, echocardiographic characteristics, and treatment regimens were reviewed, retrospectively. The median age of the patients was 33.5 months (range: 3-168 months). Coronary artery aneurysms were detected in 35 patients (29%) at the time of diagnosis. Twenty-eight patients had coronary aneurysms small or medium in size, one had a large, and seven had giant coronary aneurysms. CAA persisted in 8 cases in the follow-up, all of which were large or giant aneurysms. A ten month-old girl with a giant coronary aneurysm was referred to coronary bypass surgery in the subacute phase of follow-up, due to myocardial ischemia. Eighteen patients were unresponsive to the initial IVIG therapy (%15), of whom 10 were diagnosed as cKD and 8 were iKD. Patients who did not respond to initial IVIG therapy, had higher white blood cell (WBC) count, higher C-reactive protein (CRP) and lower albumin levels than those who did (P < 0.05). In univarite analysis; CRP, WBC and albumin were found to be significant predictors of nonresponse to initial IVIG therapy, while a stepwise multiple linear regression analysis showed that WBC count and albumin levels were significantly correlated with nonresponse to initial treatment with IVIG. Our study showed that WBC count and albumin levels might be used as predictors of nonresponse to the IVIG therapy in Turkish children with KD.

Predictors of intravenous immunoglobulin resistance and coronary artery aneurysm in patients with Kawasaki disease.

BACKGROUND: Patients with Kawasaki disease (KD) who have intravenous immunoglobulin (IVIG) resistance are at increased risk for development of coronary artery abnormalities. Although in Japan several risk scoring systems are able to predict patients with IVIG-resistant (KD), they do not accurately predict non-responders in other regions. AIM: The objectives of this study were to determine the predictors of IVIG resistance and coronary artery aneurysm (CAA) and to develop risk scoring systems for predicting IVIG-resistant KD in the Thai population. METHODS: A total of 217 patients with KD between 2004 and 2014 were retrospectively reviewed. All patients including 116 with complete KD and 101 with incomplete KD were diagnosed and treated with 2 g/kg IVIG. RESULTS: Twenty-six patients (85% male) with IVIG-resistant KD had a reduced platelet count and increased neutrophil-to-lymphocyte ratio compared with those with an IVIG response. Fifty-five patients with CAA eight weeks after diagnosis had a longer duration of fever (≥8 days) and increased platelet count (≥550 × 109/L) than those with non-CAA. Based on analysis by multivariate logistic regression, haematocrit ≤30%, platelet count ≤300 × 109/L, aspartate aminotransferase ≥40 U/L and neutrophil-to-lymphocyte ratio ≥3.2 were predictors of IVIG resistance. The new scoring system using these significant factors had a sensitivity of 80.8% and a specificity of 66.8% in identifying patients with IVIG resistance. Japanese scoring systems had low sensitivity and specificity. CONCLUSIONS: KD patients with reduced mean haemoglobin, increased AST level, increased neutrophil-to-lymphocyte ratio and reduced platelet count should be considered for conjunctive therapy such as a corticosteroid in combination with standard treatment. Duration of fever ≥8 days and platelet count ≥550 × 109/L were predictors of CAA. To prevent cardiovascular complications, patients should be treated promptly after KD has been diagnosed.

Duration of high-dose aspirin therapy does not affect long-term coronary artery outcomes in Kawasaki disease.

BackgroundHigh-dose aspirin (HDA) is used with intravenous immunoglobulin (IVIg) in Kawasaki disease (KD). Practice regarding HDA varies, and it is unclear whether HDA duration affects the long-term course.MethodsWe retrospectively studied KD patients at our hospital for over 10 years. Patients were categorized as having received HDA for 0, 1-7, or >7 days. Primary outcome was the maximum coronary Z-score at diagnosis and follow-up; secondary outcomes included inflammatory markers.ResultsOne hundred and three patients had HDA duration documented, of which 35 patients had coronary artery abnormalities (CAAs) at diagnosis. There was no difference in demographics or inflammatory markers between the HDA groups, and no difference in HDA duration between patients with or without CAAs. Seventeen patients received no HDA; they had longer illness and defervescence duration before diagnosis, and were less likely to receive IVIg. For CAAs, multivariate regression revealed that HDA duration did not predict the coronary Z-score at 9-15 months. Higher Z-score at diagnosis was associated with higher Z-score at 9-15 months.ConclusionThe only factor associated with coronary Z-score at 9-15 months was the Z-score at diagnosis. At our institution, longer illness and defervescence duration and the lack of IVIg administration were associated with not administering HDA. HDA duration did not affect the clinically relevant outcomes, particularly CAA persistence.

Failure to Predict High-risk Kawasaki Disease Patients in a Population-based Study Cohort in Germany.

BACKGROUND: Diverse scores on high-risk Kawasaki disease (KD) patients have proven a good prognostic validity in the Japanese population. However, data on non-Japanese have been inconclusive. Do the Kobayashi, Egami and Sano scores or application of up-to-date statistical methods (Random Forest) predict response to standard intravenous immunoglobulin (IVIG) therapy and the risk of persistent coronary artery aneurysm (CAA) in patients with KD in a mainly Caucasian population in Germany? METHODS: Data on 442 children (German population-based survey, 2013 and 2014) were used to assess the prognostic validity of the Kobayashi, Egami and Sano scores for being refractory to IVIG treatment and for predicting the risk of persistent CAA. Additionally, an up-to-date statistical approach (Random Forest) was applied to identify a potentially more valid score. RESULTS: A total of 301 children were eligible for assessment of their response to IVIG treatment. Among those, 177 children were followed-up for 1 year to identify persistent CAA. Although all scores were significantly associated with being refractory to IVIG (relative risk range between 2.32 and 3.73), the prognostic properties were low (likelihood ratio positive: 1.83-4.57; sensitivity in the range of 0.28-0.53). None of the scores was a significant predictor of CAA 1 year after acute illness. Application of statistical analysis such as Random Forest did not yield a more valid score. CONCLUSIONS: None of the available scores appears to be appropriate for identifying high-risk Caucasian children with KD who might need intensified therapy.

Rare case of pulmonary involvement in an adult with Kawasaki disease.

Kawasaki disease is an acute, self-limited, febrile vasculitis typically seen in early childhood. Pulmonary involvement is uncommon and is not part of the conventional diagnostic criteria. We add to the literature a unique case of a 22year-old male with Kawasaki disease and pulmonary involvement. It illustrates the importance of recognizing unusual presentations of Kawasaki disease and highlights the possibility of pulmonary abnormalities on physical and imaging examination. Awareness of such presentations can help avoid delayed diagnosis, prevent the development of coronary aneurysms, and allow careful observation for imaging resolution.