Neutrophil percentage-to-albumin ratio is a potential marker of intravenous immunoglobulin resistance in Kawasaki disease.

Intravenous immunoglobulin (IVIG) resistance in Kawasaki disease (KD) was associated with coronary artery lesions. Neutrophil percentage-to-albumin ratio (NPAR) is an index of mortality in several inflammatory diseases. This study focused on the association of NPAR with IVIG- resistance in KD. Clinical and laboratory data of 438 children with KD before IVIG treatment were retrospectively analyzed. Notably, high NPAR was associated with older age, high WBC, NP, ALT, total bilirubin and CRP, as well as with high the incidence of IVIG-resistance, and with low hemoglobin (Hb), PLT, ALB and sodium levels. NPAR (OR: 2.366, 95% CI: 1.46-3.897, p = 0.001) and Hb (OR: 0.967, 95% CI: 0.944-0.989, p = 0.004) were independent risk factors for IVIG-resistance. NPAR showed linear relation with IVIG-resistance (p for nonlinear = 0.711) and the nonlinear correlation was found between IVIG-resistance and Hb (p for nonlinear = 0.002). The predictive performance of NPAR was superior to Beijing model (z = 2.193, p = 0.028), and not inferior to Chongqing model (z = 0.983, p = 0.326) and the combination of NPAR and Hb (z = 1.912, p = 0.056). These findings revealed that NPAR is a reliable predictor of IVIG-resistance.

Candesartan Attenuates Vasculitis in a Mouse Model of Kawasaki Disease Induced by Candida albicans Water-Soluble Fraction.

BACKGROUND: The standard treatment for Kawasaki disease is immunoglobulin therapy, but the high frequency of coronary sequelae in immunoglobulin-refractory cases indicates a need for further improvement in treatment. METHODS: Kawasaki disease-like vasculitis was induced in 5-week-old DBA/2 mice by intraperitoneal administration of 0.5 mg Candida albicans water-soluble fraction (CAWS) daily for 5 days followed by daily administration of candesartan, an angiotensin receptor blocker. The vasculitis suppression effect was confirmed histologically and serologically in mice sacrificed at 28 days after the start of candesartan. RESULTS: The area of inflammatory cell infiltration at the aortic root was 2.4±1.4% in the Control group, 18.1±1.9% in the CAWS group, and 7.1±2.3%, 5.8±1.4%, 7.6±2.4%, and 7.9±5.0% in the CAWS+candesartan 0.125-mg/kg, 0.25-mg/kg, 0.5-mg/kg, and 1.0-mg/kg groups, respectively (p=0.0200, p=0.0122, p=0.0122, and p=0.0200 vs. CAWS, respectively). The low-dose candesartan group also showed significantly reduced inflammatory cell infiltration. A similar trend was confirmed by immunostaining of macrophages and TGFß receptors. Measurement of the inflammatory cytokines IL-1ß, IL-6, and TNF-α confirmed the anti-vasculitis effect of candesartan. CONCLUSIONS: Candesartan inhibited vasculitis even at clinical doses used in children, making it a strong future candidate as an additional treatment for immunoglobulin-refractory Kawasaki disease.

Prediction Models for Intravenous Immunoglobulin Non-Responders of Kawasaki Disease Using Machine Learning.

BACKGROUND AND OBJECTIVE: Intravenous immunoglobulin (IVIG) is a prominent therapeutic agent for Kawasaki disease (KD) that significantly reduces the incidence of coronary artery anomalies. Various methodologies, including machine learning, have been employed to develop IVIG non-responder prediction models; however, their validation and reproducibility remain unverified. This study aimed to develop a predictive scoring system for identifying IVIG nonresponders and rigorously test the accuracy and reliability of this system. METHODS: The study included an exposure group of 228 IVIG non-responders and a control group of 997 IVIG responders. Subsequently, a predictive machine learning model was constructed. The Shizuoka score, including variables such as the "initial treatment date" (cutoff: < 4 days), sodium level (cutoff: < 133 mEq/L), total bilirubin level (cutoff: ≥ 0.5 mg/dL), and neutrophil-to-lymphocyte ratio (cutoff: ≥ 2.6), was established. Patients meeting two or more of these criteria were grouped as high-risk IVIG non-responders. Using the Shizuoka score to stratify IVIG responders, propensity score matching was used to analyze 85 patients each for IVIG and IVIG-added prednisolone treatment in the high-risk group. In the IVIG plus prednisolone group, the IVIG non-responder count significantly decreased (p < 0.001), with an odds ratio of 0.192 (95% confidence interval 0.078-0.441). CONCLUSIONS: Intravenous immunoglobulin non-responders were predicted using machine learning models and validated using propensity score matching. The initiation of initial IVIG-added prednisolone treatment in the high-risk group identified by the Shizuoka score, crafted using machine learning models, appears useful for predicting IVIG non-responders.

The role of serum lipid in predicting coronary artery lesions and intravenous immunoglobulin resistance in Kawasaki disease: a cohort study.

OBJECTIVE: To assess the predictive value of the serum lipid profile for initial intravenous immunoglobulin (IVIG) resistance and coronary artery lesions (CALs) in patients with Kawasaki disease (KD). METHODS: This retrospective cohort study enrolled patients with KD and divided them into IVIG-responsive and IVIG-resistant groups. They were also stratified based on the presence of CALs (CALs and non-CALs groups). Clinical, echocardiographic and biochemical values were evaluated. A subgroup analysis was performed on complete and incomplete KD. Predictors of initial IVIG resistance and CALs were determined by multivariate logistic regression analysis. RESULTS: A total of 649 KD patients were enrolled: 151 had CALs and 76 had initial IVIG resistance. Low-density lipoprotein cholesterol (LDL-C) was significantly lower in the IVIG-resistant group than in the IVIG-responsive group. LDL-C and apolipoprotein (Apo) B were significantly lower in the CALs group compared with the non-CALs group. Multivariate logistic regression failed to identify the serum lipid profile (LDL-C, Apo A or Apo B) as an independent risk factor for initial IVIG resistance or CALs in KD patients. CONCLUSION: KD patients might have dyslipidaemia in the acute phase, but the serum lipid profile might not be suitable as a single predictor for initial IVIG resistance or CALs.

Knowledge framework of intravenous immunoglobulin resistance in the field of Kawasaki disease: A bibliometric analysis (1997-2023).

BACKGROUND: Kawasaki disease (KD) is an autoimmune disease with cardiovascular disease as its main complication, mainly affecting children under 5 years old. KD treatment has made tremendous progress in recent years, but intravenous immunoglobulin (IVIG) resistance remains a major dilemma. Bibliometric analysis had not been used previously to summarize and analyze publications related to IVIG resistance in KD. This study aimed to provide an overview of the knowledge framework and research hotspots in this field through bibliometrics, and provide references for future basic and clinical research. METHODS: Through bibliometric analysis of relevant literature published on the Web of Science Core Collection (WoSCC) database between 1997 and 2023, we investigated the cooccurrence and collaboration relationships among countries, institutions, journals, and authors and summarized key research topics and hotspots. RESULTS: Following screening, a total of 364 publications were downloaded, comprising 328 articles and 36 reviews. The number of articles on IVIG resistance increased year on year and the top three most productive countries were China, Japan, and the United States. Frontiers in Pediatrics had the most published articles, and the Journal of Pediatrics had the most citations. IVIG resistance had been studied by 1889 authors, of whom Kuo Ho Chang had published the most papers. CONCLUSION: Research in the field was focused on risk factors, therapy (atorvastatin, tumor necrosis factor-alpha inhibitors), pathogenesis (gene expression), and similar diseases (multisystem inflammatory syndrome in children, MIS-C). "Treatment," "risk factor," and "prediction" were important keywords, providing a valuable reference for scholars studying this field. We suggest that, in the future, more active international collaborations are carried out to study the pathogenesis of IVIG insensitivity, using high-throughput sequencing technology. We also recommend that machine learning techniques are applied to explore the predictive variables of IVIG resistance.

Development of an immunoinflammatory indicator-related dynamic nomogram based on machine learning for the prediction of intravenous immunoglobulin-resistant Kawasaki disease patients.

BACKGROUND: Approximately 10-20% of Kawasaki disease (KD) patients suffer from intravenous immunoglobulin (IVIG) resistance, placing them at higher risk of developing coronary artery aneurysms. Therefore, we aimed to construct an IVIG resistance prediction tool for children with KD in Shanghai, China. METHODS: Retrospective analysis was conducted on data from 1271 patients diagnosed with KD and the patients were randomly divided into a training set and a validation set in a 2:1 ratio. Machine learning algorithms were employed to identify important predictors associated with IVIG resistance and to build a predictive model. The best-performing model was used to construct a dynamic nomogram. Moreover, receiver operating characteristic curves, calibration plots, and decision-curve analysis were utilized to measure the discriminatory power, accuracy, and clinical utility of the nomogram. RESULTS: Six variables were identified as important predictors, including C-reactive protein, neutrophil ratio, procalcitonin, CD3 ratio, CD19 count, and IgM level. A dynamic nomogram constructed with these factors was available at https://hktk.shinyapps.io/dynnomapp/. The nomogram demonstrated good diagnostic performance in the training and validation sets (area under the receiver operating characteristic curve = 0.816 and 0.800, respectively). Moreover, the calibration curves and decision curves analysis indicated that the nomogram showed good consistency between predicted and actual outcomes and had good clinical benefits. CONCLUSION: A web-based dynamic nomogram for IVIG resistance was constructed with good predictive performance, which can be used as a practical approach for early screening to assist physicians in personalizing the treatment of KD patients in Shanghai.

Relationship between ocular manifestations, laboratory findings, echocardiographic findings, and intravenous immunoglobulin resistance in Kawasaki disease.

BACKGROUND: This study investigates the incidence of ocular involvement in Kawasaki disease (KD) and evaluates the relationship between ocular manifestations, laboratory findings, echocardiographic findings, and intravenous immunoglobulin (IVIG) resistance. METHODS: We conducted a cross-sectional study with 58 KD patients from June 2021 to March 2023. For all patients, a complete ophthalmologic examination and echocardiography were performed in the acute phase before starting the treatment. We analyzed the age, sex, mean of white blood cell (WBC) count, platelet count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), echocardiographic findings and IVIG responses for all patients and compared the group with ocular involvement with the group without involvement. RESULTS: The incidence of bilateral acute conjunctivitis was 70.7%, while that of acute uveitis was 30%. Patients with uveitis had significantly higher rates of Coronary artery dilatation and IVIG resistance, as well as higher mean levels of WBC, platelet, and CRP compared to those without uveitis. (P < 0.05). Additionally, the age of patients with uveitis involvement was lower than those without involvement. No significant relationships existed between ESR, AST, or ALT values and uveitis (P > 0.05). Furthermore, no significant correlations existed between any examined items and acute bilateral conjunctivitis. CONCLUSION: Uveitis in KD is significantly associated with coronary artery dilatation, IVIG resistance, higher WBC count, platelet count, and CRP level.

C-reactive protein to albumin ratio as a prognostic tool for predicting intravenous immunoglobulin resistance in children with kawasaki disease: a systematic review of cohort studies.

BACKGROUND: Intravenous immunoglobulin (IVIG) is the primary treatment for Kawasaki disease (KD). However, 10-20% of KD patients show no response to IVIG treatment, making the early prediction of IVIG resistance a key focus of KD research. Our aim is to explore the application of the C-reactive protein to albumin ratio (CAR) for predicting IVIG resistance in children with KD through meta-analysis. METHODS: Cochrane Library, PubMed, MEDLINE, EMbase, CNKI, WanFang, the Chinese Biomedical Database, and CQVIP were searched up to November 2023 for cohort studies on predicting IVIG-resistant KD using the CAR. Articles were selected based on pre-established inclusion and exclusion criteria after extracting literature data and assessing them using the QUADAS-2.0 tool for evaluating the accuracy of diagnostic tests. Stata 15.0 software was used for meta-analysis. RESULTS: Four Chinese and English literature reports were included in this meta-analysis. The results revealed the presence of a threshold effect and high heterogeneity among the included studies. The combined sensitivity for CAR predicting IVIG-resistant KD was calculated as 0.65 (95% CI 0.58-0.72), specificity as 0.71 (95% CI 0.57-0.81), and the area under the curve (AUC) as 0.70 (95% CI 0.66-0.74) using the random-effects model. The combined positive likelihood ratio was 2.22 (95% CI 1.35-3.65), the combined negative likelihood ratio was 0.49 (95% CI 0.35-0.69), and the diagnostic odds ratio was 5 (95% CI 2-10). CONCLUSION: CAR is an auxiliary predictive indicator with moderate diagnostic value that provides guidance in the early treatment of the disease, demonstrating a certain predictive value that warrants further investigation. However, CAR cannot yet be considered as a definitive diagnostic or exclusionary marker for IVIG-resistant KD. Therefore, multi-center, large sample, and high-quality long-term follow-up trials are warranted to confirm the current findings.

Protective role of forsythoside B in Kawasaki disease-induced cardiac injury: Inhibition of pyroptosis via the SIRT1-NF-κB-p65 signaling pathway.

Kawasaki disease (KD), an acute exanthematous febrile pediatric illness involving systemic non-specific inflammatory reactions in small- and medium-sized arteries, poses a significant risk of coronary artery and myocardial inflammatory injury. Developing new KD treatments with improved safety and fewer side-effects is highly desirable. Forsythoside B (FTS-B), extracted from the Forsythia suspensa plant, exerts anti-inflammatory activity by inhibiting NF-κB, which is regulated by SIRT1, the reduced expression of which is strongly associated with cardiovascular disease. However, it has yet to be established whether FTS-B influences KD-related inflammatory damage. In this study, we investigated the effects of FTS-B on inflammation in cellular and murine models of KD. Our findings revealed that KD is associated with cardiac dysfunction and inflammatory injury to myocardial and human coronary artery endothelial cells (HCAECs), resulting in a pyroptosis-feedback loop. Both cellular and KD models were characterized by reduced SIRT1 expression and increased NF-κB p65 expression. Contrastingly, the rates of pyroptosis in both murine model myocardial tissues and HCAECs were significantly alleviated in response to FTS-B treatment. Also in both models, we detected an increase of SIRT1 expression and a decrease in the expression of p65. Further examination of the protective mechanism of FTS-B using the SIRT1-specific inhibitor, EX 527, revealed that this inhibitor blocked the palliative effects of FTS-B on inflammatory injury-induced pyroptosis. These results highlight the potential utility of the SIRT1-NF-κB-p65 pathway as a therapeutic target for KD treatment and demonstrate that FTS-B can alleviate KD-induced cardiac and HCAEC inflammatory injury via inhibition of pyroptosis.

Association of Previous Antibiotics Use and Kawasaki Disease: A Cohort Study of 106,908 Patients.

BACKGROUND: Microbial imbalance in the gut from antibiotic use may be an etiologic factor of Kawasaki disease (KD). We aimed to identify the association between the use of antibiotics and the development of KD, considering various antibiotic profiles. METHODS: A population-based, case-control study was performed using data from the Health Insurance Review and Assessment Service database. Children <5 years of age, who were diagnosed with KD between 2016 and 2019, were identified. Propensity score-matched controls were selected from the general population in a 1:5 ratio. Four separate study cohorts were created according to different periods of antibiotic use: (1) within 28 days and (2) 12 months after birth and (3) within 6 months and (4) 12 months from the index date. Profiles regarding antibiotic use were compared between patients with KD and matched controls. RESULTS: We included 17,818 patients with KD and 89,090 matched controls. Use of antibiotics within 6 months [odds ratio (OR): 1.18; 95% confidence interval (CI): 1.12-1.26] and 12 months (OR: 1.23; 95% CI: 1.14-1.32) from the index date were associated with the development of KD. The association between antibiotic use and KD was most prominent in patients who had received 3 or more types of antibiotics within 12 months from the index date (OR: 1.26; 95% CI: 1.17-1.37). CONCLUSIONS: Antibiotic use within the preceding 6 or 12 months was associated with KD. Alteration in gut microbiota due to antibiotic usage might play a role in the development of KD.

The impact of glucocorticoids therapy on cutaneous wounds in Kawasaki disease: A meta-analysis of randomized controlled trials.

Kawasaki disease (KD) is one of the most challenging diseases that is defined as an acute vasculitis that affects the coronary arteries primarily in children. It causes complications if left untreated at early stages, ultimately leading to death. Corticosteroids have been recognized to treat and cause great impact on the patients with KD. Glucocorticoid is one of the main corticosteroids that are being used to treat KD and cutaneous wounds. However, ineffectiveness of a few glucocorticoids can limit the efficacy of this treatment. This study particularly aimed to elucidate the impact of glucocorticoids on cutaneous wounds in KD. To perform the meta-analysis, a comprehensive literature survey was conducted to unveil the studies and research conducted on Kawasaki patients that revealed different glucocorticoids in the form of specific interventions influencing KD. The literature was searched using numerous keywords, screened and data was extracted to perform the meta-analysis and then it was conducted using the metabin function of R package meta. A total of 2000 patients from both intervention and control groups were employed to carry out the meta-analysis to analyse and evaluate the impact of glucocorticoids on curing KD and cutaneous wounds in patients. The results disclosed that glucocorticoids along with other steroids, mainly IVIG (intravenous immunoglobulin), was an effective intervention to patients suffering from Kawasaki. The results depicted significant outcomes with the values (risk ratio [RR]: 1.08, 95% confidence interval [CI]: 0.58-2.00, p < 0.01) and enlightened the fact that adopting different glucocorticoids may significantly improve the efficacy of skin lesions along with KD. Hence, interventions of glucocorticoids must be utilized in the clinical practice to reduce the incidence of skin wounds and adverse effects caused due to KD.

NLRC4 methylation and its response to intravenous immunoglobulin therapy in Kawasaki disease: a case control study.

BACKGROUND: Kawasaki disease (KD) is a systemic vasculitis accompanied by many systemic physiological and biochemical changes. Elucidating its molecular mechanisms is crucial for diagnosing and developing effective treatments. NLR Family CARD Domain Containing 4 (NLRC4) encodes the key components of inflammasomes that function as pattern recognition receptors. The purpose of this study was to investigate the potential of NLRC4 methylation as a biomarker for KD. METHODS: In this study, pyrosequencing was utilized to analyze NLRC4 promoter methylation in blood samples from 44 children with initial complete KD and 51 matched healthy controls. Methylation at five CpG sites within the NLRC4 promoter region was evaluated. RESULTS: Compared to controls, NLRC4 methylation significantly decreased in KD patients (CpG1: p = 2.93E-06; CpG2: p = 2.35E-05; CpG3: p = 6.46E-06; CpG4: p = 2.47E-06; CpG5: p = 1.26E-05; average methylation: p = 5.42E-06). These changes were significantly reversed after intravenous immunoglobulin (IVIG) treatment. ROC curve analysis demonstrated remarkable diagnostic capability of mean NLRC4 gene methylation for KD (areas under ROC curve = 0.844, sensitivity = 0.75, p = 9.61E-06, 95% confidence intervals were 0.762-0.926 for mean NLRC4 methylation). In addition, NLRC4 promoter methylation was shown to be significantly negatively correlated with the levels of central granulocyte percentage, age, mean haemoglobin quantity and mean erythrocyte volume. Besides, NLRC4 promoter methylation was positively correlated with lymphocyte percentage, lymphocyte absolute value. CONCLUSIONS: Our work revealed the role of peripheral NLRC4 hypomethylation in KD pathogenesis and IVIG treatment response, could potentially serve as a treatment monitoring biomarker, although its precise functions remain to be elucidated.

Thyroid hormone may predict treatment failure in Kawasaki disease.

BACKGROUND: In systemic inflammatory conditions, inflammatory cytokines can cause low thyroid hormone levels. There are no reports discussing the relation between thyroid hormone levels and response to treatment for Kawasaki disease. METHODS: We investigated 67 patients who underwent treatment in the acute phase of Kawasaki disease. We divided patients into two groups based on their response to initial intravenous immunoglobulin (IVIG) treatment: the responder group (n = 40), and the non-responder group (n = 27). The serum levels of the thyroid hormones free triiodothyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) were compared before and after treatment in all patients, and between responder and non-responder groups. RESULTS: The FT3, FT4, and TSH levels were low before the initial treatment and increased significantly after treatment (p < 0.05). The FT3, FT4, and TSH levels before treatment were significantly lower in the non-responder group than in the responder group (p < 0.05). Logistic regression analysis suggested that the addition of pre-treatment FT4 values to Gunma score was useful in predicting treatment failure. CONCLUSIONS: Thyroid hormone and TSH levels were lower in the non-responder group than in the responder group in the initial IVIG treatment for Kawasaki disease. This study suggests that Kawasaki disease in the acute phase is associated with low thyroid hormone levels and TSH. It is possible that these hormone levels predict response to the initial IVIG.

Inhibition of IL-1 Ameliorates Cardiac Dysfunction and Arrhythmias in a Murine Model of Kawasaki Disease.

BACKGROUND: Kawasaki disease (KD) is an acute febrile illness and systemic vasculitis often associated with cardiac sequelae, including arrhythmias. Abundant evidence indicates a central role for IL (interleukin)-1 and TNFα (tumor necrosis factor-alpha) signaling in the formation of arterial lesions in KD. We aimed to investigate the mechanisms underlying the development of electrophysiological abnormalities in a murine model of KD vasculitis. METHODS: Lactobacillus casei cell wall extract-induced KD vasculitis model was used to investigate the therapeutic efficacy of clinically relevant IL-1Ra (IL-1 receptor antagonist) and TNFα neutralization. Echocardiography, in vivo electrophysiology, whole-heart optical mapping, and imaging were performed. RESULTS: KD vasculitis was associated with impaired ejection fraction, increased ventricular tachycardia, prolonged repolarization, and slowed conduction velocity. Since our transcriptomic analysis of human patients showed elevated levels of both IL-1ß and TNFα, we asked whether either cytokine was linked to the development of myocardial dysfunction. Remarkably, only inhibition of IL-1 signaling by IL-1Ra but not TNFα neutralization was able to prevent changes in ejection fraction and arrhythmias, whereas both IL-1Ra and TNFα neutralization significantly improved vasculitis and heart vessel inflammation. The treatment of L casei cell wall extract-injected mice with IL-1Ra also restored conduction velocity and improved the organization of Cx43 (connexin 43) at the intercalated disk. In contrast, in mice with gain of function of the IL-1 signaling pathway, L casei cell wall extract induced spontaneous ventricular tachycardia and premature deaths. CONCLUSIONS: Our results characterize the electrophysiological abnormalities associated with L casei cell wall extract-induced KD and show that IL-1Ra is more effective in preventing KD-induced myocardial dysfunction and arrhythmias than anti-TNFα therapy. These findings support the advancement of clinical trials using IL-1Ra in patients with KD.

Initial intravenous immunoglobulin therapy without aspirin for acute Kawasaki disease: a retrospective cohort study with a Bayesian inference.

OBJECTIVE: To clarify the necessity of acetylsalicylic acid (ASA) administration combined with intravenous immunoglobulin (IVIG) therapy in the treatment of acute Kawasaki disease. DESIGN: Retrospective cohort study. SETTING: Multicentre. PARTICIPANTS: This study included 735 patients with Kawasaki disease aged ≤10 years and hospitalised between 4 and 10 days of illness in eight Japanese hospitals from January 2016 to December 2020. EXPOSURES: High-dose (HD) ASA was administered with initial IVIG to 333 patients in 6 hospitals (HD group). ASA was not administered routinely to 402 patients in the other two hospitals, and low-dose ASA was only administered when patients developed coronary artery lesions or pericardial effusion (non-HD group). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the presence of coronary artery lesions, defined as a coronary artery diameter >+2.5 SD of body surface area within 1 month of onset. The secondary outcome was responsiveness to the initial IVIG therapy. Adjusted risk ratios for the outcomes were calculated using modified Poisson regression models. Bayesian analysis was conducted to estimate the posterior probability of the treatment effect of HD ASA under several prior distributions. RESULTS: The incidence of coronary artery lesions was not significantly higher in the HD group than in the non-HD group (12/333 (3.6%) vs 15/402 (4.0%)). The proportion of non-responders to initial IVIG was similar between the two groups (HD group: 78/333 (23%); non-HD group: 83/402 (22%)). In the Bayesian analysis, considering a difference of ≤2% to be of no clinical importance, there was only a 9.3% chance of reduced risk of coronary artery lesions in the HD group compared with the non-HD group even with a strongly enthusiastic prior for HD treatment. CONCLUSIONS: Compared with HD ASA treatment, treatment without ASA in the acute phase of Kawasaki disease was not associated with increased complications from Kawasaki disease.

Hemolytic anemia associated with intravenous immunoglobulin in Kawasaki disease.

BACKGROUND: The administration of high-dose intravenous immunoglobulin (IVIG) is a standard treatment for the management of Kawasaki disease (KD). IVIG is known to be a highly effective and safe treatment. CASE PRESENTATION: We report the development of hemolytic anemia in seven children receiving repeated doses of IVIG. The children were aged 3-44 months and included 4 girls and 3 boys. All children received 10% IVIG and a second course of immunoglobulin because they did not respond to the first course of immunoglobulin. Two received high-dose aspirin (50 mg/kg), and five received low-dose aspirin (5 mg/kg). Two patients required additional methylprednisolone pulse therapy (30 mg/kg) after the second dose of immunoglobulin, and three patients received oral prednisolone therapy for defervescence. Three patients showed coronary artery dilation during hospitalization and normalized within two months. Pretreatment hemoglobin averaged 11.3-14.2 g/dL, and post-hemolytic anemia hemoglobin ranged from 7.4 to 9.6 g/dL, with a difference of 1.7-6.8 g/dL. Reticulocytes were increased to 3.3-13.2%. Peripheral blood smears showed normochromic normocytic anemia, and anisopoikilocytosis. All children were positive for warm-type antibodies with IgG+, C3d- in direct antiglobulin test, and the blood group was A + in five and B + in two. None of the patients received immunomodulatory therapy or red blood cell transfusions. They were followed for a year and all recovered. CONCLUSION: Especially, in non-O blood group KD patients who are refractory to initial IVIG and require a second dose of IVIG or 10% formulation the possibility of immune hemolytic anemia should be carefully considered, and close follow-up should be maintained after therapy.

Efficacy and safety of infliximab in the treatment of Kawasaki disease: A systematic review and meta-analysis.

Infliximab is a monoclonal antibody specifically binding tumor necrosis factor-alpha and has been approved for the treatment of several inflammatory disorders. However, the efficacy of infliximab in primary treatment of Kawasaki disease (KD) or retreatment of intravenous immunoglobulin (IVIG)-resistant KD in children is controversial. Therefore, we conducted a meta-analysis to compare the efficacy of infliximab alone or in combination with IVIG to IVIG. Eligible randomized and non-randomized trials were retrieved by searching literature databases prior to May 31, 2023. Pooled odds ratio (OR) and 95% confidence interval (95% CI) were calculated for dichotomous variables, and mean difference (MD) with 95% CI was estimated for continuous variables. A total of 14 eligible studies comprising 1257 participants were included. In refractory KD, infliximab alone was associated with a higher effectiveness rate (OR = 4.48, 95% CI 2.67-7.52) and defervescence rate (OR = 5.01, 95% CI 2.99-8.37) and resulted in a 1.08-day-shorter duration of fever (95% CI 0.61-1.55, P < 0.001) and 1.36-day-shorter length of hospital stay (95% CI 0.65-2.08) compared with IVIG. Incidences of coronary artery lesions (CALs), newly developing CALs, and CAL regression did not differ between both groups. For initial treatment of KD, infliximab in addition to IVIG led to a nominally significant higher effectiveness rate (OR = 2.26, 95% CI 1.02-5.01) and a larger reduction of right coronary artery Z score (MD = -0.24, 95% CI -0.27 to -0.21) but did not show additional efficacy in improving other outcomes. The safety profile was similar between both groups.   Conclusion: The meta-analysis demonstrates that infliximab alone is a well-tolerated and effective treatment for IVIG-resistant KD. The additional efficacy of infliximab to IVIG for initial treatment of KD is limited. More large and high-quality trials are needed to confirm the efficacy of infliximab, especially for intensification of primary treatment for KD. What is Known: • Infliximab is a novel monoclonal antibody specifically blocking tumor necrosis factor-alpha and is approved for treatment of several immune-mediated inflammatory disorders. • The efficacy of infliximab in treating children with Kawasaki disease is controversial. What is New: • Infliximab is an effective and safe treatment for children with refractory Kawasaki disease but adds limited efficacy to intravenous immunoglobulin for initial treatment of Kawasaki disease.

Subsequent development of Kawasaki disease following acute human adenovirus infection among siblings.

We report a middle-childhood girl presented with high-grade fever and headache for 4 days. Following this, the child developed mucocutaneous symptoms. She had a notable family history of autoimmune disease. Tests revealed increased inflammatory markers. On the sixth day of illness, a two-dimensonal echocardiogram showed an enlarged coronary artery, diagnosed as incomplete Kawasaki disease (KD) and treated with IVIG and aspirin.Within a week, her younger sibling, an early-childhood girl presented with features of viral prodrome, developed mucocutaneous lesions and subcutaneous oedema of limbs. Her investigations also showed elevated inflammatory markers and echocardiographic changes, diagnosed as incomplete KD.The subsequent development of KD in siblings, both showing initial viral symptoms and a family history of autoimmune disease, led to the suspicion of a potential viral trigger. This was confirmed through viral PCR studies for human adenovirus (type 3). These cases highlight an unusual occurrence of KD developing in siblings following acute adenoviral infection.