Development Of Coronary Artery Abnormalities Research Articles

Markers of Endothelial Dysfunction in Kawasaki Disease: An Update.

Kawasaki disease (KD) is a medium vessel vasculitis that has a special predilection for coronary arteries. Cardiovascular complications include the development of coronary artery abnormalities (CAAs) and myocarditis. Endothelial dysfunction (ED) is now recognized to be a key component in the pathogenesis of KD and is believed to contribute to the development of CAAs. ED has been evaluated by several clinical parameters. However, there is paucity of literature on laboratory markers for ED in KD. The evaluation of ED can be aided by the identification of biomarkers such as oxidative stress markers, circulating cells and their progenitors, angiogenesis factors, cytokines, chemokines, cell-adhesion molecules, and adipokines. If validated in multicentric studies, these biomarkers may be useful for monitoring the disease course of KD. They may also provide a useful predictive marker for the development of premature atherosclerosis that is often a concern during long-term follow-up of KD. This review provides insights into the current understanding of the significance of ED in KD.

Kawasaki disease and the environment: an enigmatic interplay.

Kawasaki disease (KD) is a common systemic vasculitis of childhood. Although it has been almost 6 decades since Dr. Tomisaku Kawasaki reported the first case series of KD, the underlying cause remains a mystery. KD is a self-limiting disease. However, a dreaded complication is development of coronary artery abnormalities (CAAs). KD is the most common cause of acquired heart disease in children in the developed world and is being increasingly reported from developing countries too. Over the years, significant observations have been made about epidemiology of KD. It usually affects children below 5, has male preponderance and has significantly higher incidence in North East Asian countries. While several hypotheses have been proffered for etiology of KD, none have been conclusive. These include associations of KD epidemics in Japan and the United Stated with changes in tropospheric wind patterns suggesting wind-borne agents, global studies showing peaks of incidence related to season, and increased rates in populations with a higher socioeconomic profile related to hygiene hypothesis and vaccination. Furthermore, the self-limiting, febrile nature of KD suggests an infectious etiology, more so with sudden decline noted in cases in Japan with onset of COVID-19 mitigation measures. Finally, single nucleotide polymorphisms have been identified as possible risk alleles in patients with KD and their significance in the pathogenesis of this disease are also being defined. The purpose of this review is to elucidate the puzzling associations of KD with different environmental factors. Looking at patterns associated with KD may help us better predict and understand this disease.

CD40 gene polymorphism and its expression in children with Kawasaki disease from North India: a preliminary case-control study and meta-analysis.

CD40 gene single-nucleotide polymorphisms (SNPs) have been associated with susceptibility and development of coronary artery abnormalities (CAAs) in children with Kawasaki disease (KD) in Japanese, Chinese, and Taiwanese populations. However, data on SNPs of the CD40 gene in patients with KD from the Indian subcontinent are not available. We studied the CD40 gene polymorphisms and its expression in children with KD from North India. SNPs of the CD40 gene (rs4810485, rs1535045) were studied using Sanger sequencing. CD40 expression was studied by flow cytometry. Meta-analysis was carried out to assess the role of both SNPs of the CD40 gene in KD. GRADEpro GDT software (v.3.2) was used to assess the "certainty of evidence." Forty-one patients with KD and 41 age-, sex-matched febrile controls were enrolled. However, none of the alleles and genotypes of the CD40 gene were found to be associated with KD. CD40 expression was higher in KD and in KD with CAAs compared to controls, but it failed to reach statistical significance. In a meta-analysis, the T allele of rs153045 was found to be significantly associated with KD (OR = 1.28; 95% confidence interval (: 1.09-1.50; p = 0.002). The GRADE of evidence for this outcome, however, is of " very low certainty." The present study found no association between SNPs (rs4810485 and rs153045) and susceptibility to KD. This could be a reflection of a modest sample size. CD40 expression was higher in KD and in KD with CAAs. In the meta-analysis, the T allele of rs153045 was significantly associated with KD. Our study confirms a significant genetic heterogeneity in KD among different ethnicities.

Approach to resistant IVIG Kawasaki disease in children

Kawasaki disease (KD) is an acute febrile illness of early childhood characterized by vasculitis of the medium-sized arteries. There is no diagnostic test for KD because the cause is unknown, so diagnosis relies on the recognition of the diagnostic clinical criteria. The most feared sequela of KD is development of coronary artery abnormalities, which occur in 20-25% of untreated children. IVIG reduces this risk in 2-5% when administrated within 10 days from the onset of fever. Here is reported the case of an infant which resulted resistant to 2 consecutive doses of IVIG. Glucocorticoids are recommended as an appropriate therapy in IVIG resistant Kawasaki disease.

Analysis of Age, Sex, Lack of Response to Intravenous Immunoglobulin, and Development of Coronary Artery Abnormalities in Children With Kawasaki Disease in Japan

Initial intravenous immunoglobulin (IVIG)-refractory status and prolonged fever are established risk factors for the development of coronary artery abnormalities (CAAs) among patients with acute-phase Kawasaki disease (KD). However, whether different risk factors exist for initial unresponsiveness to IVIG and CAA development remains unclear. To evaluate whether different risk factors exist for initial unresponsiveness to IVIG and CAA development among patients with KD (stratified by age at disease onset). This retrospective cohort study included a consecutive sample of 2414 patients from a database of patients with KD from October 1, 1999, to September 30, 2019. The data were based on annual surveys (response rate, 100%) using hospital medical records across Wakayama Prefecture, Japan. Data were analyzed from March 6 to March 26, 2022. The patient's age and diagnosis of KD by board-certified pediatricians using the criteria established by the Japan KD Research Committee. Initial unresponsiveness to IVIG, defined as treatment with optional or advanced therapies, and development of CAAs. Echocardiograms performed 1 month after KD onset using the Japanese Ministry of Health criteria evaluated the presence or absence of CAAs. Odds ratios (ORs) with 95% CIs of patient age at KD onset for unresponsiveness to IVIG and developing CAAs were calculated using multivariable logistic regression models. A total of 2414 patients (1403 male patients [58.1%]; median age at onset of KD, 25 months [range, 1-212 months]) were included in the study: 550 younger than 12 months, 1342 aged 12 to 47 months, and 522 older than 47 months. A total of 535 patients (22.2%) received optional or advanced treatment and 68 patients (2.8%) developed CAAs 1 month after disease onset. The sex-adjusted OR among patients younger than 12 months for unresponsiveness to IVIG was 0.77 (95% CI, 0.59-0.99) and for development of CAAs was 1.94 (95% CI, 1.07-3.52); among those older than 47 months, the OR for unresponsiveness to IVIG was 1.32 (95% CI, 1.05-1.67) and for development of CAAs was 2.47 (95% CI, 1.39-4.39). After adjusting for IVIG administration, ORs among boys older than 47 months for unresponsiveness to IVIG was 1.14 (95% CI, 0.84-1.56) and for development of CAAs was 2.15 (95% CI, 1.08-4.30); among girls younger than 12 months, the OR for unresponsiveness to IVIG was 1.02 (95% CI, 0.65-1.60) and for development of CAAs was 3.79 (95% CI, 1.21-11.90). The results of this study suggest that risks of unresponsiveness to IVIG and the development of CAAs differ between infants with KD and older patients with KD. Residual risk factors for KD-related CAAs other than initial unresponsiveness to IVIG should be addressed, particularly in infants.

Association of SNP (rs1042579) in thrombomodulin gene and plasma thrombomodulin level in North Indian children with Kawasaki disease.

Kawasaki disease (KD) is the commonest systemic vasculitis in children. It predisposes to development of coronary artery abnormalities (CAAs). Thrombomodulin (THBD) gene polymorphism rs1042579 is associated with high risk of cerebrovascular diseases. However, association of THBD polymorphism (rs1042579) and plasma thrombomodulin (TM) levels with susceptibility to KD and CAAs remains unclear. Polymorphism in THBD gene (rs1042579) was analysed in 50 KD patients and 50 age, gender and ethnicity matched controls using Sanger sequencing. Plasma TM levels were measured by ELISA. Mean plasma TM level (± SD) in KD patients was 2549.41 (± 853.18) pg/ml and in controls was 2298.03 (± 869.14) pg/ml; p = 0.042. Mean plasma TM levels in CC genotype was 2299.98 (± 834.88) pg/ml and in CT/TT genotype was 2837.96 (± 857.14) pg/ml; p = 0.005. Genotyping data did not reveal significant differences in patients with KD as compared to controls (p = 0.25), and in KD patients with and without CAAs (p = 0.407). Odds of finding T allele in cases were 2.07 times greater than in controls (p = 0.093). This is the first study from India, and second in the world, that investigates association of THBD gene polymorphism with KD. This is also the first study to assess plasma TM levels in KD patients. Our data show that plasma TM levels were significantly higher in KD patients with CT/TT genotypes. Further, the polymorphism rs1042579 at exon 1 of THBD gene was found to be more common in KD patients than in controls although the difference was not statistically significant.

Status of treatment and outcome in Kawasaki disease in the Kinki area of Japan.

The treatment guidelines for acute Kawasaki disease (KD) have been revised several times. Moreover, the criterion used to define coronary artery abnormalities (CAAs) has changed from the coronary artery's internal diameter to the Z-score. Because KD treatment and CAA evaluation methods vary between hospitals, we investigated the actual status of acute KD treatment and development of CAAs under the 2012 Japanese treatment guidelines for acute KD. The 24th Japanese Nationwide Survey on Kawasaki Disease yielded 2,618 patients who developed KD in the Kinki area in 2016. We sent a secondary questionnaire to each participating hospital and used the resulting data to investigate the frequency of CAAs according to Z-score, treatment by KD treatment stage, and predictors of CAAs. The response rate was 80.0%. Data of 1,426 patients without major data deficiencies were examined. The frequency of CAAs was 3.0% when based on coronary artery internal diameters and 8.8% when based on Z-scores. Intravenous immunoglobulins combined with corticosteroids were administered as initial treatment in 12.8% of cases and as second-line treatment in 16.8% of cases. Corticosteroids, cyclosporine A, infliximab, and plasma exchange were used at similar frequencies for third-line treatment. A pretreatment maximum coronary artery Z-score of ≥1.9 and age <1 year were associated with significantly higher incidences of CAAs. Using the Z-score resulted in three-fold increase in the number of patients diagnosed with CAAs. A pretreatment maximum coronary artery Z-score of ≥1.9 and age <1 year are useful predictors of CAAs.

Prednisolone Suppresses the Extracellular Release of HMGB-1 and Associated Inflammatory Pathways in Kawasaki Disease.

Innate immune activity plays an essential role in the development of Kawasaki disease (KD) vasculitis. Extracellular release of high mobility group box-1 (HMGB-1), an endogenous damage-associated molecular pattern protein that can activate the innate immune system and drive host inflammatory responses, may contribute to the development of coronary artery abnormalities in KD. Prednisolone (PSL) added to intravenous immunoglobulin treatment for acute KD may reduce such abnormalities. Here, we evaluate the dynamics of HMGB-1 and therapeutic effects of PSL on HMGB-1-mediated inflammatory pathways on KD vasculitis in vitro. Serum samples were collected prior to initial treatment from patients with KD, systemic juvenile idiopathic arthritis (sJIA), and from healthy controls (VH), then incubated with human coronary artery endothelial cells (HCAECs). Following treatment of KD serum-activated HCAECs with PSL or PBS as a control, effects on the HMGB-1 signaling pathway were evaluated. Compared to that from VH and sJIA, KD serum activation induced HCAEC cytotoxicity and triggered extracellular release of HMGB-1. KD serum-activated HCAECs up-regulated extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and, p38 phosphorylation in the cytoplasm and nuclear factor kappa B (NF-κB) phosphorylation in the nucleus and increased interleukin (IL)-1β and tumor necrosis factor (TNF)-α production. PSL treatment of KD serum-activated HCAECs inhibited extracellular release of HMGB-1, down-regulated ERK1/2, JNK, p38, and NF-κB signaling pathways, and decreased IL-1β and TNF-α production. Our findings suggest that extracellular HMGB-1 plays an important role in mediating KD pathogenesis and that PSL treatment during the acute phase of KD may ameliorate HMGB-1-mediated inflammatory responses in KD vasculitis.

Profile of Kawasaki disease at a tertiary care center in India.

Background:Kawasaki disease (KD) is the most common cause of acquired heart disease in developed countries. KD is increasingly being reported from India; however, studies involving the large number of patients are few.Methods:All children presenting to the center from January 2017 to December 2019, diagnosed to have KD, were retrospectively included in the study. Clinical and laboratory profiles, including echocardiograms, were reviewed. Factors contributing to intravenous immunoglobulin (IVIg) refractoriness and the development of coronary artery abnormalities (CAA) were assessed.Results:A total of 39 children with KD presented to the center during the study. While 32 received initial treatment at our center, seven were referred after the initial IVIg infusion. The age range was 2 months to 11 years (mean 42.15 ± 38.51 months). More than two-thirds of the cohort was male (n = 27/39). Mucosal involvement was the commonest clinical abnormality for the group, followed by rash. Hemoglobin was significantly lower in the group with coronary artery involvement (P = 0.001). CAA (61.5%), incomplete KD, and atypical features were much more common in infants compared to the rest. Refractoriness to treatment was significantly more common in infants (P = 0.029).Conclusions:A significant proportion of infants with KD had cardiac involvement. Infants were more likely to have IVIg-resistant disease.

Seasonal Variation in Epidemiology of Kawasaki Disease-Related Coronary Artery Abnormalities in Japan, 1999-2017.

BackgroundEpidemiological studies show a U-shaped tendency in Kawasaki disease (KD)-related coronary artery abnormalities (CAAs) across age categories. Since studies suggest seasonal variations in KD onset, this study aimed to clarify the epidemiologic features of CAAs, considering the seasons of KD-occurrence.MethodsWe analyzed 2,106 (males = 1,215, females = 891) consecutive KD cases from October 1999 through September 2017 using our electronic database of annual surveys, targeting all hospitals with pediatric departments across Wakayama, Japan. The primary outcome was the presence/absence of CAAs measured by echocardiography 1 month after KD onset. Odds ratios (ORs) and 95% confidence intervals (CIs) of combined patient age and sex for CAAs were calculated using logistic regression models adjusted for four seasons.ResultsThe median age was 25 (range, 1–212) months. The proportion of males decreased with increasing age. The youngest age group (<6 months) showed an inverse summer/autumn to winter/spring ratio (>1.0) in KD-occurrence. CAAs were observed in 2.8% of cases (males = 3.4%, females = 2.1%), which significantly lessened in summer than in other seasons. Moreover, 50% (n = 4/8) of cases with giant aneurysms experienced KD in autumn. Adjusted ORs for CAAs among males aged ≥60 months (3.0; 95%, CI 1.2–7.5) and females aged <6 months (3.6; 95%, CI 1.1–11.8) were significantly higher than those among males aged 12–35 months.ConclusionsCumulative 18-year data of consecutive KD cases from one area suggest the influence of interactions between patient age and sex on the development of KD-related CAAs. The season of KD-occurrence may reflect the diversity of agents.

Macrophage activation syndrome in children with Kawasaki disease: an experience from a tertiary care hospital in northwest India.

To carry out a review of clinical characteristics, laboratory profiles, management and outcomes of patients with Kawasaki disease (KD) and macrophage activation syndrome (MAS). Medical records of patients treated for KD and MAS between January 1994 and December 2019 were reviewed. Patient demographics, clinical signs, laboratory values, coronary artery abnormalities, treatments and outcomes of patients with KD and MAS were recorded. We also performed a review published studies on the subject. Of the 950 cases with KD, 12 (1.3%; 10 boys, 2 girls) were diagnosed with MAS. The median age at diagnosis was 4 years (range 9 months-7.5 years). The median interval between onset of fever and diagnosis of KD was 11 days (range 6-30). Thrombocytopenia was seen in 11 patients. The median pro-brain natriuretic peptide value was 2101 pg/ml (range 164-75911). Coronary artery abnormalities were seen in 5 (41.7%) patients; 2 had dilatation of the left main coronary artery (LMCA), 1 had dilatation of both the LMCA and right coronary artery (RCA), 1 had dilatation of the RCA and 1 had bright coronary arteries. All patients received IVIG as first-line therapy for KD. MAS was treated with i.v. methylprednisolone pulses followed by tapering doses of oral prednisolone. Additional therapy included i.v. infliximab (n = 4), second-dose IVIG (n = 1) and oral ciclosporin (n = 1). MAS is an unusual and underrecognized complication of KD. In our cohort of 950 patients with KD, 1.3% had developed MAS. KD with MAS is associated with an increased propensity towards development of coronary artery abnormalities.

Relationship between post-IVIG IgG levels and clinical outcomes in Kawasaki disease patients: new insight into the mechanism of action of IVIG.

The dosing of intravenous immunoglobulin (IVIG) therapy for Kawasaki disease (KD) has been a matter of debate for decades, with recent studies implicating that larger doses lead to better outcomes. Despite this, few have investigated post-IVIG infusion immunoglobulin G (IgG) levels in relation to outcomes of KD such as response to IVIG and development of coronary artery abnormalities (CAAs). The present study investigated how varying levels of post-infusion IgG affected these outcomes. We collected demographic and laboratory data, including post-infusion IgG, from children with KD who were admitted to six hospitals in Japan between 2006 and 2012. We conducted multivariate analyses to examine the relationship between independent variables and non-response to IVIG and development of CAAs. We used random forest, a decision tree-based machine learning tool, to investigate the marginal effect of varying post-infusion IgG levels on non-response to IVIG and development of CAAs. Of 456 patients included in the study, 130 (28.5%) were non-responders and 38 (8.3%) developed CAAs. Sodium, post-infusion IgG, and AST were significantly associated with non-response. Post-infusion IgG and sodium were significantly associated with CAA development. The random forest plots revealed a decrease in non-response and CAA rates with increasing post-infusion IgG until post-infusion IgG was near the median (2821mg/dL), after which the non-response and CAA rates leveled off. Greater post-infusion IgG is associated with better response to IVIG and decreased CAA development in KD patients, but this effect levels off at post-infusion IgG levels greater than the median. Key points • Though previous studies have shown that post-intravenous immunoglobulin (IVIG) infusion immunoglobulin G (IgG) is associated with non-response to IVIG therapy and coronary artery abnormality (CAA) development in Kawasaki disease (KD) patients, no study has investigated the relationship between varying levels of post-infusion IgG and these clinical outcomes. • Our study showed that non-response to IVIG therapy and CAA development in Kawasaki disease patients follow a decreasing trend with increasing post-infusion IgG at post-infusion IgG levels below the median. • At values of post-infusion IgG greater than the median, non-response and CAA development rates remain relatively constant with increasing post-infusion IgG. • Our study suggests that when post-infusion IgG is greater than the median, IgG may have fully bound to the therapeutic targets of KD, and in these patients, there may be limited benefit in administering additional IVIG.

High-Versus Low-Dose Aspirin in the Treatment of Kawasaki Disease

Research Article| April 01 2020 High-Versus Low-Dose Aspirin in the Treatment of Kawasaki Disease AAP Grand Rounds (2020) 43 (4): 44. https://doi.org/10.1542/gr.43-4-44 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation High-Versus Low-Dose Aspirin in the Treatment of Kawasaki Disease. AAP Grand Rounds April 2020; 43 (4): 44. https://doi.org/10.1542/gr.43-4-44 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search toolbar search search input Search input auto suggest filter your search All PublicationsAll JournalsAAP Grand RoundsPediatricsHospital PediatricsPediatrics In ReviewNeoReviewsAAP NewsAll AAP Sites Search Advanced Search Topics: aspirin low dose, fever, immunoglobulins, intravenous, kawasaki's disease Source: Platt B, Belarski E, Manaloor J, et al. Comparison of risk of recrudescent fever in children with Kawasaki disease treated with intravenous immunoglobulin and low-dose vs high-dose aspirin. JAMA Netw Open. 2020; 3(1): e1918565; doi: https://doi.org/10.1001/jamanetworkopen.2019.18565Google Scholar Investigators from Indiana University, Indianapolis, IN, conducted a retrospective study to compare rates of recrudescent fever and coronary artery (CA) abnormalities in children treated with IV immunoglobulin (IVIG) and either low- or high-dose aspirin (ASA) for treatment of Kawasaki disease (KD). Study participants were children with KD treated within 10 days of symptom onset with 2 g/kg of IVIG and ASA at Riley’s Hospital for Children, Indianapolis, IN, between 2007 and 2018. Eligible children were identified using ICD-9 and ICD-10 codes; the medical records of eligible children were reviewed, and information was abstracted on demographics, symptoms before admission, clinical course during hospitalization and follow-up, echocardiography results, and dose of ASA. Initial ASA doses were categorized as low (<10 mg/kg/d) or high (>10 mg/kg/d). The primary outcome was recrudescent fever, defined as a rectal temperature >38.0°C or axillary temperature >37.5°C within 14 days of initial treatment that necessitated retreatment. Secondary outcomes were development of CA abnormalities and length of initial hospital stay. Outcomes in children treated with low- or high-dose ASA were compared using regression analyses after controlling for confounding variables. Subgroup analyses, limited to study patients with complete KD, also were conducted. Data were analyzed in 260 children with a median age of 2.5 years. There were 142 patients treated with low-dose ASA (median dose, 4.4 mg/kg/d), and 118 received high-dose ASA (median dose, 75.5 mg/kg/d). Most of the children in the low-dose group were treated before 2016, whereas most of those receiving high-dose ASA were treated after 2015. The 2 groups were similar for most other characteristics except that the percentage of children with incomplete KD was significantly higher among those in the high-dose group (44.1% vs 28.9% for those in the low-dose group; P = .01). Among those receiving low-dose ASA, the rate of recrudescent fever was 27.5% versus 26.0% in those receiving high-dose ASA. After adjusting for age <1 year and incomplete KD, the OR for recrudescent fever was 1.63 (95% CI, 0.89–2.97). Among the 167 study children with complete KD, the OR for recrudescent fever was 1.87 (95% CI, 0.82–4.23), when comparing the low- to high-dose groups. There was also no significant difference in rates of CA abnormalities between children in the low- and high-dose groups (7.4% and 9.4%, respectively; OR, 1.02; 95% CI, 0.55–1.87). The median length of hospital stay was 3 days for both groups (P = .27). The authors conclude that there was no difference in rates of recrudescent fever or CA abnormalities among children with KD treated with IVIG and either low- or high-dose ASA. Dr Spar has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.... You do not currently have access to this content.

Immunogenetics of Kawasaki disease.

Kawasaki disease (KD) is a medium vessel vasculitis that affects young children. Despite extensive research over the last 50years, the etiology of KD remains an enigma. Seasonal change in wind patterns was shown to have correlation with the epidemics of KD in Japan. Occurrence of disease in epidemiological clusters, seasonal variation, and a very low risk of recurrence suggest that KD is triggered by an infectious agent. The identification of oligoclonal IgA response in the affected tissues suggests an antigen-driven inflammation. The recent identification of a viral antigen in the cytoplasm of bronchial ciliated epithelium also favors infection as the main trigger for KD. Pointers that suggest a genetic basis of KD include a high disease prevalence in North-East Asian populations, a high risk among siblings, and familial occurrence of cases. Dysregulated innate and adaptive immune responses are evident in the acute stages of KD. In addition to the coronary wall inflammation, endothelial dysfunction and impaired vascular remodeling contribute to the development of coronary artery abnormalities (CAAs) and thrombosis. Genetic aberrations in certain intracellular signaling pathways involving immune effector functions are found to be associated with increased susceptibility to KD and development of coronary artery abnormalities (CAAs). Several susceptible genes have been identified through genome-wide association studies (GWAS) and linkage studies (GWLS). The genes that are studied in KD can be classified under 4 major groups-enhanced T cell activation (ITPKC, ORAI1, STIM1), dysregulated B cell signaling (CD40, BLK, FCGR2A), decreased apoptosis (CASP3), and altered transforming growth factor beta signaling (TGFB2, TGFBR2, MMP, SMAD). The review aims to highlight the role of several genetic risk factors that are linked with the increased susceptibility to KD.

Platelet Count Variation and Risk for Coronary Artery Abnormalities in Kawasaki Disease

Platelet count is considered as a biomarker for the development of coronary artery abnormalities (CAAs) among Kawasaki disease (KD) patients. However, previous studies have reported inconsistent results. We addressed the controversial association of platelet count with CAAs using a large-scale dataset. A retrospective cohort study was conducted using KD survey data from Japan (2015-2016; n = 25,448). Classifying patients by intravenous immunoglobulin (IVIG) responsiveness, we described the trends in platelet count using the lowest and highest values along with the specific illness days. Multivariate logistic regression analysis was performed to evaluate the association between platelet count and CAAs, adjusting for relevant factors. Platelet counts rapidly decreased from admission, reached the lowest count at 6-7 days, and peaked after 10 days. Platelet counts in IVIG non-responders decreased with a lower minimum value than IVIG responders, but subsequently rebounded toward a higher maximum. Compared with patients with normal platelet counts (150-450 × 10/L), patients with abnormally high platelet counts (>450 × 10/L) were more likely to have CAAs at admission (adjusted odds ratio: IVIG responders, 1.50 [95% confidence interval 1.20-1.87] and non-responders, 1.46 [1.01-2.12]). By contrast, IVIG non-responding patients whose counts were below normal (<150 × 10/L) after hospitalization were at higher risk for developing CAAs (2.27 [1.44-3.58]). Platelet count varied widely by illness day and was confounded by IVIG responsiveness, which might have contributed to previous inconsistent findings. KD patients with abnormally high platelet counts at admission or abnormally low counts after hospitalization were at higher risk for CAAs.

Clinico-laboratory profile of Kawasaki disease with arthritis in children.

Kawasaki disease (KD) is associated with several musculoskeletal manifestations. Although arthritis has been reported to occur in 2.3-31% of children with KD, there is paucity of detailed studies on the subject. We report our experience on arthritis in children with KD. Data were collated from a review of records of patients diagnosed with KD and arthritis during the period January 1994-June 2019. Eight hundred sixty-five children (male:female 29:11) were diagnosed with KD during this period-of these, 40 (4.6%) had arthritis. Median day of diagnosis of KD was 17days. Twenty-nine (72.5%), 8 (20%), and 3 (8.6%) children developed arthritis in acute, subacute, and convalescent phases of KD, respectively. Oligoarticular involvement was observed in 32 (80%) children and among these, 7 (20%) had monoarthritis. Predominant joints involved were knee (74.3%), ankle (40%), and hip (28.6%). Thirty-two children (80%) were treated with non-steroidal anti-inflammatory drugs (NSAIDs). Median duration of arthritis was 10days (range, 2-180days) with uneventful recovery in all cases. Three (7.5%) children had coronary artery ectasia which regressed on follow-up.Conclusion: Arthritis in KD is usually non-erosive, self-limiting, and responds well to a short course of NSAIDs.What is Known:• Arthritis has been reported to occur in 2.3-31% of children with KD.• Arthritis in KD is usually oligoarticular, non-erosive, and responds well to short course of non-steroidal anti-inflammatory drugs.What is New:• Children with KD and arthritis do not appear to be at increased risk of development of coronary artery abnormalities.• Arthritis in children with KD can result in diagnostic confusion, and diagnosis of KD may get delayed.

Kawasaki syndrome: immunomodulatory benefit and potential toxin neutralization by intravenous immune globulin

Kawasaki Syndrome (KS) is an acute multi-system vasculitis of infancy and early childhood associated with the development of coronary artery abnormalities. The prevalence of cardiovascular abnormalities can be significantly reduced by treating patients during the first 10 days of illness with high-dose intravenous immune globulin (IVIG). Despite the widely held belief that KS is caused by an infectious agent, the aetiology of this illness remains controversial. Recent immunological and microbiological studies suggest a potential role for staphylococcal and streptococcal toxins (superantigens) in the pathogenesis of KS. Confirmation of these findings could result in more effective diagnostic and therapeutic approaches for the treatment of this common cause of acquired heart disease in children.

Recent advances in the diagnosis of Kawasaki disease

Kawasaki disease (KD) has been increasing recently in Korea. Although the delayed diagnosis of KD can cause coronary artery abnormalities, no specific test is available. Thus, optimal guidelines for early diagnosis and treatment of KD are the best way to prevent the development of coronary artery abnormalities. The 2017 updated American Heart Association guidelines for diagnosis, treatment, and long-term management of KD are informative for physicians who face with children having manifestations suggestive of KD. Key Words: Aneurysm; Coronary Vessels; Early Diagnosis; Mucocutaneous Lymph Node Syndrome; Secondary Prevention

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.

Low risk of treatment resistance in Down syndrome with Kawasaki disease

A Japanese nationwide survey has reported that Down syndrome (DS) is a less-frequently occurring comorbidity in Kawasaki disease (KD). Although altered immune responses are frequently observed in DS, no studies have focused on the treatment response and risk for coronary artery abnormalities (CAA) in DS patients with KD. The aim of this study was therefore to evaluate the clinical manifestations, treatment response and prevalence of CAA in DS with KD. We retrospectively reviewed the medical records of DS patients with KD from 2005 through 2012. The survey questionnaires were sent to facilities nationwide, and clinical data regarding KD in DS were collected. A control group consisted of non-DS patients with KD who were managed at Toho University. Of the 94233 children diagnosed with acute KD from 2005 to 2012, 16 children with acute KD also had DS (0.017%). The DS-KD patients were significantly older than the non-DS patients (median, 8years vs 1year, P<0.05, respectively). Half of the DS patients had incomplete KD. Although 50% of the DS children were at high risk of immunoglobulin resistance, all children responded to initial treatment and none had CAA. All DS-KD patients responded to initial i.v. immunoglobulin (IVIG) or aspirin despite having a high risk of IVIG resistance, and none of the DS patients had CAA. This suggests that the risk of treatment resistance and development of CAA may be not higher in DS patients with acute KD.