KD Patients Research Articles

The Most Common Clinical Features of Kawasaki Disease Patients in King Abdulaziz Medical City.

BackgroundKawasaki disease (KD) is an acute idiopathic vasculitis affecting the small and medium-sized arteries especially coronary artery (CA). it occurs in childhood mostly below five years of age.ObjectiveThis study aims to identify the most common clinical features among KD patients in King Abdulaziz Medical City in Jeddah, Saudi Arabia from 1/1/1982 to 31/12/2018.MethodsA case series study was conducted in all KD patients that were admitted to the King Abdulaziz Medical City from 1/1/1982 to 31/12/2018 except those who were diagnosed in other hospitals or whose diagnosis has later changed. The identification of patient was done by using the International Classification of Diseases (ICD) coding for KD (ICD9 446.1). Our data consisted of the patient’s file number, age at presentation, gender, whether the patients received IVIG treatment or not, number of days of fever before starting IVIG treatment, response to IVIG treatment, season in which the symptoms started and clinical features based on body’s system. ResultThe study included 18 patients, 11 males showed that (55.6%) of patients met the criteria of typical KD and most of them were less than five years old. In addition, most patients were reported to have polymorphous rash, cough, irritability, vomiting, and a murmur. All patients who received intravenous immunoglobulin (IVIG) treatment which demonstrated an improvement even though those who started the treatment after 10 days of fever.ConclusionIn typical KD patients, the distribution of the clinical features was almost identical. However, there were some variations in them among atypical KD patients. Moreover, Evan though KD in our region is not common as in Japan, the incidence of giant aneurism was higher. In addition to that, this study and other study conducted in Saudi Arabia found that screened patients reported tachycardia more than patients in Japan.RecommendationAs KD is still idiopathic, we recommend more details to be collected from the patients, especially consanguinity as it is common in Saudi Arabia

A case report of atypical Kawasaki disease presented with severe elevated transaminases and literature review

BackgroundKawasaki disease (KD) is the most common cause of acquired heart disease among children in developed countries, in which the resulting coronary artery (CA) abnormalities cause myocardial ischemia, infarction, and death. Prompt diagnosis was essential, and supplemental information should be used to assist the diagnosis when classical clinical criteria are incomplete. The elevated levels of serum transaminases in most KD patients are mild. Herein, a case of atypical KD child with severely elevated transaminase was reported.Case presentationA child with clinical manifestations of fever, high C-reactive protein (CRP) and severely elevated transaminases was reported. The treatment effect of antibiotic and liver-protecting drugs was not satisfactory. A bilateral diffuse dilation of the CA was detected on echocardiography on day 5 of the illness; thus, atypical KD was diagnosed. Elevated transaminases declined rapidly to normal after the treatment of intravenous immunoglobulin (IVIG). A 1-month follow-up revealed that CA returned to normal, and 2-month, 6-months, and 1-year follow-up revealed the child was in good general health.ConclusionsThis case highlighted that atypical KD clinical symptoms were diverse, and severely elevated transaminases might provide a clue to healthcare providers for the diagnosis and management of atypical KD.

The effectiveness of infliximab for Kawasaki disease in children: systematic review and meta-analysis.

BackgroundKawasaki disease (KD) is a self-limited illness that results in coronary artery aneurysms (CAAs) and threatens children’s health and lives. The therapeutic effects of single intravenous immunoglobulin gamma (IVIG) vs. infliximab (IFX) (with or without IVIG) in young children with KD remain unclear. Thus, we made a meta-analysis and systematic review, including all of the studies which have evaluated the effectiveness and safety of IFX and IVIG KD patients.MethodsThe databases of the Cochrane Library, PubMed and Embase websites were searched for articles appearing from inception until December 31, 2020. Clinical studies that compared IFX either as initial therapy plus IVIG or rescue therapy after IVIG (IFX group) failure compared with IVIG treatment alone (IVIG group) in treating KD patients were included.ResultsThe meta-analysis included nine studies characterizing 712 patients. The treatment response was significantly higher in the adjunctive IFX therapy group than in the IVIG therapy group [odds ratio (OR) 2.64; 95% CI: 1.52–4.59; P=0.0005]. Subgroup analysis, the effect of IFX therapy on treatment response is more effectiveness in the group of the high-risk KD patients than IVIG therapy (OR 6.07; 95% CI: 2.30–16.04; P=0.0003; random-effects model). Further analysis showed no difference in the improvement of CAAs in short-term follow-up between the two groups. However, adding IFX either as initial therapy or as additional therapy all showed an advantageous effect regarding the ∆Z score of the left anterior descending (LAD) (MD =0.29; 95% CI: 0.27–0.31; P<0.00001) and right coronary artery (RCA) (MD =0.24; 95% CI: 0.22–0.26; P<0.00001). Further, IFX exhibited significant effect on the treatment response compared with IVIG therapy in the Asian group (OR, 2.84; 95% CI: 1.51–5.36; P=0.001; random-effects model), and the beneficial effects of IFX were given without increasing the risk of AEs.ConclusionsThis meta-analysis emphasizes the importance of IFX on the treatment response in the high-risk KD patients. IFX may play a role in the Asian KD patients and prevention of progressive CAA, and does not increase the risk of AEs in KD patients.

Transcriptional and phenotypic analysis of distinct T-cell subsets may reveal novel pathogenetic and diagnostic signatures of Kawasaki disease

Abstract Kawasaki disease (KD) is an acute vasculitis occurring in children &amp;lt;5yo that can result in coronary artery lesions. Our study aims to define novel pathogenetic and diagnostic signatures through flow cytometry and gene expression of T cell subsets. Peripheral Blood Mononuclear Cells of twenty-four KD patients at diagnosis (KD), twelve febrile patients (FC) and eighteen age-matched healthy controls (HC) were collected. Frequency of T regulatory cells (Treg), peripheral T follicular helper cells (pTfh) and maturational T cell subsets (Naïve, Central Memory, CM; Effector Memory, EM; terminally differentiated memory, TEMRA) were assessed by FACS (CytoFLEX-Beckman Coulter). Transcriptional levels of 96-genes in sort-purified CM, Treg and EM have been analysed by Fluidgm (Biomark). We found that KD have lower frequency of CM and EM compared to HC (p=0.003 and p=0.005), lower frequency of pTfh cells compared to HC (p=0,008), and in line with previous literature, lower Treg compared to HC (p=0.07). Instead, FC have a higher frequency of EM (p= 0.002; p=0.001) and TEMRA (p=0.004; p=0.006) and lower Naive (p=0.005; p=0.003) compared with both HC and KD. At transcriptional level, a distinct signature was found in EM of FC, with 26 and 16 differentially expressed genes (DEGs) compared to KD and HC. These preliminary data suggest that KD present a distinct phenotypic and transcriptional T cell signature, suggesting additional diagnostic and pathogenic insights able to distinguish KD from FC. Future studies with a similar multi OMIC approach could help identifying prognostic signature in KD.

A 10-year cross-sectional retrospective study on Kawasaki disease in Iranian children: incidence, clinical manifestations, complications, and treatment patterns

BackgroundKawasaki disease (KD) as an acute, systemic vasculitis is the leading cause of acquired heart disease in children under the age of 5 years.MethodsA 10-year cross-sectional retrospective study was designed to assess 190 Iranian children with KD during 2008–2018. Demographic data, clinical and laboratory manifestations from the onset of symptoms to diagnosis, clinical signs and symptoms, and subsequent treatments were evaluated to predict hospitalization stay, complications, and response to treatment.ResultsChildren with KD had a male-to-female ratio of 1.18:1 and an average age of 36 months. There was an insignificantly more incidence of KD in cold seasons. The most frequent symptoms were fever (92.6%), oral mucus membrane changes (75.8%), bilateral bulbar conjunctival injection (73.7%), polymorphous skin rash (73.2%), peripheral extremity changes (63.7%), and cervical lymphadenopathy (60.0%). The rate of gastrointestinal, cardiac, joint, and hepatic complications was determined to be 38.4, 27.9, 6.8, and 4.2%, respectively. 89.5% of patients received intravenous immunoglobulin (IVIG) plus aspirin as the first line of treatment, while, 16.3% of them needed an extra second line of treatment. Significantly low serum sodium levels and high platelet counts were detected in KD patients with cardiac complications. Cardiac complications often were more encountered in patients who did not respond to the first line of treatment. Higher platelet count, lower serum sodium amount, and C-reactive protein (CRP) level were significantly associated with a need for an additive second line of treatment. A significant relationship between hospitalization stay and hemoglobin level was found.ConclusionAs most of the clinical manifestations and complications were following other reports released over the past few years, such data can be confidently used to diagnose KD in Iran. Seasonal incidence and a positive history of recent infection in a notable number of patients may provide clues to understand possible etiologies of KD. Laboratory markers can successfully contribute to health practitioners with the clinical judgment of the need for additional treatments, possible complications, and hospitalization duration.

Inhibition of IL-6 in the LCWE Mouse Model of Kawasaki Disease Inhibits Acute Phase Reactant Serum Amyloid A but Fails to Attenuate Vasculitis.

ObjectiveKawasaki disease (KD) is the most common cause of acquired pediatric heart disease in the developed world. 10% of KD patients are resistant to front-line therapy, and no interventions exist to address secondary complications such as myocardial fibrosis. We sought to identify proteins and pathways associated with disease and anti-IL-1 treatment in a mouse model of KD.MethodsVasculitis was induced via Lactobacillus casei cell wall extract (LCWE) injection in 5-week-old male mice. Groups of mice were injected with LCWE alone, LCWE and IL-1 receptor antagonist anakinra, or saline for controls. Upper heart tissue was assessed by quantitative mass spectrometry analysis. Expression and activation of STAT3 was assessed by immunohistochemistry, immunofluorescence and Western blot, and IL-6 expression by RNA-seq and ELISA. A STAT3 small molecular inhibitor and anti-IL-6R antibody were used to evaluate the role of STAT3 and IL-6 in disease development.ResultsSTAT3 was highly expressed and phosphorylated in cardiac tissue of LCWE-injected mice, and reduced following anakinra treatment. Il6 and Stat3 gene expression was enhanced in abdominal aorta of LCWE-injected mice and reduced with Anakinra treatment. IL-6 serum levels were enhanced in LCWE-injected mice and normalized by anakinra. However, neither inhibition of STAT3 nor blockade of IL-6 altered disease development.ConclusionProteomic analysis of cardiac tissues demonstrates differential protein expression between KD-like, control and anakinra treated cardiac tissue. STAT3 and IL-6 were highly upregulated with LCWE and normalized by anakinra treatment. However, both STAT3 and IL-6 were dispensable for disease development indicating they may be bystanders of inflammation.

P76 Management of Giant Coronary Artery Aneurysms as a Coronary Sequelae of Kawasaki Disease – Surgical or Conservative Management?

Abstract Introduction Kawasaki Disease (KD) is the commonest childhood acquired heart disease in developed countries, predominantly affecting children younger than 5 years’ of age. These patients are at high risks of developing coronary arterial aneurysms (CAA) and CAA with absolute internal luminal diameters measuring ≥8mm or Z-score ≥10 are classified as giant coronary aneurysms (GCA). Case Report A 19-year-old girl with previous history of Kawasaki disease was diagnosed with giant coronary aneurysms on echocardiograms. Her subsequent CT coronary angiography showed large aneurysms in the right coronary artery (29mm x 25mm) and left anterior descending artery (10mm x 10mm) with signs of calcification. However, surprisingly, despite the evidence of large coronary aneurysms, she was completely asymptomatic and was physically active, participating in competitive sports. Her cardiac MRI scan 17 years after KD onset showed right coronary perfusion deficit in the distal right coronary territory but with no evidence of myocardial infarction. A repeated cardiac CT was performed and showed delayed filling of the distal right coronary artery. However, it was uncertain at this point if the aneurysm was causing true ischaemia or simply delayed perfusion. An ECG stress test was subsequently performed for further investigation which showed no significant abnormality. After having a detailed discussion in the MDT and with colleagues from San Diego, USA, a conservative approach was decided to be in the patient’s best interest. She has been advised to avoid competitive or strenuous exercise due to the associated risks. She is fit-and-well, and is currently on Warfarin variable dose and Aspirin 75mg OD, with annual cardiac MRI surveillance. Discussion 20% of KD patients develop CAA and approximately 5% of KD patients have evidence of GCA. Unlike small and medium CAA, GCA regress in a much slower and more constant rate, and they never achieve complete resolution. A Japanese retrospective study showed the 10-year coronary event-free survival rates in small, medium and giant CAA as 100%, 96% and 61% respectively (p&amp;lt;.001). Patients with GCA are at significantly increased risks of coronary complications and major cardiac events (48%). Despite maximal medical treatment, patients with GCA have high risks of aneurysm rupture which is associated with high mortality rates. These patients are also at lifelong risks of atherosclerosis and stenosis which may lead to myocardial ischaemia and even death. Therefore, it is absolutely essential to control for cardiovascular risk factors and adhere to strict treatment regime. These patients also require lifelong, uninterrupted cardiology follow-up in a specialist KD clinic. Catheter and surgical interventions may be indicated in some patients. There have been recent attempts in combining CABG with downsizing reconstruction for GCA in an attempt to decrease GCA diameter and improve the coronary flow rate to prevent thrombosis which has shown quite promising results. However, the decisions whether to undergo a surgical intervention should be tailored to each individual, taking into consideration all aspects of a patient, including their disease status and social life. Conclusion With an increasing prevalence of KD in UK, it is essential to always consider the diagnosis of KD in a febrile child with raised inflammatory markers, especially in patients presenting with prolonged fever (longer than 4-5 days) as a delay in commencing treatment poses a significantly increased risk of developing coronary complications which are associated with high morbidity and mortality rates.

Tight junction protein ZO-1 in Kawasaki disease

BackgroundKawasaki disease (KD) is a form of systemic febrile vasculitis that is complicated with coronary artery lesions (CAL). The tight junctions that maintain the intestinal barrier also play a role in systemic inflammatory diseases. Serum zonula occludens-1 (ZO-1) expression was found to be significantly lower in asthmatic patients, and another study reported that elevated systemic ZO-1 was positively correlated with inflammation in cirrhotic patients. A murine model of KD vasculitis demonstrated that vasculitis depended on intestinal barrier dysfunction, which is maintained by tight junctions. In this study, we aimed to investigate the role of the tight junction zonula occludens-1 (ZO-1) in the treatment response of intravenous immunoglobulin (IVIG) and the occurrence of CAL formation in KD patients.MethodsWe enrolled 40 KD patients, 12 healthy controls, and 12 febrile controls in this study. The serum levels of tight junction ZO-1 were determined by enzyme-linked immunosorbent assay.ResultsThe serum ZO-1 level was higher in the fever control group but did not reach a statistical significance. KD patients who received a second dose of IVIG treatment due to initial IVIG unresponsiveness had a higher serum levels of tight junction ZO-1, but without statistical significance (2.15 ± 0.18 vs. 2.69 ± 0.31 ng/mL, p = 0.058). KD patients who developed a CAL demonstrated a significant lower serum tight junction ZO-1 levels than KD without CAL formation (1.89 ± 0.16 vs. 2.39 ± 0.15 ng/mL, p = 0.027). After multiple logistic regression analysis, ZO-1 levels [(95% confidence interval (CI): 0.058 ~ 0.941, odds ratio (OR) = 0.235, p = 0.041)] showed as the risk factor for CAL formation.ConclusionSerum levels of tight junction ZO-1 levels were lower in KD patients than fever controls and associated with CAL formation.

Comparison of IVIG resistance predictive models in Kawasaki disease.

We aimed to compare the ten different scores (by Kobayashi, Egami, Harada, Formosa, Sano, Piram et al., Wu et al., Yang et al., Tan et al., and Kanai et al.) to assess their performance in predicting IVIG resistance in Turkish children. Complete and incomplete KD patients diagnosed with KD at Hacettepe University between June 2007 and September 2019 were evaluated retrospectively. A total of 129 patients, 79 boys (61.2%), with a median age 36 (IQR 19.5-57.0) months were evaluated. Sixteen patients (12.4%) had IVIG resistance. Sensitivity was low for all the ten scores. Tan, Sano, and Egami predictive models had the highest specificity (97.3, 89.4, 86.7%, respectively). Almost all scoring systems distinguished the group of patients with low risk for IVIG resistance but could not differentiate IVIG-resistant patients. Multivariate analysis for the laboratory features showed that platelet count <300 × 109/L and GGT serum levels were independent risk factors for IVIG resistance (OR: 3.896; 95% CI: 1.054-14.404; p = 0.042 and OR: 1.008; 95% CI: 1.001-1.015; p = 0.050). The current scoring systems had a low sensitivity for predicting the risk for IVIG resistance in Turkish children. On the other hand, increased serum GGT levels and low platelet count were risk factors for predicting IVIG resistance. Intravenous immunoglobulin (IVIG) resistance may be observed in 10-20% of patients diagnosed with Kawasaki disease. Coronary artery involvement is more frequent in IVIG-resistant patients. It is important to predict the patients who might develop IVIG resistance to improve prognosis. The performance of the IVIG resistance predictive models in Kawasaki disease in our population is limited due to the low sensitivity.

Integrin \u03b12 gene polymorphism is a risk factor of coronary artery lesions in Chinese children with Kawasaki disease

BackgroundKawasaki disease (KD) is a systemic vasculitis, and the formation of coronary artery lesions(CAL) is its most common sequela. Both genetic and environmental factors are considered to be important factors of in KD. Integrin α2 (ITGA2) is a transmembrane receptor that is associated with susceptibility to several diseases, but its relevance to KD with CAL is unclear.MethodsWe genotyped ITGA2 rs1126643 in 785 KD patients with the CAL and no-CAL(NCAL) (300 patients with CAL, and 485 age- and sex-matched patients with NCAL). OR (95% CI) and adjusted OR (95% CI) were used to evaluate the intensity of the association.ResultsWe found a significantly increased risk of KD with CAL associated with ITGA2 rs1126643 genotypes (CT vs CC: adjusted OR = 1.57, 95% CI = 1.16–2.12, P = 0.0032; CT/TT vs CC: adjusted OR = 1.49, 95% CI = 1.12–2.00, P = 0.0068; T vs C: adjusted OR = 1.66, 95% CI = 1.16–2.51, P = 0.0165). Moreover, we found that carriers of the CT/TT genotype had a significant risk of KD with coronary artery lesion susceptibility for children ≤60 months of age, and the CT/TT genotype was significantly associated with an increased risk of SCAL formation and MCAL formation when compared with the CC genotype.ConclusionITGA2 rs1126643 was associated with increased susceptibility and severity of CAL in KD.

Clinical aspects for differential diagnosis of Kawasaki disease shock syndrome: a case control study

BackgroundBecause of the absence of a specific diagnostic test and pathognomonic clinical features, physicians must rely on the presence of specific clinical criteria and laboratory data that support the diagnosis of KD. To help clinicians distinguish KD, KDSS, septic shock, and TSS earlier, we suggest differential diagnosis and treatment guideline.MethodsMedical records of immunocompetent patients who were admitted to the pediatric department with a diagnosis of KDSS, septic shock or TSS (SS group) were retrospectively reviewed. In addition, KD patients were selected by seasonal matching to each case of KDSS patient by date of admission (± 2 weeks).ResultsThere were 13 patients with KDSS, 35 patients with SS group, and 91 patients with KD. In comparison between KDSS and septic shock group, KDSS group had significantly higher rate of coronary aneurysm incidence, and higher left ventricle dysfunction rate. In comparison between KDSS and TSS, patients with KDSS had a significantly higher erythrocyte sedimentation rate (ESR) and significantly lower creatinine. Receiver operation characteristic curve revealed that the optimal ESR cut off value for determining the KDSS was 56.0 (sensitivity 75.0%, specificity of 100.0%) and the optimal creatinine cut off value for determining the TSS was 0.695 (sensitivity 76.9%, specificity 84.6%).ConclusionsClinical symptoms, laboratory finding, echocardiography, and culture studies can be used to differentiate KD, KDSS, septic shock and TSS.

Visual System Impairment in a Mouse Model of Krabbe Disease: The Twitcher Mouse.

Krabbe disease (KD, or globoid cell leukodystrophy; OMIM #245200) is an inherited neurodegenerative condition belonging to the class of the lysosomal storage disorders. It is caused by genetic alterations in the gene encoding for the enzyme galactosylceramidase, which is responsible for cleaving the glycosydic linkage of galatosylsphingosine (psychosine or PSY), a highly cytotoxic molecule. Here, we describe morphological and functional alterations in the visual system of the Twitcher (TWI) mouse, the most used animal model of Krabbe disease. We report in vivo electrophysiological recordings showing defective basic functional properties of the TWI primary visual cortex. In particular, we demonstrate a reduced visual acuity and contrast sensitivity, and a delayed visual response. Specific neuropathological alterations are present in the TWI visual cortex, with reduced myelination, increased astrogliosis and microglia activation, and around the whole brain. Finally, we quantify PSY content in the brain and optic nerves by high-pressure liquid chromatography-mass spectrometry methods. An increasing PSY accumulation with time, the characteristic hallmark of KD, is found in both districts. These results represent the first complete characterization of the TWI visual system. Our data set a baseline for an easy testing of potential therapies for this district, which is also dramatically affected in KD patients.

Kawasaki disease in Latvia 2012–2019: epidemiology and rate of resistance to initial treatment

IntroductionKawasaki disease (KD) is an acute febrile illness of early childhood, characterised by vasculitis of the coronary and medium-sized arteries. The incidence of the disease differs worldwide, but the incidence of KD has not been established in Latvia. The aim of the study was to describe the epidemiological characteristics and estimate the incidence rate and resistance to initial treatment of KD among hospitalised children in Latvia.Material and methodsThe study was a descriptive, population-based study, which used hospital discharge records of patients &lt; 18 years old diagnosed with KD in the years 2012–2019. Incidence rate was calculated using the number of KD patients and corresponding national census data.Resultshere were 36 KD patients in Latvia. The median age at admission was 2.8 years, with 67% of cases under 5 years of age, and the male/female ratio was 1.3 : 1. The mean annual incidence rate was 1.3 per 100,000 children 0–18 years old, and 2.9 per 100,000 for children &lt; 5 years old. The mean length of hospital stay was 14 days. Coronary artery dilatation was recorded in 8% of the patients (all of whom were male). Every patient received intravenous immunoglobulin (IVIG), with a median of 7 days from fever onset to IVIG administration. Refractory treatment was reported in 25% of cases.ConclusionsThis is the first epidemiological study of KD in Latvia. The incidence rates are lower than those reported for other European countries. The percentage of refractory treatment was higher than in other studies.

Neutrophil extracellular trap from Kawasaki disease alter the biologic responses of PBMC.

Kawasaki disease (KD), also known as mucocutaneous lymph node syndrome, is an acute systemic vasculitis syndrome that mainly occurs in infants under 5 years of age. In the current manuscript, we were aiming to analyze the role of neutrophil extracellular traps (NETs) in the pathogenesis of KD, especially their interplay with peripheral blood mononuclear cells (PBMCs). Neutrophils were exposed to 20 nM phorbol myristate acetate (PMA), we found that neutrophils of KD patients were more likely to form NETs compared with healthy controls (HCs). Furthermore, PBMCs were cultured with NETs for 24 h, and we observed that NETs significantly increased the cell viability, suppressed cell apoptosis, and enhanced the pro-inflammatory cytokines production and NF-κB activation in PBMCs from KD patients. In addition, with the stimulation of NETs, the expression of vascular endothelial growth factor A (VEGF-A) and hypoxia-inducible factor-1α (HIF-1α) were increased, which were related with the pathological mechanism of KD. At last, we examined the activation of phosphoinositide 3 kinase (PI3K)/Akt signaling, and we found NETs treatment obviously enhanced the activation of PI3K and Akt. In conclusion, these findings suggested that the formation of NETs may alter the biologic responses of PBMC and affect the vascular injury in KD.

Neutrophil-to-lymphocyte ratio and scoring system for\xa0predicting coronary artery lesions of Kawasaki\xa0disease

BackgroundKawasaki disease (KD) causes coronary artery lesions (CAL) and is the leading cause of acquired heart disease in children. The aim of this study is to evaluate the risk factors and set-up a scoring system for predicting CAL of KD.MethodsWe retrospectively reviewed a total of 478 patients diagnosed with KD. We compared age, gender, laboratory data, and treatment response in two groups and developed a scoring system for predicting CAL.ResultsDuring the study period, 365 of these patients had complete medical records of coronary surveys by echocardiography. Anemia, hypoalbuminemia, C reactive protein (CRP), alanine aminotransferase, neutrophil count, and neutrophil/lymphocyte ratio (NLR) showed significant differences with CAL formation. We determined the cut-off value using a receiver-operating-characteristic (ROC) curve, and following multivariate logistic regression analysis, four independent risk factors demonstrated a significant difference with CAL formation, including CRP > 103 mg/L, NLR > 3.5, male gender, and intravenous immunoglobulin (IVIG) resistance. We established a score system based on the above evaluation, for which a ROC curve was performed, and a total score of ≥ 2 points showed a sensitivity of 60.8% and a specificity of 70.6%, with an area under the ROC curve of 0.696.ConclusionsIdentifying children at risk is important in order to prevent CAL from developing. Four independent risk factors that can predict CAL formation were CRP > 103 mg/L, NLR > 3.5, male gender, and IVIG resistance. This first report incorporated NLR into score systems to predict CAL reinforces previously well-known risk factors for the CAL formation among KD patients.

Bleeding risk associated with combination thromboprophylaxis therapy is low for patients with coronary artery aneurysms after Kawasaki disease

BackgroundKawasaki disease (KD) may lead to coronary artery aneurysms (CAA) with potential for thrombosis. We aimed to determine the bleeding risk during thromboprophylaxis regimens with dual and triple therapy. MethodsKD patients with medium to large CAAs receiving combination thromboprophylaxis therapy (dual or triple therapy with acetylsalicylic acid (ASA), clopidogrel, low molecular weight heparin (LMWH) or warfarin) were reviewed (1979–2017). Treatment periods <30 days were excluded. Bleeding events were classified using the Bleeding Academic Research Consortium (BARC) Score. The incidence of bleeding events per patient year of exposure was determined for each regimen. Resultsn = 98 of 3022 KD (23 females:75 males) were included. Median age at diagnosis was 2.6 years (IQR: 0.6–6.2), median maximum CAA z-score was 18.0 (range: 5–65.5, IQR: 10.8–28.0, m = 6) and median follow-up duration was 6.5 years (IQR: 2.5–20.2). The incidence of type ≥2 bleeds per patient-year for each regimen was 0 (ASA + clopidogrel+LMWH), 0.03 (ASA + clopidogrel), 0.06 (ASA + warfarin), 0.06 (ASA + clopidogrel+warfarin), and 0.1 (ASA + LMWH) in ascending order. 31 bleeding events requiring medical attention (type ≥2) occurred in 30 patients (median age 7.8 years). Of the 17 type ≥2 bleeds on warfarin with an International Normalised Ratio (INR) available, 13 occurred with an INR >3. For patients receiving triple therapy (dual antiplatelet with anticoagulant), there were 57 bleeding events over 20 treatment periods. ConclusionsThe overall bleeding risk was low in KD patients receiving combination thromboprophylaxis, and not significantly different across all regimens. Type ≥2 bleeding events that occurred on warfarin were most frequently associated with high INR values.

Circulating microRNAs differentiate Kawasaki Disease from infectious febrile illnesses in childhood

BackgroundKawasaki Disease (KD) is an acute vasculitis of unknown etiology in children that can lead to coronary artery lesions (CAL) in 25% of untreated patients. There is currently no diagnostic test for KD, and the clinical presentation is often difficult to differentiate from other febrile childhood illnesses. Circulating microRNAs (miRNAs) are small noncoding RNA molecules that control gene expression by inducing transcript degradation or by blocking translation. We hypothesize that the expression of circulating miRNAs will differentiate KD from non-KD febrile illnesses in children. MethodsCirculating miRNA profiles from 84 KD patients and 29 non-KD febrile controls (7 viral and 22 bacterial infections) were evaluated. 3 ul of serum from each subject was submitted to 3 freeze/heat cycles to ensure miRNA release from microvesicles or interaction with serum proteins. miRNAs were reverse transcribed using a pool of primers specific for each miRNA. Real-time PCR reactions were performed in a 384 well plate containing sequence-specific primers and TaqMan probes in the ABI7900. ‘. ResultsKD patients (3.6 ± 2.2 yrs., 58% male) were found to have a unique circulating miRNA profile, including upregulation of miRNA-210-3p, −184, and -19a-3p (p < .0001), compared to non-KD febrile controls (8.5 ± 6.1 yrs., 72% male). ConclusionsCirculating miRNAs can differentiate KD from infectious febrile childhood diseases, supporting their potential as a diagnostic biomarker for KD.

Treatment change and coronary artery abnormality in incomplete Kawasaki disease.

Incomplete Kawasaki disease (iKD) showed a higher incidence of coronary artery abnormalities (CAAs) than complete KD. However, the incidence of CAAs among iKD patients may have changed recently. We examined KD patients from recent nationwide surveys conducted between 2013 and 2016 and compared them with the results of a previous survey (2001-2002). Of 63270 KD patients, 13770 patients (22%) had iKD. They showed a higher incidence of convalescent-phase CAAs (cCAAs, 2.8%) than complete KD (2.1%). The incidence of cCAAs in patients with one or two symptoms (6.7%) was significantly higher than those with three or four symptoms (2.6%) (P < 0.0001). Intravenous immunoglobulin (IVIG) treatment was administered to 80% of iKD patients; 30% of them received IVIG before the fifth illness day (early treatment) and 12% of patients received IVIG after the seventh illness day (late treatment). In the previous survey, the incidence of cCAAs was higher in both iKD (5.9%) and cKD (4.4%). Intravenous immunoglobulin was administered to 62% of iKD patients; 26% of them received early treatment, and 16% received late treatment. The incidence of cCAAs remained higher among iKD patients than cKD patients but this difference was reduced by the increased proportion of iKD patients treated with IVIG and those at an earlier time point. It is important to recognize the possibility that patients may have iKD and perform echocardiography even if they present with a few principal symptoms.

Elevated levels of pentraxin 3 correlate with neutrophil counts and coronary artery dilation during acute Kawasaki disease, as a predictor of coronary artery lesions

Abstract Kawasaki disease (KD) is the leading cause of acquired heart disease in the developed world. 25–30% of untreated patients will develop irreversible coronary artery lesions (CAL). Pentraxin-3 (PTX-3), has been well studied in inflammatory diseases, in particular vascular endothelial dysfunction associated with cardiovascular disease. We hypothesized that PTX-3 played an important role in the development of KD associated CAL, and investigated circulating levels of PTX-3 in KD patients serum. Children with acute KD were followed from diagnosis through normalization of the clinical markers of inflammation. Blood draws and echocardiograms were conducted at several timepoints, acute (prior to IVIG treatment), sub-acute (5–10 days after IVIG treatment), and convalescent (1–4 months after KD diagnosis) phases. In this study we enrolled 70 children with KD, which included 26 (37%) who presented with CAL. Patients included in this study came from a diverse ethnic background. We observed a significant increase in PTX-3 levels during acute KD phase, compared to sub-acute and convalescent phases. PTX-3 levels during acute KD were significantly higher among KD patients with CAL. Further, PTX-3 levels were significantly correlated to coronary artery diameter size during acute KD and neutrophil counts throughout KD progression regardless of coronary artery diameter. We observed PTX-3 levels highly correlated to neutrophil counts, a known source of PTX-3 in acute inflammation and an important player in the development of KD vasculitis. Therefore, we propose PTX-3 as a novel factor associated with acute KD and in the development of KD associated CAL, and neutrophil derived PTX-3 as an important player of KD vascular dysfunction.

Serum IP-10 and IL-17 from Kawasaki disease patients induce calcification-related genes and proteins in human coronary artery smooth muscle cells in vitro

BackgroundKawasaki disease (KD) is one of the major causes of heart disease and vasculitis in children under 5 years old in the world. Clinical evidence has shown that coronary artery calcification may develop in KD patients, however the mechanism has not been elucidated. Previous studies have found that interferon-γ-inducible protein (IP)-10 and interleukin (IL)-17 can be elevated and may play a role in KD development and coronary artery lesion formation. The purpose of this in vitro study was to investigate the possible role of plasma circulating IP-10 and IL-17 of KD patients in vascular calcification development and its underlying mechanism.ResultHuman coronary artery smooth muscle cells (HCASMCs) were used in this study. We found that HCASMCs treated with IP-10/IL-17-containing KD serum and co-treated with IP-10/IL-17 recombinant proteins could induce a phenotype that may promote vascular calcification by the bone morphogenetic protein (BMP) 6 autocrine effect. Moreover, the BMP6 autocrine stimulation in IP-10/IL-17 co-treated HCASMCs could upregulate the smad1/5-runx2 signaling activation, thus increasing the expression of bone matrix-related proteins, i.e., osteopontin, osteocalcin, and alkaline phosphatase.ConclusionsThe presented in vitro results provided new insights into the comprehension of the pathogenesis of vascular calcification in SMCs in KD progression. Although additional in vivo experimental models should be completed to confirm the in vivo relevance of these in vitro findings, the results related to the autocrine role of BMP6 may provide a new direction for theranostic drug development to treat KD.