Kawasaki Disease Patients Research Articles

Prediction Model for Diagnosis of Kawasaki Disease Using iTRAQ-Based Analysis.

A quick prediction method may help confirm the diagnosis of Kawasaki disease (KD), and reduce the risk of coronary artery lesions. The purpose of this study was to evaluate potential candidate diagnostic serum proteins in KD using isobaric tagging for relative and absolute quantification (iTRAQ) gel-free proteomics. Ninety two subjects, including 68 KD patients (1.6 ± 1.2 years, M/F 36/32) and 24 fever controls with evident respiratory tract infection (2.1 ± 1.2 years, M/F 13/11) were enrolled. Medical records were reviewed for demographic and laboratory data. The iTRAQ gel-free proteomics was used to screen serum proteins completely and compare the difference between two groups followed by specific validation with ELISA. The candidate proteins and conventional laboratory items were selected for the prediction model of KD diagnosis by support vector machine. Five selected candidate proteins, including protein S100-A8, protein S100-A9, protein S100-A12, neutrophil defensin 1, and alpha-1-acid glycoprotein 1 were identified for developing the prediction model of KD diagnosis. They were used to develop an efficient KD prediction model with an area under receiver operating characteristic (auROC) value of 0.92 (95% confidence interval: 0.84, 0.98). These protein biomarkers were significantly correlated with the conventional laboratory items as follows: C-reactive protein, glutamic pyruvic transaminase, white blood count, platelet, segment and hemoglobin. These conventional laboratory items were used to develop a prediction model of KD diagnosis with an auROC value of 0.88 (95% confidence interval: 0.80, 0.96). Our result demonstrated that the prediction model with combined five selected candidate protein levels may be a good diagnostic tool of KD. Further prediction model with combined six conventional laboratory data is also an acceptable alternative method for KD diagnosis.

Effectiveness and safety of dual antiplatelet therapy in coronary aneurysms caused by Kawasaki disease in children: study protocol for a multicenter randomized clinical trial.

BackgroundMedium or large coronary artery aneurysm (CAA) is a serious complication of Kawasaki disease (KD) and may cause thrombosis, coronary artery stenosis, and even myocardial infarction at different stages of the disease. Dual antiplatelet therapy (aspirin plus clopidogrel) is considered for prophylaxis of coronary thrombosis in KD presenting with more than medium CAAs based on adult coronary artery disease experience and expert consensus. This paper describes the study protocol for a randomized controlled trial that measures the clinical effectiveness and safety of dual antiplatelet therapy in the thromboprophylactic treatment of KD.MethodsThe present study is a multicenter, open-label, randomized controlled trial (RCT) with a 12-month follow-up. KD patients with medium or large CAAs (Z-value ≥5), evaluated by echocardiogram and clinicians before treatment, are randomized in a 1:1 ratio and assigned to aspirin therapy alone (Control group), or dual antiplatelet (aspirin plus clopidogrel) therapy (Experimental group). Antiplatelet therapy is given to the KD patients from the time of diagnosis until the coronary artery returns to normal. Weekly or monthly follow-up visits are conducted to record compliance, recovery, and biochemical indicators and continue for one year. The primary outcome is the incidence of thrombus throughout the disease and the effective of dual antiplatelet. The secondary outcomes are the safety of dual antiplatelet drugs, platelet-related indicators, inflammatory indicators, biochemical indexes and drug-related indicators during the study period. Patients who do not meet the inclusion criteria of the RCT trial or those unwilling to provide informed consent enter the registration trial.DiscussionThis is the first study to evaluate the effectiveness and safety of dual antiplatelet therapy in coronary aneurysms caused by Kawasaki disease in children. It is hoped that this study will play an important and significant role in improving the prognosis and long-term quality of life for children with KD complicated by CAAs.Trial registrationChinese Clinical Trial Registry, ChiCTR1800019181. Registered on Oct 30, 2018.

#25: Contemporaneous Evaluation of Kawasaki Disease and Multisystem Inflammatory Syndrome in Children Cases in Northern Virginia

BackgroundMultisystem inflammatory syndrome in children (MIS-C) has a temporal association with SARS-coronavirus 2 (SARS-CoV-2) infection and can present similarly to Kawasaki disease (KD). After the Centers for Disease Control and Prevention issued a MIS-C case definition in May 2020, we implemented local diagnostic and management strategies to standardize the care for patients with MIS-C encouraging limited laboratory evaluation of non-toxic patients presenting with a febrile illness. We then sought to re-evaluate our diagnostic and management recommendations to ensure appropriate resource utilization for children with MIS-C and KD.MethodsPatients with MIS-C and KD were identified via convenience sampling of Pediatric Infectious Diseases clinical records at Inova Children’s Hospital from May 1, 2020 to August 28, 2020. Manual chart review was done to extract clinical points of interest and the two cohorts were compared with descriptive statistics. Abdominal symptoms included pain, emesis, and diarrhea. Respiratory symptoms included shortness of breath, tachypnea, cough, and need for mechanical ventilation. Musculoskeletal symptoms included pain and edema. Neurologic symptoms included headache, dizziness, altered mental status, and irritability.Results7 patients with KD and 14 patients with MIS-C were identified. No patients with KD had presenting hypotension and 9 patients with MIS-C had presenting hypotension (p < 0.01). Oral changes were seen in 5 patients with KD and 3 patients with MIS-C (p = 0.05). Conjunctival injection, rash, abdominal symptoms, musculoskeletal symptoms, and neurologic symptoms were seen in some patients with KD and MIS-C with no statistically significant occurrence of these symptoms between the two cohorts. The median initial absolute lymphocyte count was 2,860/µL in KD cases whereas it was 1,325/µL in MIS-C cases (p < 0.01). The median platelet count was 367,000/ µL in KD cases versus 193,000 in MIS-C cases (p = 0.03). The median initial C-reactive protein was 11.2 mg/dL in KD cases versus 23.2 mg/dL in MIS-C cases (p < 0.01). There was no statistically significant difference in the white blood cell count, erythrocyte sedimentation rate, alanine transaminase, B-natriuretic peptide, troponin I, or ferritin values between KD and MIS-C patients. Coronary artery dilation or prominence was seen in 4 patients with KD and in 8 patients with MIS-C (p > 0.99). There were no deaths.ConclusionsFollowing national recognition of MIS-C we saw approximately 1 MIS-C case per week. Presenting hypotension, an absolute lymphocyte count less than 1400/µL, a platelet count less than 200,000/µL, and a CRP greater than 20 mg/dL best predicted MIS-C versus KD. The initial white blood cell count, alanine transaminase, erythrocyte sedimentation rate, B-natriuretic peptide, troponin I, ferritin, and initial coronary artery dilation did not readily distinguish KD from MIS-C. Thus, our diagnostic management recommending limited laboratory evaluation for non-toxic patients presenting with a febrile rash illness, fever and abdominal symptoms, or fever with conjunctival injection is reasonable.

Verification of "Japanese Scoring Systems" to Predict IVIG Resistance and Identification of Predictors for IVIG Resistance in Thai Children with Kawasaki Disease.

The objective of this study was to assess the validity of using the Kobayashi, Sano and Egami scoring systems to predict the intravenous immunoglobulin (IVIG) resistance of Kawasaki disease (KD) and to identify the predictors of IVIG resistance in our Thai population. A retrospective study involving 130 KD patients who were admitted between January 2005 and April 2018 was performed. We found that 17 (13%) KD patients did not respond to the first IVIG dose. The three scoring systems have good specificity (80.8%, 74% and 92.1%, respectively) but low sensitivity (0%, 33.3% and 22.2%, respectively). Multivariate analysis suggested that a body temperature greater than 40.2°C (odds ratio of 3.80, P value = 0.03), a neutrophil percentage greater than 74% (odds ratio of 3.82, P value = 0.03) and serum albumin less than 3g/L (odds ratio of 5.09, P value = 0.01) were predictors of IVIG resistance. Our study cannot conclude that the three Japanese scoring systems are not suitable for predicting IVIG resistance in the Thai population due to study limitations. However, a high-grade fever (≥ 40.2°C), neutrophil predominance ≥ 74% and hypoalbuminemia (serum albumin level < 3g/L) were predictors of IVIG resistance in Thai KD patients.

Predictive model based on gene and laboratory data for intravenous immunoglobulin resistance in Kawasaki disease in a Chinese population

BackgroundHere, we investigated the predictive efficiency of a newly developed model based on single nucleotide polymorphisms (SNPs) and laboratory data for intravenous immunoglobulin (IVIG) resistance in Kawasaki disease (KD) in a Chinese population.MethodsData relating to children with KD were acquired from a single center between December 2015 and August 2019 and used to screen target SNPs. We then developed a predictive model of IVIG resistance using previous laboratory parameters. We then validated our model using data acquired from children with KD attending a second center between January and December 2019.ResultsAnalysis showed that rs10056474 GG, rs746994GG, rs76863441GT, rs16944 (CT/TT), and rs1143627 (CT/CC), increased the risk of IVIG-resistance in KD patients (odds ratio, OR > 1). The new predictive model, which combined SNP data with a previous model derived from laboratory data, significantly increased the area under the receiver-operator-characteristic curves (AUC) (0.832, 95% CI: 0.776-0.878 vs 0.793, 95%CI:0.734-0.844, P < 0.05) in the development dataset, and (0.820, 95% CI: 0.730-0.889 vs 0.749, 95% CI: 0.652-0.830, P < 0.05) in the validation dataset. The sensitivity and specificity of the new assay were 65.33% (95% CI: 53.5-76.0%) and 86.67% (95% CI: 80.2-91.7%) in the development dataset and 77.14% (95% CI: 59.9-89.6%) and 86.15% (95% CI: 75.3-93.5%) in the validation dataset.ConclusionAnalysis showed that rs10056474 and rs746994 in the SMAD5 gene, rs76863441 in the PLA2G7 gene, and rs16944 or rs1143627 in the interleukin (IL)-1B gene, were associated with IVIG resistant KD in a Chinese population. The new model combined SNPs with laboratory data and improved the predictve efficiency of IVIG-resistant KD.

Identifying Circulating MicroRNA in Kawasaki Disease by Next-Generation Sequencing Approach.

Kawasaki disease (KD) typically occurs in children aged under 5 years and can cause coronary artery lesions (CALs). Early diagnosis and treatment with intravenous immunoglobulin can reduce the occurrence of CALs; therefore, identifying a good biomarker for diagnosing KD is essential. Here, using next-generation sequencing in patients with recurrent KD, those with viral infection, and healthy controls, we identified dysregulated circulating microRNAs as diagnostic biomarkers for KD. Pathway enrichment analysis illustrated the putative role of these miRNAs in KD progression. Their expression levels were validated using real-time polymerase chain reaction (qPCR). Fifteen dysregulated circulating miRNAs (fold changes >2 and <0.5) were differentially expressed in the recurrent KD group compared with the viral infection and control groups. These miRNAs were significantly involved in the transforming growth factor-β, epithelial–mesenchymal transition, and cell apoptosis signaling pathways. Notably, their expression levels were frequently restored after intravenous immunoglobulin treatment. Among the candidates, miR-24-3p expression level was significantly higher in patients with recurrent KD compared with healthy controls or viral infection controls (p < 0.001). Receiver operating characteristic analysis revealed that high miR-24-3p expression levels may be a potential biomarker for KD diagnosis. In conclusion, we identified miR-24-3p significantly higher in KD patients, which may be a potential diagnostic biomarker for KD.

Hepcidin in Kawasaki disease: upregulation by acute inflammation in patients having resistance to intravenous immunoglobulin therapy.

Hepcidin is an iron metabolism inhibitor that increases with chronic inflammation. However, it is unclear whether hepcidin indicates acute inflammatory response in Kawasaki disease (KD), which is an acute systemic vasculitis. In this study, we examined the serum hepcidin levels before and after intravenous immunoglobulin (IVIG) therapy in responders and non-responders to IVIG. This was a pilot prospective observational study at a university hospital. All KD patients were initially administered 2g/kg of IVIG as the first IVIG therapy (IVIG1) on day 4 to day 7 after onset. Non-responders to IVIG1 were additionally treated with the second IVIG therapy (IVIG2) using 1g/kg of IVIG. All KD patients were also treated with aspirin. We measured serum hepcidin levels before IVIG1, after IVIG1, and during the recovery period. Among the 31 KD patients, 21 patients and 5 patients improved after IVIG1 (responders-1) and IVIG2 (responders-2), respectively, but 5 patients did not improve after IVIG2 (non-responders). Serum hepcidin levels before IVIG1 were significantly higher in responders-2 (159.0ng/mL) and non-responders (240.0ng/mL), compared to responders-1 (103.0ng/mL). Serum hepcidin levels after IVIG1 were significantly higher in non-responders (163.0ng/mL), compared to responders-1 (43.4ng/mL) and responders-2 (54.6ng/mL). Serum hepcidin levels of non-responders to IVIG were higher before IVIG and remained high after IVIG. Erythrocyte-related indexes, including hemoglobin, reticulocytes, iron, and ferritin before IVIG1, were not significantly different among the three groups. Serum hepcidin might be excessively upregulated by acute inflammation in KD patients having resistance to IVIG. Key Points • Hepcidin, an iron metabolism inhibitor in chronic inflammation, increases during the acute phase of Kawasaki disease. • Hepcidin levels before IVIG of non-responders were higher than those of responders in Kawasaki disease. • Hepcidin might be excessively upregulated by acute inflammation in KD patients having resistance to IVIG.

A Retrospective Cohort Study of Intravenous Immunoglobulin Therapy in the Acute Phase of Kawasaki Disease: The Earlier, the Better?

Background Although intravenous immunoglobulin (IVIG) is expected to prevent coronary artery abnormalities of Kawasaki disease (KD) in the acute phase, the timing and effectiveness of IVIG remain to be determined. The association of timing of IVIG administration in KD patients with coronary artery abnormalities is evaluated in this cohort study. Methods We systematically studied KD patients from two participating institutions between 2015 and 2017. To reveal the effectiveness of IVIG treatment, these patients were classified into four groups regarding the time of IVIG treatment. Primary outcome was coronary artery abnormalities by echo at diagnosis and 12 months follow-up; secondary outcomes included inflammatory markers. Results A total of 1281 patients were included in this study. The best time of IVIG treatment cut-off values in 12 months follow-up for predicting coronary artery abnormalities was days 7.5 of illness onset. According to the best time of IVIG treatment cut-off values, all patients were classified into 4 groups. Group 1 was defined as earlier IVIG treatment administration on days ≤4 of the illness (n = 77). Group 2 was defined with days 5-7 (n = 817), group 3 with days 8-10 (n = 249), group 4 with days >10 (n = 138). A greater proportion of IVIG-resistant KD patients were group 4 than the other three groups, and there were significant differences (p < 0.05). The incidence of coronary artery lesions (CALs) and coronary artery aneurysms (CAAs) in group 3 and group 4 was higher than that in group 1 (p < 0.05) and group 2 (p < 0.05) during a 12-month follow-up. Additionally, the incidence of CALs in group 1 was higher than that in group 2 but without statistical significance (p > 0.05). The OR was significantly higher for those who started IVIG administration more than 7 days from the onset was positively associated with the occurrence of CALs (OR, 5.3; 95% CI, 2.0-13.9) and CAAs (OR, 13.5; 95% CI, 2.9-14.1) 12 months after initial onset. Multivariate regression revealed that the timing of IVIG treatment and IVIG-resistance was independent risk factors of CALs. Conclusions IVIG treatment less than 7 days after illness onset are found to be sufficient for preventing developing coronary artery abnormalities in KD patients. Earlier IVIG treatment administration within 4 days may not increase the higher incidence of coronary artery abnormalities and IVIG resistance (Chinese Clinical Trial Registry:ChiCTR1800015800).

Randomized trial of different initial intravenous immunoglobulin regimens in Kawasaki disease.

BackgroundWe aimed to assess the efficacy of different initial intravenous immunoglobulin (IVIG) regimens in Kawasaki disease (KD) patients to find more cost‐effective therapy options.MethodsA multicenter, open‐label, blind‐endpoint randomized controlled trial was conducted from January 2014 to December 2015. Patients with KD, within 10 days of illness, were randomly assigned to receive different IVIG regimens (Group A, 2 g/kg once; Group B, 1 g/kg for 2 consecutive days; Group C, 1 g/kg once) and aspirin 30mg/kg/d. Primary outcomes included hours to defervescence and development of coronary artery lesions during the study period. Major secondary outcomes included total fever days, total dose of IVIG, changes of laboratory data, length of stay, and hospitalization expenses. (ClinicalTrials.gov: NCT02439996).ResultsA total of 404 patients underwent randomization. No difference was found in the outcomes of defervescence among three groups at 6, 12, 24, and 36 hours after completion of initial IVIG infusion. There were no differences in the incidence of coronary artery lesions during the study period (at week 2, month 1, month 3, and month 6 of illness), changes of laboratory data, total fever days, and length of stay. Group C patients had the lowest total dose of IVIG (mean: 1.2 vs 2.2 vs 2.1 g/kg; P < 0.001) and hospitalization expenses (mean: 8443.8 vs 10798.4 vs 11011.4 Chinese Yuan; P < 0.001) than other two groups.ConclusionsA single dose of 1g/kg IVIG is a low‐cost treatment with the same efficacy as 2 g/kg IVIG and can be an option for the initial therapy of KD patients.

Clinical Features of Kawasaki Disease during SARS-CoV-2 Epidemic: A Single-Center Retrospective Study

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic, causing coronavirus disease 2019 (COVID-19), has rapidly spread worldwide. Recently, cases of Kawasaki-like syndrome associated with COVID-19 (MIS‐C/PIMS) have been reported in the USA and Europe. However, the clinical features of Kawasaki disease (KD) in Japan during the SARS-CoV-2 epidemic remain unclear. Therefore, this retrospective study aimed to evaluate the clinical features of KD in our department during the year of the COVID-19 pandemic (2020). Data were obtained from 45 KD patients who underwent acute-phase treatment from January 2018 to December 2020. The patients were divided into three groups: (1) 2018 group, in which 18 patients receiving acute-phase treatment during 2018; (2) 2019 group, in which 17 patients receiving acute-phase treatment during 2019; and (3) 2020 group, in which 10 patients receiving acute-phase treatment during 2020. The comparison of the clinical findings, treatments, and outcomes among the three groups (2018 vs. 2019 vs. 2020 group) revealed a significant difference in the rate of the male gender (72.2% vs. 41.2% vs. 10.0%, P &lt; 0.010), recurrence (0.0% vs. 0.0% vs. 25.0%, P = 0.015), and coronary artery lesions (16.7% vs. 0.0% vs. 0.0%, P = 0.044). No patients required ventilation assistance or inotropic agents and met the diagnostic criteria of MIS‐C/PIMS. Further studies are warranted to elucidate the clinical features of KD during the SARS-CoV-2 epidemic.

Intimal thickening and disruption of the media occur in the arterial walls of coronary arteries not associated with coronary arterial aneurysms in patients with Kawasaki disease

BackgroundCoronary artery aneurysm (CAA) is an important complication of Kawasaki disease (KD) that is associated with arterial structure damage. However, few studies have examined structural changes in coronary arteries that are not associated with CAA.MethodsWe examined coronary arteries in KD patients with CAAs who underwent follow-up coronary angiography (CAG) and optical coherence tomography (OCT). Coronary arterial branches with no abnormal findings during the most recent CAG were classified into two groups. Arteries with an acute-phase CAA that later regressed were classified as group R; arteries with no abnormal findings on either acute or convalescent phase CAG were classified as group N. Coronary arterial wall structural changes were compared between groups using OCT.ResultsFifty-seven coronary arterial branches in 23 patients were evaluated by OCT. Thirty-six branches showed no abnormality during the most recent CAG. Both groups R and N comprised 18 branches. Maximum intimal thicknesses in groups R and N were 475 and 355 µm, respectively (p = 0.007). The incidences of media disruption were 100% and 67%, respectively (p = 0.02). Calcification, macrophage accumulation, and thrombus were not found in either group.ConclusionsIntimal thickening and disruption of the media occur in coronary arteries with acute phase CAAs that later regress in the convalescent phase, as well as in arteries with normal CAG findings in the acute and convalescent phases.

Serum tenascin-C predicts resistance to steroid combination therapy in high-risk Kawasaki disease: a multicenter prospective cohort study

BackgroundTenascin-C (TN-C) is an extracellular matrix glycoprotein related to tissue inflammation. Our previous retrospective study conducted in 2016 revealed that the serum tenascin-C level was higher in patients with Kawasaki disease (KD) who were resistant to intravenous immunoglobulin (IVIG) and developed coronary artery lesions (CALs). The present study is a prospective cohort study to assess if the serum level of tenascin-C could be used as a novel biomarker to predict the risk of resistance to initial treatment for high-risk patients.MethodsA total of 380 KD patients were registered and provided serum samples for tenascin-C measurement before commencing their initial treatment. Patients who did not meet the inclusion criteria were excluded from analysis; of the 181 remaining subjects, there were 144 low-risk patients (Kobayashi score: ≤4 points) and 37 high-risk patients (Kobayashi score: ≥5 points). The initial treatments for low-risk patients and high-risk patients were conventional therapy (IVIG with aspirin) and prednisolone combination therapy, respectively. The patient clinical and laboratory data, including the serum tenascin-C level, were compared between initial treatment responders and non-responders.ResultsIn the low-risk patients, there was no significant difference in the median levels of serum tenascin-C between the initial therapy responders and non-responders. However, in the high-risk patients, the median serum tenascin-C level in initial therapy non-responders was significantly higher than that in initial therapy responders (175.8 ng/ml vs 117.6 ng/ml).ConclusionsSerum tenascin-C could be a biomarker for predicting the risk of high-risk patients being non-responsive to steroid combination therapy.Trial registrationThis study was a prospective cohort study. It was approved by the ethics committee of each institute and performed in accordance with the Declaration of Helsinki.

FNDC1 Polymorphism (rs3003174 C > T) Increased the Incidence of Coronary Artery Aneurysm in Patients with Kawasaki Disease in a Southern Chinese Population.

BackgroundA large number of studies demonstrated that the key to the occurrence and development of Kawasaki disease (KD) is the over-activation of immune cells and the generation of various inflammatory factors, leading to the imbalance of the immune system. Recently, mutations in the FNDC1 gene have been shown to be associated with inflammatory responses. However, there have been no reports on the relationship between FNDC1 gene and KD so far.MethodsWe enrolled 1611 controls and 1459 patients with KD, including 372 patients with coronary artery aneurysm (CAA) and 179 patients with coronary artery lesion (CAL). The relationship between FNDC1 rs3003174 polymorphism and KD with CAA or without CAA was investigated.ResultsThis study showed no evidence that the association between FNDC1 rs3003174 C>T polymorphism and KD susceptibility was statistically significant (CT versus CC: adjusted odds ratio (OR) =0.897, 95% confidence interval (CI) =0.769–1.045, P=0.162; TT versus CC: adjusted OR=0.995, 95% CI=0.786–1.260, P=0.968; dominant model: adjusted OR=0.916, 95% CI=0.792–1.059, P=0.235; and recessive model: adjusted OR=1.055, 95% CI=0.845–1.316, P=0.638). However, our further stratified analysis in the control and KD group bore out that the incidence of TT genotype of FNDC1 rs3003174 C > T polymorphism was higher than that of CC/CT genotype in KD patients stratified by CAA (adjusted OR=1.437, 95% CI=1.034–1.996, P=0.031). Moreover, a stratified analysis of age and gender in KD patients indicated that the rs3003174 TT genotype increased the risk of CAA formation in aged ≦60 months (CC/CT vs TT: adjusted OR=1.580, 95% CI=1.106–2.259, P=0.012) and male (CC/CT vs TT: adjusted OR=1.653, 95% CI=1.101–2.481, P=0.015) KD patients.ConclusionThe results of this study demonstrated that the FNDC1 rs3003174 C>T polymorphism may be a hazard factor in the formation of CAA in KD patients that was not disclosed before.

IL-37b alleviates endothelial cell apoptosis and inflammation in Kawasaki disease through IL-1R8 pathway

Kawasaki disease (KD) is an acute vasculitis of pediatric populations that may develop coronary artery aneurysms if untreated. It has been regarded as the principal cause of acquired heart disease in children of the developed countries. Interleukin (IL)-37, as one of the IL-1 family members, is a natural suppressor of inflammation that is caused by activation of innate and adaptive immunity. However, detailed roles of IL-37 in KD are largely unclear. Sera from patients with KD displayed that IL-37 level was significantly decreased compared with healthy controls (HCs). QRT-PCR and western blot analyses showed that the expression level of IL-37 variant, IL-37b, was remarkably downregulated in human umbilical vein endothelial cells (HUVECs) exposed to KD sera-treated THP1 cells. Therefore, we researched the role of IL-37b in the context of KD and hypothesized that IL-37b may have a powerful protective effect in KD patients. We first observed and substantiated the protective role of IL-37b in a mouse model of KD induced by Candida albicans cell wall extracts (CAWS). In vitro experiments demonstrated that IL-37b alleviated endothelial cell apoptosis and inflammation via IL-1R8 receptor by inhibiting ERK and NFκB activation, which were also recapitulated in the KD mouse model. Together, our findings suggest that IL-37b play an effective protective role in coronary endothelial damage in KD, providing new evidence that IL-37b is a potential candidate drug to treat KD.

Facial nerve palsy may indicate coronary artery lesions in Kawasaki disease.

Facial nerve palsy (FNP) is extremely rare in Kawasaki disease (KD) and the incidence is just 0.9-1.3%. Our objective was to study the clinical features and prognosis of KD accompanied with FNP and to determine whether FNP indicated an increased risk of coronary artery lesions (CALs) in KD. An observational study was performed on 9 patients diagnosed as KD accompanied with FNP in Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China between September 2012 and December 2019. Patients were followed up from September 2012 till September 2020. Clinical features, laboratory and echocardiography findings, treatments, and prognosis were analyzed retrospectively. And the clinical data of patients with FNP (group A, n = 9) were compared to matched KD patients without FNP (group B, n = 27) in order to determine whether FNP indicated an increased risk of CALs in KD. The matching factors included sex, age, days of illness at the intravenous immunoglobulin use, and classic/incomplete KD forms. Clinical data of 9 patients were analyzed in this study. Patients tended to be younger than 24months of age (88.9%) and 55.6% were under 12months. Median onset of FNP was day 10 of illness. Eight patients (88.9%) showed unilateral FNP. The levels of laboratory inflammatory markers (White blood cells count, neutrophil percentage, C-reactive protein, erythrocyte sedimentation rate, etc.) were significantly increased in most cases. CALs were noted in 8 of 9 patients (88.9%). Coronary artery aneurysms occurred in 4 cases (44.4%) and the remaining 4 patients showed coronary artery dilation. All patients were given intravenous immunoglobulin therapy (2g/kg), aspirin (30-50mg/kg/day), and short-term dexamethasone. During follow-up, both FNP and CALs were completely recovered in all patients. The duration time of FNP ranged from 10 to 130days. And the time for CALs to normal ranged from 12 to 282days. The occurrence of CALs was significantly higher in patients with FNP than those without FNP (88.9% vs. 25.9%, P < 0.05). KD accompanied with FNP is rare but may indicate an increased risk of CALs. Clinicians should take KD into consideration when children suffer from long-term fever with FNP, even with incomplete diagnostic features. With a long-term follow-up, both FNP and CALs have a good prognosis. • Facial nerve palsy may indicate an increased risk of coronary artery lesions in Kawasaki disease. • Clinicians should take Kawasaki disease into consideration when children suffer from long-term fever with facial nerve palsy, even with incomplete diagnostic features. • Facial nerve palsy and coronary artery lesions have a good prognosis in a long-term follow-up.

Long-Term Hypermethylation of FcγR2B in Leukocytes of Patients with Kawasaki Disease.

The Fc gamma receptor family contains several activating receptors and the only inhibitory receptor, FcγR2B. In this study, we investigated the dynamic methylation change of FcγR2B in different stages of Kawasaki disease (KD). We enrolled a total of 116 participants, which included patients with febrile diseases as controls and KD patients. Whole blood cells of KD patients were collected prior to intravenous immunoglobulin (IVIG) treatment (KD1), three to seven days after IVIG (KD2), three weeks after IVIG treatment (KD3), six months after IVIG (KD4), and one year after IVIG treatment (KD5). In total, 76 KD patients provided samples in every stage. Leukocytes of controls were also recruited. We performed DNA extraction and pyrosequencing. FcγR2B methylation levels were higher in KD3 compared to both the controls and KD1. A significantly higher methylation of FcγR2B was found in KD5 when compared with KD1. FcγR2B methylation levels in the IVIG-resistant group were lower than those in the IVIG-responsive group at KD1-3 (p = 0.004, 0.004, 0.005 respectively). This study is the first to report the dynamic change of FcγR2B methylation and to demonstrate long-term hypermethylation one year after disease onset. Hypomethylation of FcγR2B is associated with IVIG resistance.

Kawasaki Disease Patient Stratification and Pathway Analysis Based on Host Transcriptomic and Proteomic Profiles.

The aetiology of Kawasaki disease (KD), an acute inflammatory disorder of childhood, remains unknown despite various triggers of KD having been proposed. Host ‘omic profiles offer insights into the host response to infection and inflammation, with the interrogation of multiple ‘omic levels in parallel providing a more comprehensive picture. We used differential abundance analysis, pathway analysis, clustering, and classification techniques to explore whether the host response in KD is more similar to the response to bacterial or viral infections at the transcriptomic and proteomic levels through comparison of ‘omic profiles from children with KD to those with bacterial and viral infections. Pathways activated in patients with KD included those involved in anti-viral and anti-bacterial responses. Unsupervised clustering showed that the majority of KD patients clustered with bacterial patients on both ‘omic levels, whilst application of diagnostic signatures specific for bacterial and viral infections revealed that many transcriptomic KD samples had low probabilities of having bacterial or viral infections, suggesting that KD may be triggered by a different process not typical of either common bacterial or viral infections. Clustering based on the transcriptomic and proteomic responses during KD revealed three clusters of KD patients on both ‘omic levels, suggesting heterogeneity within the inflammatory response during KD. The observed heterogeneity may reflect differences in the host response to a common trigger, or variation dependent on different triggers of the condition.

Refractory Kawasaki disease: modified methylprednisolone regimen decreases coronary artery dilatation.

The use of corticosteroids in Kawasaki disease (KD) is still controversial. The aim of this study was to investigate the safety and effectiveness of modified methylprednisolone (mPSL) regimen as an initial treatment for refractory KD. This is a real-world observational study. We identified refractory KD with a self-developed scoring system. Patients were divided into the intravenous immunoglobulin (IVIG) + mPSL group and the IVIG group. Clinical outcomes and changes in coronary arteries after the treatment during a 12-week period were observed. Propensity-score matching was used to analyze those patients with similar baseline characteristics. Of a total of 168 patients, 104 patients were assigned into the IVIG group and 64 patients into the IVIG + mPSL group. The therapeutic response rate of the IVIG + mPSL group was significantly higher than that of the IVIG group (98.4 vs 76.0%, P < 0.05). The IVIG + mPSL group had a shorter duration of fever and a higher rate of C-reactive protein decline than the IVIG group (1.17 ± 0.64 vs 1.81 ± 1.16 days; 88.1 vs 83.5%; P < 0.05). The luminal diameter and Z-score of the left circumflex coronary artery (LCX) were significantly smaller and lower in the IVIG + mPSL group than that in the IVIG group at weeks 2 and 12. Modified mPSL regimen has minimal side effects. It might improve the initial response to IVIG and decrease the dilation of LCX for refractory KD. Modified mPSL regimen (2-4 mg/kg/day, divided into 2-3 doses for 3-5 days, then 1 mg/kg/day, once a day for 3-5 days, then oral prednisone was tapered over 3-5 weeks in 5-7 days steps) as an intensive initial treatment can decrease LCX dilation in high-risk IVIG-resistant KD patients. Our self-developed scoring system has been proven validated and can be used to identify high-risk IVIG-resistant KD patients in North China. The present study provides an alternative therapeutic regimen for high-risk refractory KD patients.

High Dose Intravenous IgG Therapy Modulates Multiple NK Cell and T Cell Functions in Patients With Immune Dysregulation.

Intravenous immunoglobulin (IVIG) is an effective immunomodulatory treatment for immune dysregulation diseases. However, the mechanisms by which it reduces systemic inflammation are not well understood. NK cell cytotoxicity is decreased by IVIG in women with reduced fertility, but IVIG effects on NK cells in immune dysregulation are less clear. We hypothesized that IVIG modulation of lymphocyte function, especially in NK cells, is important for resolution of inflammation. Our aim was to identify IVIG-induced changes in a cohort of patients with Kawasaki disease (KD) and those that occur broadly in pediatric patients with various immune dysregulatory diseases. Peripheral blood mononuclear cells (PBMCs) of patients with KD or autoimmune/inflammatory diseases were phenotyped pre and post high dose IVIG treatment by flow cytometry. In KD patients, after IVIG infusion Treg cell frequency and the proportion of activated CD25+ immunoregulatory CD56bright NK cells was increased, and multiple lymphocyte subsets showed increased expression of the lymphoid tissue homing receptor CD62L. Importantly, IVIG treatment decreased the frequency of cells expressing the degranulation marker CD107a among cytotoxic CD56dim NK cells, which was reflected in a significant reduction in target cell killing and in decreased production of multiple pro-inflammatory mediators. Interestingly, the activating receptor CD336 was expressed on a higher proportion of CD56bright NK cells after IVIG in both KD and autoimmune/inflammatory patients while other NK receptors were increased differentially in each cohort. In autoimmune/inflammatory patients IVIG induced the proliferation marker CD71 on a higher percentage of CD56dim NK cells, and in contrast to KD patients, CD107a+ cells were increased in this subset. Furthermore, when PBMCs were stimulated ex vivo with IL-2 or Candida antigen in autologous plasma, more of the CD4+ T cells of KD patients expressed CD25 after IVIG therapy but fewer cytotoxic T cells were degranulated based on CD107a expression. In summary, IVIG treatment in patients with immune dysregulation has multiple effects, especially on NK cell subsets and CD4+ T cells, which are compatible with promoting resolution of inflammation. These novel findings provide insight into the immunomodulatory actions of IVIG in autoimmune and inflammatory conditions.

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