Acute Phase Of Kawasaki Disease Research Articles

Different dose aspirin plus immunoglobulin (DAPI) for prevention of coronary artery abnormalities in Kawasaki disease: Study protocol for a multi-center, prospective, randomized, open-label, blinded end-point, non-inferiority trial

BackgroundKawasaki disease is a pediatric acute systemic vasculitis that specifically involves the coronary arteries. Timely initiation of immunoglobulin plus aspirin is necessary for diminishing the incidence of coronary artery abnormalities (CAAs). The optimal dose of aspirin, however, remains controversial. The trial aims to evaluate if low-dose aspirin is noninferior to moderate-dose in reducing the risk of CAAs during the initial treatment of Kawasaki disease. MethodsThis is a multi-center, prospective, randomized, open-label, blinded endpoint, noninferiority trial to be conducted in China. The planned study duration is from 2023 to 2026. Data will be analyzed according to intention-to-treat principles. Participants are children and adolescents under the age of 18 with Kawasaki disease, recruited from the inpatient units. A sample size of 1,346 participants will provide 80% power with a one-sided significance level of 0.025. Qualifying children will be randomized (1:1) to receive either intravenous immunoglobulin (2 g/kg) plus oral moderate-dose aspirin (30-50 mg·kg−1·d−1) until the patient is afebrile for at least 48 hours, or immunoglobulin plus low-dose aspirin (3-5 mg·kg−1·d−1) as initial treatment. The primary outcome will be the occurrence of CAAs at 8 weeks after immunoglobulin infusion. Independent blinded pediatric cardiologists will assess the primary endpoint using echocardiography. ConclusionsThere is a shortage of consensus on the dose of aspirin therapy for Kawasaki disease due to the lack of evidence. The results of our randomized trial will provide more concrete evidence for the efficacy and adverse events of low- or moderate-dose aspirin in the acute phase of Kawasaki disease. Trial Registrationwww.chictr.org.cn: ChiCTR2300072686.

Ubiquitin ligase MDM2 mediates endothelial inflammation in Kawasaki disease vasculitis development.

Kawasaki disease (KD) often complicates coronary artery lesions (CALs). Despite the established significance of STAT3 signaling during the acute phase of KD and signal transducer and activator of transcription 3 (STAT3) signaling being closely related to CALs, it remains unknown whether and how STAT3 was regulated by ubiquitination during KD pathogenesis. Bioinformatics and immunoprecipitation assays were conducted, and an E3 ligase, murine double minute 2 (MDM2) was identified as the ubiquitin ligase of STAT3. The blood samples from KD patients before and after intravenous immunoglobulin (IVIG) treatment were utilized to analyze the expression level of MDM2. Human coronary artery endothelial cells (HCAECs) and a mouse model were used to study the mechanisms of MDM2-STAT3 signaling during KD pathogenesis. The MDM2 expression level decreased while the STAT3 level and vascular endothelial growth factor A (VEGFA) level increased in KD patients with CALs and the KD mouse model. Mechanistically, MDM2 colocalized with STAT3 in HCAECs and the coronary vessels of the KD mouse model. Knocking down MDM2 caused an increased level of STAT3 protein in HCAECs, whereas MDM2 overexpression upregulated the ubiquitination level of STAT3 protein, hence leading to significantly decreased turnover of STAT3 and VEGFA. MDM2 functions as a negative regulator of STAT3 signaling by promoting its ubiquitination during KD pathogenesis, thus providing a potential intervention target for KD therapy.

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

ObjectiveTo clarify the necessity of acetylsalicylic acid (ASA) administration combined with intravenous immunoglobulin (IVIG) therapy in the treatment of acute Kawasaki disease.DesignRetrospective cohort study.SettingMulticentre.ParticipantsThis study included 735 patients with Kawasaki...

Thyroid hormone may predict treatment failure in Kawasaki disease.

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

CD14 down-modulation as a real-time biomarker in Kawasaki disease.

The objectives of this study were to investigate the pathophysiology of Kawasaki disease (KD) from immunological and oxidative stress perspectives, and to identify real-time biomarkers linked to innate immunity and oxidative stress in KD. We prospectively enrolled 85 patients with KD and 135 patients with diverse conditions including immune, infectious and non-infectious diseases for this investigation. Flow cytometry was used to analyse the surface expression of CD14, CD38 and CD62L on monocytes, along with a quantitative assessment of CD14down-modulation. Additionally, oxidative stress levels wereevaluated using derivatives of reactive oxygen metabolites (d-ROMs) and antioxidant capacity measured by a free radical elective evaluator system. During the acute phase of KD, we observed a prominent CD14 down-modulation on monocytes, reflecting the indirect detection of circulating innate immune molecular patterns. Moreover, patients with KD showed a significantly higher CD14 down-modulation compared with infectious and non-infectious disease controls. Notably, the surface expression of CD14 on monocytes was restored concurrently withresponses to intravenous immunoglobulin and infliximab treatment in KD. Furthermore, d-ROM levels in patients with KD were significantly elevated compared with patients with infectiousand non-infectious diseases. Following intravenous immunoglobulin treatment, oxidative stress levels decreased in patients with KD. Monitoring CD14 down-modulation on monocytes in real-time is a valuable strategy for assessing treatment response, distinguishing KD relapse from concomitant infections and selecting second-line therapy after IVIG treatment in KD patients. The interplay between inflammation and oxidative stress likely plays a crucial role in the development of KD.

Early Clinical Evaluation of Coronary Artery Lesions in Kawasaki Disease.

The purpose of this study is to analyze the early clinical features of coronary artery lesion (CAL) in Kawasaki disease (KD), evaluate systemic inflammation indicators, and enhance early recognition of CAL in the acute phase of KD. A total of 314 children with KD were divided into those with CAL (CAL group) and without CAL (NCAL group) using echocardiographic results, and their clinical data were retrospectively analyzed. For KD patients, male, children aged 3 to 9 years, and those with fever longer than 6 days before intravenous immunoglobulin (IVIG) use were more likely to have CAL. There were significant differences in sex, age, and fever time (P < .05). Moreover, some laboratory indicator test results revealed there was a significant difference between N-terminal pro-brain natriuretic peptide (NT-pro-BNP) and interleukin-6 (IL-6), and the CAL (P < .05). This study has certain guiding significance for early clinical evaluation.

Evidence-based guidelines for the diagnosis and treatment of Kawasaki disease in children in China (2023)

Kawasaki disease (KD) is an acute self-limiting vasculitis, and it is the most common cause of acquired heart disease in children under 5 years old. One of the improvement goals in pediatric quality control work for the year 2023, as announced by the National Health Commission, is to reduce the incidence of cardiac events and KD-related mortality in children with KD. In order to standardize the diagnosis, treatment, and long-term management practices of KD in China, and effectively prevent and reduce the incidence of coronary artery lesions and long-term adverse effects, the guideline working group followed the principles and methods outlined by the World Health Organization and referenced existing evidence and experiences to develop the "Evidence-based guidelines for the diagnosis and treatment of Kawasaki disease in children in China (2023)". The guidelines address the clinical questions regarding the classification and definition of KD, diagnosis of different types of KD, treatment during the acute phase of KD, application of echocardiography in identifying complications of KD, and management of KD combined with macrophage activation syndrome. Based on the best evidence and expert consensus, 20 recommendations were formulated, aiming to provide guidance and decision-making basis for healthcare professionals in the diagnosis and treatment of KD in children.

Human Umbilical Cord Mesenchymal Stem Cells Repair Endothelial Injury and Dysfunction by Regulating NLRP3 to Inhibit Endothelial Cell Pyroptosis in Kawasaki Disease.

Vascular endothelial inflammation and endothelial dysfunction are the main causes of endothelial injury in Kawasaki disease (KD). Human umbilical cord-derived mesenchymal stem cells (Huc-MSCs) have multiple functions in immune regulation. This study examined whether Huc-MSCs inhibited endothelial inflammation and improved endothelial function in KD through constructing cell and in vivo animal KD vasculitis models. The pyroptosis factor NOD-like receptor protein 3 (NLRP3) was involved in the inflammatory process in the acute phase of KD. After tail vein injection of Huc-MSCs, inflammatory cell infiltration and the expression of pyroptosis-related proteins in the LCWE-induced KD mouse vasculitis model were significantly reduced. In vitro, NLRP3-dependent pyroptosis successfully induced human umbilical vein endothelial cell (HUVEC) damage. Huc-MSCs effectively increased the abilities of impaired HUVECs to proliferate, migrate, invade, and form vessel-like tubes, while inhibiting their apoptosis, suggesting that Huc-MSCs can reduce inflammation and improve vascular endothelial function by inhibiting the NLRP3-dependent pyroptosis pathway in KD, providing a possibility and novel target for KD endothelial injury and dysfunction.

Current knowledge of TNF-α monoclonal antibody infliximab in treating Kawasaki disease: a comprehensive review.

Kawasaki disease (KD), an autoinflammatory disease primarily affecting young children, characterized by consisting of acute systemic vasculitis and coronary artery involvement in severe cases. Intravenous immunoglobulin gamma (IVIG) combined with aspirin therapy is the first-line regimen for the prevention of coronary aneurysms in the acute phase of KD. The etiology and pathogenesis of KD are unclear, but its incidence is increasing gradually, especially in the cases of IVIG-naïve KD and refractory KD. Conventional therapies for refractory KD have unsatisfactory results. At present, infliximab (IFX), a human-murine chimeric monoclonal antibody that specifically blocks tumor necrosis factor-α (TNF-α), has made great progress in the treatment of KD. This review revealed that IFX infusion (5 mg/kg) could effectively modulate fever, reduce inflammation, improve arthritis, diminish the number of plasma exchange, decrease hospitalizations, and prevent the progression of coronary artery lesions. The adverse effects of IFX administration included skin rash, arthritis, respiratory disease, infusion reaction, hepatomegaly, and vaccination-associated complications. But the incidence of these adverse effects is low. The clear optimal application protocol of the application of IFX for either initial combination therapy or salvage therapy in KD is still under investigation. In addition, there are no effective biomarkers to predict IFX resistance. Further multicenter trials with large sample size and long-term follow-up are still needed to validate the clinical efficacy and safety of IFX for IVIG-resistant KD or refractory KD.

Non-cardiac sequelae of Kawasaki Disease. The survey study of 90 cases and literature review

Introduction and objectiveThe best-known long-term complications of Kawasaki Disease (KD) are coronary artery aneurysms. However, there are numerous case reports about other unusual chronic complications. These data are only anecdotal, and more systematic observation is missing. We aimed to detect and describe chronic non-cardiac complications of KD.Material and methodsWe surveyed parents of children with KD diagnosed between 2014 and 2019 by phone with the use of standardized questionnaire. Clinical data about the acute phase of the disease, treatment, outcome, and symptoms and signs observed within three months since KD diagnosis were recorded from the caregivers. We recruited children from 3 children’s hospitals in Warsaw and a support group on social media.ResultsNinety children met the inclusion criteria. Parents of 30 children (33%) reported some neurologic sequelae, with persistent irritability being the most common, followed by sleep disturbances, aggression, and chronic fatigue. Seventeen children (19%) suffered either arthralgia or unspecific pain in the upper and lower extremities. In nine children (10%), either atopic or seborrheic dermatitis began shortly after KD. Five children (6%) presented with ophthalmic complications.ConclusionsVarious unspecific complications may emerge after the acute phase of KD. Although correlation does not imply causation, and possible explanations of observed abnormalities are numerous, our data may enhance clinicians’ awareness of frequent and poorly understood findings observed after KD in children. It also might help reassure parents that what they observe lies within a range of common and usually transient KD sequelae.

Coronary Artery Involvement in Kawasaki Disease-Echocardiographic Evaluation of Cases in a Tertiary Care Hospital

Background: Kawasaki disease (KD) is the leading cause of childhood acquired heart disease. Cardiovascular manifestations can be prominent in the acute phase of the illness. Echocardiography is useful in recognizing these cardiac manifestations. We carried out a retrospective study by analyzing the data of Kawasaki disease patients in a tertiary care hospital. Methods: The prevalence of coronary artery dilatation and clinical outcome were documented. Clinical, laboratory, and echocardiographic findings were obtained at baseline and 1 week, 6 weeks after initial therapy with intravenous immunoglobulin in addition to high doses of Aspirin which reduces the risk of coronary artery aneurysm. Results: One hundred and forty-nine patients with mean age 3± 2 years old, 60% males with Kawasaki disease were included. One hundred and thirty-two patients had coronary involvement (left main coronary artery 36.37 %, left anterior descending artery 28.03%, right main coronary artery 24.25%, circumflex branch in 11.37%). Administration of intravenous immunoglobulin (IVIG) and aspirin has greatly reduced the incidence of coronary lesions in affected children. The initial cardiac findings developed over first few weeks of illness resolved in most of the cases in the subsequent echocardiogram studies after IVIG. The mean duration to normalization of abnormal echocardiography findings is 6±3 months. Conclusion: Coronary artery involvement is seen in most of children with Kawasaki disease. Intravenous gamma globulin and aspirin has been reported to reduce the likelihood of development of giant coronary artery aneurysms and appears to have a direct beneficial effect on abnormalities in cardiac function associated with the acute phase of Kawasaki disease. Cardiovasc j 2023; 15(2): 144-150

Expression of Eosinophilic Subtype Markers in Patients with Kawasaki Disease.

Purpose: Eosinophils may rise to a higher level in the acute phase of Kawasaki disease (KD) both before and after intravenous immunoglobulin (IVIG) therapy. A substantial body of research was carried out on the association between KD and allergic diseases. Eosinophils play an important role in type 2 inflammation. Recent studies have shown that there are two distinct subtypes of eosinophils. In addition to their role in inflammation, lung-resident eosinophils (rEOS) also regulate homeostasis. Inflammatory eosinophils (iEOS) reflect type 2 inflammation in tissues. iEOS were considered the primary eosinophils in non-severe allergic asthma, while rEOS were thought to be the primary eosinophils in severe non-allergic eosinophilic asthma. This case–control study aimed to investigate the marker expression of eosinophilic subtypes in KD patients. Materials and Methods: The marker expressions of eosinophilic subtypes in the leukocytes of patients with KD were evaluated by the recently established KDmarkers online tool, a web server including gene expression data. Finally, the results were validated with a quantitative reverse transcriptase polymerase chain reaction (RT-PCR). We analyzed the mRNA expression levels of SELL and IL10RA in leukocytes from KD patients and febrile children. Results: Included in our screening tools were transcriptome arrays, which provided clues showing the importance of rEOS, whose role was identified by three genes (lower IL10RA, higher SELL, and SERPINB1 than controls). In contrast, the iEOS representative gene CD101 was not elevated in KD. It was found that the gene IL10RA, a marker of inflammatory eosinophilic leukocytes, was more highly expressed in the leukocytes of KD patients (n = 43) than febrile controls (n = 32), especially those without coronary artery lesions (CAL) (n = 26). Before treatment, SELL expression was higher in leukocytes of CAL patients (CAL, 1.33 ± 0.18, n = 39; non-CAL, 0.87 ± 0.12, n = 55; p = 0.012). SELL was significantly higher after half a year compared to febrile controls. Conclusions: To our knowledge, this is the first study to demonstrate that KD patients have increased SELL than febrile controls after 6 months of treatment. We present evidence here that dynamically different eosinophilic involvement exists between KD patients with and without CAL. The role of eosinophilic subtypes in KD patients warrants further investigation.

Abstract P083: Progression Of Vascular Dysfunction In A Mouse Model Of Kawasaki Disease

Progression of vascular dysfunction in a mouse model of Kawasaki disease Alina Saiyid, Shubhnita Singh, Ariane Bruder-Nascimento, Thiago Bruder-Nascimento Kawasaki disease (KD) is an acute, self-limited vasculitis and the most common cause of acquired cardiovascular disease in young children. Although severe vascular inflammation is already well-established in KD, how the arteries functionally behave in acute and convalescent phases is poorly understood. Herein, we sought to investigate the vascular function using a mouse model of KD.KD was induced by the Candida albicans water-soluble fraction model (CAWS, 4mg/day for 5 days) in C57BL6/J male mice (5-6-week-old). Mice were divided into 3 groups: control (G0, PBS injections), 7-days post 1 CAWS injection (G7), and 28-days post 1 CAWS injection (G28). Heart and abdominal aorta (AA) were harvested for vasculitis characterization. Vascular function was studied in AA via wire myograph.G7 presented an increase in TNFα and IL1β gene expression in the heart and AA, but without clear vasculitis (analyzed by histology). However, G28 exhibited a severe immune cell infiltration in the aortic root, coronary arteries, and AA. In G7, AA displayed a drastic reduction in vascular response to norepinephrine [maximal response (Emax in mN): C: 5.4 ± 0.6 vs. G7: 2.0 ± 0.5*, *p&lt;0.05], such attenuation was abolished by pre-treating the AA with L-NAME (nitric oxide synthase inhibitor). In G28, a mild change was observed in maximal response; however, increased sensitivity was found (pD2: C: 6.0 ± 0.4 vs. G28: 6.8 ± 0.3*, *p&lt;0.05). After L-NAME pre-treatment, the difference persisted indicating a NO-dependent response. Furthermore, a severe endothelial dysfunction, characterized by impaired relaxation of acetylcholine, was observed in G28 [Emax (%): C: 85.7 ± 8.4 vs. G28: 54.8 ± 6.4*, *p&lt;0.05].In conclusion, the acute phase of KD is associated with impaired vascular contractility via an excess of NO, which could justify some children presenting shock in clinic. In the convalescent phase (G28), the arteries are injured and likely with an irreversible phenotype. Thus, an adequate and punctual treatment for KD is highly requested.

Spontaneous defervescence and its prediction in the acute phase of Kawasaki disease.

BackgroundIn Kawasaki disease (KD), fever occasionally resolves spontaneously before 10 days from the onset, right after diagnosing. However, there is not enough evidence of intravenous immunoglobulin (IVIG) treatment in this case. The aim of this study was to investigate the relationship between spontaneous defervescence and coronary artery aneurysm and to develop a scoring model for its prediction in acute KD.MethodsAll patients admitted for acute KD in Asan Medical Center were considered for inclusion. Acute management involved the administration of 2 g/kg of IVIG and 5 mg/kg/day of aspirin. The patient whose temperature was <37.5°C for more than 48 h from the diagnosis was discharged under the judgment of spontaneous defervescence, without IVIG administration.ResultsThe incidence of coronary artery aneurysm was 5.7% in 94 defervesced patients and 4.6% in the 1,277 patients treated with IVIG in the subacute phase (P = 0.593), and 2.5 and 2.2% in respective patient groups in the convalescent phase (P = 0.924). A scoring model which predicted spontaneous defervescence under the combination of C-reactive protein ≤10mg/dL and ≥2 conditions of no rash, neutrophil ≤65%, and/or alanine aminotransferase ≤80 IU/L, was developed and showed 80.7% sensitivity, 68.8% specificity, 15.8% positive predictive value, and a 97.8% negative predictive value.ConclusionThe incidence of coronary artery aneurysm in patients with the defervesced KD was not different from the IVIG treated patients. In the cases suitable for the predictive model, patients can wait for the spontaneous defervescence under intensive observation by medical professionals.

RNA Sequencing Reveals Beneficial Effects of Atorvastatin on Endothelial Cells in Acute Kawasaki Disease.

Background Damage to the coronary arteries during the acute phase of Kawasaki disease (KD) is linked to inflammatory cell infiltration, myointimal proliferation, and endothelial cell (EC) dysfunction. To understand the response of ECs to KD treatment, we studied the genome-wide transcriptional changes in cultured ECs incubated with KD sera before and after treatment with or without atorvastatin. Methods and Results RNA sequencing of human umbilical vein ECs incubated with pooled sera from patients with acute KD before or after treatment with intravenous immunoglobulin and infliximab revealed differentially expressed genes in interleukin-1, tumor necrosis factor-α, and inflammatory cell recruitment pathways. Subacute sera pooled from patients treated with intravenous immunoglobulin, infliximab, and atorvastatin uniquely induced expression of NOS3, Kruppel like factor (KLF2, and KLF4 (promotes EC homeostasis and angiogenesis) and ZFP36 ring finger protein (ZFP36) and suppressor of cytokine signaling 3 (SOCS3) (suppresses inflammation), and suppressed expression of TGFB2 and DKK1 (induces endothelial-mesenchymal transition) and sphingosine kinase 1 (SPHK1) and C-X-C motif chemokine ligand 8 (CXCL8) (induces inflammation). Conclusions These results suggest that atorvastatin treatment of patients with acute KD may improve EC health, reduce mediators of inflammation produced by ECs, and block KD-induced myofibroblast proliferation.

The role of myocarditis in the acute phase of Kawasaki as a predictor of the future coronary aneurysm: a case–control study

BackgroundThis study aimed to evaluate the relationship between cardiac troponin I and T (cTnI, cTnT) and creatine kinase (CK)-MB during the acute phase of Kawasaki disease (KD) and the development of coronary artery involvement (CAI).ResultsNinety children diagnosed with KD and 38 attending ambulatory clinics as controls were enrolled in this study. Serum levels of cardiac enzymes were measured in all case and control groups. Serial echocardiograms were performed in KD patients during the acute, subacute and convalescence phases. Thirty-six percent of patients had CAI during the acute phase of KD; this rate was 21% and 18% in the echocardiography in the sub-acute and convalescent-phase, respectively. Elevated serum cTnI and cTnT levels were seen in 15.5% and 10% of KD patients, respectively, but not in the controls (P < 0.01). Patients with abnormal echocardiography had significantly higher levels of CK-MB but cTnI and cTnT. Cardiac troponins have high specificity, and CK-MB had a high sensitivity for predicting CAI in KD.ConclusionSubclinical myocarditis occurs during KD, and serum cardiac troponin levels are significantly elevated, but cardiac biomarkers cannot predict CAI in the future.

The EIF2AK4/rs4594236 AG/GG Genotype Is a Hazard Factor of Immunoglobulin Therapy Resistance in Southern Chinese Kawasaki Disease Patients.

Background: Kawasaki disease (KD) is an acute, self-limited vasculitis disorder of unknown etiology in children. Immunologic abnormalities were detected during the acute phase of KD, which reflected that the effect cells of the activated immune system markedly increased cytokine production. High-dose intravenous immunoglobulin (IVIG) therapy is effective in resolving inflammation from KD and reducing occurrence of coronary artery abnormalities. However, 10%–20% of KD patients have no response to IVIG therapy, who were defined as IVIG resistance. Furthermore, these patients have persistent inflammation and increased risk of developing coronary artery aneurysm (CAA). EIF2AK4 is a stress sensor gene and can be activated by pathogen infection. In addition, the polymorphisms of EIF2AK4 were associated with various blood vessel disorders. However, it remains unclear whether the EIF2AK4 gene polymorphisms were related to IVIG therapy outcome in KD patients. Methods: EIF2AK4/rs4594236 polymorphism was genotyped in 795 IVIG response KD patients and 234 IVIG resistant KD patients through TaqMan, a real-time polymerase chain reaction. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of association between EIF2AK4/rs4594236 polymorphism and IVIG therapeutic effects. Results: Our results showed that the EIF2AK4/rs4594236 AG/GG genotype was significantly associated with increased risk to IVIG resistance compared to the AA genotype (AG vs. AA: adjusted ORs = 1.71, 95% CIs = 1.17–2.51, and p = 0.0061; GG vs. AA: adjusted ORs = 2.09, 95% CIs = 1.36–3.23, and p = 0.0009; AG/GG vs. AA: adjusted ORs = 1.82, 95% CIs = 1.27–2.63, and p = 0.0013; and GG vs. AA/AG: adjusted ORs = 1.45, 95% CI = 1.04–2.02, and p = 0.0306). Furthermore, the stratified analysis of age and gender in the KD cohort indicated that male patients carrying the rs4594236 AG/GG genotype tends to be more resistant to IVIG therapy than female patients. Conclusion: These results suggested that EIF2AK4/rs4594236 polymorphism might be associated with increased risk of IVIG resistance in southern Chinese KD patients.

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.

Corticosteroids for the treatment of Kawasaki disease in children.

Kawasaki disease (KD), or mucocutaneous syndrome, is the leading cause of childhood-acquired heart disease in high-income countries. There is much controversy on how best to treat children with KD and in particular who may benefit from additional treatment beyond the standard intravenous immunoglobulin (IVIG) and aspirin, such as the addition of corticosteroids. This is an update of the review first published in 2017. To assess the impact of corticosteroid use on the incidence of coronary artery abnormalities in KD as either first-line or second-line treatment. The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL and two trials registers to 8 February 2021. We searched the reference lists of relevant articles for additional studies. We selected randomised controlled trials involving children with all severities of KD who were treated with corticosteroids, including different types of corticosteroids, different durations of treatment, and where corticosteroids were used alone or in conjunction with other accepted KD treatments. We included trials using corticosteroids for both first- and second-line treatment. Two review authors independently selected studies, assessed study quality and extracted data using standard Cochrane methods. We performed fixed-effect model meta-analyses with odds ratios (ORs) or mean difference (MD) with 95% confidence intervals (CIs). We used a random-effects model when there was heterogeneity. We assessed the certainty of the evidence using GRADE. The outcomes of interest were incidence of coronary artery abnormalities, serious adverse events, mortality, duration of acute symptoms (such as fever), time for laboratory parameters to normalise, length of hospital stay and longer-term coronary morbidity. This update identified one new study, therefore the analysis included eight trials consisting of 1877 participants. Seven trials investigated the use of corticosteroids in first-line treatment and one investigated second-line treatment. The trials were all of good methodological quality. On pooled analysis, corticosteroid treatment reduced the subsequent occurrence of coronary artery abnormalities (OR 0.32, 95% CI 0.14 to 0.75; 8 studies, 986 participants; moderate-certainty evidence), without resultant serious adverse events (0 events; 6 studies, 737 participants; moderate-certainty) and mortality (0 events; 8 studies, 1075 participants; moderate-certainty evidence). In addition, corticosteroids reduced the duration of fever (MD -1.34 days, 95% CI -2.24 to -0.45; 3 studies, 290 participants; low-certainty evidence), time for laboratory parameters (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)) to normalise (MD -2.80 days, 95% CI -4.38 to -1.22; 1 study, 178 participants; moderate-certainty evidence), and length of hospital stay (MD -1.01 days, 95% CI -1.72 to -0.30; 2 studies, 119 participants; moderate-certainty evidence). None of the included studies reported long-term (greater than one year after disease onset) coronary morbidity. Moderate-certainty evidence shows that use of steroids in the acute phase of KD can be associated with reduced coronary artery abnormalities, reduced inflammatory markers and shorter duration of hospital stay when compared to no corticosteroids. There were no serious adverse events or deaths reported with or without corticosteroid use. Low-certainty evidence shows use of corticosteroids can reduce duration of clinical symptoms (fever and rash). None of the included studies reported on long-term (greater than one year after disease onset) coronary morbidity. Evidence presented in this systematic review agrees with current clinical guidelines on the use of corticosteroids in the first-line treatment in KD.

Combination of fecal calprotectin and initial coronary dimensions to predict coronary artery lesions persistence in Kawasaki disease

Kawasaki Disease (KD) is systemic vasculitis involving medium-sized vessels in children. The aim of our study is to determine if fecal calprotectin (FC) could be useful in predicting the development or persistence of coronary artery lesions (CALs) in KD. We conducted a prospective monocentric study including all consecutive diagnoses of. Clinical, laboratory, echocardiographic data were recorded during the acute and subacute phase, including FC. Correlations among laboratory values, FC, clinical manifestations, IVIG-responsiveness and CALs development were investigated. We enrolled 26 children (76.9% boys; median age 34.5 months). The combination of FC > 250 microg/g and z-score > 2 during the acute phase was associated with the persistence of CALs (p = 0.022). A z-score > 2 alone during the acute phase was not related to CALs during the subacute stage (p > 0.05). A neutrophil percentage > 70% and WBC > 15,000/mmc during the acute phase significantly correlated with the presence of CALs during the subacute phase (p = 0.008). C-reactive protein (CRP) > 13 mg/dL at KD onset was significantly associated with the presence of CALs during the acute (p = 0.017) and subacute phase (p = 0.001). The combination of FC > 250 microg/g and a z-score > 2 during the acute phase of KD may be used as a predictor of CALs persistence. It can be useful especially in children with an initial CRP < 13 mg/dl.