Publications by authors named "Chisato Shimizu"

80 Publications

Anakinra Treatment in Patients with Acute Kawasaki Disease with Coronary Artery Aneurysms: A Phase I/IIa Trial.

J Pediatr 2021 Dec 23. Epub 2021 Dec 23.

Kawasaki Disease Research Center, Department of Pediatrics, University of California San Diego and Rady Children's Hospital, San Diego, CA. Electronic address:

Objectives: To determine the safety, pharmacokinetics, and immunomodulatory effects of 2-6 weeks of anakinra therapy in patients with acute Kawasaki disease with a coronary artery aneurysm (CAA).

Study Design: We performed a Phase I/IIa dose-escalation study of anakinra (2-11 mg/kg/day) in 22 patients with acute Kawasaki disease with CAA. We measured interleukin (IL)-1RA concentrations after the first dose and trough levels up to study week 6. Markers of inflammation and coronary artery z-scores were assessed pretreatment and at 48 hours, 2 weeks, and 6 weeks after initiation of therapy.

Results: Up to 6 weeks of anakinra (up to 11 mg/kg/day) was safe and well tolerated by the 22 participants (median age, 1.1 years), with no serious adverse events attributable to the study drug. All participants were treated with intravenous immunoglobulin (IVIG), and 20 also received infliximab (10 mg/kg) before initiation of anakinra. Serum levels of IL-6, IL-8, and tumor necrosis factor α decreased similarly in patients with Kawasaki disease treated with IVIG, infliximab, and anakinra compared with age- and sex-matched patients with Kawasaki disease treated only with IVIG and infliximab. Anakinra clearance increased with illness day at diagnosis. Simulations demonstrated that more frequent intravenous (IV) dosing may result in more sustained concentrations without significantly increasing the peak concentration compared with subcutaneous (SC) dosing.

Conclusions: Both IV and SC anakinra are safe in infants and children with acute Kawasaki disease and CAA. IV dosing every 8-12 hours during the acute hospitalization of patients with Kawasaki disease may result in a sustained concentration while avoiding frequent SC injections. The efficacy of a short course of IV therapy during hospitalization should be studied. TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT02179853.
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http://dx.doi.org/10.1016/j.jpeds.2021.12.035DOI Listing
December 2021

Temporal clustering of Kawasaki disease cases around the world.

Sci Rep 2021 11 19;11(1):22584. Epub 2021 Nov 19.

Department of Pediatrics, UCSD School of Medicine, University of California San Diego and Rady Children's Hospital San Diego, 9500 Gilman Dr., La Jolla, CA, 92037, USA.

In a single-site study (San Diego, CA, USA), we previously showed that Kawasaki Disease (KD) cases cluster temporally in bursts of approximately 7 days. These clusters occurred more often than would be expected at random even after accounting for long-term trends and seasonality. This finding raised the question of whether other locations around the world experience similar temporal clusters of KD that might offer clues to disease etiology. Here we combine data from San Diego and nine additional sites around the world with hospitals that care for large numbers of KD patients, as well as two multi-hospital catchment regions. We found that across these sites, KD cases clustered at short time scales and there were anomalously long quiet periods with no cases. Both of these phenomena occurred more often than would be expected given local trends and seasonality. Additionally, we found unusually frequent temporal overlaps of KD clusters and quiet periods between pairs of sites. These findings suggest that regional and planetary range environmental influences create periods of higher or lower exposure to KD triggers that may offer clues to the etiology of KD.
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http://dx.doi.org/10.1038/s41598-021-01961-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8605018PMC
November 2021

Severe delayed hypersensitivity reactions to IL-1 and IL-6 inhibitors link to common HLA-DRB1*15 alleles.

Ann Rheum Dis 2021 Nov 17. Epub 2021 Nov 17.

Neurology, University of California San Francisco, San Francisco, California, USA.

Objectives: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, delayed hypersensitivity reaction (DHR). We observed DRESS to inhibitors of interleukin 1 (IL-1) or IL-6 in a small group of patients with Still's disease with atypical lung disease. We sought to characterise features of patients with Still's disease with DRESS compared with drug-tolerant Still's controls. We analysed human leucocyte antigen (HLA) alleles for association to inhibitor-related DHR, including in a small Kawasaki disease (KD) cohort.

Methods: In a case/control study, we collected a multicentre series of patients with Still's disease with features of inhibitor-related DRESS (n=66) and drug-tolerant Still's controls (n=65). We retrospectively analysed clinical data from all Still's subjects and typed 94/131 for HLA. European Still's-DRESS cases were ancestry matched to International Childhood Arthritis Genetics Consortium paediatric Still's cases (n=550) and compared for HLA allele frequencies. HLA association also was analysed using Still's-DRESS cases (n=64) compared with drug-tolerant Still's controls (n=30). KD subjects (n=19) were similarly studied.

Results: Still's-DRESS features included eosinophilia (89%), AST-ALT elevation (75%) and non-evanescent rash (95%; 88% involving face). Macrophage activation syndrome during treatment was frequent in Still's-DRESS (64%) versus drug-tolerant Still's (3%; p=1.2×10). We found striking enrichment for HLA-DRB1*15 haplotypes in Still's-DRESS cases versus INCHARGE Still's controls (p=7.5×10) and versus self-identified, ancestry-matched Still's controls (p=6.3×10). In the KD cohort, DRB1*15:01 was present only in those with suspected anakinra reactions.

Conclusions: DRESS-type reactions occur among patients treated with IL-1/IL-6 inhibitors and strongly associate with common HLA-DRB1*15 haplotypes. Consideration of preprescription HLA typing and vigilance for serious reactions to these drugs are warranted.
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http://dx.doi.org/10.1136/annrheumdis-2021-220578DOI Listing
November 2021

Effect of ethanol on astaxanthin and fatty acid production in the red yeast Xanthophyllomyces dendrorhous.

J Appl Microbiol 2021 Oct 24. Epub 2021 Oct 24.

Department of Environmental and Life Sciences, School of Food and Nutritional Sciences, University of Shizuoka, Shizuoka, Japan.

Aim: The effects of detergent, ethanol and ethanol with plant meadowfoam oil on the growth of the red heterobasidomycete Xanthophyllomyces dendrorhous and on the production of astaxanthin (3,3'-dihydroxy-β,β-carotene-4,4'-dione) and fatty acids in this red yeast were investigated.

Methods And Results: Ethanol supplementation at a final concentration of 0.8% (v/v) caused an increase in the growth, astaxanthin production and fatty acid production of treated X. dendrorhous compared with untreated X. dendrorhous. Supplementation of meadowfoam oil with 0.8% ethanol further improved the growth and astaxanthin production of X. dendrorhous. Fatty acid compositions following supplementation with various concentrations of ethanol and oil were also analysed. With 0.8% ethanol supplementation, the ratio of linoleic acid (C18:2) and α-linolenic acid (C18:3ω3, ALA) decreased. Conversely, with 1.8% ethanol supplementation, the ALA ratio increased.

Conclusions: Ethanol can serve as a promoting factor for coproduction of astaxanthin and fatty acids in X. dendrorhous, whereas simultaneous supplementation of ethanol and meadowfoam oil can cause further astaxanthin production.

Significance And Impact Of Study: Astaxanthin is widely used in various functional products because of its antioxidant activity. This study shows that X. dendrorhous can coproduce astaxanthin and functional fatty acids at high levels following supplementation with ethanol.
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http://dx.doi.org/10.1111/jam.15335DOI Listing
October 2021

Characterization of SARS-CoV-2 and common cold coronavirus-specific T-cell responses in MIS-C and Kawasaki disease children.

Eur J Immunol 2022 01 27;52(1):123-137. Epub 2021 Oct 27.

Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, USA.

The immunopathogenesis of multisystem inflammatory syndrome (MIS-C) in children that may follow exposure to SARS-CoV-2 is incompletely understood. Here, we studied SARS-CoV-2-specific T cells in MIS-C, Kawasaki disease (KD), and SARS-CoV-2 convalescent controls using peptide pools derived from SARS-CoV-2 spike or nonspike proteins, and common cold coronaviruses (CCC). Coordinated CD4+ and CD8+ SARS-CoV-2-specific T cells were detected in five MIS-C subjects with cross-reactivity to CCC. CD4+ and CD8+ T-cell responses alone were documented in three and one subjects, respectively. T-cell specificities in MIS-C did not correlate with disease severity and were similar to SARS-CoV-2 convalescent controls. T-cell memory and cross-reactivity to CCC in MIS-C and SARS-CoV-2 convalescent controls were also similar. The chemokine receptor CCR6, but not CCR9, was highly expressed on SARS-CoV-2-specific CD4+ but not on CD8+ T cells. Only two of 10 KD subjects showed a T-cell response to CCC. Enumeration of myeloid APCs revealed low cell precursors in MIS-C subjects compared to KD. In summary, children with MIS-C mount a normal T-cell response to SARS-CoV-2 with no apparent relationship to antecedent CCC exposure. Low numbers of tolerogenic myeloid DCs may impair their anti-inflammatory response.
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http://dx.doi.org/10.1002/eji.202149556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8646471PMC
January 2022

Biomarkers of inflammation and fibrosis in young adults with history of Kawasaki disease.

Int J Cardiol Heart Vasc 2021 Oct 1;36:100863. Epub 2021 Sep 1.

Dept. of Pediatrics, University of California San Diego, La Jolla, CA, United States.

Background: Myocardial histology from autopsies of young adults with giant coronary artery aneurysms following Kawasaki disease (KD) shows bridging fibrosis beyond the territories supplied by the aneurysmal arteries. The etiology of this fibrosis is unknown, but persistent, low-level myocardial inflammation and microcirculatory ischemia are both possible contributing factors. To investigate the possibility of subclinical myocardial inflammation or fibrosis, we measured validated biomarkers in young adults with a remote history of KD.

Methods: We measured plasma calprotectin, galectin-3 (Gal-3), growth differentiation factor-15 (GDF-15), soluble ST2 (sST2), and serum procollagen type 1C-terminal propeptide (P1CP) in 91 otherwise healthy young adults with a remote history of KD and in 88 age-similar, healthy controls. KD subjects were stratified by coronary artery aneurysm (CAA) status and history of remote myocardial infarction (MI).

Results: After correction for multiple testing, calprotectin, Gal-3, and GDF-15 levels were significantly higher in subjects with persistent CAA (n = 26) compared with KD subjects with remodeled CAA (n = 20, p = 0.005, 0.001, 0.0036, respectively). In a multivariable regression model with CA status as the main predictor and adjusting for sex, MI history, and interval from KD onset, CA status was a significant predictor (Persistent CAA vs KD Normal CA) of calprotectin, Gal-3, GDF-15 and sST2 levels (p = 0.004, <0.001, 0.007, and 0.049, respectively).

Conclusions: These results suggest that ongoing inflammation and fibrosis may be occurring in individuals with persistent CAA. Longitudinal follow-up is needed to clarify the clinical significance of these elevated biomarker levels in this patient population that requires life-long monitoring.
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http://dx.doi.org/10.1016/j.ijcha.2021.100863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413893PMC
October 2021

Immune response to intravenous immunoglobulin in patients with Kawasaki disease and MIS-C.

J Clin Invest 2021 10;131(20)

Department of Pediatrics and.

BACKGROUNDMultisystem inflammatory syndrome in children (MIS-C) is a rare but potentially severe illness that follows exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Kawasaki disease (KD) shares several clinical features with MIS-C, which prompted the use of intravenous immunoglobulin (IVIG), a mainstay therapy for KD. Both diseases share a robust activation of the innate immune system, including the IL-1 signaling pathway, and IL-1 blockade has been used for the treatment of both MIS-C and KD. The mechanism of action of IVIG in these 2 diseases and the cellular source of IL-1β have not been defined.METHODSThe effects of IVIG on peripheral blood leukocyte populations from patients with MIS-C and KD were examined using flow cytometry and mass cytometry (CyTOF) and live-cell imaging.RESULTSCirculating neutrophils were highly activated in patients with KD and MIS-C and were a major source of IL-1β. Following IVIG treatment, activated IL-1β+ neutrophils were reduced in the circulation. In vitro, IVIG was a potent activator of neutrophil cell death via PI3K and NADPH oxidase, but independently of caspase activation.CONCLUSIONSActivated neutrophils expressing IL-1β can be targeted by IVIG, supporting its use in both KD and MIS-C to ameliorate inflammation.FUNDINGPatient Centered Outcomes Research Institute; NIH; American Asthma Foundation; American Heart Association; Novo Nordisk Foundation; NIGMS; American Academy of Allergy, Asthma and Immunology Foundation.
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http://dx.doi.org/10.1172/JCI147076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8516453PMC
October 2021

Recurrent Lobar Hemorrhages and Multiple Cortical Superficial Siderosis in a Patient of Alzheimer's Disease With Homozygous APOE ε2 Allele Presenting Hypobetalipoproteinemia and Pathological Findings of F-THK5351 Positron Emission Tomography: A Case Report.

Front Neurol 2021 7;12:645625. Epub 2021 Jul 7.

Department of Neurology, Gunma University Graduate School of Medicine, Maebashi, Japan.

In Alzheimer's disease, the apolipoprotein E gene ε2 allele is a protective genetic factor, whereas the ε4 allele is a genetic risk factor. However, both the ε2 and the ε4 alleles are genetic risk factors for lobar intracerebral hemorrhage. The reasons for the high prevalence of lobar intracerebral hemorrhage and the low prevalence of Alzheimer's disease with the ε2 allele remains unknown. Here, we describe the case of a 79-year-old Japanese female with Alzheimer's disease, homozygous for the ε2 allele. This patient presented with recurrent lobar hemorrhages and multiple cortical superficial siderosis. The findings on the C-labeled Pittsburgh Compound B-positron emission tomography (PET) were characteristic of Alzheimer's disease. F-THK5351 PET revealed that the accumulation of F-THK 5351 in the right pyramidal tract at the pontine level, the cerebral peduncle of the midbrain, and the internal capsule, reflecting the lesions of the previous lobar intracerebral hemorrhage in the right frontal lobe. Moreover, F-THK5351 accumulated in the bilateral globus pallidum, amygdala, caudate nuclei, and the substantia nigra of the midbrain, which were probably off-target reaction, by binding to monoamine oxidase B (MAO-B). F-THK5351 were also detected in the periphery of prior lobar hemorrhages and a cortical subarachnoid hemorrhage, as well as in some, but not all, areas affected by cortical siderosis. Besides, F-THK5351 retentions were observed in the bilateral medial temporal cortices and several cortical areas without cerebral amyloid angiopathy or prior hemorrhages, possibly where tau might accumulate. This is the first report of a patient with Alzheimer's disease, carrying homozygous ε2 allele and presenting with recurrent lobar hemorrhages, multiple cortical superficial siderosis, and immunohistochemically vascular amyloid β. The F-THK5351 PET findings suggested MAO-B concentrated regions, astroglial activation, Waller degeneration of the pyramidal tract, neuroinflammation due to CAA related hemorrhages, and possible tau accumulation.
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http://dx.doi.org/10.3389/fneur.2021.645625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294698PMC
July 2021

Inflammasome Activation in Children With Kawasaki Disease and Multisystem Inflammatory Syndrome.

Arterioscler Thromb Vasc Biol 2021 09 15;41(9):2509-2511. Epub 2021 Jul 15.

Division of Cardiology, Department of Medicine (W.-T.W., M.H., J.Y.-J.S.), University of California, San Diego, La Jolla.

[Figure: see text].
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http://dx.doi.org/10.1161/ATVBAHA.121.316210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387357PMC
September 2021

Lacosamide-induced sinus node dysfunction followed by severe agranulocytosis.

BMC Neurol 2021 Jun 8;21(1):217. Epub 2021 Jun 8.

Department of Neurology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, 371-8511, Gunma, Japan.

Background: Lacosamide (LCM) is the antiepileptic drug approved by the U.S. Food and Drug Administration in 2008 that facilitates slow activation of the voltage-gated sodium channels. Neutropenia and cardiac events including sinus node dysfunction (SND) and atrioventricular block have been previously reported as adverse effects of LCM. To date, there have been no reports of severe agranulocytosis resulting in death associated with LCM. Additionally, there have been no reports of concomitant SND and agranulocytosis after LCM administration. Herein we report the first case of LCM-induced severe SND followed by agranulocytosis.

Case Presentation: The patient with focal epilepsy was initiated on LCM 100 mg/day and the dose was increased to 200 mg/day on the 9 hospital day. Severe SND developed on the 10 hospital day and LCM was discontinued. Thereafter agranulocytosis appeared on the 11 hospital day, and the patient died from septic shock on the 15 hospital day.

Conclusions: This case illustrates the need for careful follow-up of the electrocardiogram and the complete blood cell counts when initiating LCM. Moreover, it should be noticed that various side effects may occur simultaneously in the early period of LCM use, even for a short time and at low dosages.
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http://dx.doi.org/10.1186/s12883-021-02253-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185934PMC
June 2021

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

Int J Mol Sci 2021 May 26;22(11). Epub 2021 May 26.

Faculty of Medicine, Imperial College London, London SW7 2AZ, UK.

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.
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http://dx.doi.org/10.3390/ijms22115655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198135PMC
May 2021

An AI-guided signature reveals the nature of the shared proximal pathways of host immune response in MIS-C and Kawasaki disease.

bioRxiv 2021 Aug 9. Epub 2021 Aug 9.

A significant surge in cases of multisystem inflammatory syndrome in children (MIS-C, also called Pediatric Inflammatory Multisystem Syndrome - PIMS) has been observed amidst the COVID-19 pandemic. MIS-C shares many clinical features with Kawasaki disease (KD), although clinical course and outcomes are divergent. We analyzed whole blood RNA sequences, serum cytokines, and formalin fixed heart tissues from these patients using a computational toolbox of two gene signatures, i.e., the 166-gene viral pandemic (ViP) signature, and its 20-gene severe (s)ViP subset that were developed in the context of SARS-CoV-2 infection and a 13-transcript signature previously demonstrated to be diagnostic for KD. Our analyses revealed that KD and MIS-C are on the same continuum of the host immune response as COVID-19. While both the pediatric syndromes converge upon an -centric cytokine storm, suggestive of shared proximal pathways of immunopathogenesis, they diverge in other laboratory parameters and cardiac phenotypes. The ViP signatures also revealed unique targetable cytokine pathways in MIS-C, place MIS-C farther along in the spectrum in severity compared to KD and pinpoint key clinical (reduced cardiac function) and laboratory (thrombocytopenia and eosinopenia) parameters that can be useful to monitor severity.
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http://dx.doi.org/10.1101/2021.04.11.439347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057241PMC
August 2021

Identification of novel locus associated with coronary artery aneurysms and validation of loci for susceptibility to Kawasaki disease.

Eur J Hum Genet 2021 Dec 26;29(12):1734-1744. Epub 2021 Mar 26.

Section of Paediatric Infectious Disease, Department of Infectious Disease, Imperial College London, London, UK.

Kawasaki disease (KD) is a paediatric vasculitis associated with coronary artery aneurysms (CAA). Genetic variants influencing susceptibility to KD have been previously identified, but no risk alleles have been validated that influence CAA formation. We conducted a genome-wide association study (GWAS) for CAA in KD patients of European descent with 200 cases and 276 controls. A second GWAS for susceptibility pooled KD cases with healthy paediatric controls from vaccine trials in the UK (n = 1609). Logistic regression mixed models were used for both GWASs. The susceptibility GWAS was meta-analysed with 400 KD cases and 6101 controls from a previous European GWAS, these results were further meta-analysed with Japanese GWASs at two putative loci. The CAA GWAS identified an intergenic region of chromosome 20q13 with multiple SNVs showing genome-wide significance. The risk allele of the most associated SNV (rs6017006) was present in 13% of cases and 4% of controls; in East Asian 1000 Genomes data, the allele was absent or rare. Susceptibility GWAS with meta-analysis with previously published European data identified two previously associated loci (ITPKC and FCGR2A). Further meta-analysis with Japanese GWAS summary data from the CASP3 and FAM167A genomic regions validated these loci in Europeans showing consistent effects of the top SNVs in both populations. We identified a novel locus for CAA in KD patients of European descent. The results suggest that different genes determine susceptibility to KD and development of CAA and future work should focus on the function of the intergenic region on chromosome 20q13.
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http://dx.doi.org/10.1038/s41431-021-00838-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994355PMC
December 2021

Improved Neuroimaging Findings and Cognitive Function in a Case of High-altitude Cerebral Edema.

Intern Med 2021 Apr 23;60(8):1299-1302. Epub 2020 Nov 23.

Department of Neurology, Geriatrics Research Institute and Hospital, Japan.

High-altitude cerebral edema (HACE) is a rare condition of acute mountain sickness that manifests as consciousness disturbance and truncal ataxia. Neuroimaging shows vasogenic edema with microbleeds in the white matter and the corpus callosum. We herein report a case of HACE in which the patient showed widespread hyperintense signals with extensive microbleeds in the white matter and corpus callosum on MRI, as well as cognitive dysfunction. Rehabilitation to improve the higher brain function facilitated the recovery of the patient's cognitive impairment and was accompanied by improved MRI findings.
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http://dx.doi.org/10.2169/internalmedicine.5747-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112975PMC
April 2021

Successful basilar artery dilatation in pure bilateral cerebral peduncular infarctions using balloon angioplasty.

eNeurologicalSci 2020 Dec 10;21:100282. Epub 2020 Oct 10.

Department of Neurology, Geriatrics Research Institute and Hospital, 3-26-8 Otomocho, Maebashi, Gunma 371-0847, Japan.

•An extremely rare case of bilateral cerebral peduncular infarctions (BCPI) is reported.•The detection of the pure Mickey Mouse ears sign on MRI is an indicator of a need for reperfusion therapy.•Severe stenosis of the basilar artery (BA) and a poor collateral supply from both posterior cerebral arteries were seen.•Balloon angioplasty for the BA stenosis ameliorated the stenosis and produced a favorable outcome.
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http://dx.doi.org/10.1016/j.ensci.2020.100282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569187PMC
December 2020

Temporal Clusters of Kawasaki Disease Cases Share Distinct Phenotypes That Suggest Response to Diverse Triggers.

J Pediatr 2021 02 22;229:48-53.e1. Epub 2020 Sep 22.

School of Global Policy and Strategy, University of California San Diego, La Jolla, CA.

Objective: To test the hypothesis that cases of Kawasaki disease within a temporal cluster have a similar pattern of host response that is distinct from cases of Kawasaki disease in different observed clusters and randomly constructed clusters.

Study Design: We designed a case-control study to analyze 47 clusters derived from 1332 patients with Kawasaki disease over a 17-year period (2002-2019) from a single clinical site and compared the cluster characteristics with those of 2 control groups of synthetic Kawasaki disease clusters. We defined a "true" Kawasaki disease cluster as at least 5 patients within a 7-day moving window. The observed and synthetic Kawasaki disease clusters were compared with respect to demographic and clinical characteristics and median values for standard laboratory data using univariate analysis and a multivariate, rotated empirical orthogonal function analysis.

Results: In a univariate analysis, the median values for age, coronary artery z-score, white blood cell count, erythrocyte sedimentation rate, C-reactive protein, and age-adjusted hemoglobin for several of the true Kawasaki disease clusters exceeded the 95th percentile for the 2 synthetic clusters. REOF analyses revealed distinct patterns of demographic and clinical measures within clusters.

Conclusions: Cases of Kawasaki disease within a cluster were more similar with respect to demographic and clinical features and levels of inflammation than would be expected by chance. These observations suggest that different triggers and/or different intensities of exposures result in clusters of cases of Kawasaki disease that share a similar response pattern. Analyzing cases within clusters or cases who share demographic and clinical features may lead to new insights into the etiology of Kawasaki disease.
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http://dx.doi.org/10.1016/j.jpeds.2020.09.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506475PMC
February 2021

Biomarkers for the Discrimination of Acute Kawasaki Disease From Infections in Childhood.

Front Pediatr 2020 22;8:355. Epub 2020 Jul 22.

Sanquin Research and Landsteiner Laboratory, Department of Blood Cell Research, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands.

Kawasaki disease (KD) is a vasculitis of early childhood mimicking several infectious diseases. Differentiation between KD and infectious diseases is essential as KD's most important complication-the development of coronary artery aneurysms (CAA)-can be largely avoided by timely treatment with intravenous immunoglobulins (IVIG). Currently, KD diagnosis is only based on clinical criteria. The aim of this study was to evaluate whether routine C-reactive protein (CRP) and additional inflammatory parameters myeloid-related protein 8/14 (MRP8/14 or S100A8/9) and human neutrophil-derived elastase (HNE) could distinguish KD from infectious diseases. The cross-sectional study included KD patients and children with proven infections as well as febrile controls. Patients were recruited between July 2006 and December 2018 in Europe and USA. MRP8/14, CRP, and HNE were assessed for their discriminatory ability by multiple logistic regression analysis with backward selection and receiver operator characteristic (ROC) curves. In the discovery cohort, the combination of MRP8/14+CRP discriminated KD patients ( = 48) from patients with infection ( = 105), with area under the ROC curve (AUC) of 0.88. The HNE values did not improve discrimination. The first validation cohort confirmed the predictive value of MRP8/14+CRP to discriminate acute KD patients ( = 26) from those with infections ( = 150), with an AUC of 0.78. The second validation cohort of acute KD patients ( = 25) and febrile controls ( = 50) showed an AUC of 0.72, which improved to 0.84 when HNE was included. When used in combination, the plasma markers MRP8/14, CRP, and HNE may assist in the discrimination of KD from both proven and suspected infection.
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http://dx.doi.org/10.3389/fped.2020.00355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388698PMC
July 2020

Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2.

JAMA 2020 07;324(3):259-269

Section of Paediatric Infectious Disease, Department of Infectious Disease, Imperial College London, London, United Kingdom.

Importance: In communities with high rates of coronavirus disease 2019, reports have emerged of children with an unusual syndrome of fever and inflammation.

Objectives: To describe the clinical and laboratory characteristics of hospitalized children who met criteria for the pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PIMS-TS) and compare these characteristics with other pediatric inflammatory disorders.

Design, Setting, And Participants: Case series of 58 children from 8 hospitals in England admitted between March 23 and May 16, 2020, with persistent fever and laboratory evidence of inflammation meeting published definitions for PIMS-TS. The final date of follow-up was May 22, 2020. Clinical and laboratory characteristics were abstracted by medical record review, and were compared with clinical characteristics of patients with Kawasaki disease (KD) (n = 1132), KD shock syndrome (n = 45), and toxic shock syndrome (n = 37) who had been admitted to hospitals in Europe and the US from 2002 to 2019.

Exposures: Signs and symptoms and laboratory and imaging findings of children who met definitional criteria for PIMS-TS from the UK, the US, and World Health Organization.

Main Outcomes And Measures: Clinical, laboratory, and imaging characteristics of children meeting definitional criteria for PIMS-TS, and comparison with the characteristics of other pediatric inflammatory disorders.

Results: Fifty-eight children (median age, 9 years [interquartile range {IQR}, 5.7-14]; 20 girls [34%]) were identified who met the criteria for PIMS-TS. Results from SARS-CoV-2 polymerase chain reaction tests were positive in 15 of 58 patients (26%) and SARS-CoV-2 IgG test results were positive in 40 of 46 (87%). In total, 45 of 58 patients (78%) had evidence of current or prior SARS-CoV-2 infection. All children presented with fever and nonspecific symptoms, including vomiting (26/58 [45%]), abdominal pain (31/58 [53%]), and diarrhea (30/58 [52%]). Rash was present in 30 of 58 (52%), and conjunctival injection in 26 of 58 (45%) cases. Laboratory evaluation was consistent with marked inflammation, for example, C-reactive protein (229 mg/L [IQR, 156-338], assessed in 58 of 58) and ferritin (610 μg/L [IQR, 359-1280], assessed in 53 of 58). Of the 58 children, 29 developed shock (with biochemical evidence of myocardial dysfunction) and required inotropic support and fluid resuscitation (including 23/29 [79%] who received mechanical ventilation); 13 met the American Heart Association definition of KD, and 23 had fever and inflammation without features of shock or KD. Eight patients (14%) developed coronary artery dilatation or aneurysm. Comparison of PIMS-TS with KD and with KD shock syndrome showed differences in clinical and laboratory features, including older age (median age, 9 years [IQR, 5.7-14] vs 2.7 years [IQR, 1.4-4.7] and 3.8 years [IQR, 0.2-18], respectively), and greater elevation of inflammatory markers such as C-reactive protein (median, 229 mg/L [IQR 156-338] vs 67 mg/L [IQR, 40-150 mg/L] and 193 mg/L [IQR, 83-237], respectively).

Conclusions And Relevance: In this case series of hospitalized children who met criteria for PIMS-TS, there was a wide spectrum of presenting signs and symptoms and disease severity, ranging from fever and inflammation to myocardial injury, shock, and development of coronary artery aneurysms. The comparison with patients with KD and KD shock syndrome provides insights into this syndrome, and suggests this disorder differs from other pediatric inflammatory entities.
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http://dx.doi.org/10.1001/jama.2020.10369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281356PMC
July 2020

High-Throughput Screening of Kawasaki Disease Sera for Antiviral Antibodies.

J Infect Dis 2020 11;222(11):1853-1857

Department of Pediatrics, University of California, San Diego, La Jolla, California, USA.

Clinical features of Kawasaki disease (KD) display overlap with common pediatric viral illnesses, leading some to hypothesize that a viral infection is the inciting event for KD. To investigate viral infection history in KD patients, we performed comprehensive serological profiling using a high-throughput phage immunoprecipitation sequencing assay covering the complete reference protein sequences of known viruses with human tropism. KD and matched febrile control sera did not demonstrate differences in antiviral antibody profiles. We conclude that in the acute and subacute phases of disease, KD patients do not exhibit serologic evidence of exposure to known viruses that differs from controls.
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http://dx.doi.org/10.1093/infdis/jiaa253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171798PMC
November 2020

Biomarkers of Inflammation and Fibrosis in Kawasaki Disease Patients Years After Initial Presentation With Low Ejection Fraction.

J Am Heart Assoc 2020 01 27;9(1):e014569. Epub 2019 Dec 27.

Department of Pediatrics University of California San Diego School of Medicine La Jolla CA.

Background Coronary artery aneurysms and myocarditis are well-recognized complications of Kawasaki disease (KD) but no systematic evaluation of the consequences of myocarditis has been performed in the subset presenting with low ejection fraction (EF). We postulated that more severe myocardial inflammation as evidenced by low EF during the acute phase could lead to late myocardial fibrosis. Methods and Results We measured the carboxyterminal propeptide of procollagen type I (PIPC), soluble suppressor of tumorigenicity 2, galectin-3 (Gal-3), growth-differentiation factor-15, and calprotectin by ELISA in late convalescent blood samples from 16 KD patients who had an EF ≤55% on their initial echocardiogram. Results were compared with samples from sex- and age-matched KD patients with initial EF >60%. In the univariate analysis, the median Gal-3 and PIPC levels in the low EF group were significantly higher than those in the normal EF group (Gal-3: low EF 6.216 versus normal EF 4.976 mg/dL =0.038, PIPC: low EF 427.4 versus normal EF 265.2 mg/dL, =0.01). In a multivariable analysis, there were significant differences for Gal-3 and PIPC levels between the low and normal EF groups, adjusting for age, sex, and worst z score. Conclusions Convalescent KD patients with a history of low EF during the acute illness had significantly elevated levels of Gal-3 and PIPC when compared with matched-control KD patients with normal EF. These findings raise concern for myocardial fibrosis as a potential late sequela of the more severe myocarditis experienced by a subset of KD patients during the acute phase.
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http://dx.doi.org/10.1161/JAHA.119.014569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988139PMC
January 2020

Phase I/IIa Trial of Atorvastatin in Patients with Acute Kawasaki Disease with Coronary Artery Aneurysm.

J Pediatr 2019 12 24;215:107-117.e12. Epub 2019 Sep 24.

Kawasaki Disease Research Center, Department of Pediatrics, University of California San Diego, La Jolla, CA; Rady Children's Hospital-San Diego, San Diego, CA.

Objectives: To determine the safety, tolerability, pharmacokinetics, and immunomodulatory effects of a 6-week course of atorvastatin in patients with acute Kawasaki disease with coronary artery (CA) aneurysm (CAA).

Study Design: This was a Phase I/IIa 2-center dose-escalation study of atorvastatin (0.125-0.75 mg/kg/day) in 34 patients with Kawasaki disease (aged 2-17 years) with echocardiographic evidence of CAA. We measured levels of the brain metabolite 24(S)-hydroxycholesterol (24-OHC), serum lipids, acute-phase reactants, liver enzymes, and creatine phosphokinase; peripheral blood mononuclear cell populations; and CA internal diameter normalized for body surface area before atorvastatin treatment and at 2 and 6 weeks after initiation of atorvastatin treatment.

Results: A 6-week course of up to 0.75 mg/kg/day of atorvastatin was well tolerated by the 34 subjects (median age, 5.3 years; IQR, 2.6-6.4 years), with no serious adverse events attributable to the study drug. The areas under the curve for atorvastatin and its metabolite were larger in the study subjects compared with those reported in adults, suggesting a slower rate of metabolism in children. The 24-OHC levels were similar between the atorvastatin-treated subjects and matched controls.

Conclusions: Atorvastatin was safe and well tolerated in our cohort of children with acute Kawasaki disease and CAA. A Phase III efficacy trial is warranted in this patient population, which may benefit from the known anti-inflammatory and immunomodulatory effects of this drug.
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http://dx.doi.org/10.1016/j.jpeds.2019.07.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878161PMC
December 2019

HLA-C variants associated with amino acid substitutions in the peptide binding groove influence susceptibility to Kawasaki disease.

Hum Immunol 2019 Sep 20;80(9):731-738. Epub 2019 May 20.

Department of Pathology, HLA Laboratory, Penn State Hershey Medical Center, Hershey, PA, USA.

Kawasaki disease (KD) is a pediatric vasculitis caused by an unknown trigger in genetically susceptible children. The incidence varies widely across genetically diverse populations. Several associations with HLA Class I alleles have been reported in single cohort studies. Using a genetic approach, from the nine single nucleotide variants (SNVs) associated with KD susceptibility in children of European descent, we identified SNVs near the HLA-C (rs6906846) and HLA-B genes (rs2254556) whose association was replicated in a Japanese descent cohort (rs6906846 p = 0.01, rs2254556 p = 0.005). The risk allele (A at rs6906846) was also associated with HLA-C*07:02 and HLA-C*04:01 in both US multi-ethnic and Japanese cohorts and HLA-C*12:02 only in the Japanese cohort. The risk A-allele was associated with eight non-conservative amino acid substitutions (amino acid positions); Asp or Ser (9), Arg (14), Ala (49), Ala (73), Ala (90), Arg (97), Phe or Ser (99), and Phe or Ser (116) in the HLA-C peptide binding groove that binds peptides for presentation to cytotoxic T cells (CTL). This raises the possibility of increased affinity to a "KD peptide" that contributes to the vasculitis of KD in genetically susceptible children.
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http://dx.doi.org/10.1016/j.humimm.2019.04.020DOI Listing
September 2019

Author Correction: Clustering and climate associations of Kawasaki Disease in San Diego County suggest environmental triggers.

Sci Rep 2019 May 9;9(1):7401. Epub 2019 May 9.

Department of Pediatrics, University of California San Diego, La Jolla, CA, 92093, USA.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-019-42137-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506480PMC
May 2019

Extensive Ethnic Variation and Linkage Disequilibrium at the Locus: Different Genetic Associations Revealed in Kawasaki Disease.

Front Immunol 2019 21;10:185. Epub 2019 Mar 21.

Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.

The human Fc-gamma receptors (FcγRs) link adaptive and innate immunity by binding immunoglobulin G (IgG). All human low-affinity FcγRs are encoded by the locus containing functional single nucleotide polymorphisms (SNPs) and gene copy number variants. This locus is notoriously difficult to genotype and high-throughput methods commonly used focus on only a few SNPs. We performed multiplex ligation-dependent probe amplification for all relevant genetic variations at the locus in >4,000 individuals to define linkage disequilibrium (LD) and allele frequencies in different populations. Strong LD and extensive ethnic variation in allele frequencies was found across the locus. LD was strongest for the -ORF haplotype (rs759550223+rs76277413), which leads to expression of FcγRIIc. In Europeans, the -ORF haplotype showed strong LD with, among others, rs201218628 (-Q27W, = 0.63). LD between these two variants was weaker ( = 0.17) in Africans, whereas the -ORF haplotype was nearly absent in Asians (minor allele frequency <0.005%). The -ORF haplotype and rs1801274 (-H131R) were in weak LD ( = 0.08) in Europeans. We evaluated the importance of ethnic variation and LD in Kawasaki Disease (KD), an acute vasculitis in children with increased incidence in Asians. An association of rs1801274 with KD was previously shown in ethnically diverse genome-wide association studies. Now, we show in 1,028 European KD patients that the -ORF haplotype, although nearly absent in Asians, was more strongly associated with susceptibility to KD than rs1801274 in Europeans. Our data illustrate the importance of interpreting findings of association studies concerning the locus with knowledge of LD and ethnic variation.
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http://dx.doi.org/10.3389/fimmu.2019.00185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437109PMC
January 2020

Circulating Markers of Inflammation Persist in Children and Adults With Giant Aneurysms After Kawasaki Disease.

Circ Genom Precis Med 2019 04 7;12(4):e002433. Epub 2019 Mar 7.

University of California San Diego School of Medicine (J.O., C.S., S.H., A.M.K., L.B.D., A.H.T., J.C.B.).

Background: The sequelae of Kawasaki disease (KD) vary widely with the greatest risk for future cardiovascular events among those who develop giant coronary artery aneurysms (CAA). We sought to define the molecular signature associated with different outcomes in pediatric and adult KD patients.

Methods: Molecular profiling was conducted using mass spectrometry-based shotgun proteomics, transcriptomics, and glycomics methods on 8 pediatric KD patients at the acute, subacute, and convalescent time points. Shotgun proteomics was performed on 9 KD adults with giant CAA and matched healthy controls. Plasma calprotectin was measured by ELISA in 28 pediatric KD patients 1 year post-KD, 70 adult KD patients, and 86 healthy adult volunteers.

Results: A characteristic molecular profile was seen in pediatric patients during the acute disease, which resolved at the subacute and convalescent periods in patients with no coronary artery sequelae but persisted in 2 patients who developed giant CAA. We, therefore, investigated persistence of inflammation in KD adults with giant CAA by shotgun proteomics that revealed a signature of active inflammation, immune regulation, and cell trafficking. Correlating results obtained using shotgun proteomics in the pediatric and adult KD cohorts identified elevated calprotectin levels in the plasma of patients with CAA. Investigation of expanded pediatric and adult KD cohorts revealed elevated levels of calprotectin in pediatric patients with giant CAA 1 year post-KD and in adult KD patients who developed giant CAA in childhood.

Conclusions: Complex patterns of biomarkers of inflammation and cell trafficking can persist long after the acute phase of KD in patients with giant CAA. Elevated levels of plasma calprotectin months to decades after acute KD and infiltration of cells expressing S100A8 and A9 in vascular tissues suggest ongoing, subclinical inflammation. Calprotectin may serve as a biomarker to inform the management of KD patients following the acute illness.
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http://dx.doi.org/10.1161/CIRCGEN.118.002433DOI Listing
April 2019

Clustering and climate associations of Kawasaki Disease in San Diego County suggest environmental triggers.

Sci Rep 2018 11 12;8(1):16140. Epub 2018 Nov 12.

Department of Pediatrics, University of California San Diego, La Jolla, CA, 92093, USA.

Kawasaki Disease (KD) is the most common cause of pediatric acquired heart disease, but its etiology remains unknown. We examined 1164 cases of KD treated at a regional children's hospital in San Diego over a period of 15 years and uncovered novel structure to disease incidence. KD cases showed a well-defined seasonal variability, but also clustered temporally at much shorter time scales (days to weeks), and spatiotemporally on time scales of up to 10 days and spatial scales of 10-100 km. Temporal clusters of KD cases were associated with strongly significant regional-scale air temperature anomalies and consistent larger-scale atmospheric circulation patterns. Gene expression analysis further revealed a natural partitioning of KD patients into distinct groups based on their gene expression pattern, and that the different groups were associated with certain clinical characteristics that also exhibit temporal autocorrelation. Our data suggest that one or more environmental triggers exist, and that episodic exposures are modulated at least in part by regional weather conditions. We propose that characterization of the environmental factors that trigger KD in genetically susceptible children should focus on aerosols inhaled by patients who share common disease characteristics.
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http://dx.doi.org/10.1038/s41598-018-33124-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232126PMC
November 2018

Bifid T waves on the ECG and genetic variation in calcium channel voltage-dependent beta 2 subunit gene (CACNB2) in acute Kawasaki disease.

Congenit Heart Dis 2019 Mar 5;14(2):213-220. Epub 2018 Nov 5.

Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, California.

Background: We previously described the association of genetic variants in calcium channel genes and susceptibility to Kawasaki disease (KD), an acute, self-limited vasculitis, and the most common cause of acquired cardiac disease in children. Abnormal repolarization of cardiomyocytes and changes in T wave morphology have been reported in KD but have not been studied systematically.

Methods: We analyzed acute and convalescent ECG T wave morphology in two independent cohorts of KD subjects and studied the association between bifid T waves and genetic variants in previously reported genes with SNVs associated with cardiac repolarization.

Results: Bifid T waves in limb leads were identified in 24% and 27% of two independent cohorts of acute KD subjects. Calcium channel voltage-dependent beta 2 subunit gene (CACNB2) (rs1409207) showed association with bifid T waves in both cohorts (nominal P = .04 and P = .0003, respectively). This CACNB2 polymorphism also showed association with KD susceptibility in a previously published KD genome wide association study data (nominal P = .009).

Conclusion: This genotype/phenotype association study uncovered a variant in CACNB2 that may be associated with both KD susceptibility and bifid T waves, a novel signature of altered myocardial repolarization. The present study combined with published reports suggests that genetic variants in calcium channels and intracellular calcium signaling play a prominent role in shaping susceptibility to KD.
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http://dx.doi.org/10.1111/chd.12696DOI Listing
March 2019

Kawasaki Disease Outcomes and Response to Therapy in a Multiethnic Community: A 10-Year Experience.

J Pediatr 2018 12 26;203:408-415.e3. Epub 2018 Sep 26.

Rady Children's Hospital San Diego, San Diego, CA; Department of Pediatrics, University of California, San Diego, La Jolla, CA. Electronic address:

Objectives: To describe the epidemiology, response to therapy, and outcomes of Kawasaki disease in a multiethnic community with a large Hispanic and Asian population.

Study Design: We analyzed prospectively collected data from 788 unselected patients with Kawasaki disease diagnosed and treated at a single medical center over a 10-year period.

Results: The average incidence of Kawasaki disease in children <5 years in San Diego County over the 10 years from 2006 to 2015 was 25 per 100 000 children, with the greatest incidence (50 per 100 000) for Asian/Pacific Islanders. Compared with other race/ethnicities, Asian/Pacific Islander patients with Kawasaki disease were younger, were diagnosed earlier in the course of their fever, had higher levels of inflammatory markers, and were more likely to develop aneurysms. There was no difference across race/ethnicity groups in response to intravenous immunoglobulin therapy. Filipino children had the highest recurrence rates (9.1%; 95% CI, 3.0%-22.6%) and 12 of 788 patients (1.5%) had a first- or second-degree relative with a history of Kawasaki disease. After correcting for age of onset, sex, and illness day at diagnosis, Asian/Pacific Islander children had an increased risk of developing aneurysms (aOR, 2.37; 95% CI, 1.37-4.11; P  = .002). Overall, 180 of 788 patients (22.8%) had a maximal Z score of 2.5-10.0 and 14 of the 788 patients (1.8%) had a maximal Z score ≥10.0 despite 84% of these patients being treated within 10 days of fever onset.

Conclusions: Our data provide new insights into the natural history of treated Kawasaki disease in a multiethnic population. Patient race/ethnicity influenced susceptibility to Kawasaki disease, timing of diagnosis, coronary artery outcome, and recurrence rates.
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http://dx.doi.org/10.1016/j.jpeds.2018.07.090DOI Listing
December 2018

Diagnosis of Kawasaki Disease Using a Minimal Whole-Blood Gene Expression Signature.

JAMA Pediatr 2018 10 1;172(10):e182293. Epub 2018 Oct 1.

Section of Paediatrics, Imperial College London, London, United Kingdom.

Importance: To date, there is no diagnostic test for Kawasaki disease (KD). Diagnosis is based on clinical features shared with other febrile conditions, frequently resulting in delayed or missed treatment and an increased risk of coronary artery aneurysms.

Objective: To identify a whole-blood gene expression signature that distinguishes children with KD in the first week of illness from other febrile conditions.

Design, Setting, And Participants: The case-control study comprised a discovery group that included a training and test set and a validation group of children with KD or comparator febrile illness. The setting was pediatric centers in the United Kingdom, Spain, the Netherlands, and the United States. The training and test discovery group comprised 404 children with infectious and inflammatory conditions (78 KD, 84 other inflammatory diseases, and 242 bacterial or viral infections) and 55 healthy controls. The independent validation group comprised 102 patients with KD, including 72 in the first 7 days of illness, and 130 febrile controls. The study dates were March 1, 2009, to November 14, 2013, and data analysis took place from January 1, 2015, to December 31, 2017.

Main Outcomes And Measures: Whole-blood gene expression was evaluated using microarrays, and minimal transcript sets distinguishing KD were identified using a novel variable selection method (parallel regularized regression model search). The ability of transcript signatures (implemented as disease risk scores) to discriminate KD cases from controls was assessed by area under the curve (AUC), sensitivity, and specificity at the optimal cut point according to the Youden index.

Results: Among 404 patients in the discovery set, there were 78 with KD (median age, 27 months; 55.1% male) and 326 febrile controls (median age, 37 months; 56.4% male). Among 202 patients in the validation set, there were 72 with KD (median age, 34 months; 62.5% male) and 130 febrile controls (median age, 17 months; 56.9% male). A 13-transcript signature identified in the discovery training set distinguished KD from other infectious and inflammatory conditions in the discovery test set, with AUC of 96.2% (95% CI, 92.5%-99.9%), sensitivity of 81.7% (95% CI, 60.0%-94.8%), and specificity of 92.1% (95% CI, 84.0%-97.0%). In the validation set, the signature distinguished KD from febrile controls, with AUC of 94.6% (95% CI, 91.3%-98.0%), sensitivity of 85.9% (95% CI, 76.8%-92.6%), and specificity of 89.1% (95% CI, 83.0%-93.7%). The signature was applied to clinically defined categories of definite, highly probable, and possible KD, resulting in AUCs of 98.1% (95% CI, 94.5%-100%), 96.3% (95% CI, 93.3%-99.4%), and 70.0% (95% CI, 53.4%-86.6%), respectively, mirroring certainty of clinical diagnosis.

Conclusions And Relevance: In this study, a 13-transcript blood gene expression signature distinguished KD from other febrile conditions. Diagnostic accuracy increased with certainty of clinical diagnosis. A test incorporating the 13-transcript disease risk score may enable earlier diagnosis and treatment of KD and reduce inappropriate treatment in those with other diagnoses.
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http://dx.doi.org/10.1001/jamapediatrics.2018.2293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233768PMC
October 2018

[Charcot-Marie-Tooth disease showing transient central nervous system lesions after a large amount of alcohol intake: A case report].

Rinsho Shinkeigaku 2018 Aug 31;58(8):479-484. Epub 2018 Jul 31.

Department of Neurology, Gunma University Graduate School of Medicine.

A 23-year-old man experienced numbness in the perioral region and right arm, and right leg weakness on the second day after drinking a large amount of alcohol during foreign travel. His symptoms disappeared but then reappeared repetitively. Cerebral MRI performed on the third day after onset showed multiple white matter lesions; however, these lesions disappeared 26 days after onset. Neurological examination and nerve conduction studies revealed demyelinating polyneuropathy. Genetic testing for Charcot-Marie-Tooth disease, X-linked dominant 1 (CMTX1) due to GJB1 mutation was conducted based on the symptoms of transient central nervous system lesions and polyneuropathy exhibited by the patient and his mother. As a result, a c.530T>C (p.V177A) substitution in exon 2 of GJB1 was identified. CMTX1 patients should be advised to avoid excessive drinking because this could induce central nervous system lesions.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001130DOI Listing
August 2018
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