bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 93: Analysis of Serum Levels of Procalcitonin and Serum Amyloid A as Biomarkers of Intravenous immunoglobulin-resistant Kawasaki Disease
Authors: Mizuno Yumi , Furuno Kenji , Fukazawa Mitsuharu , Aoki Tomonobu
Published: March 2022

Aim:
Immune globulin is the most effective treatment of Kawasaki Disease, however, 15-20% of patients with Kawasaki disease (KD) is resistant to 2g/kg of IVIG (refractory case), and those patients are high risk for complication of coronary artery abnormalities, to detect these refractory KD before treatment of acute phase is very important to determine their treatment, but the methods to predict the refractory case is not yet established. We analyze the relation of IVIG-resistant Kawasaki disease and serum levels of procalcitonin (PCT) or serum amyloid A (SAA).

Method:
192 patients with KD were involved in this study, and 48 were IVIG-resistant cases. Refractory case was defined as patients who needed additional treatment with IVIG and/or steroid after the first treatment with total 2g/kg of IVIG. Serum levels of PCT and SAA were measured before treatment, and the relationship to clinical course was analyzed.

Result:
Median level of PCT of patients with IVIG-resistant KD was 2.24 ng/ml and those with non- IVIG-resistant KD was 0.47 ng/ml, and median levels of PCT of patients with IVIG-resistant KD was significantly higher than those with non- IVIG-resistant KD (p<0.01). Median level of SAA of patients with IVIG-resistant KD was 753.6 μg/ml and those with non- IVIG-resistant KD was 635.9μg/ml and there was no significant difference. We compared the accuracy of prediction of IVIG resistant KD by PCT and SAA using receiver operating characteristic (ROC) analysis. The areas under the receiver operating characteristic curve(AUC) of PCT, SAA and CRP was 0.75, 0.57 and 0.63 respectively. For identification of IVIG-resistant patients, a cut-off point, sensitivity and specificity of PCT, SAA and CRP were as follows, 1.5 ng/ml, 77% and 61%, 444 μg/ml, 83% and 32% and 7.7 mg/dl, 73% and 59%, respectively.

Conclusion:
As PCT levels of patients with IVIG-resistant Kawasaki disease were significantly higher than those with non- IVIG-resistant KD, PCT could be one of the predictor of IVIG-resistant KD.
Abstract 96: Changes In HDL Cholesterol During The Acute Phase of Kawasaki Disease
Authors: Nihei Koichi , Ito Chieko , Park Juhyon , Mishima Noriko , Nakamura Hiroaki , Nasuno kiyoto , Fujiwara Junko , Sekine Takashi
Published: March 2022

To determine the correlations between changes in high-density lipoprotein cholesterol (HDL-C) and other blood variables during the acute phase of Kawasaki disease (KD), we investigated changes in the plasma level of HDL-C, serum apolipoproteins and number of peripheral blood monocytes. 26 Japanese patients with KD were subjects of this study. Plasma HDL-C decreased during the 1st week of illness, and increased during the 2nd week. The mean levels of minimum HDL-C in KD patients treated with total intravenous immunoglobulin (IVIG) dose ≧ 4g/kg, was significantly lower than those treated with total IVIG dose < 4g/kg (p=0.0005). There was a strong direct correlation between minimum HDL-C in KD patients and HDL-C on 5th day of KD onset (r=0.71, p < 0.0001). Assessing the performance of plasma HDL-C on 5th day of KD onset in predicting the necessity for high-dose IVIG treatment to KD, ROCs were plotted and the AUC was 0.82. A cutoff value of 16mg/dl had a specificity of 0.82 and sensitivity of 0.80 for predicting those.

The apo A-I and A-II levels were correlated with plasma HDL-C, respectively. And the peripheral blood monocytes counts which correlated with serum levels of macrophage-colony stimulating factor, were not correlated with plasma HDL-C.

Plasma HDL-C levels during the 1st week of illness might serve as a predictor for non-responder to low-dose IVIG treatment in patients with acute KD.
Abstract 97: Resistance Values in the Limbs are Useful for Estimating the Severity of Kawasaki Disease.
Authors: Nomura Yuichi , Masuda Kiminori , Morita Yasuko , Ninomiya Yumiko , Ueno Kentaro , Eguchi Taisuke , Kawano Yoshifumi
Published: March 2022

Vascular permeability is one of the characteristics of vasculitis in Kawasaki disease (KD) and is closely related to indurative edema. Evaluating indurative edema may be useful for estimating the severity of KD. Indurative edema is correlated with resistance values in the limbs. Therefore, we evaluated the efficacy of resistance values in the limbs in KD patients, as measured by a multiple-frequency bioelectrical-impedance method, for estimating the severity of KD.

Patients and Methods:
In 38 patients with the acute phase of KD (before intravenous immunoglobulin treatment; IVIG), 32 with the sub-acute phase (after IVIG), and 49 controls, we measured resistance (impedance; IMP) in each child’s total body, forearm, and lower leg at frequencies of 0 and infinity (IMP-0 and IMP-∞, respectively) using MLT-550N (Sekisui ). Corrected Imp values (coIMP; Imp x limb’s cross-sectional area/ limb’s length) were also examined.

Results:
IMP values were not different among patients with the acute and sub-acute phases of KD and controls. However, coIMP values in the forearm of patients in the acute phase of KD were significantly higher than those of controls (coIMP-0 Ωcm: 197±50 vs. 164±35, P<0.001, coIMP-∞; 151±42 vs. 125±36, P=0.003). These values were decreased to 181±46 Ωcm for coIMP-0 and 144±44 Ωcm for coIMP-∞ at the sub-acute phase and were still significantly higher than those of controls. Values of coIMP in the lower leg showed similar changes to those in the forearm. The values of coIMP in the forearm of IVIG non-responders at the acute phase were higher than those of responders, but this difference was not significant.

Conclusion:
Values of co-IMP in the forearm might be useful for estimating the severity of KD.
Abstract O.06: Epidemiology of Kawasaki Disease in Canada (2004-2011)
Authors: McCrindle Brian W , O’Shea Sunita , Lew Brendan , Masood Sameer , Bock Dirk , Lai Lillian S , Dillenburg Rejane F , Bernknopf Bailey , Chahal Nita , Yeung Rae S , Manlhiot Cedric
Published: March 2022

Introduction:
We have previously documented in consecutive triennial systematic surveillances a rise in the incidence of KD in Ontario, Canada between 1995 and 2004 followed by a stabilization at 24-26 cases per 100,000 children <5 year old per year between 2004 and 2009. Previous studies have been limited to the province of Ontario; we sought to determine the incidence of KD across Canada and by province.

Methods:
We queried the Canadian hospital discharge database (Canadian Institute for Health Information) for hospital admissions associated with a discharge diagnosis of KD (either primary or secondary) between 2004 and 2011. Multiple admissions for a given patient were not counted as separate incident cases unless >2 months from the original admission and associated with IVIG treatment. Denominators were derived from population data from the 2001, 2006 and 2011 Censuses.

Results:
The annual incidence of KD during the study period was 21.9, 6.8 and 1.1 cases per 100,000 children <5 years, 5-9 years and 10-14 years old, respectively (4,340 cases total). Stratification by region showed the lowest incidence to be in Saskatchewan (11.8/100,000 children <5 year old), followed by Manitoba (17.3), Alberta (17.7), Quebec (18.1), British Columbia (20.6), Atlantic Provinces (22.5) and finally Ontario (27.5, similar to that noted on previous systematic surveillances). The incidence remained stable over the study period, confirming the plateau reached in the previous systematic Ontario surveillance between 2004-2009. An increased incidence was noted for children <5 years old, male gender and winter months. There was a moderate correlation between proportion of the provincial population of Asian descent and KD incidence (r=0.58). Coronary artery aneurysms affected 5.8% of patients, and 1.9% experienced major cardiac complications or had cardiac interventions.

Conclusions:
The previous increase in the incidence of KD has plateaued, indicating that the true annual incidence fluctuates between 20-22 and 24-27 cases per 100,000 children <5 years for Canada as a whole, and 24-27 cases for the province of Ontario. Differences in annual incidence observed between provinces remain to be explained, but may reflect racial, genetic or environmental factors.
Abstract O.09: French observatory of Kawasaki disease in adults: 24 observations.
Authors: Fraison Jean-Baptiste , Seve Pascal , Gommard-Menesson Emmeline , Dauphin Claire , Mahr Alfred , Landron Cedric , Nathalie Costedoat-Chalumeau , Epaulard Olivier , Boutin Le Thi Huong , Piram Maryam , Mékinian Arsène , Roblot Pascal , Oziol Eric , Hot Arnaud , Chalhoub Gihane , Galempoix Jean-Marc , Marchand Guillaume , Humbert Sébastien , Humbert Philippe , Morlat Philippe , Puéchal Xavier , Guillevin Loic , Koné-Paut Isabelle , Fain Olivier
Published: March 2022

Introduction:
Kawasaki disease (KD) is a vasculitis that occurs mostly among children and exceptionally in adults. We report data from a French observatory of adult KD.

Patients and methods:
Adult patients diagnosed with KD in 16 French centers were included. Patients were classified as complete KD or incomplete KD according to IKDC or probable KD.

Results:
We included 24 patients with a median age of 29 years (22-39) and a sex ratio (M / F) 2.42, 12 complete KD, 9 incomplete KD and 3 probable KD without any other cause. Time to diagnosis was 13 days (10-20.5). Main events were: fever (100%), extremities changes (21/24, 87.5%), rash (22/24, 92%), conjunctivitis (16/24, 16, 66%), cheilitis (15/24, 63%), strawberry tongue (11/24, 46%), adenopathy (10/24, 42%), cardiac abnormalities (11/24, 46%), cardiogenic shock (n = 1), myo-pericarditis (n = 3) and left heart failure (n = 1).

Median CRP was 228mg/L (166-311), SGOT: 68 IU/L (51-139), SGPT: 125 IU/L (69-190), platelets 372 G/L (209-630) and leukocytes 16 G/L (8.3-20).

Cardiac involvement was researched in 23 patients (96%) by achieving: echocardiography (20/24), coronary scanners (6/24), coronary angiography (5/24), cardiac MRI (2/24) and stress tests (2/24).

An arteritic vascular disease was found in 11 patients (46%): coronary aneurysms (8/24, 33%), coronary arteritis (10/24; 42%) and peripheral arteritis (2/24, 8.3%) with acute lower limb ischemia (1/24, 4.2%) and splenic infarction (1/24, 4.2%).

Patients received:
intravenous immunoglobulin (17/24; 71%): aspirin (21/24, 88%).

After 6 months, it persisted 5 aneurysm (20.8%). Complications noticed during the last follow-up were: heart failure (1/24, 4.3%), aneurysm (3/24, 12.5%).

Conclusion:
The adult KD is a rare disease that can have bad prognosis in short or long term and leave irreversible damage. The high rate of cardiac complication could be due to the long diagnosis delay, the absence of the gold standard treatment in 30% of cases or a selectional bias due to the difficulty to diagnose this disease in adulthood.
Abstract O.20: Deep RNA Sequencing Reveals a Transcriptional Profile of Cytotoxic T Lymphocyte Activation, Antigen Presentation, Immunoglobulin Production, and Type I Interferon Response in Kawasaki Disease Arteritis
Authors: Rowley Anne H , Wylie Kristine , Kim Kwang-Youn A , Pink Adam J , Reindel Rebecca , Baker Susan C , Shulman Stanford T , Yang Amy , Orenstein Jan M , Lingen Mark W , Weinstock George , Wylie Todd
Published: March 2022

Introduction:
Subacute/chronic arteritis (SA/C) and luminal myofibroblastic proliferation are the pathologic processes that can continue in Kawasaki Disease (KD) coronary arteries after the second week of illness, when acute neutrophilic necrotizing arteritis has subsided. The specific dysregulated immune pathways in SA/C arteritis have been unknown, hampering the development of effective immunomodulatory therapies for patients not responding to intravenous gammaglobulin therapy. Controversy exists as to whether the arteritis is lymphocyte or macrophage-mediated.

Hypothesis:
Based on our histopathologic studies, we hypothesized that the immune transcriptome of SA/C KD arteritis was primarily lymphocyte- rather than macrophage-mediated.

Methods:
RNA was isolated from paraffin-embedded CA tissues, and samples passing quality control assays were subjected to deep RNA sequencing (101 nt paired-end reads, 40-100million reads/sample). Reads were aligned to the human genome, and HTseq used to determine read counts. DESeq was used to test for differential gene expression in CA tissues from 8 KD children (median age=7 mo, median 4 wks and all >2 weeks after onset) compared to 7 controls with normal CAs (median age=5 mo). Pathways analysis was performed using Ingenuity iReport™.

Results:
1074 differentially expressed genes were identified with >1.5-fold change and q-value <0.05. The most significantly upregulated pathways included cytotoxic CD8 T lymphocyte, dendritic cell and toll-like receptor (TLR) signaling, and antigen presentation. Immunoglobulin and type I interferon-stimulated genes were significantly upregulated. 50 immune response genes encoding secreted proteins were upregulated and are candidate biomarkers of KD arteritis.

Conclusions:
The immune transcriptional profile in KD CA tissues after the second week of illness is primarily lymphocyte-mediated and compatible with an antiviral immune response. This first report of the KD CA transcriptome identifies specific dysregulated immune response pathways that can inform the development of new therapies for and biomarkers of KD vasculitis, and provides direction for future etiologic studies of this potentially fatal childhood illness.
Abstract O.25: Identification Of Pathogenic Cardiac Cd11c+ Macrophages In Nod1-mediated Coronary Arteritis, A Murine Model Of Kawasaki Disease
Authors: Motomura Yoshitomo , Kanno Shunsuke , Nishio Hisanori , Hara Toshiro , Yamasaki Sho
Published: March 2022

Kawasaki disease is characterized by granulomatous inflammation of coronary arteries. We previously reported that a synthetic Nod1 ligand FK565 induced coronary arteritis in mice similar to that of Kawasaki disease. However, the molecular mechanism underlying this site-specific vasculitis has remained elusive. We found that CD11c+ MHC class II+ cells were accumulated in heart of FK565-treated mice prior to arteritis development, which was abolished in Nod1-/- mice. In vivo depletion of mononuclear phagocytes or CD11c+ cells prevented the arteritis, whereas elimination of T cells, B cells, NK cells, and neutrophils did not alter the pathology. Morphological features and gene expression signature of the cardiac CD11c+ MHC class II+ cells suggested that this population was closely related to macrophages. Notably, various inflammatory cytokines, chemokines, lysosomes and MMPs were expressed in these cardiac CD11c+ macrophages, suggesting that this population contributed to tissue destruction. Next, we determined whether Nod1 in hematopoietic cells or non-hematopoietic cells were important for this arteritis. Bone marrow chimera mice using WT and Nod1-/- mice indicated that Nod1 in non-hematopoietic host cells, rather than in hematopoietic cells, was important for the accumulation of the cardiac CD11c+ macrophages and arteritis development. Among non-hamatopoietic cells, cardiac endothelial cells abundantly produced chemokines in response to FK565. In this respect, CCR2-deficient mice exhibited decreased cardiac CD11c+ macrophages and compromised inflammation. These results suggested that Nod1 activation in endothelial cells triggers accumulation of cardiac CD11c+ macrophages, which is a prerequisite for the development of coronary arteritis.
Abstract O.27: The Role Of CD40L And CD40 In The Pathogenesis Of Kawasaki Disease
Authors: Parsaud Leon , Arjmand Parnian , Duong Trang T , Yeung Rae S
Published: March 2022

Kawasaki Disease (KD) is characterized by acute, systemic inflammation followed by a persistent immune response localized to the coronary arteries. Lactobacillus Casei Cell Wall Extract (LCWE) contains among its active ingredients a superantigen (SAg) that induces coronary arteritis in mice. LCWE induces massive immune activation followed by apoptosis or anergy. Previous work has shown that co-stimulatory signals can rescue a subset of SAg-reactive T-cells from apoptosis. CD40-CD40L (ligand) are members of the TNF superfamily which play a role in T-cell co-stimulation. Moreover, genome wide association studies have implicated CD40/CD40L as candidate genes in the pathogenesis of KD. We hypothesize that co-stimulation via the CD40 pathway regulates survival of SAg-reactive T-cells during disease development. Using thymidine proliferation assay and flow cytometry we show that activation of CD40 signaling via agonistic anti-CD40 antibody or recombinant soluble CD40L (rsCD40L) upregulates CD86 (ligand responsible for CD28 signaling) expression, reduces active-caspase-3 expression, indicating decreased cell death and promotes lymphocyte proliferation, Additionally, using CD28 deficient mice we show that lymphocytes do not proliferate in response to SAg plus CD40 stimulation indicating that CD28 is the intermediary that mediates the proliferative effects of CD40 activation. Furthermore, platelets, which are markedly elevated in KD, produce approximately 90% of the soluble CD40L in the circulation. We show that activated platelets (CD62P+) express CD40L and promotes cell survival as evidenced by enhanced lymphocyte proliferation. Likewise, the absence of CD40L negates the proliferative effects of platelet mediated proliferation. Lastly, to determine the role of CD40 stimulation on in vivo development of KD, LCWE was injected into B6 and CD40L deficient mice. We show that inflammation in the coronary arteries does not develop in the absence of CD40L. Therefore, CD40L plays a critical role in immune activation via upregulation of CD86 on antigen presenting cells leading to enhanced co-stimulation and T-cell survival.
Abstract O.28: Macrophage Activation Syndrome Associated with Kawasaki Disease
Authors: Latino Giuseppe A , Manlhiot Cedric , McCrindle Brian W , Chahal Nita , Yeung Rae S
Published: March 2022

Introduction:
Macrophage activation syndrome (MAS) is a life threatening disease that is increasingly recognized in children with inflammatory conditions including Kawasaki disease (KD). We describe the prevalence, clinical features and outcomes of patients with MAS secondary to KD.

Methods:
All patients diagnosed and treated for KD at The Hospital for Sick Children between 2001 and 2013 were included and reviewed for features of MAS. A diagnosis of MAS required 4 out of the following clinical findings: fever, hepatosplenomegaly, cytopenia in at least 2 cell lines, hyperferritinemia, hypofibrinogenemia and/or hypertriglyceridemia, and presence of biopsy-proven hemophagocytosis.

Results:
Of 1,020 patients included in this study, 21 met MAS diagnostic criteria for an incidence of 2.1% (95% CI: 1.4-3.1%). All patients had fever, 9 (43%) hepatosplenomegaly, 10 (47%) hypofibrinogenemia and/or hypertriglyceridemia, 19 (90%) hyperferritinemia, 19 (90%) cytopenia, and 7 (33%) biopsy-confirmed hemophagocytosis. MAS was associated with: older age at KD diagnosis (median 5.7 vs. 3.0 years, p=0.06), longer fever duration prior to diagnosis (median 10 vs. 6 days, p=0.01), and higher incidence of incomplete KD (57% vs. 32%, p=0.04) and confirmed infection during acute phase (48% vs. 19%, p=0.02). Treatment included multiple IVIGs for 12 patients (57%), methylprednisolone for 15 (71%), oral prednisone for 13 (62%) and cyclosporine for 2 (10%). Median total duration of fever was 13 days (vs. 7 days, p=0.001), duration of fever after first IVIG treatment was 4 days, and median duration of hospital stay was 6 days (vs. 3 days, p=0.01). 5 patients received pRBC transfusions, 3 required ICU care, 1 had severe CNS involvement, and 1 developed multisystem organ failure dying 28 days after admission. Mild transient coronary dilatation was seen in 3 patients

Conclusions:
The clinical presentation of KD and MAS are quite similar. Both entities are syndrome complexes defined by massive immune activation and share pro-inflammatory cytokine signatures. MAS is a rare but important complication with KD. Further research is needed to optimize diagnosis and management.
Abstract O.30: Novel Biomarker for Early Diagnosis of Kawasaki Diseases
Authors: Ko Tai-Ming , Kuo Ho-Chang , Chang Jeng-Sheng , Chen Shih-Ping , Liu Yi-Min , Chen Hui-Wen , Tsai Fuu-Jen , Lee Yi-Ching , Chen Chien-Hsiun , Wu Jer-Yuarn , Chen Yuan-Tsong
Published: March 2022

Kawasaki disease (KD) is the most common cause of acquired heart disease in young children and has been suggested to be an immune-mediated condition, which was supported by our previous findings that FCGR2A, BLK, and CD40 are KD susceptibility genes. However, diagnosing KD can be difficult especially at early stage of the disease because of its varied clinical manifestations and lack of specific laboratory tests. The aim of the present study was to identify biomarkers that may aid in the early diagnosis of KD. We conducted a three-phase study: discovery, replication, and blinded validation. The 214 children with fever and clinical features suggestive of KD were recruited in Taiwan from separate geographic medical centers. By using an unbiased, large-scale, quantitative protein array, we globally analyzed the profiles of cytokines, chemokines, and cell adhesion molecules in their plasma samples. During the discovery phase [n (KD) = 37, n (control) = 20], the expression of one cell adhesion molecules, two chemokines, and three cytokines (Th-17-related), (named gene-1~6) were upregulated during the acute phase in KD patients compared to that in the controls. Receiver-operating characteristic analysis of the combined discovery and replication data [n (KD) = 77, n (control) = 77] showed that the level of gene-3 had high area under the curve values (AUC, 0.94). Using the optimal cut-off value to predict KD, the sensitivity and specificity of the gene-3 was found to be 90% and 87%, respectively. Blinded validation study also confirmed the excellent discrimination of gene-3 in identifying KD cases from non-KD cases among subjects who were highly suspected KD cases, including incomplete KD or febrile cases with scarlet fever, even in the very early stage (<4 days).With intravenous immunoglobulin treatment, levels of gene-3 returned to normal. Furthermore, we also found the downstream receptor of gene-3 was activated in the T cells of acute KD patients. Taken together, the newly identified biomarker, gene-3, may be useful in diagnosing KD and monitoring patients’ treatment responses. The selective increase of gene-3 in KD also reveals that a novel unique signal pathway involved in KD, which may provide a critical clue for further investigating the pathogenesis of KD.
Abstract O.31: Tenascin-C can be a Novel Prognostic Biomarker For Kawasaki Disease
Authors: Imanaka-Yoshida Kyoko , Okuma Yoshiaki , Matsushita Takeji , HIroe Michiaki , Takahashi Kei
Published: March 2022

Tenascin-C (TNC) is an extracellular matrix glycoprotein sparsely detected in normal but highly expressed in pathological condition associated with inflammation in variety of tissues. By taking advantage of its specific expression, TNC is applicable as a biomarker and a molecular imaging target for diagnosis of disease activity for ventricular remodeling. In blood vessels, the expression of TNC in normal is generally low but strong expression is linked with several pathological conditions such as pulmonary artery hypertension, coronary atherosclerotic intima, and aortic aneurysm/ dissection. We hypothesized that TNC could be useful for evaluating disease activity of Kawasaki Disease(KD). We measured serum level of TNC of 174 patients with KD using ELSA and found that the TNC level was significantly higher than that of the controls, and the initial treatment with intravenous immunoglobulin decreased the level. Combination of serum TNC and Kobayashi score increased the accuracy to identify cases at a high risk of unresponsiveness to high-dose intravenous immunoglobulin. Immunohistochemical analysis of autopsied cases showed that TNC was strongly expressed in coronary vascular lesion at acute stage of KD patients as well as in the Candida albicans-induced murine model of vasculitis/aneurysm. Biomechanical analysis demonstrated that vascular flexibility was reduced in TNC knockout mice. A combination of inflammation and mechanical stress to aorta induced dissecting aneurysm in TNC knockout mice. In vitro, TNC enhanced macrophage migration and cytokine synthesis, meanwhile TNC synthesis was up-regulated by various pro-inflammatory cytokines. These results suggest that TNC is expressed in vascular lesion of KD reflecting active inflammation, which has diverse functions to modulate not only inflammatory response but also regulate vascular remodeling and aneurysm formation. TNC could be a key molecule in pathophysiology and a promising biomarker of KD.
Abstract O.33: Identification of Kawasaki Disease-specific Molecules in the Sera as Microbe-associated Molecular Patterns
Authors: Kusuda Takeshi , Nakashima Yasutaka , Murata Kenji , Kanno Shunsuke , Mizuno Yumi , Ouchi Kazunobu , Waki Kenji , Hara Toshiro
Published: March 2022

Background:
Kawasaki disease (KD) is a systemic vasculitis of unknown etiology. The innate immune system is involved in its pathophysiology at the acute phase. We have recently established a novel murine model of KD coronary arteritis by oral administration of a synthetic microbe-associated molecular pattern (MAMP). On the hypothesis that specific MAMPs exist in KD sera, we have searched them to identify KD-specific molecules and to assess the pathogenesis.

Methods:
The study subjects included 117 patients with KD (median age, 21 months; range 3-96 months; male/female, 65/52) and 101 controls with other febrile illnesses (DC: median age, 16 months; range 0-121 months; male/female, 61/40), and 5 normal controls (NC: median age, 6 months; range 3-39 months; male/female, 1/4). We performed liquid chromatography-mass spectrometry (LC-MS) analysis of fractionated serum and microbial samples by ethyl acetate.

Results:
KD serum samples elicited proinflammatory cytokine responses from human coronary artery endothelial cells (HCAECs). By LC-MS analysis of KD serum samples collected at 3 different periods, we detected a variety of KD-specific molecules in the lipophilic fractions that showed distinct m/z and MS/MS fragmentation patterns in each cluster. Serum KD-specific molecules showed m/z and MS/MS fragmentation patterns almost identical to those of MAMPs obtained from Bacillus cereus, Yersinia pseudotuberculosis and Staphylococcus aureus at the 1st study period, and from MAMPs from Bacillus cereus, Bacillus subtilis/Bacillus cereus/Yersinia pseudotuberculosis and Staphylococcus aureus at the 2nd and 3rd periods. These molecules decreased after intravenous immunoglobulin (IVIG) treatment.

Conclusions:
We herein conclude that serum KD-specific molecules possess molecular structures common to MAMPs from Bacillus cereus, Bacillus subtilis, Yersinia pseudotuberculosis and Staphylococcus aureus. Discovery of these KD-specific molecules offers novel insight into the diagnosis and management of KD as well as its pathogenesis.
Abstract O.34: NT-proBNP based Algorithm for Diagnosis and Treatment of Kawasaki Disease - Are we there yet?
Authors: Dionne Audrey , Meloche-Dumas Léamarie , Fournier Anne , Dahdah Nagib
Published: March 2022

Background:
Diagnosis of Kawasaki Disease (KD) can be confusing in the absence of a confirmatory test or pathognomonic finding, especially when clinical criteria are incomplete (iKD). We have lately proposed serum NT-proBNP as an adjunctive diagnostic test.

Method:
We retrospectively tested a new diagnostic algorithm to aid in diagnosis based on NT-proBNP (Z-score for age), coronary artery dilation (CAD) at onset, and abnormal serum albumin or CRP. The goal was to assess the performance of the algorithm with respect to CAD outcome (aneurysm, dilation, or occult dilation). Occult dilation is defined as variation of coronary artery Z-score >2 within the normal range (<2.5).

Results:
The algorithm was tested on 81 KD patients who had NT-proBNP on admission at our institution between 2008 and 2013. Age at diagnosis was 3.2 ± 2.6 years, with a median of 5 diagnostic criteria (range 3-6), of whom 31/81 (38.3%) had iKD. Aneurysms occurred in 16/81 (19.8%); higher prevalence in iKD, 12/31 (38.7%) versus 4/50 (8.0%) (p=0.001). CAD affected 35/81 (43.2%), and 30/81 (37.0%) had occult CAD. With the algorithm, 80/81 (98.8%) were to be treated: based on high NT-proBNP alone for 54/81 (66.7%), on onset CAD for 13/81 (16.0%), and on high CRP or low albumin for 13/81 (16.0%). (Figure 1) Results were similar when the algorithm was applied to patients with complete or incomplete criteria. The only patient “not-to-treat” with the algorithm had iKD and transient occult CAD.

Conclusion:
This NT-proBNP based algorithm is efficient to identify and treat patients at risk of coronary involvement, despite an apparent selection bias of CA involvement. This paves the way for a prospective validation trial of the algorithm.
Abstract O.48: Intravenous Immunoglublin-Associated Hemolysis in Kawasaki Disease
Authors: Yeung Rae S , Almeida Fiona , Khajoee Vahid , Chahal Nita , Mizzi Trent , Schwartz Sarah , McCrindle Brian W , Lau Wendy
Published: March 2022

Background:
Intravenous immunoglobulin (IVIG) is the mainstay of treatment for Kawasaki Disease (KD). Due to the consolidation of IVIG manufacturers in 2008, different preparations of IVIG are currently available in Canada. An increase in adverse effects, especially hemolytic anemia, has been observed.

Objective:
To characterize the natural history of IVIG-associated hemolytic anemia in KD.

Methods:
A single-centre retrospective study was conducted at Toronto’s SickKids Hospital between January 2002 and December 2012. Medical records of all KD patients were reviewed and hemolytic anemia identified (drop in hemoglobin ≥20mg/dl post-IVIG treatment with 2 or more of the following criteria: reticulocytosis, positive direct anti-globulin test (DAT), and morphological changes on blood film). For statistical analysis, Chi-square tests and ANOVA with Tukey’s post-hoc correction for multiple comparisons were utilized.

Results:
Between 2002 and 2008, 2 of 370 patients diagnosed with KD who received Iveegam had hemolytic anemia (0.5%). After 2008, the rates of IVIG-associated hemolysis were as follows: Privigen 17% (8/48, p<0.001), Gammagard 3.3% (4/121) and Gamunex 2.3% (3/130). Retreatment rates were significantly higher in the hemolysis group (64% vs. 22%, p<0.001), and there was a trend showing more patients with larger aneurysms (Z-score >5) in the hemolysis group (17% vs. 5.3%). All patients who hemolyzed had non-O+ blood types. Out of the 17 patients with hemolysis, 9 required red cell transfusions (60%). Starting in 2012, a detailed hemolysis work-up was included as standard protocol for all KD patients. Hemolysis was mediated by anti-blood group A & B antibodies resulting in DAT positivity, but no complement fixation. This extravascular hemolysis was maximal at 72 hours post-IVIG infusion and appeared to be dose dependent.

Conclusions:
Hemolysis is seen in up to 17% of those receiving new IVIG preparations, which also appear to be less efficacious - associated with treatment failure and, possibly, poor coronary outcome. There are important implications for patient safety. Further study is required to develop evidence-based guidelines to improve our management of these children.
Abstract O.54: Alteration of Left Ventricular Performance and Aortic Elastic Properties in Patients After Kawasaki Disease With Coronary Artery Aneurysm Even Without Cardiac Ischemia
Authors: Oyamada Jun , Shimada Shunsuke , Okazaki Mieko , Toyono Manatomo
Published: March 2022

Introduction:
Recent studies have suggested that patients after Kawasaki disease (KD) have altered arterial stiffness. However, there is little evidence of the relationship between arterial stiffness and left ventricular (LV) global function of KD patients without cardiac ischemic region.

Hypothesis:
We hypothesized that the alteration in the elastic properties of the ascending aorta may influence both LV function.

Methods:
Sixty one patients after KD (age, 6.1±4.0 years) were studied, comprising 15patients with CAAs and 46 patients without CAA. All the patients with CAAs showed no cardiac ischemic region confirmed by myocardial perfusion SPECT. Using pulsed Doppler echocardiography combined with Doppler tissue imaging, mitral peak velocities during early diastole (E) and LV peak myocardial velocities during early diastole (e’) and systole (s’) were measured. The ratio of E/e’ was used as an index of filling pressure of the LV. From Doppler tissue imaging, Doppler-derived index of combined systolic/diastolic myocardial performance (Tei index) was calculated as a surrogate for LV global function. We also obtained aortic stiffness index (ASI), and aortic distensibility (AD) from the measurements of the ascending aorta with noninvasive evaluation of blood pressure.

Results:
In all the patients, febrile periods of acute stage of KD showed significantly positive correlation with ASI, and showed significantly negative correlation with AD (both p <0.05). E/e’ showed significantly positive correlations with ASI, pulse pressure and showed significantly negative correlations with s’, and AD (both p <0.05). The patients with CAAs showed significantly greater pulse pressure, LV Tei index and ASI than those without CAAs (all p <0.05).

Conclusions:
KD especially with CAAs showed subclinical abnormal LV performance that is related to altered central aortic elastic properties.
Abstract O.59: Fate of Kawasaki disease giant coronary aneurysm: Analysis of the last 10 years nationwide survey in Japan
Authors: Fukazawa Ryuji , Hamaoka Kenji , Saji Tsutomu , Kato Hitoshi , Suzuki Hiroyuki , Tsuda Etsuko , Ayusawa Mamoru , Miura Masaru , Kobayashi Tohru , Ogawa Shunichi
Published: March 2022

Background and Objective:
Long term prognosis of Kawasaki disease (KD) with giant aneurysm is not yet well understood. We conducted a nationwide survey of KD with giant aneurysm for recent 10 years, and analyzed cardiac events of those patients.

Methods:
Nationwide epidemiological survey of KD has been conducted every 2 years since 1970 in Japan. We performed questionnaire survey based on 16th - 21th (1999 - 2010) nationwide epidemiological data.

Results:
We send questioners to 275 facilities asking about 415 patients who were reported to have giant aneurysm (>=8mm), and collected the data of 334 patients (80.5%). We excluded 84 non-giant aneurysm patients and 36 duplicated cases and difined finally 214 patients. Out of 214 patients, 13 deaths and 32 AMIs were described (6.1% and 15.0%, respectively). The first AMI attack was mostly reported within a few months from KD onset (medium 5 months (0-85 months)). AMI was occurred one time in 26 patients, and two times in 6 cases. Myocardial ischemia was observed in 80% of AMI patients, and 12 patients were received coronary artery bypass graft. Thirteen patients were reported to be dead (medium 1 month (0-23 months) from KD onset). There were 6 cardiac deaths within 1 month from KD onset (5: rupture of aneurysm, 1: AMI). The others were all caused by AMI except for 2 accidental death. Four out of 6 AMI deaths were caused by the first AMI attack. For the remaining 2 AMI deaths, the period from the first AMI to second fatal AMI was 1 month and 6 month, respectively. There were no death reported byond 2 years from KD onset.

Conclusion:
AMI and cardiac death of KD with giant aneurysm occurred mostly in early phase of KD onset. Coronary rupture occurs within a month after onset, and 84% AMI and all AMI death occurs within 2 years after onset. Patients survival become promising after 2 years from onset. These evidences indicate that therapeutic strategy up to 2 years after onset is extremely important for prognosis of KD with giant aneurysm.
Abstract O.67: Carotid Intima-media Thickness In Patients With A History Of Kawasaki Disease
Authors: Dietz Sanne , Tacke Carline , Gort Johan , Kuipers Irene , de Groot Eric , Wiegman Albert , Hutten Barbara , Kuijpers Taco
Published: March 2022

Aims:
Kawasaki disease (KD) is an acute pediatric vasculitis with the development of coronary artery aneurysms (CAA) being recognized as a serious clinical complication of KD. It has been suggested that KD predisposes to premature cardiovascular disease (CVD) later in life, however, conflicting results have been reported. We therefore assessed the risk of CVD in patients with a history of KD.

Methods and results:
Carotid B-mode ultrasound scans and measurements of carotid intima-media thickness (cIMT), a validated marker of CVD risk, were performed in 161 KD patients (119 with CAA, 42 without CAA based on worst-ever z-score; age range: 7-20 years). CIMT measurements were also performed in 82 unaffected family controls in the same age range.

Differences in cIMT between patients and controls were evaluated by linear regression analyses while correcting for confounders by stepwise backward elimination. Mean cIMT (±SD) was increased in patients with KD (0.378 ± 0.030 mm versus 0.360 ± 0.027 mm;
P
adjusted < 0.0001). If the difference in cIMT between patients and controls was plotted against age, in patients without CAA, increased cIMT was only apparent at young age, whereas in patients with CAA increased cIMT was observed over the entire age range.

Conclusion:
Our findings in KD patients show significant arterial wall changes in patients with a history of KD, in particular in those with CAA. In contrast to the cIMT findings at young age - irrespective of the absence or presence of CAA, the data demonstrate that - with age - the cIMT in KD patients without CAA became indistinguishable from controls but remained increased in the patients with CAA. The age-dependency of cIMT values could in part explain the variable and conflicting results of previous reports in KD. Furthermore, these explicit differences in cIMT between CAA-negative and CAA-positive patients may suggest that the pathophysiology of the arterial wall changes in KD differ from atherosclerosis. Finally, our results indicate that follow-up in patients with KD seems justified in patients with CAA, but may not be necessary in children without CAA.
Abstract 15866: Incidence and Severity of Left Atrial Scar in Older Patients With and Without Atrial Fibrillation
Authors: Mohanty Sanghamitra , Trivedi Chintan , Gianni Carola , Gunes Mahmut F , Gokoglan Yalcin , Bai Rong , Burkhardt John David , Sanchez Javier , Hranitzky Patrick , Gallinghouse G. J , Al-Ahmad Amin , Horton Rodney , Hongo Richard , Hao Steven , Beheiry Salwa , Casella Michela , Dello Russo Antonio , Tondo Claudio , Di Biase Luigi , Natale Andrea
Published: March 2022

Background:
Atrial fibrosis or scar is considered a substrate change related to atrial fibrillation (AF); by slowing conduction and increasing heterogeneity it could provide a substrate for AF. However, it is still not known whether AF causes the profibrotic changes in the left atrial wall or simply facilitates the manifestation of an existing aging-related structural remodeling in older patients. We examined scar prevalence and severity in patients aged ≥ 75 years with and without AF to address this question.

Method:
Five hundred seventy one patients undergoing radio-frequency catheter ablation for AF or supraventricular tachycardia (SVT) were included in this prospective analysis and classified into 2 groups; group 1: patients with AF (n=308, 62% male, median 77.8 (75 to 91) years, 46% paroxysmal and 64% persistent AF) and group 2: patients with diagnosis of SVT (n=263, 56% male, median 80 (75 to 88) years). Left atrial (LA) scarring was determined by three-Dimensional (3D) voltage mapping. Scar was defined as an area with a bipolar voltage amplitude ≤ 0.05 mV, indistinguishable from noise. The degree of scar was described as a percentage of the LA area (mild <20%, moderate 20-60%, and severe >60%) involved.

Results:
Age and gender distribution was similar in both groups. Left atrial scar was detected in 172 (56%) patients in group 1 and 134 (51%) in group 2 (p=0.24). After adjusting for age and gender in multivariable logistic model, diagnosis of AF or SVT did not show to have any association with the incidence of scar (p=0.22). Based on the 3D mapping, 52(30%) patients were classified as having mild LA scarring, 88(51%) moderate scar and 32(19%) with severe scar in group 1. Distribution of scar severity in group 2 was: mild 50(37%), moderate 67(50%), and severe in 17(13%), which was similar to that of AF patients (p=0.248).

Conclusion:
Similar prevalence and distribution of severity of the left atrial scarring in elderly patients with and without atrial fibrillation suggest age-dependent substrate remodeling to be the major contributor of scar formation. Our results indicate that scar could facilitate atrial fibrillation in predisposed subjects only.
Abstract 15878: GSK-3α in Fibroblasts Attenuates Cardiac Fibrosis and Dysfunction Induced by Pressure Overload Through Modulation of TGFβ1
Authors: Zhai Peiyong , Shirakabe Akihiro , Magrys Bonaventure , Sadoshima Junichi
Published: March 2022

Glycogen synthase kinase-3α (GSK-3α) is a ubiquitously expressed S/T kinase that has versatile functions. Cardiac-specific loss of GSK-3α has outcomes that contrast with those of systemic deletion of GSK-3α after myocardial infarction, indicating cell type-specific roles of GSK-3α. However, the role of GSK-3α in fibroblasts (FB) remains to be defined. We hypothesized that GSK-3α in FB attenuates cardiac fibrosis (CF) and dysfunction in response to pressure overload (PO), and subjected FB-specific GSK-3α knockout mice (GSK-3αf/f/FSP-Cre, KO) and littermate GSK-3αf/f mice (CT) to 4 weeks of PO induced by transverse aortic constriction. The CF (%) was greater in KO than in CT (1.9±0.2 vs 1.1±0.1, p<0.01) after sham operation, showing that loss of GSK-3α in FB causes CF at baseline. After PO, CF was increased in both KO and CT, and there was much more in KO than in CT (7.9±1.3 vs 3.8±0.4, p<0.01). There was significantly more type I and type III collagen in KO than in CT after PO. Cardiac FB (%) measured by positive HSP47 staining area was more in KO than in CT after PO (22±1 vs 11±1, p<0.005). These data suggest that loss of GSK-3α in FB promotes CF. The lung weight/body weight (mg/g) was greater in KO than in CT (11.3±1.8 vs 7.7±0.7, p<0.05) after PO, indicating that KO had more severe lung congestion. Left ventricular (LV) ejection fraction (EF) and fractional shortening (FS) were not significantly different between sham KO and CT. The EF (45±5% vs 58±3%, p<0.05) and FS (19±2% vs 25±2%, p<0.05) were lower in KO than in CT after PO. LV ±dP/dts (mmHg/s) were lower in KO than in CT after PO (+dP/dt, 5306±358 vs 7536±541, p<0.01; -dP/dt, 6250±404 vs 8893±353, p<0.001) although they were not significantly different between sham KO and CT. LV end-diastolic pressure was higher in KO than in CT (15±2 vs 9±2, p<0.05) after PO. These data show that loss of GSK-3α in FB exacerbates PO-induced cardiac dysfunction. More TGFβ1 was observed in cardiac FB in KO than in CT after PO. In neonatal rat cardiac FB, knockdown of GSK-3α increased the levels of TGFβ1, phospho-Smad3, α-smooth muscle actin, and Ki67-positive cells, showing that GSK-3α inhibits proliferation and myofibroblast transformation of FB. In conclusion, GSK-3α in FB protects against PO-induced CF and dysfunction through inhibition of TGFβ1.
Abstract 15897: Identification of Candidates for Novel Interatrial Shunt Devices Through Non-invasive Testing in Patients With Heart Failure and Preserved Ejection Fraction
Authors: Yadlapati Ajay , Dixon Debra , Beussink-Nelson Lauren , Gajjar Mark , Mitter Sumeet S , Sanjiv Sanjiv J
Published: March 2022

Introduction:
Interatrial shunt devices (IASD) are a novel therapeutic option for heart failure and preserved ejection fraction (HFpEF). IASDs work by decompressing the overloaded left atrium (LA) via shunting of blood to the right atrium (RA). Thus, optimal candidates for the IASD intervention will have an elevated pressure gradient between the LA and RA. We hypothesized that increased LA-RA gradient could be diagnosed non-invasively by echo.

Methods:
A total of 293 consecutive patients with HFpEF who also underwent invasive hemodynamic testing were were identified. All patients underwent comprehensive echo, including tissue Doppler. Patients were categorized into 2 groups based on the LA-RA pressure gradient (PCWP-RA pressure) at time of invasive hemodynamic testing (PCWP-RAP > 10 mmHg [large pressure gradient] vs. PCWP 0-5 mmHg [low pressure gradient]), and clinical, laboratory, and echocardiography parameters were compared between groups.

Results:
Mean age was 64±12 years, 59% were female, 36% were African American, and comorbidities were common. Of the 293 patients, n=58 had PCWP-RAP gradient of 0-5 mmHg and n=114 had PCWP-RAP > 10 mmHg, with the rest of the patients (n=56) in the PCWP-RAP 5-10 mmHg range. Patients with an elevated PCWP-RAP gradient were more often female and obese and less likely to have a history of atrial fibrillation (Table). On echocardiography, the 2 parameters that were most different between groups were TAPSE and lateral e’ velocity such that an elevated ratio of TAPSE to lateral e’ velocity identified patients with HFpEF who were most likely to have an elevated PCWP-RAP gradient > 10 mmHg (area under the ROC curve = 0.69 [95% CI 0.60-0.78]; P=0.001).

Conclusions:
An elevated TAPSE/lateral e’ velocity ratio on echo in HFpEF is associated with invasive PCWP-RAP gradient > 10 mmHg at rest and may aid in the identifying suitable HFpEF candidates who would benefit from an IASD.
Abstract 15899: The Effect of Cerebral Oxygenation on Cardiac Arrest Outcomes: A Multicenter Pilot Observational Study
Authors: Parnia Sam , Yang Jie , Nguyen Robert T , Ahn Anna , Inigo-Santiago Loren , Zhu Jiawen , Nasir Asad , Golder Kim , Ravishankar Shreyas , Bartlett Pauline , Xu Jianjin , Pogson David , Cooke Sarah , Walker Christopher , Spearpoint Ken , Kitson David , Melody Teresa , Chilwan Mehboob , Schoenfeld Elinor R , Richman Paul S , Mills Barbara , Wichtendahl Nancy , Nolan Jerry , Singer Adam J , Brett Stephen , Perkins Gavin D , Deakin Charles D
Published: March 2022

Background:
Cardiac arrest (CA) is associated with morbidity and mortality due to cerebral ischemia. We therefore tested the hypothesis that higher regional cerebral oxygenation (rSO2) during resuscitation is associated with improved return of spontaneous circulation (ROSC), survival and neurological outcomes at hospital discharge. We further examined the validity of rSO2 as a test to predict these outcomes.

Methods:
Multicenter prospective study of in-hospital CA (IHCA). Inclusion criteria: IHCA, age≥18 years, Prolonged CPR≥5 minutes. Patients were recruited consecutively during working hours between 08/2011-09/2014. Survival with a favorable neurological outcome was defined as a Cerebral Performance Category (CPC)1-2.

Results:
Among 504 IHCA events, 183 (36%) met inclusion criteria. Overall 62/183 (33.9%) achieved ROSC, while 13/183(7.1%) achieved CPC1-2 at discharge. Higher mean±SD rSO2 was associated with ROSC vs. no ROSC (51.8±11.2% vs. 40.9±12.3%) and CPC1-2 vs. CPC3-5 (56.1±10.0% vs. 43.8±12.8%), both P<0.001). Mean rSO2 during the last 5 minutes of CPR best predicted ROSC (AUC=0.76:95% CI:0.69-0.83); rSO2≥25% provided 100% sensitivity (95%CI:94%-100%), 100% negative predictive value (NPV) (95%CI:79%-100%); rSO2 ≥65% provided: 99% specificity (95%CI:95%-100%), 93% positive predictive value (PPV) (95%CI:66%-100%) for ROSC. Time with rSO2>50% during CPR best predicted CPC1-2 (AUC=0.79: 95%CI:0.70-0.88). Specifically, ≥60% CPR time with rSO2>50% provided 77% sensitivity (95%CI:46%-95%), 72% specificity (95%CI:65%-79%) and 98% NPV (95%CI: 93%-100%) for CPC1-2.

Conclusions:
Cerebral oximetry allows real-time non-invasive cerebral oxygenation monitoring during CPR. Higher cerebral oxygenation during CPR is associated with ROSC and neurologically favorable survival to hospital discharge. Achieving higher rSO2 during resuscitation may optimize the chances of CA favorable outcomes.