Identifying Downregulation of Autophagy Markers in Kawasaki Disease

Kawasaki disease (KD) is the most common cause of heart disease acquired in childhood. Even if treated with high-dose intravenous immunoglobulin G (IVIG) at the early stage; children are still at risk of developing coronary artery lesions. Accumulating evidence suggests that autophagy is enhanced in various heart diseases. Evaluating the pathogenic role of autophagy in KD and coronary artery lesions (CAL) may aid in identifying a potential therapeutic target for the treatment or prevention of the disease. Blood samples were obtained from 20 children with KD at the onset of disease and 21 days after IVIG therapy. Twenty children with other causes of febrile disease and 20 healthy children were included as controls. Total RNA was extracted from white blood cells; and autophagy-related gene mRNA expression levels were measured using real-time polymerase chain reaction. The patients with KD had downregulated levels of LC3B mRNA (0.50 ± 0.06 vs. 1.67 ± 0.15; p < 0.001), BECN1 mRNA (0.70 ± 0.08 vs. 1.43 ± 0.23; p < 0.05), and ATG16L1 mRNA (0.28 ± 0.04 vs. 0.96 ± 0.16; p < 0.01) compared to the febrile control group. The values of these parameters all increased significantly 21 days after the IVIG therapy as follows: LC3B mRNA (1.77 ± 0.29 vs. 0.50 ± 0.06; p < 0.001), BECN1 mRNA (1.67 ± 0.36 vs. 0.70 ± 0.08; p < 0.05), and ATG16L1 mRNA (2.96 ± 0.43 vs. 0.28 ± 0.04; p < 0.001), while the level of ATG16L1 mRNA persists low in KD patients with CAL. Our results showed the autophagy-related genes expressions in KD and their change after IVIG administration. This suggests that autophagy may have a protective effect on KD.

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Serum Lp-PLA2 Level Predicting Coronary Artery Lesions in Children with Kawasaki Disease

The Heart Surgery Forum ◽

10.1532/hsf.3833 ◽

2021 ◽

Vol 24 (4) ◽

pp. E611-E618

Author(s):

Xiong Zhang ◽

Ya-Wang Shao ◽

Ya-Lan Zhang ◽

Yi Liu

Keyword(s):

Coronary Artery ◽

Kawasaki Disease ◽

Color Doppler ◽

Intima Media Thickness ◽

Enzyme Linked Immunosorbent Assay ◽

Control Group ◽

Healthy Children ◽

Coronary Artery Lesions ◽

Cell Counts ◽

Ifn Γ

Background: Kawasaki disease (KD) is an inflammatory disease associated with coronary vasculitis in children. In this study, we explored the correlation between Lipoprotein associated phospholipase A2 (Lp-PLA2) and coronary artery lesions (CAL) in children with KD. Methods: Ninety-three children with KD were divided into a normal coronary artery (NCA, 54 cases) group and coronary artery lesions (CAL, 39 cases) group, according to the results of echocardiography. Another 42 healthy children were selected as the control group. The serumal levels of Lp-PLA2, Interferon-γ(IFN-γ) and Interleukin-6 (IL-6) were determined by using an enzyme-linked immunosorbent assay. In addition, erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP) level were analyzed. The left main coronary artery (LMCA), diameters of left anterior descending coronary artery (LADC), right proximal coronary artery (PRCA), and carotid intima-media thickness (IMT) were obtained by color Doppler ultrasound. The correlation between the above indexes and KD was analyzed. Results: The levels of white blood cell counts (WBC), ESR, CRP, IFN-γ, IL-6 and Lp-PLA2 as well as IMT were significantly increased in KD children (P < 0.05), and the levels of CRP, IFN-γ, IL-6 and Lp-PLA2 as well as IMT in the CAL group increased more significantly (P < 0.05). An increasing trend also has been described in the diameters of LMCA, LADC and PRCA for KD children with CAL compared with with NCA. The results of logistic regression analysis showed that the elevated levels of CRP, IFN-γ, IL-6 and Lp-PLA2 were independent risk factors for KD with CAL. Correlation analysis showed that Lp-PLA2 level was positively correlated with the levels of IFN-γ, IL-6 and CRP in CAL group and NCA group (respectively, all P < 0.01). In addition, a similar correlation was also described between Lp-PLA2 level and the diameters of LMCA, LADC and PRCA in CAL group (respectively, all P < 0.01). Conclusion: Lp-PLA2 may participate in the pathological mechanism of KD. Detection of the serum Lp-PLA2 level can be used in the diagnosis of KD disease and the assessment of coronary artery lesions in KD children.

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Efficacy and Limitation of Infliximab Treatment for Children with Kawasaki Disease Intractable to Intravenous Immunoglobulin Therapy: Report of an Open-label Case Series

The Journal of Rheumatology ◽

10.3899/jrheum.110877 ◽

2012 ◽

Vol 39 (4) ◽

pp. 864-867 ◽

Cited By ~ 55

Author(s):

MASAAKI MORI ◽

TOMOYUKI IMAGAWA ◽

RYOKI HARA ◽

MASAKO KIKUCHI ◽

TAKUMA HARA ◽

...

Keyword(s):

Coronary Artery ◽

Kawasaki Disease ◽

Intravenous Immunoglobulin ◽

Ivig Therapy ◽

High Dose ◽

Infliximab Treatment ◽

Coronary Artery Lesions ◽

Open Label ◽

Intravenous Immunoglobulin Therapy ◽

Cell Counts

Objective.Kawasaki disease (KD) is an acute febrile disease in infants and young children. Five percent to 8% of cases will be complicated with coronary dilatation or aneurysm, although introduction of high-dose intravenous immunoglobulin (IVIG) therapy has provided remarkable results for reducing the frequency of cardiac involvement. We describe the results of an open-label trial of infliximab, an anti-tumor necrosis factor-α monoclonal antibody, for suppressing the progression of coronary artery lesions in cases of KD refractory to extensive IVIG therapy. Plasma exchange (PE) was available as a rescue therapy for patients refractory to infliximab.Methods.Twenty eligible patients fulfilled the diagnostic criteria for KD, and were primarily treated with IVIG up to 4 g/kg. “Refractory to IVIG” was defined as persisting or reemerging fever > 38°C and positive fractional changes of C-reactive protein, white blood cell counts, or neutrophil counts 48 hours after IVIG infusion. These cases were treated with infliximab, 5 mg/kg, which should begin within 10 days of disease onset. PE for patients refractory to infliximab was performed with 5% albumin.Results.There was rapid improvement of inflammatory symptoms as well as normalization of the inflammatory markers. Sequential examination by echocardiography up to disease Day 30 revealed that the inflamed and mildly dilated coronary artery at the beginning of the study regressed to normal size in the convalescent phase. Two out of 20 patients showed incomplete improvement of inflammatory symptoms after infliximab treatment, and were provided with PE therapy, with no complications.Conclusion.Eighteen of 20 patients were effectively treated with infliximab, and 2 cases were effectively treated with PE to prevent progression to coronary artery lesions. No adverse event such as anaphylactoid reaction, heart failure, severe infectious diseases, or tuberculosis was observed in this trial.

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Functional benefits of corticosteroid and IVIG combination therapy in a coronary artery endothelial cell model of Kawasaki disease

Pediatric Rheumatology ◽

10.1186/s12969-020-00461-6 ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Takashi Inoue ◽

Shokei Murakami ◽

Kenji Matsumoto ◽

Akio Matsuda

Keyword(s):

Coronary Artery ◽

Kawasaki Disease ◽

Combination Therapy ◽

Molecular Mechanisms ◽

Ivig Therapy ◽

Unknown Etiology ◽

High Dose ◽

Ivig Resistance ◽

Tnf Α ◽

Clinical Benefits

Abstract Background Kawasaki disease (KD) is the most common pediatric systemic vasculitides of unknown etiology. Recent clinical studies led to reappraisal of the usefulness of initial combination therapy of intravenous immunoglobulin (IVIG) plus a corticosteroid for patients with severe KD. However, the molecular mechanisms underlying the clinical benefits of that combination therapy remain unclear. Here, we used cultured human coronary artery endothelial cells (HCAECs), as a mimic of KD, to study the possible mechanisms responsible for the clinical benefits of adding a corticosteroid to standard IVIG therapy for patients with severe KD. Methods HCAECs were stimulated with TNF-α, IL-1α or IL-1β in the presence and absence of high-dose IgG and/or dexamethasone (DEX). The mRNA and protein concentrations for high-mobility group box-1 (HMGB1), IL-1α, IL-6 and granulocyte-colony stimulating factor (G-CSF) in the culture supernatants were measured by quantitative PCR (qPCR) and ELISA, respectively. Apoptosis was evaluated by the caspase 3/7 activities. Results DEX, but not IgG, significantly inhibited apoptosis caused by inflammatory stimuli, resulting in effective reduction of HMGB1 and IL-1α protein release by HCAECs. As previously reported, DEX or IgG alone significantly suppressed TNF-α-induced production of IL-6 and G-CSF and mRNA expression, but induction of those cytokines by IL-1 s (IL-1α and IL-1β) was resistant to high-dose IgG. Conclusions A corticosteroid can effectively inhibit the release of HMGB1 and IL-1α, which may be involved in IVIG resistance in KD. Since high-dose IgG does not have such beneficial anti-cytotoxic effects, adding a corticosteroid to standard IVIG therapy may help prevent the progression of IVIG resistance in KD.

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Association of PECAM-1 Gene Polymorphisms with Kawasaki Disease in Chinese Children

Disease Markers ◽

10.1155/2017/2960502 ◽

2017 ◽

Vol 2017 ◽

pp. 1-6 ◽

Cited By ~ 4

Author(s):

Zhuoying Li ◽

Dong Han ◽

Jie Jiang ◽

Jia Chen ◽

Lang Tian ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Kawasaki Disease ◽

Gene Polymorphisms ◽

Cell Adhesion Molecule ◽

Systemic Vasculitis ◽

Healthy Children ◽

Coronary Artery Lesions ◽

Artery Disease ◽

The Relationship

Kawasaki disease (KD) is an acute systemic vasculitis complicated by development of coronary artery lesions. PECAM-1 is a kind of cell adhesion molecule, which plays an important role in coronary artery disease. The relationship between PECAM-1 gene polymorphisms and their susceptibility to Kawasaki diseases (KD) is still unclear. In our study, we examined the PECAM-1 gene polymorphisms in 44 KD patients and 59 healthy children and revealed the correlation of PECAM-1 gene polymorphisms in KD children with and without coronary artery lesions (CAL).

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The IL-1B Gene Polymorphisms rs16944 and rs1143627 Contribute to an Increased Risk of Coronary Artery Lesions in Southern Chinese Children with Kawasaki Disease

Journal of Immunology Research ◽

10.1155/2019/4730507 ◽

2019 ◽

Vol 2019 ◽

pp. 1-7 ◽

Cited By ~ 4

Author(s):

Lan Yan Fu ◽

Xiantao Qiu ◽

Qiu Lian Deng ◽

Ping Huang ◽

Lei Pi ◽

...

Keyword(s):

Coronary Artery ◽

Kawasaki Disease ◽

Gene Polymorphisms ◽

Chinese Population ◽

Healthy Children ◽

Nucleotide Polymorphisms ◽

Coronary Artery Lesions ◽

Multicenter Studies ◽

Southern Chinese ◽

Increased Risk

Background. Kawasaki disease (KD) is a systemic form of self-limited vasculitis in children less than five years old, and the main complication is coronary artery injury. However, the etiology of KD remains unclear. The IL-1B polymorphisms rs16944 GG and rs1143627 AA and their diplotype GA/GA have been associated with significantly increased risk of intravenous immunoglobulin (IVIG) resistance in a Taiwanese population, but the relationship between rs16944 A/G and rs1143627 G/A and coronary artery lesions (CALs) in patients with KD has not been investigated. The present study is aimed at investigating whether the rs16944 A/G and rs1143627 G/A polymorphisms in IL-1B were associated with KD susceptibility and CALs in a southern Chinese population. Methods and Results. We recruited 719 patients with KD and 1401 healthy children. Multiplex PCR was used to assess the genotypes of single nucleotide polymorphisms (SNPs), including two SNPs of IL-1B, rs16944 A/G and rs1143627 G/A. According to the results, no significant association was observed between the IL-1B (rs16944 and rs1143627) polymorphisms and KD risk in the patients compared with the healthy controls in our southern Chinese population. However, in further stratified analysis, we found that children younger than 12 months with the rs16944 GG and rs1143627 AA genotypes of IL-1B had a higher risk of CALs than those with the AA/AG genotypes of rs16944 and GG/AG genotypes of rs1143627 (OR=2.28, 95% CI=1.32-3.95, P=0.0032, adjusted OR=2.33, 95% CI=1.34-4.04, P=0.0027). Conclusions. Our results indicated that there was no association between the rs16944 A/G and rs1143627 G/A gene polymorphisms and KD susceptibility. However, the rs16944 GG and rs1143627 AA genotypes of IL-1B may significantly impact the risk of CAL formation in children younger than 12 months, which may contribute to the pathogenesis of KD. These findings need further validation in multicenter studies with larger sample sizes.

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Parental Awareness of Oral Health and Nutritional Behavior in Children with Congenital Heart Diseases Compared to Healthy Children

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17197057 ◽

2020 ◽

Vol 17 (19) ◽

pp. 7057

Author(s):

Nelly Schulz-Weidner ◽

Thushiha Logeswaran ◽

Maximiliane Amelie Schlenz ◽

Norbert Krämer ◽

Julia Camilla Bulski

Keyword(s):

Oral Health ◽

Infective Endocarditis ◽

Oral Hygiene ◽

Congenital Heart ◽

Early Stage ◽

Heart Diseases ◽

Parental Knowledge ◽

Control Group ◽

Healthy Children ◽

Daily Consumption

Parents of children with congenital heart disease (CHD) seem to underestimate the importance of optimized oral health. The low priority for a good oral hygiene and a healthy diet can be a risk factor for odontogenic bacteremia and infective endocarditis. The aim of this study was the evaluation of the disease awareness and dental knowledge of the parents using a questionnaire. Therefore, parents from 107 children with CHD and a healthy control group (HCG) consisting of 101 children both aged 2 to 6 years were asked to complete a questionnaire containing items about the general health, oral hygiene behavior, preventive measures, dental visits and intake of potential drinks and cariogenic nutrition of their child. The results of the present study show that the CHD group had a poorer oral health behavior than the HCG. Healthy children brushed their teeth significantly more often (65.4%) than the CHD children (45.1%). Only 75% of CHD children used fluorides in their daily life in comparison to 86.6% of the healthy children, 8.7% of their parents neglected completely fluoride supplementation. Of all CHD children 23.1% in comparison to 8.1% of the controls had never visited a dentist before. Furthermore, the daily consumption of cariogenic food and drinks was generally higher in the CHD group. These findings demonstrate a need for improvement in parental knowledge of the efficiency of different measures to improve dental health. This important oral health for CHD children from the early stage of life is obvious, especially regarding their risk for odontogenic bacteria and infective endocarditis.

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The Benefits and Respective Side-Effects of PE Therapy for Intractable Kawasaki Disease

Journal of Clinical Medicine ◽

10.3390/jcm10051062 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1062

Author(s):

Masaaki Mori ◽

Susumu Yamazaki ◽

Takuya Naruto

Keyword(s):

Kawasaki Disease ◽

Effective Means ◽

Ivig Therapy ◽

Treatment Method ◽

Treatment Result ◽

High Dose ◽

Line Treatment ◽

Coronary Artery Lesions ◽

First Line ◽

First Line Treatment

Kawasaki disease (KD) is a vasculitis syndrome that frequently develops coronary artery lesions (CALs). In the treatment of KD, the utility of high-dose intravenous immuno-globulin (IVIG) therapy has already been clarified, and it has been established as the first-line treatment method. However, since approximately 10% of patients are refractory to this IVIG therapy and 2.6% of all patients have coronary sequelae, 500 children with KD still remain every year in Japan. In this disease, it is necessary to calm inflammation within 10 days of onset in order to suppress CALs caused by a large amount of persistent inflammatory cytokines. Indeed, the early suppression of inflammation is an effective means of suppressing the onset of CALs. Here, we describe the pathophysiology of Kawasaki disease and plasma exchange (PE), which is a therapeutic method that can calm the hyper-cytokine state of this disease. The treatment result of PE for IVIG-refractory Kawasaki disease is outstanding, and an extremely large effect can be expected if it can be started before the appearance of CALs. It seems that it should always be considered as one of the powerful additional treatments in the future.

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Impact of Early Treatment with High-Dose Intravenous Immunoglobulin on Incidence of Kawasaki Disease Complications in Iranian Children

Journal of Family & Reproductive Health ◽

10.18502/jfrh.v15i4.7890 ◽

2021 ◽

Author(s):

Alireza Karimi Yazdi ◽

Parvin Akbariasbagh ◽

Yahya Aghighi ◽

Seyyed Reza Raeeskarami ◽

Khadije Toomaj ◽

...

Keyword(s):

Hearing Loss ◽

Coronary Artery ◽

Kawasaki Disease ◽

Acetylsalicylic Acid ◽

Sensorineural Hearing Loss ◽

Coronary Artery Aneurysm ◽

Artery Aneurysm ◽

High Dose ◽

Coronary Artery Lesions ◽

The Impact

Objective: Kawasaki disease (KD) occurs in five-year-old or younger children. This study aimed to evaluate the impact of high-dose intravenous immunoglobulin plus acetylsalicylic acid therapy on the prevention and treatment of coronary artery lesions and to evaluate the impact of high-dose acetylsalicylic acid (ASA) on the hearing of the patients. Materials and methods: In this retrospective cohort study, 31 patients with KD were followed from January 2012 to December 2015. The clinical, para-clinical, color Doppler echocardiogram and audiometry results were evaluated. Results: Overall, seven cases (22.6%) developed coronary artery aneurysm (CAA) in the acute phase of the disease, of whom only two still had CAA at the end of the treatment (6%). One of the five children with CAA recovery had a delay in the onset of treatment and one of two patients with persistent CAA at the end of treatment was admitted within the first 10 days. There was no evidence-based abnormal liver biochemical test. None of the patients developed sensorineural hearing loss (SNHL) on audiometry tests conducted before and after treatment. Conclusion: Recovery of coronary artery lesions was 71.43% after 28 days of the onset of treatment. The distribution of coronary artery aneurysm was not different in terms of the time of the treatment initiation (P-Value = 0.371). None of the children had a sensorineural hearing loss (SNHL) 48 hours and 4 weeks after treatment.

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Functional benefits of corticosteroid and IVIG combination therapy in a coronary artery endothelial cell model of Kawasaki disease

10.21203/rs.3.rs-16532/v2 ◽

2020 ◽

Author(s):

Takashi Inoue ◽

Shokei Murakami ◽

Kenji Matsumoto ◽

Akio Matsuda

Keyword(s):

Coronary Artery ◽

Kawasaki Disease ◽

Combination Therapy ◽

Molecular Mechanisms ◽

Ivig Therapy ◽

Unknown Etiology ◽

High Dose ◽

Ivig Resistance ◽

Tnf Α ◽

Clinical Benefits

Abstract Background Kawasaki disease (KD) is the most common pediatric systemic vasculitides of unknown etiology. Recent clinical studies led to reappraisal of the usefulness of initial combination therapy of intravenous immunoglobulin (IVIG) plus a corticosteroid for patients with severe KD. However, the molecular mechanisms underlying the clinical benefits of that combination therapy remain unclear. Here, we used cultured human coronary artery endothelial cells (HCAECs), as a mimic of KD, to study the possible mechanisms responsible for the clinical benefits of adding a corticosteroid to standard IVIG therapy for patients with severe KD.Methods HCAECs were stimulated with TNF-α, IL-1α or IL-1β in the presence and absence of high-dose IgG and/or dexamethasone (DEX). The mRNA and protein concentrations for high-mobility group box-1 (HMGB1), IL-1α, IL-6 and granulocyte-colony stimulating factor (G-CSF) in the culture supernatants were measured by quantitative PCR (qPCR) and ELISA, respectively. Apoptosis was evaluated by the caspase 3/7 activities.Results DEX, but not IgG, significantly inhibited apoptosis caused by inflammatory stimuli, resulting in effective reduction of HMGB1 and IL-1α protein release by HCAECs. As previously reported, DEX or IgG alone significantly suppressed TNF-α-induced production of IL-6 and G-CSF and mRNA expression, but induction of those cytokines by IL-1s (IL-1α and IL-1β) was resistant to high-dose IgG.Conclusions A corticosteroid can effectively inhibit the release of HMGB1 and IL-1α, which may be involved in IVIG resistance in KD. Since high-dose IgG does not have such beneficial anti-cytotoxic effects, adding a corticosteroid to standard IVIG therapy may help prevent the progression of IVIG resistance in KD.

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Association of Thrombomodulin Gene C1418T Polymorphism with Susceptibility to Kawasaki Disease in Chinese Children

Disease Markers ◽

10.1155/2018/1064380 ◽

2018 ◽

Vol 2018 ◽

pp. 1-5 ◽

Cited By ~ 1

Author(s):

Yapeng Lu ◽

Rui Liu ◽

Luting Zha ◽

Shan Yuan ◽

Lang Tian ◽

...

Keyword(s):

Coronary Artery ◽

High Risk ◽

Kawasaki Disease ◽

Protein C ◽

Systemic Vasculitis ◽

Vascular Diseases ◽

Healthy Children ◽

Coronary Artery Lesions ◽

Ivig Resistance ◽

Anticoagulant System

Kawasaki disease (KD) is an acute systemic vasculitis that predominantly affects children and can result in coronary artery lesions (CALs). Thrombomodulin (TM) is a critical cofactor in the protein C anticoagulant system. The TM C1418T (rs1042579) polymorphism is associated with a high risk of cardiac-cerebral vascular diseases. But the association of the TM C1418T polymorphism with susceptibility to KD, CAL formation, and intravenous immunoglobulin (IVIG) resistance is still unclear. In our study, we examined the TM C1418T polymorphism in 122 children with KD and 126 healthy children and revealed the correlation between the TM C1418T polymorphism and KD, CAL formation, and IVIG resistance.

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