Predisposing factors, pathogenesis and therapeutic intervention of Kawasaki disease

Galeotti, Caroline; Kaveri, Srini V.; Cimaz, Rolando; Koné‐Paut, Isabelle; Bayry, Jagadeesh

doi:10.1016/j.drudis.2016.08.004

Cited by 53 publications

(44 citation statements)

References 101 publications

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“…Traditional viewpoints propose that the immune system is abnormally activated in the acute stage of KD. Blood vessels are damaged by a large number of cytokines and anti-endothelial cytotoxic antibodies (Andreozzi et al, 2017;Galeotti et al, 2016), and the level of immune globulin generally increases (Menikou, Langford & Levin, 2019). However, in this study, IgA and IgG in the peripheral blood of the KD group decreased, which may be related to the following factors.…”

Section: Discussioncontrasting

confidence: 56%

Effects of changes on gut microbiota in children with acute Kawasaki disease

Shen¹,

Ding²,

Yang³

et al. 2020

PeerJ

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Background Kawasaki disease (KD) is an acute febrile illness of early childhood. The exact etiology of the disease remains unknown. At present, research on KD is mostly limited to susceptibility genes, infections, and immunity. However, research on the correlation between gut microbiota and KD is rare. Methods Children with a diagnosis of acute KD and children undergoing physical examination during the same period were included. At the time of admission, the subjects’ peripheral venous blood and feces were collected. Faecal samples were analyzed for bacterial taxonomic content via high-throughput sequencing. The abundance, diversity, composition, and characteristic differences of the gut microbiota in KD and healthy children were compared by alpha diversity, beta diversity, linear discriminant analysis and LDA effect size analysis. Blood samples were used for routine blood examination, biochemical analysis, and immunoglobulin quantitative detection. Results Compared with the control group, the community richness and structure of gut microbiota in the KD group was significantly reduced (Chao1 richness estimator, mean 215.85 in KD vs. mean 725.76 in control, p < 0.01; Shannon diversity index, mean 3.32 in KD vs. mean 5.69 in control, p < 0.05). LEfSe analysis identified two strains of bacteria significantly associated with KD: Bacteroidetes and Dorea. Bacteroidetes were enriched in healthy children (mean 0.16 in KD vs. mean 0.34 in control, p < 0.05). Dorea was also enriched in healthy children but rarely existed in children with KD (mean 0.002 in KD vs. mean 0.016 in control, p < 0.05). Compared with the control, IgA and IgG in the KD group decreased (IgA, median 0.68 g/L in KD vs. median 1.06 g/L in control, p < 0.001; IgG, median 6.67 g/L in KD vs. median 9.71 g/L in control, p < 0.001), and IgE and IgM levels were not significantly changed. Conclusions Dysbiosis of gut microbiota occurs in children with acute KD and may be related to the etiology or pathogenesis of KD. It is worth noting that for the first time, we found that Dorea, a hydrogen-producing bacterium, was significantly reduced in children with acute KD. Overall, our results provide a theoretical basis for the prevention or diagnosis of KD based on intestinal microecology.

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Section: Discussioncontrasting

confidence: 56%

Effects of changes on gut microbiota in children with acute Kawasaki disease

Shen¹,

Ding²,

Yang³

et al. 2020

PeerJ

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“…KD is an acute vasculitis that predominantly targets the medium-sized arteries, particularly the coronary artery, and which leads to the development of coronary artery aneurysm if untreated with IVIG. Although IVIG therapy significantly reduces the occurrence of coronary aneurysm and the morbidity and mortality associated with KD, some patients are resistant to this therapy; thus, additional therapies are still needed 2 , 15 . In the present study, we demonstrated that IL-10 supplementation by AAV gene delivery almost completely prevented inflammatory responses, such as inflammatory cell infiltration and the expression of cytokines, and the subsequent development of cardiac fibrosis and dysfunction in CAWS-induced vasculitis, a murine model of KD.…”

Section: Discussionmentioning

confidence: 99%

“…Clinical and experimental studies implicated a number of inflammatory cytokines are implicated in the pathogenesis of KD 2 , 15 . Among these, TNF-α is one of the most important cytokines in the development of KD.…”

Section: Discussionmentioning

confidence: 99%

Adeno-associated Virus Vector-mediated Interleukin-10 Induction Prevents Vascular Inflammation in a Murine Model of Kawasaki Disease

Nakamura

Watanabe

Kimura

et al. 2018

Sci Rep

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Kawasaki disease (KD), which is the leading cause of pediatric heart disease, is characterized by coronary vasculitis and subsequent aneurysm formation. Although intravenous immunoglobulin therapy is effective for reducing aneurysm formation, a certain number of patients are resistant to this therapy. Because interleukin-10 (IL-10) was identified as a negative regulator of cardiac inflammation in a murine model of KD induced by Candida albicans water-soluble fraction (CAWS), we investigated the effect of IL-10 supplementation in CAWS-induced vasculitis. Mice were injected intramuscularly with adeno-associated virus (AAV) vector encoding IL-10, then treated with CAWS. The induction of AAV-mediated IL-10 (AAV-IL-10) significantly attenuated the vascular inflammation and fibrosis in the aortic root and coronary artery, resulting in the improvement of cardiac dysfunction and lethality. The predominant infiltrating inflammatory cells in the vascular walls were Dectin-2+CD11b+ macrophages. In vitro experiments revealed that granulocyte/macrophage colony-stimulating factor (GM-CSF) induced Dectin-2 expression in bone marrow-derived macrophages and enhanced the CAWS-induced production of tumor necrosis factor-α (TNF-α) and IL-6. IL-10 had no effect on the Dectin-2 expression but significantly inhibited the production of cytokines. IL-10 also inhibited CAWS-induced phosphorylation of ERK1/2, but not Syk. Furthermore, the induction of AAV-IL-10 prevented the expression of TNF-α and IL-6, but not GM-CSF and Dectin-2 at the early phase of CAWS-induced vasculitis. These findings demonstrate that AAV-IL-10 may have therapeutic application in the prevention of coronary vasculitis and aneurysm formation, and provide new insights into the mechanism underlying the pathogenesis of KD.

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“…This treatment has been administered in IVIG-resistant patients with success regarding fever and inflammatory parameters, however, with no differences regarding cardiac disease (Burns et al, 2005, 2008; Son et al, 2011). Other immunosuppressive agents have occasionally been used such as: cyclosporine, cyclophosphamide, methotrexate, and plasma exchange in resistant KD patients to IVIG, steroids, and anti-TNFα (Galeotti et al, 2016). …”

Section: Kawasaki Diseasementioning

confidence: 99%

IL-1 Inhibition May Have an Important Role in Treating Refractory Kawasaki Disease

Dusser

Koné‐Paut

2017

Front. Pharmacol.

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Kawasaki disease (KD) is an acute inflammatory vasculitis occurring in young children before 5 years and representing at this age, the main cause of acquired heart disease. A single infusion of 2 g/kg of intravenous immunoglobulins along with aspirin has reduced the frequency of coronary artery aneurysms from 25 to 5%. However, 10–20% of patients do not respond to standard treatment and have an increased risk of cardiac complications and death. The development of more potent therapeutic approaches of KD is an urgent need. Phenotypical and immunological similarities between KD and systemic juvenile idiopathic arthritis led to the hypothesis that KD could be considered as an autoinflammatory disease. New insights regarding KD’s pathogenesis have merged from the combination of genetic and transcriptomic data revealing the key role of interleukin-1 (IL-1) signaling in the pathogenesis of the vasculitis. Once activated, IL-1α and IL-1β trigger a local proinflammatory environment-inducing vasodilatation and attracting monocytes and neutrophils to sites causing tissue damage and stress. Both IL-1α and IL-1β have been shown to induce myocarditis and aneurysm formation in Lactobacillus casei cell-wall extract mouse model of KD; both being successfully improved with IL-1 blockade treatment such as anakinra. Treatment failure in patients with the high-risk inositol-triphosphate 3-kinase C genotype was associated with highest basal and stimulated intracellular calcium levels, increased cellular production of IL-1β, and IL-18, and higher circulating levels of both cytokines. Three clinical trials of IL-1 blockade enrolling KD patients are currently being conducted in Western Europe and in USA, they could change KD outcome.

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Predisposing factors, pathogenesis and therapeutic intervention of Kawasaki disease

Cited by 53 publications

References 101 publications

Effects of changes on gut microbiota in children with acute Kawasaki disease

Effects of changes on gut microbiota in children with acute Kawasaki disease

Adeno-associated Virus Vector-mediated Interleukin-10 Induction Prevents Vascular Inflammation in a Murine Model of Kawasaki Disease

IL-1 Inhibition May Have an Important Role in Treating Refractory Kawasaki Disease

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