Study design and rationale to assess Doxycycline Efficacy in preventing coronary Artery Lesions in children with Kawasaki disease (DEAL trial) – A phase II clinical trial

Bratincsák, András; Limm-Chan, Blair; Nerurkar, Vivek R.; Ching, Lauren L.; Reddy, Venu; Lim, Eunjung; Shohet, Ralph V.; Melish, Marian E.

doi:10.1016/j.cct.2017.11.014

Cited by 2 publications

(3 citation statements)

References 28 publications

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“…Additionally, elevated MMP25 and MMP17 can be used as biomarkers alongside MMP9 to improve diagnosis and accelerate drug development. 59 Interestingly, doxycycline-an inhibitor of MMPs-has already been shown to reduce ECM degradation and prevent the development of CALs in an animal model of KD and a small clinical trial, 17,66 suggesting that patients with KD, including those with CALs, may benefit from MMP antagonist treatment, especially for our identified MMP25 and MMP17.…”

Section: Discussionmentioning

confidence: 95%

Single-Cell Transcriptome Reveals Potential Mechanisms for Coronary Artery Lesions in Kawasaki Disease

Chen,

Yang,

Zhang

et al. 2024

ATVB

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BACKGROUND: Coronary artery lesions (CALs) are the most common and major complication of Kawasaki disease (KD) in developed countries. However, the underlying immunologic mechanisms of CAL development in KD remain unclear. METHODS: Here, we conducted single-cell transcriptome analyses of 212 210 peripheral blood mononuclear cells collected from a cross-sectional cohort of 16 children, including 4 patients with KD with CALs, 5 patients with KD without CALs, 4 healthy controls, and 3 febrile controls. RESULTS: KD altered the proportion of peripheral blood mononuclear cells, including an increasing trend in inflammatory cells (megakaryocytes and monocytes) and a decreasing trend in lymphocytes (eg, CD4 + T, CD8 + T, mucosal-associated invariant T, natural killer, and γδ T cells), highlighting the potential presence of lymphopenia phenomenon in KD. Our data indicated the presence of inflammatory cytokine storm in patients with KD with CALs, caused by systemic upregulation of TNFSF13B, CXCL16, TNFSF10, and IL1RN, mainly produced by monocytes (especially for the Mono_CD14-CD16 cluster) and megakaryocytes. We also found that myeloid cells of patients with KD, particularly in those with CALs, might play a role in vascular injury (eg, increased MMP [matrix metalloproteinase] 9, MMP17, and MMP25) and immune cell recruitment. The immune landscape of patients with KD with CALs was featured by lower exhaustion levels in natural killer cells, a high cytotoxic state in the CD8_Pro cluster, and activation of the complement system in monocytes. Additionally, the activation of B cells was more pronounced in the early stage of KD. CONCLUSIONS: Collectively, this study provides a comprehensive understanding of the roles of various immune cells and inflammatory cytokine storms in the development of CALs in KD and offers a valuable resource for identifying novel therapeutic targets for patients with KD with CALs.

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Section: Discussionmentioning

confidence: 95%

Single-Cell Transcriptome Reveals Potential Mechanisms for Coronary Artery Lesions in Kawasaki Disease

Chen,

Yang,

Zhang

et al. 2024

ATVB

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“…TNFα can drive metalloproteinase mmp9 activity to cause elastin breakdown. Doxycycline has been shown to prevent this (86), and human data will come from the currently open trial (87). A number of studies show marked myocarditis in these models with late fibrosis (88); however, following troponins is generally not clinically relevant.…”

Section: Models Systems Of Kd (See Table 1)mentioning

confidence: 99%

“…Limited reports of successful treatment with anti-B cell monoclonal antibodies (anti-CD20) also support a role for B cell activation in KD pathogenesis (140). Based on data regarding MMP in murine models, doxycycline is also being used (87). Supplementation with statins also has a currently recruiting trial ongoing.…”

Section: Other Treatmentsmentioning

confidence: 99%

Antibodies and Immunity During Kawasaki Disease

Hicar

2020

Front. Cardiovasc. Med.

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The cause of Kawasaki disease (KD), the leading cause of acquired heart disease in children, is currently unknown. Epidemiology studies support that an infectious disease is involved in at least starting the inflammatory cascade set off during KD. Clues from epidemiology support that humoral immunity can have a protective effect. However, the role of the immune system, particularly of B cells and antibodies, in pathogenesis of KD is still unclear. Intravenous immunoglobulin (IVIG) and other therapies targeted at modulating inflammation can prevent development of coronary aneurysms. A number of autoantibody responses have been reported in children with KD and antibodies have been generated from aneurysmal plasma cell infiltrates. Recent reports show that children with KD have similar plasmablast responses as other children with infectious diseases, further supporting an infectious starting point. As ongoing studies are attempting to identify the etiology of KD through study of antibody responses, we sought to review the role of humoral immunity in KD pathogenesis, treatment, and recovery.

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Study design and rationale to assess Doxycycline Efficacy in preventing coronary Artery Lesions in children with Kawasaki disease (DEAL trial) – A phase II clinical trial

Abstract: This study was registered on clinicaltrials.gov (NCT01917721).

Cited by 2 publications

References 28 publications

Single-Cell Transcriptome Reveals Potential Mechanisms for Coronary Artery Lesions in Kawasaki Disease

Single-Cell Transcriptome Reveals Potential Mechanisms for Coronary Artery Lesions in Kawasaki Disease

Antibodies and Immunity During Kawasaki Disease

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