Vascular phenotypes and innate immune responses following Kawasaki disease and toxic shock syndrome

© 2017 Dr. Katherine Ya-Hui ChenBackground: The pathogenesis of cardiovascular disease begins in early life. Inflammation is increasingly recognised to play a pivotal role in the initiation and progression of atherosclerotic cardiovascular disease. It is unclear whether acute childhood vascular inflammation results in heightened cardiovascular risk and reflects an underlying increased inflammatory predisposition. Understanding the host immune susceptibility determinants and the impact of early life vascular inflammation on the subsequent development of subclinical atherosclerosis could assist in improving diagnostics, prognostication, and treatment. This thesis focuses on two childhood diseases characterised by acute inflammation involving the cardiovascular system, Kawasaki disease (KD) and toxic shock syndrome (TSS). Aims: Part 1: To identify the macro-and microvascular phenotypes associated with subclinical atherosclerosis in individuals following KD or TSS. Part 2: To investigate differences in innate immune responses following KD or TSS that might underlie host susceptibility. Methods: Part 1: A case-control study of 60 KD, 22 TSS, and 60 control participants; cases were investigated at least two years after their acute illness. Non-invasive measurements of extra-cardiac arterial structure (carotid and aortic intima-media thickness) and function (pulse wave velocity, carotid artery distensibility and diameter compliance) were done. Retinal microvascular parameters were measured in both an Australian and Singaporean cohort. Part 2: In-vitro cytokine production induced by Toll-like receptor and inflammasome ligand stimulation was measured in whole blood. Results: Part 1: Compared to control participants, Individuals following KD had increased aortic intima-media thickness and reduced carotid distensibility, indicative of heightened cardiovascular risk. Furthermore, KD participants, particularly of Asian ethnicity, had wider retinal venules with an incremental increase in those with coronary artery abnormalities, also in keeping with an increase in cardiovascular risk. Individuals following TSS had reduced retinal fractal dimension but no other adverse differences in the macro- and microvascular parameters. Part 2: Compared to control participants, individuals following KD had reduced interleukin (IL)-1 receptor antagonist production in response to stimulation with double stranded RNA and increased IL-6 production in response to incubation with Lyovec™ (a lyophilised cationic lipid-based transfection reagent). Toxic shock syndrome participants had increased pro-inflammatory cytokine production (interferon-, IL-1, IL-6) in response to stimulation with bacterial ligands (peptidoglycan, lipopolysaccharide). Conclusions: Part 1: Extra-cardiac vascular phenotypes indicative of increased cardiovascular risk have been found in individuals following KD. These findings suggest that these individuals should minimise their modifiable cardiovascular risk factors. Limited evidence for increased cardiovascular risk was found following TSS, suggesting that differing causes of childhood vascular inflammation may have varying impact on the development of subclinical atherosclerosis. Part 2: Individuals with previous KD or TSS have decreased anti-inflammatory and increased pro-inflammatory responses (respectively) to innate immune stimulation. The findings indicate either an inherent immunological susceptibility and/or trained innate immunity following the acute illness.