Kawasaki disease: Diagnostic and prognostic markers, and treatment of coronary artery lesions

Abstract

Background: The acute vasculitis, Kawasaki disease (KD) is the most common pediatric acquired heart disease in young children (less than 5 years old) in the developed world. Long-term sequelae of coronary artery aneurysms are reported in 25% of untreated/delayed treatment and 5% of treated cases. Early diagnosis and treatment are key to avoiding the most severe and long-term complications. Currently there are no laboratory-based tests for the diagnosis and prognosis of KD, or treatments that specifically target the tissue degradation and vascular remodeling involved in the development of coronary artery (CA) aneurysms. Standard KD treatment includes broad spectrum anti-inflammatory drugs, none of which specifically targets the tissue degradation and vascular remodeling that leads to KD-associated CA aneurysms. Materials and Methods: We characterized the inflammatory and vascular markers associated with KD, CA aneurysms, and intravenous gamma globulin (IVIG) resistance in serum samples longitudinally collected from 116 KD patients. KD patients who presented with CA aneurysms were offered enrollment to a phase II prospective, randomized, double-blinded placebo-controlled study of doxycycline for the treatment of KD associated CA aneurysms. Doxycycline was selected for evaluation as a novel treatment for KD-associated CA aneurysms due to its known anti-inflammatory properties that specifically target proteins associated with KD inflammation. Results: Using the patient's convalescent serum samples as self-controls, we identified panel of 10 biomarkers – five immune factors (granulocyte colony stimulating factor/ colony stimulating factor 3 [G-CSF/CSF3], interleukin [IL]-6, C-C motif chemokine ligand 2/monocyte chemotactic protein 1 [CCL2/MCP-1], C-X-C motif chemokine ligand 10/10kDa interferon gamma-induced protein [CXCL10/IP-10], C-X-C motif chemokine ligand 11/interferon-inducible T-cell alpha chemoattractant [CXCL11/ITAC]) and five vascular markers (neutrophil elastase [ELANE], matrix metalloproteinase [MMP]-3, MMP-9, pentraxin 3 [PTX3], soluble E-selectin [sELAM-1]), which demonstrated significant upregulation in the acute phase of KD, with strong performance in identifying acute phase KD samples. Stratifying KD serum samples by IVIG treatment response revealed a panel of four biomarkers - three immune factors (IL-1a, IL-25/IL-17F, tumor necrosis factor beta/lymphotoxin alpha [TNF-b/LTA]) and one vascular marker (pappalysin-1 [dPAPP-A]), which demonstrated significantly elevated levels among those resistant to IVIG treatment, at all clinical phases of KD. Comparing acute phase KD samples among those with and without CA aneurysms identified acute phase PTX3 significantly elevated in KD patients with CA as compared to those with normal CA, suggesting this protein as a novel factor in the development of KD-associated CA aneurysms. Comparisons of absolute and changes in CA diameter Z-scores among KD patients with CA aneurysms treated with doxycycline as compared to those who receive standard KD treatment did not demonstrate statistically significant differences. Conclusions: These findings provide a platform for laboratory-based diagnostic and prognostic markers of KD, CA aneurysms, and IVIG resistance. Further, the findings of the doxycycline treatment clinical trial did not reveal an advantage in using doxycycline treatment for the development or progression of CA aneurysms in KD over current standard of care.