MMP9 as a response identification biomarker for doxycycline in Kawasaki disease

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ABSTRACT Kawasaki disease (KD) is the leading cause of acquired heart disease in children of the developed world. It presents as an acute self-limiting illness with fever and inflammation of the skin and mucous membranes. In KD, the immune system triggered by a so far unknown extrinsic factor induces multisystem vasculitis including the coronary arteries. Even following current therapeutic guidelines, 30% of children with KD will have coronary artery dilation (CAD). Patients with CAD may face permanent and potentially devastating complications, such as coronary vasculopathy, myocardial infarction and even death. Currently there is no available treatment or prevention of CAD in children with KD. In the acute phase of KD, activated macrophages and lymphocytes in the wall of the coronary arteries induce matrix metalloproteinase 9 (MMP-9) that is responsible for elastin degradation causing CAD and aneurysm. Doxycycline (a common antibiotic and a known inhibitor of MMP-9) was shown to decrease MMP-9-mediated coronary elastin breakdown and improve coronary outcome in animal models of KD. Doxycycline administration was also demonstrated to reduce MMP-9 activity in the aortic wall of adults with abdominal aortic aneurysm. Our preliminary and published data demonstrates that pro- MMP-9 is a sensitive biomarker to detect inflammation in children during the acute phase of KD when CAD occurs, and doxycycline may prevent the progression of CAD in children with KD. Based on these data, we will test the following two hypotheses: 1) doxycycline administration in children during the acute phase of KD will decrease the circulating level of MMP-9; and 2) doxycycline treatment during the acute phase of KD is safe and effective to prevent the progression of CAD and aneurysm formation in children. Specific aim 1: To characterize the change in circulating pro-MMP-9 and MMP-9 levels in response to a 3- week oral administration of doxycycline in children during the acute phase of KD, by the quantification of pro- MMP-9 and MMP-9 levels (measured by ELISA) in serum samples of children before and after a 3-week course of doxycycline treatment, and comparing the changes to controls of children with acute KD and no doxycycline treatment. Specific aim 2: To assess the change in coronary artery diameter in response to a 3- week oral administration of doxycycline in children during the acute phase of KD, by assessing the size of coronary arteries using established echocardiographic standards during 4 time-points in the acute phase of KD and comparing to controls of children with acute KD and no doxycycline treatment. Based on the results of this pilot study, we will develop a prospective, multi-center, blinded controlled clinical trial to assess the efficacy of doxycycline treatment in the prevention of CAD and aneurysm. If doxycycline proves to be beneficial, we will propose a change of the currently accepted treatment protocol of children with KD to include doxycycline for the prevention of coronary artery aneurysms and potentially fatal complications.