Long-term CV events risk low among patients with Kawasaki disease

Anne H. Rowley, MD

In the February issue of Pediatrics, Holve and colleagues report the results of an important study to identify adverse cardiovascular outcomes in a cohort of patients diagnosed with Kawasaki disease at age 5 years or younger with a mean follow-up of 14.9 years. The study revealed a low rate of adverse cardiovascular outcomes through age 21 years in children who survived to at least age 15 years. This is reassuring news, but it is important to carefully consider the study design and how the study impacts the discussion that a clinician caring for a patient with Kawasaki disease will have with the patient’s family about prognosis.

Most importantly, about 80% of patients with Kawasaki disease in this study did not develop any coronary artery abnormalities following the illness. In this group of children, there is no evidence at present of long-term sequelae of Kawasaki disease. The recommendations of the American Heart Association for this group of patients is that no antiplatelet therapy is needed, no restrictions need to be placed on physical activity, and that routine cardiovascular risk assessments and counseling be performed at 5-year intervals (Newburger JW. Pediatrics. 2004;114:1708-1733). Although the Kawasaki disease research community remains interested in whether this group of patients might be at increased risk for atherosclerosis in later adult life, there is no direct evidence at the present time to support this concern, even in Japan where there is a high prevalence of Kawasaki disease and decades of follow-up (Fukazawa R. J Nippon Med Sch. 2009;76:124-133). Further follow-up is likely to answer this question, but from our current knowledge, no adverse cardiovascular events would be expected in these patients at a mean of 15 years after the onset of Kawasaki disease. In the secondary analysis, in which the authors sought evidence of adverse events at time points prior to age 15 years, they report one fatality from coronary artery disease in a 5-year-old who reportedly had no aneurysms develop from Kawasaki disease at age 2 years. Few details are provided for this case, but it seems most likely that echocardiography images were either poor, not performed at 2 to 3 weeks after onset or not evaluated using coronary artery z scores (to assess for coronary artery dilation by body surface area) than that the patient had normal coronary arteries following the illness.

In contrast, patients who develop large or “giant” persistent coronary artery aneurysms (usually those with delayed or missed diagnoses) are at significant risk of adverse outcomes during their lifetimes and require careful cardiology follow-up. It is not clear how many of the 25 patients with persistent aneurysms had giant aneurysms, as coronary artery z scores are not provided by the authors. Because two patients with adverse outcomes were on warfarin and therefore likely had giant aneurysms, at a minimum 2/25 (8%) had an adverse event (death or coronary artery bypass surgery) by age 14 years. For these patients, the American Heart Association recommends antiplatelet and antithrombotic therapy, restrictions on physical activity and careful follow-up with stress testing and angiography at regular intervals. Because these two events occurred prior to age 15 year, they were not considered part of the primary outcomes by the authors’ study design. Nonetheless, these events are important to consider when determining prognosis and having discussions with families.

One of the most pressing Kawasaki disease research questions is the level of risk for patients with small- to moderate-sized aneurysms that later undergo reduction or normalization in luminal diameter. The most appropriate follow-up for these patients is in evolution, and further study is needed to determine their prognosis. However, because luminal myofibroblastic proliferation with its potential for arterial occlusion can occur in damaged Kawasaki disease coronary arteries, and would result in a normalization of luminal diameter prior to causing stenosis, these patients may still be at risk for cardiovascular events, and some such patients have had fatal outcomes (Orenstein JM. PLoS One. 2012;7:e38998.). Multicenter collaborative studies with long follow-up periods are likely necessary to answer the question of prognosis for these patients with Kawasaki disease.

What can the clinician take away from the study by Holve and colleagues? In children with Kawasaki disease who have adequate echocardiographic assessments showing normal coronary arteries at diagnosis and at 2 to 3 weeks after onset, it is appropriate to reassure the family that the prognosis is excellent and to recommend a heart-healthy lifestyle. However, in those children who develop significant coronary artery disease, there is substantial risk of adverse outcomes, and only with careful cardiology care and follow-up can these adverse events be minimized (presumably excellent cardiology care may have contributed to low rates of adverse cardiovascular events in patients with persistent aneurysms in the Kaiser Permanente system). With regard to children with coronary aneurysms who have subsequent normalization of lumen diameter, risk is likely to be lower but remains unclear, and cardiology follow-up is recommended. Further long-term follow-up studies of patients with Kawasaki disease by Kaiser Permanente investigators and other researchers are greatly needed. In future studies, it will be optimal to report outcomes by Kawasaki disease risk group. Discussion with families about the prognosis for their child following Kawasaki disease should be guided by the presence or absence of coronary artery disease in the first month after onset, and the severity of the coronary artery disease in those who develop abnormalities.