REVIEW ARTICLE Kawasaki Disease Diagnosis, Management, and Long-term Implications Gary M. Satou, MD, Joseph Giamelli, MD, and Michael H. Gewitz, MD Abstract: Kawasaki disease (KD) is an acute inflammatory vascu- litis of childhood which was initially described more than 4 decades ago, yet the specific etiology remains unknown. It has become the most common cause of acquired cardiovascular disease in children in the United States. Advances in clinical therapies have reduced, but not eliminated, the incidence of coronary artery abnormalities in affected children. Pathophysiology seems to include an intense elaboration of cytokines, endothelin, and other vasoactive mediators resulting in the development of vascular endothelial changes that may leave a permanent impact on vascular integrity. Treatment with intravenous immune globulin and aspirin remains the primary man- agement strategy and steroid therapy remains contoversial. In severe circumstances, coronary reperfusion strategies are required, and coronary artery surgery in children with KD has been required, albeit infrequently. KD may be a harbinger for early onset coronary artery disease in adults. Recently developed AHA recommendations have amended diagnostic strategies and indicated a stratified ap- proach to the long-term follow up of this enigmatic yet widespread disease. Key Words: Kawasaki disease, coronary artery aneurysm, acquired heart disease in children (Cardiology in Review 2007;15: 163–169) K awasaki Disease (KD) was first described in Japan by Dr. Tomosaku Kawasaki in 1967 and was originally called mucocutaneous lymph node syndrome. 1 Nearly 4 decades later, it continues to be a regularly seen inflammatory disor- der without a clearly delineated etiology, at times posing potentially life-threatening cardiac complications. Neverthe- less, continued advances in the care of children afflicted by this syndrome have resulted in reduction of both morbidity and mortality. The clinical presentation of KD is somewhat variable, but classically consists of fever of at least several days’ duration, accompanied by varying degrees of nonpuru- lent conjunctivitis, generalized exanthem, oral-mucosal and extremity changes, and cervical lymphadenopathy (Table 1). Although there is no specific “diagnostic test,” KD is usually associated with a constellation of specific laboratory features (Table 2) which can be useful for diagnosis and can occa- sionally provide prognostic insight. DEMOGRAPHICS The incidence of KD in the United States ranges from 9.1 to 16.9 cases per 100,000 children younger than 5 years old. 2 Worldwide, Japan continues to have the highest preva- lence with an annual incidence of approximately 112 cases per 100,000 children younger than 5 years old. 3 Interestingly, the disease seems to have a distinct seasonality with temporal “clustering” in a bimodal fashion. A preponderance of cases are documented in January and June/July (Fig. 1). 4 There also seems to be a proclivity for specific demographic subgroups. The majority of patients are younger than 5 years old (nearly 80%), and boys are affected 1.5 times more often than girls. Even in the United States, children of Asian ancestry are affected more frequently than any other population subgroup, and children of Hispanic origin are less frequently affected than other US subgroups. ETIOLOGY AND PATHOGENESIS The specific inciting etiologic agent in KD remains unproven, but the seasonality noted above seems to imply a recurring infectious vector. Multiple agents have previously been suspected, including various bacteria, rickettsia, viral agents, and even dust mite antigens. 5 There is still an unset- tled controversy regarding antigenic or superantigen patho- genic mechanisms. However, whatever the etiologic agent, pathogenesis in KD is likely to include an initial immune- mediated response to the agent and during the acute phase, activation and increased proliferation of monocytes, macro- phages, T cells, B lymphocytes, and immunoglobulins. 6–8 Increased cytokine release also occurs, including several interleukins and tumor necrosis factor-alpha (TNF-). 9,10 Expression of vascular-endothelium activation occurs with increased levels of intercellular adhesion molecules, vascular endothelial growth factor, and platelet-derived growth factor. Elevated levels of cellular enzymes, such as matrix metallo- proteinase, have also been described. 11 Figure 2 illustrates a proposed cascade of events at the cellular level, starting with the initial insult and resulting in vessel injury. 11 From the Section of Pediatric Cardiology, Maria Fareri Children’s Hospital, Westchester Medical Center/New York Medical College, Valhalla, New York. Correspondence: Gary M. Satou, MD, Division of Pediatric Cardiology, New York Medical College, 618 Munger Pavillion, Valhalla, NY 10595. E-mail: gary_satou@nymc.edu. Copyright © 2007 by Lippincott Williams & Wilkins ISSN: 1061-5377/07/1504-0163 DOI: 10.1097/CRD.0b013e31802ea93f Cardiology in Review • Volume 15, Number 4, July/August 2007 163