Haruto, known as “Hari,” is the four-year-old son of the Tonagas, a second generation Japanese American family. Hari has been fussy and irritable over the last several days. His parents felt he had a “spring cold” and initially were not concerned. He had a low grade fever during the day (38.5°C) that did not respond to acetaminophen. Over the next four days Hari became increasingly irritable. He vomited once and would not eat. His parents noticed that his hands and feet appeared red and seemed to be swollen. Although Hari usually ran around the house, walking now seemed painful and he complained when his mother asked him to play. His mother took his temperature several times during the day and noted that Hari’s fever varied, peaking at 39.5°C in the evening. Alarmed, Hari’s parents brought him to their pediatrician, Dr. Janet. Dr. Janet noted that Hari was extremely irritable during physical examination. His temperature was confirmed to be 40°C. There was erythema and swelling of his hands and feet and movement of his limbs caused Hari to complain. He had cracks in his lips (fissures), his tongue was red and swollen (described as a “strawberry tongue”), and he had a “measlelike” rash on his back and groin. Dr. Janet noted that both of Hari’s conjunctiva were red, and the superficial bulbar vessels were prominent (bulbar conjunctival injection). Hari had a single enlarged cervical lymph node on his right side. Dr. Janet was quite concerned about Hari’s illness. She considered a number of infectious etiologies including adenovirus or measles infection and number of bacterial etiologies such as group A beta-hemolyticstreptococcal infection. However, Hari’s symptoms (and to some extent his Asiatic background) suggested Kawasaki disease, an idiopathic condition for which there are no specific diagnostic test. Because 25 percent of untreated Kawasaki disease patients develop coronary artery disease, which is often serious and may ultimately result in death, Dr. Janet had Hari admitted to a pediatric referral center experienced in acute care. On admission Dr. Janet’s initial impression of possible Kawasaki disease was confirmed. Hari was immediately treated with a single high dose of intravenous immunoglobulin (IVIG) given over a twelve-hour period. An initial blood sample showed a very high level of C-reactive protein (a nonspecific marker of inflammation elevated in Kawaski disease). High-dose aspirin was also started, and echocardiography was performed. Hari’s temperature and level of C-reactive protein were carefully monitored over the next days. C-reactive protein levels fell over three days post-IVIG therapy, and Hari was afebrile by day four. Low-dose aspirin therapy was continued for an additional ten days. Echocardiographic finding initially and two weeks after therapy showed abnormal width of the left anterior descending coronary artery (termed a z-score), raising concern over the possibility of coronary artery aneurysm formation (which can be associated with serious consequences such as chronic vascular disease and sudden cardiac death). A repeat echocardiogram at seven weeks posttherapy was considered normal, and Hari was scheduled for a repeat echocardiogram at six months.
Discussion
Kawasaki disease (first described by Tomisaku Kawasaki in the 1970s) is a potentially fatal disease, predominantly of young children. The frequency of the disease varies greatly with geographic area and ethnic background and is most frequent in Japan, Korea, and Taiwan. The current frequency in Japan is 260 cases per 100,00 children under age five (the ages at which the disease is most common) and the frequency appears to be increasing. The frequency of the disease is ten to twenty times lower in the United States and Europe (about 18 cases per 100,000 children under age five in the United States) with a stabile incidence. Individuals of Asiatic (predominantly Japanese) origin show a higher rate of disease incidence even when living in relatively low-incidence areas, and evidence suggests that susceptibility is familial. However, no one genetic factor is associated with the disease (although variation in several genes associated with immune response does confer increased risk of disease and serious clinical outcomes). Although Kawasaki disease is much more frequent in certain populations, the disease is not limited to these groups and occurs in all ethnicities. There is strong evidence to suggest that the etiology of the disease depends on an infectious agent, but no agent has been definitively identified. The disease frequency shows seasonal variation, has occurred in widespread epidemics in Japan as well as smaller localized disease clusters, and is associated with the formation of IgA antibodies, which react with cytoplasmic inclusions found in patients and are believed to be an otherwise unknown RNA virus. Unfortunately, there is no good animal model for the disease. The pathophysiology of the disease in relation to vascular effects is complex. Kawasaki disease results in an inflammation of the arteries (arteritis), most significantly in but not limited to the coronary arteries. The arteritis has an acute neutrophilic phase, resulting in a self-limited necrotizing pathology occurring during the first two weeks of the disease. The acute phase results in necrosis of the endothelium and media, occasionally extending to the adventitia, which can form large saccular aneurysms that thrombose and may rupture. Later in the disease, a more generalized chronic vasculitis occurs that is most prominent in the coronary arteries. This chronic phase is mediated by lymphocytic cells and eosinophils and affects the adventitia progressing inward. During this more chronic phase, a proliferation of medial “myofibroblasts” occurs (which is distinct from atherosclerotic disease). The proliferation may result in obstruction of vessels. The chronic phase may persist indefinitely and ultimately result in death from coronary vascular disease months or even years after Kawaski disease is first diagnosed. Kawaski disease is currently believed to be an exaggerated response to an undefined infectious agent (or agents) in genetically susceptible individuals, which results in both acute and potentially chronic vasculitis and vascular abnormalities of greatest consequence in the coronary vessels.
Although Kawaski disease results in marked increases in nonspecific indicators of inflammation, diagnosis is based on clinical signs and symptoms. The currently accepted clinical diagnostic criteria for the disease are detailed in the Supplementary Readings. Therapy with IVIG has an excellent response rate in the disease. The mode of action of the therapy is still not understood but is likely to rely on the generalized anti-inflammatory effects of IVIG and possibly the presence of specific antibody in the IVIG reactive with the putative infectious agent. Whatever the mechanism, rapid IVIG therapy prevents the appearance of the abnormalities in the coronary vasculature likely to result in serious cardiac disease. The effect of aspirin therapy is controversial but is likely to act as an anti-inflammatory (in high doses) and prevent platelet-mediated thrombosis in lower doses. More intensive treatment with immunosuppressive agents is needed for the approximately 20 percent of patients who are resistant to combined IVIG and aspirin therapy.
Etiology and Pathogenesis
Kawasaki disease with transient arteritis of the coronary arteries.
Questions
1. Given the signs and symptoms noted in the case, should the pediatrician have had an equally strong index of suspicion for Kawaski disease in a non-Asiatic patient?
2. What are other infectious diseases a pediatrician might consider in a similar case?
3. Why is C-reactive protein used as an index of disease severity in Kawaski patients?
4. Are C-reactive protein levels a useful initial screen for Kawaski disease in patients?
5. What might be the short- and long-term consequences of failure to treat Kawaski disease?