Christena L. Turner

Kawasaki Disease: A Brief History

Tomisaku Kawasaki published the first English-language report of 50 patients with Kawasaki disease (KD) in 1974. Since that time, KD has become the leading cause of acquired heart disease among children in North America and Japan. Although an infectious agent is suspected, the cause remains unknown. However, significant progress has been made toward understanding the natural history of the disease and therapeutic interventions have been developed that halt the immune-mediated destruction of the arterial wall. We present a brief history of KD, review progress in research on the disease, and suggest avenues for future study. Kawasaki saw his first case of KD in January 1961 and published his first report in Japanese in 1967. Whether cases existed in Japan before that time is currently under study. The most significant controversy in the 1960s in Japan was whether the rash and fever sign/symptom complex described by Kawasaki was connected to subsequent cardiac complications in a number of cases. Pathologist Noboru Tanaka and pediatrician Takajiro Yamamoto disputed the early assertion of Kawasaki that KD was a self-limited illness with no sequelae. This controversy was resolved in 1970 when the first Japanese nationwide survey of KD documented 10 autopsy cases of sudden cardiac death after KD. By the time of the first English-language publication by Kawasaki in 1974, the link between KD and coronary artery vasculitis was well-established. KD was independently recognized as a new and distinct condition in the early 1970s by pediatricians Marian Melish and Raquel Hicks at the University of Hawaii. In 1973, at the same Hawaiian hospital, pathologist Eunice Larson, in consultation with Benjamin Landing at Los Angeles Childrens Hospital, retrospectively diagnosed a 1971 autopsy case as KD. The similarity between KD and infantile periarteritis nodosa (IPN) was apparent to these pathologists, as it had been to Tanaka earlier. What remains unknown is the reason for the simultaneous recognition of this disease around the world in the 1960s and 1970s. There are several possible explanations. KD may have been a new disease that emerged in Japan and emanated to the Western World through Hawaii, where the disease is prevalent among Asian children. Alternatively, KD and IPN may be part of the spectrum of the same disease and clinically mild KD masqueraded as other diseases, such as scarlet fever in the preantibiotic era. Case reports of IPN from Western Europe extend back to at least the 19th century, but, thus far, cases of IPN have not been discovered in Japan before World War II. Perhaps the factors responsible for KD were introduced into Japan after the World War II and then reemerged in a more virulent form that subsequently spread through the industrialized Western world. It is also possible that improvements in health care and, in particular, the use of antibiotics to treat infections caused by organisms including toxin-producing bacteria reduced the burden of rash/fever illness and allowed KD to be recognized as a distinct clinical entity. Itsuzo Shigematsu, Hiroshi Yanagawa, and colleagues have conducted 14 nationwide surveys in Japan. These have indicated that: 1) KD occurred initially in nationwide epidemics but now occurs in regional outbreaks; 2) there are ∼5000 to 6000 new cases each year; 3) current estimates of incidence rates are 120 to 150 cases per 100 000 children <5 years old; 4) KD is 1.5 times more common in males and 85% of cases occur in children <5 years old; and 5) the recurrence rate is low (4%). In 1978, David Morens at the Centers for Disease Control and Prevention published a case definition based on Kawasakis original criteria. The Centers for Disease Control and Prevention developed a computerized database in 1984, and a passive reporting system currently exists in 22 states. Regional investigations and national surveys suggest an annual incidence of 4 to 15 cases per 100 000 children <5 years of age in the United States. The natural history of KD reveals that coronary artery aneurysms occur as a sequela of the vasculitis in 20% to 25% of untreated children. Echocardiography can be successfully used to detect coronary artery dilatation and aneurysms in virtually all patients. Patients with no acute phase coronary artery changes detected by echocardiogram are clinically asymptomatic at least 10 years later. The Japanese Ministry of Health has established a registry of 6500 children who will be followed longitundinally to determine the natural history of the illness. No similar registry of patients exists in the United States. Studies of KD pathogenesis show a progression of arterial lesions accompanying KD vasculitis and a number of immunoregulatory changes, including a deficiency of circulating CD8+ suppressor/cytotoxic T cells; an abundance of circulating B cells spontaneously producing immunoglobulins; and circulating, activated monocytes. Biochemical and immunologic evidence suggests endothelial cell activation and injury. Although the cause of KD remains unknown, clinical trials have established effective therapies, despite the absence of a proven cause. Intravenous immunoglobulin (IVIG) plus aspirin lowers the rate of coronary artery aneurysms from 20% to between 3% and 5%. In 1988, the Committee on Infectious Diseases of the American Academy of Pediatrics endorsed IVIG treatment as recommended therapy for KD. Questions remain regarding treatment of patients who fail to respond to an initial dose of IVIG. The role of steroids or other antiinflammatory agents in the treatment of KD is controversial. Areas for further research include: 1) a more sensitive case definition that includes laboratory and echocardiographic data, as well as clinical signs and symptoms; 2) development of a diagnostic test based on the biology of inflammation and acute endothelial cell damage that, in the absence of the causative agent, could be used to identify children with KD; 3) studies of index cases and their families to identify relevant genetic factors; and 4) long-term follow-up of patients into their third and fourth decades with monitoring for late cardiovascular sequelae.

Seasonality and Temporal Clustering of Kawasaki Syndrome

Background: The distribution of a syndrome in space and time may suggest clues to its etiology. The cause of Kawasaki syndrome, a systemic vasculitis of infants and children, is unknown, but an infectious etiology is suspected. Methods: Seasonality and clustering of Kawasaki syndrome cases were studied in Japanese children with Kawasaki syndrome reported in nationwide surveys in Japan. Excluding the years that contained the 3 major nationwide epidemics, 84,829 cases during a 14-year period (1987–2000) were analyzed. To assess seasonality, we calculated mean monthly incidence during the study period for eastern and western Japan and for each of the 47 prefectures. To assess clustering, we compared the number of cases per day (daily incidence) with a simulated distribution (Monte Carlo analysis). Results: Marked spatial and temporal patterns were noted in both the seasonality and deviations from the average number of Kawasaki syndrome cases in Japan. Seasonality was bimodal with peaks in January and June/July and a nadir in October. This pattern was consistent throughout Japan and during the entire 14-year period. Some years produced very high or low numbers of cases, but the overall variability was consistent throughout the entire country. Temporal clustering of Kawasaki syndrome cases was detected with nationwide outbreaks. Conclusions: Kawasaki syndrome has a pronounced seasonality in Japan that is consistent throughout the length of the Japanese archipelago. Temporal clustering of cases combined with marked seasonality suggests an environmental trigger for this clinical syndrome.

Failure to diagnose Kawasaki disease at the extremes of the pediatric age range.

To learn about physician practices in diagnosing Kawasaki disease, we surveyed general pediatricians and pediatric infectious disease physicians by questionnaire. A high proportion of general pediatricians (>50%) and infectious disease subspecialists (25%) did not consider the diagnosis of Kawasaki disease in children younger than 6 months and older than 8 years. Failure to consider the diagnosis at the extremes of the pediatric age range puts children at risk because coronary artery abnormalities occur more often in young infants and adolescents with Kawasaki disease.

Delayed Diagnosis by Physicians Contributes to the Development of Coronary Artery Aneurysms in Children With Kawasaki Syndrome

Background: A diagnosis of Kawasaki syndrome is based on clinical criteria with nonspecific laboratory findings, and there is a substantial risk of coronary artery aneurysms if treatment with intravenous immunoglobulin is delayed. In this study, we examined the contributions of sociodemographic factors and parent and physician behavior to the development of coronary artery aneurysms in children with Kawasaki syndrome. Methods: We performed a retrospective, case-control chart review of Kawasaki syndrome patients treated at our institution during an 11-year period (1991–2002). Of 324 patients, 21 patients had coronary artery aneurysms and were matched with 81 Kawasaki syndrome control patients without coronary artery aneurysms. Results: Patients who developed coronary artery aneurysms were more likely to have had their diagnosis established after 10 days of fever as a result of a delay in physician recognition of Kawasaki syndrome. In addition, these patients were also more likely to have been hospitalized at an outside facility with an erroneous diagnosis, to have had a greater number of healthcare visits before diagnosis, to have sought medical care in Mexico, to lack medical insurance and to speak Spanish as a primary language. Independent predictors of delayed diagnosis included incomplete clinical signs of Kawasaki syndrome, seeking health care in Mexico, and being hospitalized at an outside facility with a different diagnosis. Conclusions: Increased risk of coronary artery aneurysms is associated with a delay in diagnosis by physicians and not with a delay in seeking medical consultation by parents. Sociodemographic factors influence the likelihood that patients will have a delayed diagnosis.

The Two Emergences of Kawasaki Syndrome and the Implications for the Developing World

Kawasaki syndrome (KS) is the most common cause of acquired pediatric heart disease in the developed world. There have been 2 distinctive patterns for the emergence of KS that are likely related to several factors including exposure to the causative agent(s) and host genetics. In Europe and North America where we presume the genetic susceptibility seems to be low, KS has existed in the pediatric population for more than a century and is associated with relatively low incidence. In Japan where genetic susceptibility is presumed to be high, KS seems not to have existed before the early 1950s. This relatively recent exposure has resulted in 3 nationwide epidemics and a high current endemic rate of 200 per 100,000 in children less than 5 years. If our history of alternative patterns of the emergence of KS is valid, it may prove useful as a predictive tool for countries including India, where clusters of KS cases have been recently reported. This article examines the historical evidence in support of a 2-tiered emergence of KS in Euro-America and Japan and then returns briefly to discuss its implications for the pediatric populations of India and the health care delivery systems in the developing world.

Sensitivity of the Kawasaki Case Definition for Detecting Coronary Artery Abnormalities

Although developed as an epidemiological tool, the Kawasaki Disease (KD) case definition has become a clinical tool used to detect and treat children with KD. Based on our experience treating 103 cases at Childrens Hospital, San Diego from January 1998 through December 2000, we found that the Center for Disease Control (CDC) KD case definition results in failure to detect children with coronary artery abnormalities (CAA). Using published nomograms for coronary artery diameters based on body surface area, we determined the prevalence of CAA in all children receiving IVIG treatment for Kawasaki disease at Childrens Hospital, San Diego. There were 102 patients with one recurrence. 86/103 cases met the Center for Disease Control case definition (typical KD) and 17/103 did not (atypical KD). CAA occurred in 42/86(49%) typical KD cases and 10/17 atypical KD cases (59%). These data demonstrate that 50%(52/103) of KD patients have detectable CAA. Five patients developed coronary aneurysms- 2 in the atypical group (12%) and 3 in the typical group (3.5%). The sensitivity of the KD case definition for detecting children with CAA was only 0.81(42/42+10). With this level of sensitivity for CAA detection, reliance on the CDC case definition as the sole clinical tool for diagnosis results in physician failure to detect children with CAA. Because there is an effective treatment, clinicians need a case definition that is highly sensitive. As the treatment is relatively safe, specificity of the case definition is less important. Efforts to revise the clinical case definition in order to improve its sensitivity for CAA are warranted. New criteria may include clinical laboratory findings such as leukocyte count or ESR. Revisions may eliminate current criteria such as cervical lymphadenopathy. Candidate clinical case definitions should undergo prospective testing with CAA detection as the primary outcome.

Kawasaki Disease: Do We Need a New Case Definition?

Misdiagnosis or missed diagnosis of Kawasaki disease (KD) is a problem in the United States (U.S.). To learn about current practice in diagnosing KD, we conducted a questionnaire survey of general pediatricians in San Diego County and U.S. members of the Pediatric Infectious Disease Society. Responses were obtained from 132/227 (58.1%) generalists and 345/651 (53.0%) subspecialists. Half of the general pediatricians and 90% of the pediatric subspecialists reported having made the diagnosis of KD in febrile patients (pts) who did not fulfill 4/5 clinical criteria. When asked about clinical criteria that trigger consideration of KD, generalists and subspecialists listed fever, rash, and conjunctival injection as the top three clinical signs. Cervical lymphadenopathy was considered an important criterion by the generalists (69/131, 52.7%) but not by the subspecialists (34/334, 10.2%). Despite the well-documented occurrence of KD throughout the pediatric age group, 71/124 (57.3%) generalists and 86/325 (26.5%) subspecialists did not consider the diagnosis in pts <6 mos of age. Similarly, 64/124 (51.6%) generalists and 81/324 (25.0%) did not consider the diagnosis of KD in pts >8 yrs. Laboratory studies reported to be most helpful in establishing the diagnosis of KD were (generalists;subspecialists): erythrocyte sedimentation rate (68.2%;74.2%), complete blood count (58.1%;40.0%), platelet count (51.9%;32.1%), urinalysis (46.5%;41.2%), and echocardiogram (45.0%;52.1%). Education about KD in the U.S. must emphasize that this disease can occur across the entire pediatric age range. Physicians have found the case definition to be overly specific and inadequately sensitive in establishing the diagnosis of KD. Formulation of a new case definition for improved sensitivity in early detection of KD cases may be warranted.

Structuring Culture for Change: Strategy, Participation, and Collective Purpose in a Japanese Factory

Organizational culture in Japanese firms has often been used as an independent variable to explain both economic success and, more recently, economic troubles. The Japanese work ethic and lifetime employment stand in for culture in the former case and Japanese reliance on rigid traditions and hierarchy stand in for culture in the latter. This article examines a Japanese factory campaign designed to prepare for recent and ongoing challenges to employment practices and business strategies by “strengthening culture” and “creating new values.” Factory managers worked to create support for their goals in face of department, section, and worker responses ranging from enthusiasm to apathy or opposition. An analysis of this campaign shows that culture is a social process, not a given body of knowledge and practice. It also shows how that process is carried out within a particular economic institution by particular actors.

Making Tea, Making Japan: Cultural Nationalism in Practice

ing comparison might be to examine that system against other domestic social programs and institutions. That comparison would likely yield few surprises and a great deal of symmetry, prompting one to ask one of the biggest questions of all: to what extent are we committed to the full inclusion and basic needs of our nation’s citizens—including and well beyond the question of healthcare? In addition to marshaling a trove of data from the historical record, Starr brings his rich insider perspective to the narrative, drawing from his experience as a Senior Advisor on health policy in the Clinton White House. This is first-rate scholarship and will be a must-read for anyone seeking an authoritative analysis of the U.S. healthcare system.

Kawasaki Disease: A Climate Connection?

The winter/spring seasonality of KD has been recognized for over two decades and a recent study found that KD incidence in San Diego (SD) County was positively associated with average monthly precipitation (r=0.52, p<0.001) (Bronstein et al., Ped Inf Dis J. 2000;19:1087-91). Based on this observation, 246 KD cases from SD County over 6.75 yrs were analyzed for additional climate associations. Fifty-eight clusters (=2 pts within 4 d) were identified and 15/58 had 3 or 4 pts. These 15 clusters were temporally associated with strong, anomalously negative 700mb heights (lower than average pressure), in a broad lower midaltitude swath offshore of California, indicating an active storm track and quite likely wet conditions in SD County starting 6 days prior to the onset of the first case in the cluster and waning by 4 days after onset. Rainfall tended to precede the onset of a KD cluster. In 10 of the 15 clusters, we found preceding precipitation of at least 0.1“recorded in the 6-day interval before the first case in the cluster. Analysis of an additional 23 consecutive SD County cases from 2000-2001 revealed distinct clusters associated with weather patterns similar to those described above. Examination of 278 pts from Los Angeles Childrens Hospital from 1994-2000 revealed similar patterns of atmospheric circulation but without the distinct wet signature that was noted for the SD cases. Analysis of 36,955 cases from Japan (1993-1998) for clustering and climate associations is in progress. Additional parameters including wind, humidity, cloud cover, weather type, visibility, barometric pressure, and dry-wet transitions will be explored in relation to KD clusters in California and Japan. The accurate specification of weather patterns related to the onset of KD may lead to formulation of new hypotheses regarding etiology.