Elsevier

The Lancet

Volume 364, Issue 9433, 7 August 2004, Pages 533-544
The Lancet

Seminar
Kawasaki syndrome

https://doi.org/10.1016/S0140-6736(04)16814-1Get rights and content

Summary

Kawasaki syndrome is an acute, self-limited vasculitis that occurs in children of all ages and presents a challenge for the clinician: the disorder can be difficult to recognise; there is no diagnostic laboratory test; there is an extremely effective therapy; and there is a 25% chance of serious cardiovascular damage if the treatment is not given early in the course of the disease. This review includes discussion of the history of the syndrome, the diagnostic challenges, epidemiology, aetiology, pathology, immunopathogenesis, therapy, genetic influences, and the long-term cardiovascular sequelae.

Introduction

Tomisaku Kawasaki saw his first case of an unusual illness with rash and fever in a 4-year-old child at the Red Cross Hospital in Tokyo, Japan, in January, 1961. During the next 6 years, he saw 50 similar patients, and he published first reports on the disorder in Japanese in 19671 and in English in 1974.2 An English translation of the 1967 paper became available only in 2002.3 Reports from Japan from the 1950s described similar patients.4 However, no published reports could be found of Japanese patients with the symptom complex of Kawasaki syndrome before the 1950s. To address the question of when the syndrome first appeared in Japan, researchers reviewed the records of 7618 children admitted to the Tokyo University Hospital between 1940 and 1954 for 15 different rash/fever diagnoses. They found 144 patients with one of these rash/fever diagnoses, of whom only five met all the clinical criteria for Kawasaki syndrome.5 None of these patients was seen before 1950. That study coupled with other historical inquiry suggests that cases of the disorder were not seen in Japan before the 1950s.

The most important issue about the syndrome in the 1960s in Japan was whether the illness described by Kawasaki was connected to subsequent cardiac complications noted in some cases. Noboru Tanaka, a pathologist, and Takajiro Yamamoto, a paediatrician, disputed Kawasaki's early assertion that the syndrome had no long-term sequelae.4 The controversy was resolved in 1970 when a nationwide survey in Japan identified ten autopsy cases of children who had died from complications of coronary-artery aneurysms after Kawasaki syndrome.6 By the time Kawasaki's paper was published in English in 1974, the link between the syndrome and coronary-artery vasculitis was well established.

Kawasaki syndrome was independently recognised as a new and distinct disorder in the early 1970s by Melish and Hicks at the University of Hawaii.4, 7, 8 Different features of the same complex of signs and symptoms were emphasised by these investigators, who focused on the urethritis and sterile pyuria and the inflammation of small and large joints that accompanied the illness in almost a third of patients. In 1973, Larson and Landing retrospectively diagnosed a 1971 autopsy case as Kawasaki syndrome. The similarity between fatal Kawasaki syndrome and infantile polyarteritis nodosa was apparent to these pathologists, as it had been to Tanaka earlier.9

Case reports of infantile polyarteritis nodosa from western Europe extend back to the 19th century.10 What remains unknown is the reason for the simultaneous recognition of fatal and non-fatal Kawasaki syndrome around the world in the 1960s and 1970s.10 Several hypotheses have been proposed. The syndrome could have newly emerged in Japan and emanated elsewhere through Hawaii, where the disease is most prevalent among Asian-American children. Alternatively, Kawasaki syndrome and infantile polyarteritis nodosa could be part of the continuum of the same disease, and clinically mild Kawasaki syndrome masqueraded as other diseases such as measles or scarlet fever before the advent of vaccines and antibiotics.

Section snippets

Diagnosis

Kawasaki syndrome is self-limited; the signs and symptoms evolve over the first 10 days of illness then gradually resolve spontaneously in most children, even in the absence of specific therapy (figure 1). Coronary-artery aneurysms develop in 20–25% of cases; their development is clinically silent in most cases and may be recognised only years later at the time of sudden death or myocardial infarction.11, 12 Treatment with high-dose intravenous immunoglobulin (IVIG) within the first 10 days of

Epidemiology

Kawasaki syndrome has been reported in all racial and ethnic groups and across the entire paediatric age range, although in most series 85% of patients are younger than 5 years. Patients younger than 6 months or older than 8 years are encountered infrequently but might be at increased risk of coronary-artery aneurysms.28, 29, 30, 31 The reported annual incidence rates of the syndrome per 100 000 children under 5 years of age by country range from 3 in South America to 134 in Japan, although the

Aetiology

The cause of Kawasaki syndrome remains unknown, although an infectious agent is suspected in view of the following evidence. There is a seasonal peak in the winter and spring months in most geographical areas, and geographically focal epidemics occurred in the 1970s and 1980s. The peak incidence in the toddler age-group with only rare cases in infants under 3 months of age and in adults suggests a role for transplacental antibodies conferring protection and development of protective immunity as

Pathology

Our understanding of the pathological changes of the vasculitis of Kawasaki syndrome has been impeded by the paucity of clinical material available for study. The low mortality rate coupled with primary involvement of medium-sized extraparenchymal muscular arteries, particularly the coronary arteries, which cannot be sampled during life, has precluded a comprehensive understanding of how the pathological changes in the vessel wall evolve. Although both Kawasaki syndrome and adult-type

Immunopathogenesis

Activation of the immune system is a central feature of Kawasaki syndrome, and concentrations of many proinflammatory cytokines and chemokines, including tumour necrosis factor α (TNFα), interleukins 1, 6, and 8, are higher than normal during the acute phase of the disease.55, 56, 57, 58, 59, 60 Activated monocytes/macrophages seem to have an important role in Kawasaki syndrome.61, 62, 63 These cells have been found in the vessel walls of patients who died63 and in skin biopsy samples from

Initial treatment

In 1983, Japanese investigators reported that children with Kawasaki syndrome treated with IVIG had faster resolution of fever and developed fewer coronary-artery abnormalities than historical controls.68 A multicentre, open-label, randomised trial in the USA showed that children treated with IVIG and high-dose aspirin had significantly faster resolution of fever and other inflammatory markers than children treated with high-dose aspirin alone.13 Moreover, the frequency of coronary-artery

Genetic influence

A genetic influence on disease susceptibility is suspected because Kawasaki syndrome is over-represented among Asian and Asian-American populations. Furthermore, the frequency is higher than in the general population among siblings of an index case. In Japan, the relative risk for siblings of developing the syndrome is 10.93 No sibling statistics are available for the USA or western Europe. The frequency of the disorder was two times higher than predicted in parents of children with Kawasaki

Cardiovascular complications and long-term sequelae

Large series of patients from Japan and North America have established the following features of the natural history of Kawasaki syndrome. Coronary-artery aneurysms occur as a sequela of the vasculitis in 20–25% of untreated children.111 Other cardiovascular complications of the syndrome include myocarditis, pericarditis with effusion, and valvulitis, which occurs in about 1% of patients and most commonly involves the mitral valve.112 Echocardiography is a sensitive and reliable method to

Obstacles to success

Why in the 37 years since the first description of Kawasaki syndrome as a unique clinical entity has there not been better progress in elucidation of the nature of this disease? Some impediments may include the following. The lack of a clear aetiological agent has made the classification and thus the sources of research funding unclear. Is this disease the responsibility of agencies or institutes that fund cardiovascular research, rheumatological research, or infectious diseases? To obtain

Conclusion

Although great strides have been made in the treatment of Kawasaki syndrome and in our understanding of the natural history of the disease, major questions remain unanswered. The extent to which the syndrome may eventually contribute to the burden of adult cardiovascular disease is of growing concern. Until a diagnostic test is devised, children will continue to be misdiagnosed and suffer preventable morbidity and mortality. Priorities for research should focus on devising a diagnostic test so

Search strategy and selection criteria

We reviewed translations of early Japanese articles on Kawasaki syndrome, polyarteritis nodosa, and fatal infantile periarteritis nodosa. JCB was a member of a research team that undertook extensive interviews in Japan with key figures involved in the recognition of the syndrome as a distinct clinical entity. We reviewed relevant abstracts from the seven international symposia held since 1984. We reviewed selected publications from the PubMed database identified by searches with the

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