Kawasaki Disease: A 50 year old mystery

By Stephanie Menikou, PhD student, Faculty of Medicine

picture2Kawasaki disease (KD) was first identified in 1967 by the Japanese paediatrician Tomisaku Kawasaki. He saw his first case in 1960 and over a period of six years he identified 50 cases of this distinct unusual illness.1 50 years later, we still don’t know its cause, or whether it is caused by an infectious organism, a toxin, a chemical substance or something else. Kawasaki disease has emerged as the most common cause of childhood heart disease in many developed countries.2 Over 60 countries around the globe have reported cases and currently in many countries it’s on the rise. The highest incidence rate currently recorded is in Japan with 264.8/100 000 children, followed by South Korea (134.4/100 000) and Taiwan (74.9/100 000).3 The incidence rate reported in most European countries is somewhat lower (<16/100 000).4

A major difficulty with diagnosis of Kawasaki disease is the lack of a diagnostic test. The confirmation of cases relies on clinical symptoms (prolonged fever, erythematous rash, bloodshot eyes, swollen feet, hands, lymph nodes and peeling of toes).5 Doctors are faced with a real challenge as many of these symptoms mimic those of other common childhood diseases such as staphylococcal and streptococcal infections. What has made the disease feared by parents and doctors is its association with arteritis affecting the coronary arteries which can result in coronary artery aneurysm in up to 25% of untreated patients. The development of aneurysm is usually clinically silent and may be detected even years later having been the cause of a heart attack or sudden death.5 The current treatment available is intravenous immunoglobulin combined with aspirin. However, 10 to 20% of cases fail to respond to this treatment and a range of alternative therapies are used (steroids, infliximab, anakinra, cyclosporine A).6

The epidemiology of KD is consistent with an infectious aetiology, as the disease usually occurs between the loss of maternal antibodies and acquisition of natural immunity, it is more common in boys and there is distinct seasonal variation in many countries. Evidence from climatological studies suggests a windborne agent, while genome-wide association studies have identified genetic variants associated with susceptibility to the disease. Immune complexes (antigen-antibody complexes) have also been reported in the course of the disease.

picture1Our research which is led by Professor Michael Levin focuses on two complementary approaches to identify the causative agent. Metagenomic sequencing is used to search for novel pathogens in throat swab samples from children with KD and other febrile children as controls. The second approach is the identification of antigens within immune complexes of KD patients using a proteomic pipeline. We have preliminary data of peptide sequences that could be linked to Kawasaki disease and further validation is ongoing. We are also working to develop a test based on RNA expression in blood.

We hope that further studies on Kawasaki disease will lead to identifying the causative agent of this disease. It will be the key to improve clinical management, treatment and ultimately prevention. For now the cause of Kawasaki disease remains a mystery.

References

  1. Kawasaki T. [Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children]. Arerugi. 1967;16(3):178-222.
  2. Singh S, Sharma D, Bhattad S, Phillip S. Recent Advances in Kawasaki Disease – Proceedings of the 3rd Kawasaki Disease Summit, Chandigarh, 2014. The Indian Journal of Pediatrics. 2016;83(1):47-52.
  3. Kim GB, Han JW, Park YW, Song MS, Hong YM, Cha SH, et al. Epidemiologic features of Kawasaki disease in South Korea: data from nationwide survey, 2009-2011. Pediatr Infect Dis J. 2014;33(1):24-7.
  4. Singh S, Vignesh P, Burgner D. The epidemiology of Kawasaki disease: a global update. Arch Dis Child. 2015;100(11):1084-8.
  5. Burns JC, Glodé MP. Kawasaki syndrome. The Lancet. 2004;364(9433):533-44.
  6. Eleftheriou D, Levin M, Shingadia D, Tulloh R, Klein NJ, Brogan PA. Management of Kawasaki disease. Arch Dis Child. 2014;99(1):74-83.