Update Article
The Hong Kong Practitioner VOLUME 25 / March 2003

Update on Kawasaki disease in Hong Kong
Y W Cheng 鄭恩華，L M Wong 黃立明，K T So 蘇鈞堂

Summary

Kawasaki disease is an important diagnosis to be considered when seeing a child with fever. It carries important, severe and long-term morbidity if it is missed or if intravenous gamma-globulin (IVGG) is not given before the tenth day of illness. Family physicians should be familiar with the diagnostic criteria of this common disease. They play an important role in identifying, referring and managing patients with Kawasaki disease. This article aims to highlight the diagnosis and to give an update on the aetiology of Kawasaki disease.

摘要

小兒發燒，要考慮川崎症這個重要的疾病。漏診 或者沒有在發病十天內給予靜脈注射丙種球蛋白(IVGG)，可引起嚴重後果。 家庭醫生應熟悉此病的診斷標准，他們可以對此症的辨認，轉介和治療起極大作用。 本文旨在分享診斷以及提供有關川崎症病因的最新資料。

HK Pract 2003;25:127-133


Y W Cheng, MBChB(CUHK), DCH(Ire, Int), MRCP(UK)
Medical Officer,
L M Wong, MRCP(UK), FHKAM(Paediatrics)
Medical Officer,
K T So, FRCP(Edin, Glasg), FHKAM(Paediatrics)
Chief of Service,
Department of Paediatrics and Adolescent Medicine, Tuen Mun Hospital.

Correspondence to :
Dr Y W Cheng,
Department of Paediatrics and Adolescent Medicine, Tuen Mun Hospital, Tuen Mun, NT, Hong Kong.



Introduction

In the pre-antibiotic era, rheumatic heart disease was the most common paediatric acquired heart disease. Nowadays, general practitioners or paediatricians in Hong Kong seldom come across a case of rheumatic heart disease in their daily practice. In the hospital setting, new paediatric immigrants from China still contribute a few cases of chronic rheumatic heart disease every year. Prolonged fever in an infant, heart murmur in a child and chest pain in an adolescent patient are less likely to be caused by rheumatic heart disease but they may mean another important acquired heart disease, Kawasaki disease.

Kawasaki disease has silently emerged as the most common acquired heart disease in paediatric patients in Hong Kong. It has become a challenge for researchers to find out the aetiology and more definitive treatment for this group of patients. It is important to make a prompt diagnosis and start treatment without delay in order to prevent serious cardiovascular complications.



History

Dr Kawasaki T, a Japanese paediatrician, first described this disease in 1967. He reported 50 children who presented from 1961 to 1967 with prolonged fever and discrete clinical signs/symptoms. He termed the disease mucocutaneous lymph node syndrome and finally named it as Kawasaki disease or Kawasaki syndrome.1 It was thought to be a benign disease until late 1970, 10 children with the disease died because of the coronary complications which aroused the alertness of the world about it.2



Local incidence

According to the 6 year surveillance study of the Hong Kong Kawasaki Disease Study Group, the incidence was 31.2 per 100,000 children aged below 5 and the male to female ratio was 1.63.3



Diagnosis (Table 1)

There are no definitive diagnostic tests for Kawasaki disease and the diagnosis is based on clinical features. For a diagnosis to be made, a patient has to fulfill three criteria:4


Table 1: Diagnostic criteria of Kawasaki disease: (mnemonic: FEMALE)

Fever lasting for at least 5 days; and
4 out of 5 of the following clinical features:
Eyes showed bilateral non-suppurative conjunctival injection; (Figure 1)
Mucosa of lip: erythematous, dry and fissured lips; strawberry tongue; (Figure 2)
rAsh: Pleomorphic skin rash mainly on the trunk, may be maculo-papular or erythema multiforme; (Figure 3)
Lymphadenopathy: cervical lymph node diameter greater than 1.5 cm;
Erythema of the extremities with or without edema, later peri-ungual desquamation. (Figure 4)


Figure 1: Bilateral non-suppurative conjunctival injection

 

Figure 2: Changes of oral mucosa: erythematous, dry and fissured lips



Figure 3: Polymorphous skin rash over the trunk

 

Figure 4: Peri-ungal desquamation



 

 Criterion a:
    Fever lasting for 5 days or more.
 
  Criterion b:
    4 out of 5 of the following features:
    i. Bilateral non-suppurative conjunctival injection.
    ii. Changes of oral mucosa: erythematous, dry and fissured lips; strawberry tongue.
    iii. Changes of hands and feet: erythema with or without edema, later peri-ungual desquamation.
    iv. Polymorphous skin rash: mainly on the trunk, may be maculo-papular or erythema multiforme.
    v. Cervical lymphadenopathy: node diameter greater than 1.5cm
 
  Criterion c:
    Illness cannot be explained by other known conditions.
 
Other features including arthralgia, arthritis, diarrhoea, otitis media are quite non-specific but are commonly encountered in patients with Kawasaki disease. Investigations such as chest x-ray may show pneumonitis and ultrasonography may detect acute distension (hydrops) of the gallbladder. These are also common.5


Practical hints

From my personal experience, most patients with Kawasaki disease are toddlers presenting with fever, minimal cough or runny nose (skin rashes). Most (or nearly all) children with Kawasaki disease are very irritable and I personally have not seen a comfortable child. Irritability is very commonly seen in infants with Kawasaki disease and it may be due to the aseptic meningitis.

Moreover, fever in Kawasaki disease is usually above the baseline (normal) body temperature despite regular panadol treatment in contrast to the fever pattern due to upper respiratory tract infection which is usually swinging, on and off as described by most parents.

Erythema at the site of Calmette-Guerin bacillus (BCG) inoculation is rare but it is a rather specific sign of Kawasaki disease.6,7 We have diagnosed two children early by looking at the BCG scar on admission.

Erythrocyte sedimentation rate (ESR) is usually increased in patients with Kawasaki disease. Although non-specific, it may be helpful in the general practice setting in diagnosing this disease.

The platelet counts are usually normal until one to two weeks from the onset of the disease.

In conclusion, you should consider referring an irritable child with fever for more than 5 days who did not respond to anti-pyretics and with skin rashes conjunctivitis for further evaluation. Echocardiogram may sometimes assist in making the diagnosis of Kawasaki disease in the hospital setting.



Treatment

Intravenous gamma-globulin (IVGG) and aspirin are the standard treatment for all cases of Kawasaki disease admitted to hospital, under the Hospital Authority in Hong Kong, within 10 days of diagnosis since 2001.8 Treatment in the first 10 days of illness with a single dose of IVGG, 2 grams per kg body weight and high dose (anti-inflammatory) aspirin of 80 to 100mg per kg body weight per day, reduces the prevalence of coronary abnormalities from 20-25% to 2-4%.9-11 A second dose of IVGG may be needed if fever has not subsided. Aspirin will be changed to a lower dose (anti-thrombotic) when fever has subsided and is usually maintained until 8 weeks after the onset of the disease or resolution of the coronary aneurysm.



Outcome

For Kawasaki disease, studies have found that patients with regression of the coronary artery aneurysm (CAA) still demonstrated various degrees of intimal thickening by intra-vascular ultrasound. There was more vascular constriction with acetylcholine and poorer dilatation with isosorbide dinitrate. These results suggest that regressed CAA might have endothelial dysfunction with impaired endothelium dependent vasodilatation. In addition, they might have smooth muscle dysfunction with impaired response to isosorbide dinitrate.12 In my opinion, these patients should be followed up further for development of premature atherosclerosis. Until more definitive clinical outcomes are available, it is advisable for them to avoid risk factors for atherosclerosis e.g. smoking, obesity, hypertension and hyperchole-sterolaemia.



Follow-up

It is out of the scope of this article to discuss the long-term management of Kawasaki disease but I would like to share our data and experience of our patients with Kawasaki disease. Most paediatric cardiologists in Hong Kong manage and follow-up the cases based on the risk stratification approach published by the committee on rheumatic fever, endocarditis and Kawasaki disease, the Council on cardiovascular disease in the Young, American Heart Association.13

In our hospital, we have a new case diagnosed per month on average. We have 65 patients with history of Kawasaki disease currently being followed-up in our clinic. Neither an epidemic nor a seasonal cluster has been observed. There are 42 male patients with male to female ratio of 1.8:1.0. The mean age at diagnosis was 1.6 years of age (median age 1.2 years). Seven out of the 65 patients had biochemical evidence of hepatitis with raised alanine aminotransferase (ALT) but all of them were transient. Transient coronary dilatations or ectasia of the arterial wall were commonly observed, about one third during the acute disease. But long-term complications are rare in our series (5%). One out of five patients (20%) who did not receive IVGG treatment developed coronary complications. For those 60 patients who received IVGG treatment, three of them (5%) still developed coronary complications with bilateral saccular type aneurysms requiring long-term aspirin treatment and close follow-up and monitoring.



Advances in Kawasaki disease

Despite advances in culture technique, intensive investigation and extensive research, the aetiology of Kawasaki disease remains unknown. Recent research propose super-antigen as the most likely aetiology for the condition. In order to understand what is super-antigen, one should know the different immune responses triggered by conventional antigen and by super-antigen.



Super-antigen

Conventional antigen elicits an immune response only after being ingested by an antigen-presenting cell and it expresses on the surface of the cell within a specific antigen-binding site formed by major histocompatibility complex (MHC) class II molecules. Limited number and specific type of lymphocytes will be activated.

In contrast, superantigens bind themselves to MHC class II molecules on the surface of the antigen-presenting cell without becoming ingested and at the site outside the classical binding site. The MHC-bound superantigen interacts with a T-cell receptor (TCR) by means of a variable portion of the beta-chain. All T-cells possessing a specific sequence on the TC receptor (V beta 2 T-cell) are activated by the MHC-superantigen complex, and this can activate as many as 20% of the circulating lymphocytes.17 The release of large amounts of cytokines produces a wide involvement of different organ inside the body.18

The most recently proposed aetiologic candidate has been a superantigen named toxic shock syndrome toxin-1 (TSST-1). Recent studies indicating that certain families of T-cell receptor (beta) genes (V [beta] 2 and V [beta] 8) were preferentially expressed in the peripheral blood lymphocytes of patients with Kawasaki disease.19-21

The clinical features of Kawasaki disease which are similar to those seen in patients with staphylococcal and streptococcal toxin-mediated disease can also be explained by this superantigen theory.

There is also evidence showing that different toxin concentrations elicit different immune responses and it provides an explanation why some patients with Kawasaki disease did not have full-blown features of Kawasaki disease.



Important practical points for the general practitioner

It is also important to advise discontinuation of aspirin for two weeks to avoid the risk for Reyes' syndrome for patients having contact with chickenpox.22,23 Aspirin may be replaced temporarily by another anti-platelet agents, such as dipyridamole (2-3mg/kg/does, three times per day) for patients with high risk of thrombosis.

Concerning vaccination, administration of live vaccines (i.e. measles, mumps, rubella, and varicella) should be delayed for 6 months after IVGG because antibodies may interfere with the immune responses to the vaccines.24



Conclusion

Kawasaki disease is the most common acquired paediatric heart disease in Hong Kong, which carries important, severe and long-term morbidity, particularly if IVGG was not given before the tenth day of illness. Family physicians play an important role in identifying the cases and referring them for IVGG treatment. It is also important to stop aspirin for Kawasaki patients who contact chickenpox. Vaccination with live vaccine should be delayed if indicated. Advice should also be given to patients to avoid risk factors for atherosclerosis e.g. smoking, obesity, hypertension and hyperchole-sterolaemia.

The most recently proposed aetiologic candidate for Kawasaki disease has been the super-antigen. Hopefully, further research along this line may find out the definitive aetiology and treatment for this mysterious disease.



Key messages

  1. Kawasaki disease (KD) is the most common acquired paediatric heart disease in Hong Kong.
  2. Cervical lymph node is the least common sign in KD and is absent in about half of the patients and infant with KD.
  3. Reactivation of BCG scar is said to be a specific sign of KD.
  4. Intravenous gamma globulin (IVGG) given before the 10th day of illness greatly reduces the prevalence of coronary aneurysm. It is important not to delay referring patient when KD is suspected.
  5. Patients on aspirin should be advised to stop the drug for two weeks if they have contact with chickenpox to avoid the possibility of Reye syndrome.
  6. Vaccinations with live vaccine should be delayed for 6 months after IVGG treatment.


References

  1. Kawasaki T. Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children. Clinical observation of 50 patients. Jpn J Allergy 1967;16:178-222.

  2. Kato H, Koike S, Yamamoto M, et al. Coronary aneurysms in infants and young children with acute febrile mucocutaneous lymph node syndrome. J Paediatr 1975;86:892-898.

  3. Ng YM, Sung R, So LY, et al. A 6-year surveillance of Kawasaki disease in Hong Kong. Hong Kong Kawasaki Disease Study Group, 2001.

  4. Shulman ST, Bass JL, Bierman F, et al. Management of Kawasaki syndrome: a consensus statement prepared by North American participants of the third International Kawasaki disease symposium, Tokyo, Japan, December, 1988. Paediatr Infect Dis J 1989;8:663-665.

  5. Tizard EJ, Suzuki A, Levin M, et al. Clinical aspects of 100 patients with Kawasaki disease. Arch Dis Child 1991;66:185-188.

  6. Plantin P, Blayo M, Dupre D, et al. BCG reactivation: a rare but specific sign of Kawasaki disease. Presse Med 1998 Apr 18;27(15):716.

  7. Yokota S, Tsubaki K, Kuriyama T, et al. Presence in Kawasaki disease of antibodies to mycobacterial heat-shock protein HSP65 and autoantibodies to epitopes of human HSP65 cognate antigen. Clin Immunol Immunopathol 1993 May;67(2):163-170.

  8. Yung TC, So LY, Ho HK, et al. Clinical Guideline on the use of intravenous gammaglobulin in children with Kawasaki disease: prevention or coronary artery lesions. 5:2001.

  9. Shulman ST, Inocencio J, Hirsch R. Kawasaki disease. Paediatr Clin North Am 1995;42:1205-1222.

  10. Terai M, Shulman ST. Prevalence of coronary artery abnormalities in Kawasaki disease is highly dependent on gamma globulin dose but independent of salicylate dose. J Paediatr 1997;131:888-893.

  11. Durongpisitkul K, Gururaj VJ, Park JM, et al. The prevention of coronary artery aneurysm in Kawasaki disease: a meta-analysis on the efficacy of aspirin and immunoglobulin treatment. Paediatrics 1995;96:1057-1061.

  12. Iemura M, Ishii T, Sugimura T, et al. Long term consequences of regressed coronary aneurysms after Kawasaki disease: vascular wall morphology and function. Heart 2000;83:307-311.

  13. Adnan S Dajani, et al. Report from the committee on rheumatic fever, endocarditis, and Kawasaki disease, council on cardiovascular disease in the Young, American Heart Association. Guidelines for long-term management of patients with Kawasaki disease. Circulation 1994;89:916-922.

  14. Tsuchida S, Yamanaka T, Tsuchida R, et al. Epidemiology of infant Kawasaki disease with a report of the youngest neonatal case ever reported in Japan. Acta Paediatr 1996;85:995-997.

  15. Yanagawa H, Yashiro M, Nakamura Y, et al. Results of 12 nation-wide epidemiological incidence survey of Kawasaki disease in Japan. Arch Paediatr Adolesc Med 1995;149:779-783.

  16. Fujita Y, Nakamura Y, Sakata K, et al. Kawasaki disease in families. Paediatrics 1989;84:666-669.

  17. Yamashiro Y, Nagata S, Oguchi S, et al. Selective increase of V beta 2 T cells in the small intestine mucosa in Kawasaki disease. Paediatr Res 1996;39:264-266.

  18. Curtis N, Zheng R, Lamb JR, et al. Evidence for a superantigen mediated process in Kawasaki disease. Arch Dis Child 1995;72:308-311.

  19. Yoshioka T, Matsutani T, Iwagami S, et al. Polycloncal expansion of TCRBV2- and TCRBV6-bearing T cells in patients with Kawasaki disease. Immunology 1999;96:465-472.

  20. Marrack P, Kappler J. The staphylococcal enterotoxins and their relatives. Science 1990;248:705-711.

  21. Leung DYM, Meissner HC, Fulton DR, et al. Toxic shock syndrome toxin-secreting Staphylococcus aureus in Kawasaki syndrome. Lancet 1993;342:1385-1388.

  22. Lee JH, Hung HY, Huang FY. Kawasaki disease with Reye syndrome: report of one case. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi 1992 Jan-Feb;33(1):67-71.

  23. Takahashi M, Mason W. Kawasaki syndrome, Reye syndrome, and aspirin. Paediatrics 1986;77(4):616-617.

  24. Salisbury DM, Begg NT, eds. Immunisation against infectious disease. London: HMSO, 1996:24.