Editorial

Indian Pediatrics 1999;36: 817-875

Kawasaki Disease: A Clinical Dilemma

This condition was first described by Tomisaku Kawasaki in 1967 when he reported 50 children who had presented with a distinctive clinical illness and to which he gave the name `acute febrile mucocutaneous lymph node syndrome'(1). It was initially thought to be a self-limiting benign illness, but by 1970 ten fatal cases had been reported out of which 4 had evidence of coronary artery aneurysms with thrombosis(2). Kawasaki Disease (KD) has now been described from all parts of the world and in all races(3-5). However, till very recently, reports from India had been few and far between(6-13).

KD is a systemic necrotizing vasculitis affecting the medium and small sized arteries(4,14). It is not only the commonest vasculitic disorder of children, but is also the commonest cause of acquired heart disease in children in many countries(3-5). It primarily affects infants and young children, with 80-85% of the subjects being below 4 years of age(2,4,5). Boys are affected more commonly than girls and there is an ethnic bias in favor of children of Asian (specially Japanese and Korean) and Afro- Caribbean extraction(2,4,5,14).

KD is by no means a rare disorder, with the reported annual incidence being in the range of 10-100 per 100,000 children below 5 years of age(2,4). In Japan 5000-6000 new cases of KD are diagnosed every year and the Japanese KD Registry now has upwards of 150,000 recorded children(2). Though there is little evidence of person to person spread, country wide epi- demics which spread in a wave-like pattern over a period of several months (and very remini-scent of spread of an infectoius disease) have been reported from Japan, and some other countries(2,3,15).

The diagnosis of KD is difficult because it is based entirely on the recognition of a typical temporal sequence of a constellation of clinical features, with none of the features taken individually being of any diagnostic significance(2,5). There is no laboratory test which can help the clinician in arriving at or confirming a diagnosis of KD(2,5). The difficulty is further compounded by the fact that the clinical features gradually evolve over a period of days to a few weeks, and the entire clinical spectrum is not seen at any one particular point of time. Moreover, it may be diffcult to distinguish KD from other common febrile illnesses of childhood(5,16). Early diagnosis, however, is imperative in order to avoid the risk of acute coronary vasculitis which can occur in up to 30% of cases and which can be minimized by prompt administration of intravenous immunoglobulin therapy(17-22). KD can be diagnosed on the basis of the criteria outlined in Table I(5). According to the Japanese workers, however, fever may not be an essential pre-requisite for KD and should be given the same weightage as the other 5 criteria under `B'(2) and KD may then be diagnosed if the child fulfils any 5 of the 6 criteria(2).

TABLE 1 - Criteria for Diagnosis of Kawasaki Disease(5)

KD generally has an acute febrile phase lasting up to a few weeks, a subacute phase of 2-4 weeks and a convalescent phase lasting a few months(2-4). Fever is characteristically high, unresponsive to antimicrobials and accompanied by extreme irritability(2,4). A non-pruritic rash is often seen during the febrile period. It is extremely variable in morphology and distribution, may have a perineal accentuation and, in our experience, may sometimes be so mild as to be missed entirely if not looked for specifically. The conjunctivitis is non-purulent and spares the area around the limbus. Mucosal changes are quite prominent during the acute stage. There may be a rather characteristic painful brawny edema of palms and soles, accompanied by erythema and/or induration of hands and feet and rarely, peripheral gangrene. Periungual desquamation is almost pathog-nomonic of KD but is only seen after the febrile period is over. Cervical adenopathy (at least 1 node �1.5 cm in diameter) is present in only 50% of patients, as compared to the other features enumerated above which are present in 80-90% of patients of KD(2-4).

It is easy to visualize how a diagnosis of KD can be entirely missed if the clinician does not have a high index of suspicion(2,4). Further, children with KD can have a number of other associated non-specific clinical findings affecting many different organ systems, e.g., arthralgia/arthritis, severe abdominal pain, sterile urethritis, hepatic dysfunction, aseptic meningitis, penumonia and diarrhea(2-4). KD must, therefore, be considered in the differential diagnosis of any child with an atypical febrile illness(3,4). Pediatric conditions which can mimic clinical featurs of KD include viral exanthems (specially measles), drug reactions, Stevens-Johnson Syndrome, systemic onset juvenile rheumatoid arthritis, scarlet fever and toxic shock syndrome(2-4). In majority of cases a careful clinical appraisal is all that is required in arriving at a correct diagnosis.

Laboratory findings are non-specific and include a polymorphonuclear leukocytosis, raised erythrocyte sedimentation rates and an elevated level of C-reactive protein(2-4). Thrombocytosis is quite characteristic, but may not be apparent in the crucial first 7-10 days of the illness. Liver enzymes may be elevated; pyuria may be present and the cerebrospinal fluid may show a moderate cellular response(2-4). Anti-neutrophil cytoplasmic antibodies (ANCAs) and anti-endothelial cell antibodies (AECAs) may be present(23-25).

The etiology of KD remains obscure(26). While the characteristic acute febrile clinical presentation and clustering of cases in well-defined epidemics suggests an infectious etiology, conventional bacterial and viral cultures and detailed serological studies have all been inconclusive(2-4,14). It is believed that KD may be triggered by a streptococcal/staphylococcal toxin which acts as a superantigen(27) and causes widespread immune activation. Evidence for this hypothesis comes from the selective expansion of T lymphocytes bearing Vb2 and Vb8 T-cell receptors which is seen in children with KD. This pattern is very similar to that which is seen in toxin mediated streptococcal infections(27-29). Reports of rickettsiae, retroviruses, house-dust mites and skin commensals (e.g., Propionibacterium acnes) as possible causative agents have not been confirmed(2-5). Other possible and intriguing associations include exposure to rug shampoo(30), mercury poisoning and residence close to a body to water(2-5).

Once a diagnosis of KD has been made the treatment is quite straightforward. Intravenous immunoglobulin (IVIG) given either as a single bolus of 2 g/kg or as 400 mg/kg infusion daily for 4 days, results in prompt resolution of fever and irritability(2-5,31). Aspirin is given at 100 mg/kg/day for the first 2 weeks and thereafter in doses of 3-5 mg/kg/day.

Aspirin is continued till the ESR and platelet counts return to normal and this usually takes 4-6 weeks. If coronary aneurysms have developed, aspirin may need to be continued indefinitely. Unlike all other vasculitides, steroids are contraindicated in KD(2-4). IVIG suppresses the formation of coronary aneurysms, improves myocardial perfusion and reverses lymphocyte activation(3,15,26). The mechanism of action is through down regulation of cytokine production, blockage of Fc receptors and suppression of antibody function through the anti-idiotypic pathway(2-4).

For the pediatrician it is of the utmost importance to diagnose KD in the acute stage because as many as 20-30% of untreated patients may develop coronary artery abnormalities(32). With treatment this figure can be brought down to as low as 1-2%(2-5). In the first 10 days there may be evidence of myocarditis, pericarditis or arrhythmias. In fact myocarditis occurs in virtually all patients with KD and can be demonstrated by specialized scanning techniques. The coronary arteritis which occurs during this period evolves into coronary artery aneurysms which are first seen from 10-28 days after the onset of illness(2-5). Such aneurysms usually do not develop after the first 4 weeks of illness. Death can result from acute myocarditis, arrhythmias, myocardial infarction secondary to thrombosis of an aneurysm or from  rupture of an affected coronary artery. The long term outcome depends on degree of cardiac involvement and the maximal luminal diameter of the affected coronary artery. There have been several reports of myocardial infarction, premature onset ischemic heart disease, juvenile onset atherosclerosis and sudden death occurring many years after an episode of KD(33-36). As a corollary one should try and look for a clinical history of KD in the past in all young adults who present with myocardial infarction/ischemia, specially in those individuals who have no suggestive family history and risk factors for ischemic heart disease(35,36).

There are now an increasing number of reports of `atypical' or `incomplete' KD(37-39) in which all diagnostic criteria are not fulfilled and yet the children have developed coronary artery abnormalities. It is for this reason that treatment with IVIG is often given whenever there is a strong clinical suspicion of KD even though the requisite defining criteria have not been met(37-39). For the clinician who encounters such a patient therapeutic decision making can be extremely difficult. According to Cassidy's Textbook of Pediatric Rheumato-logy(4): "when confronted with a child who possibly has KD, the physician must ask the question _`What else could it be?' If the answer is `Nothing!', it is very likely that KD is the correct diagnosis, even if the criteria are not completely fulfilled."

In India KD is perhaps not being diagnosed as frequently as it should be(6-13). This is evident from the total number of reported cases which stand at less than 25! It is incumbent on us pediatricians to familiarize ourselves with the typical constellation of clinical features which constitute KD so that prompt therapy can be instituted and the devastating cardiac complications can be avoided. None of us can afford to ignore the fact that KD, and not rheumatic fever, is now the commonest cause of acquired heart diseases in children in many countries(2-5,40). It may well be so in India as well!

Surjit Singh,
Associate Professor of Pediatric
Allergy and Immunology,
Department of Pediatrics,
Post Graduate Institute of Medical Eduation and Research,
Chandigarh 160 012, India.
E-mail:[email protected]

References

1. Kawasasi T, Kosaki F. Febrile oculo-oro-cutaneo-acro-desquamatous syndrome with or without acute non-suppurative cervical lymphadenitis in infancy and childhood: Clinical observations of 50 cases.Arerugi 1967; 16: 178-222.

2. Kawasaki T. General review and problems in Kawasaki Disease. Jpn Heart J 1995; 36: 1-12.

3. Shulman ST, DeInocencio J, Hirsch R. Kawasaki Disease. Pediatr Clin North Am 1995; 42: 1205-1222.

4. Cassidy JT, Petty RE. Vasculitis. In: Textbook of Pediatric Rheumatology, 3rd edn.Eds. Cassidy JT, Petty RE, Philadelphia, W.B. Saunders Company, 1995; pp 365-422.

5. Shulman ST, Bass JL, Bierman F, Burns JC, Chung K, Dillon MJ, et al. Managment of Kawasaki syndrome: A consensus statement prepared by North American participants of the Third International Kawasaki Disease Symposium, Tokyo, Japan, December. 1988 Pediatr Infect Dis J 1989; 8(S): 663-667.

6. Taneja A, Saxena U. Mucocutaneous lymph node syndrome. Indian Pediatr 1977; 14: 927-931.

7. Nitsure MY, Hiremath MS, Grant PK, Gulati MR, Wadia RS. Kawasaki syndrome with multiple arterial aneurysms. Indian Pediatr 1988; 25: 881-888.

8. Seshadri MS, Cherian AM, Dayal AK, Thomas K. Kawasaki syndrome. J Assoc Phys India 1989; 37: 287-288.

9. Singh S, Kumar L. Kawasaki Disease - Treatment with intravenous immunoglobulin during the acute stage. Indian Pediatr 1996; 33: 689-692.

10. Singh S, Kumar L, Trehan A, Marawaha RK. Kawasaki Disease at Chandigrah, Indian Pediatr 1997; 34: 822-825.

11. Narayanan SN, Krishan V, Sabrinathan K. Kawasaki Disease. Indian Pediatr 1997; 34: 139-143.

12. Singh S. Kawasaki Disease. In: Recent Advance in Pediatrics, vol. 9 Ed. Gupte S. New Delhi, Jaypee Brothers, 1999; pp 251-257.

13. Juneja M, Verma P. Kawasaki Disease in a 3 month female. Pediatrics Today 1998; 1: 116-118.

14. Nadel S, Levin M. Kawasaki Disease. Curr Opin Pediatr 1993; 5: 29-34.

15. Rowley AH, Shulman ST. Kawasaki syndrome. Pediatr Clin North Am 1999; 46: 313-329.

16. Kuijpers TW, Tjia KL, deJager F, Peters M, Lam J. A boy with chickenpox whose fingers peeled. Lancet 1998; 351: 1782.

17. Dahdah NS, Fournier A, Jaeggi E, van Doesburg NH, Lambert R, Dionne N, et al. Segmental myocardial contractility versus perfusion in Kawasaki Disease with coronary arterial aneurysm. Am J Cardiol 1999; 83: 48-51.

18. Nakamura Y, Yanagawa H, Kato H, Kawasaki T. Mortality rates for patients with a history of Kawasaki Disease in Japan. J Pediar 1996; 128: 75-81.

19. McConnell ME, Honnon DW, Steed RD, Gilliland MGF. Fatal obliterative coronary vasculitis in Kawasaki Disease. J Pediatr 1998; 133: 259-261.

20. Suzuki Y, lijima M, Sasaki H, Muto T, Tanaka H, Kaneko K. Tachycardia as a potential risk factor for coronary arterial lesions in Kawasaki Disease. Eur J Pediatr 1999; 158: 207-209.

21. Furusho K, Kamiya T, Nakano H, Kiyosawa N, Shinomiya K, Hayashidera T, et al. High dose intravenous gammaglobulin for Kawasaki Disease. Lancet 1984; 2: 1055-1058.

22. Newburger JW, Takahashi M, Burns JC, Beiser AS, Chung KJ, Duff CE, et al. The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med 1986; 315: 341-347.

23. Sakata K, Kita M, Imanishi J, Onouchi Z, Liu Y, Mitsui Y. Effect of Kawasaki Disease on migration of human umbilical vein endothelial cells. Pediatr Res 1995; 38: 501-505.

24. Terai M, Yasukawa K, Narumoto S, Tateno S, Oana S, Kohno Y. Vascular endothelial growth factor in acute Kawasaki Disease. Am J Cardiol 1999; 83: 337-339.

25. Fujieda M, Oishi N, Kurashigae T. Antibodies to endothelial cells in Kawasaki Disease lyse endothelial cells without cytokine pretreatment. Clin Exptl Immunol 1997; 107: 120-126.

26. Laupland KP, Dele Davies H. Epidemiology, etiology and management of Kawasaki Disease: State of the art. Pediatr Cardiol 1999; 20: 177-183.

27. Yoshioka T, Matsutani T, Iwagami S, Toyosaki-Maeda T, Yutsdo T, Tsuruta Y, et al. Polyclonal expansion of TCR-Vb2 and TCR-Vb6 bearing T cells in patients with Kawasaki Disease. Immunology 1999; 96: 465-472.

28. Mancia L, Wahlstrom J, Schiller B, Chini L, Elinder G, D' Argenio P, et al. Characterization of the TCR V-beta repertoire in Kawasaki Disease. Scand J Immunol 1998; 48: 443-449.

29. Manders SM. Toxin-mediated streptococcal and staphylococcal disease. J Am Acad Dermatol 1998; 39: 383-398.

30. Rauch AM, Glode MP, Wiggins JW, Rodriguez JG, Hopkins RS, Hurwitz ES, et al. Outbreak of Kawasaki syndrome in Denver, Colorado: Association with rug and carpet clearning. Pediatrics 1991; 87: 663-669.

31. Durongpisitkul K, Gururaj VJ, Park JM, Martin CF. The prevention of coronary artery aneurysm in Kawasaki Disease: A meta-analysis on the efficacy of aspirin and immunoglobulin treatment. Pediatrics 1995; 96: 1057-1061.

32. Fukushige J, Takashashi N, Ueda K, Hiju T, Igarashi H, Ohshima A. Long-term outcome of coronary abnormalities in patients after Kawasaki Disease. Pediatr Cardiol 1996; 17: 71-76.

33. Pounder DJ. Coronary artery aneurysms presenting as sudden death 14 years after Kawasaki Disease in infancy. Arch Pathol Lab Med 1985, 109: 874-876.

34. Fineschi V, Paglicci Reattelli L, Baroldi G. Coronary artery aneurysms in a young adult: A case of sudden death. A late sequelae of Kawasaki Disease? Int J Legal Med 1999; 112: 120-123.

35. Ishiwata S, Fuse K, Nishiyama S, Nakanishi S, Watanabe Y, Seki A. Adult coronary artery disease secondary to Kawasaki Disease in childhood. Am J Cardiol 1992; 69: 692-694.

36. Kato H, Inoue O, Kawasaki T, Fujuvara H, Watanabe T, Toshima H. Adult coronary artery disease probably due to childhood Kawasaki Disease. Lancet 1992; 340: 1127-1129.

37. Bolz D, Arbenz U, Fanconi S, Bauersfeld U. Myocarditis and coronary dilatation in the first week of life: Neonatal incomplete Kawasaki Disease? Eur J Pediatr 1998; 157: 587-589.

38. Helin I, Oskarsson G. Prolonged fever, thrombocytosis and coronary aneurysms- incomplete Kawasaki Disease or separate entity? Eur J Pediatr 1998; 157: 473-474.

39. Rowley AH, Gonzalez-Crussi F, Gidding SS. Incomplete Kawasaki Disease with coronary artery involvement. J Pediatr 1987; 110: 409- 413.

40. Taubert KA, Rowley AH, Shulman ST. Seven year national survey of Kawasaki Disease and acute rheumatic fever. Pediatr Infect Dis J 1994; 13: 704-708.