Kawasaki syndrome (KS), also known as mucocutaneous lymph node syndrome (MLNS), is a febrile illness of unknown etiology which occurs predominantly in infants and young children. Tomisaku Kawasaki1,2 first described the features of this syndrome in Japan in 1967. He saw the first case in 1961. KS is more prevalent in Japan where it seems to be endemic but has also occurred in three major epidemics. However, it now is recognized worldwide with sporadic cases and outbreaks. 3"7 In the United States, multiple cases have occurred community-wide in timeplace clusters, especially during the winter and spring. Although Kawasaki first called it mucocutaneous lymph node syndrome, it soon became evident that it is of great cardiologie significance because of the vasculitis and pancarditis it produces.
DIAGNOSIS OF KAWASAKI SYNDROME
The principal diagnostic criteria are:
* fever, persisting for more than five days;
* bilateral conjunctival injection;
* oropharyngeal inflammation including:
dry, fissured lips;
* peripheral changes of extremities including:
erythema of palms and feet;
induration of hands and feet;
desquamation of finger and toe tips (during subacute stage);
transverse grooves across fingernails two to three months after onset;
* nonsuppurative cervical lymph node enlargement (≥1.5 cm).
Unusual irritability also characterizes these children. Other less common features of the disease are lethargic behavior, meningismus, diarrhea, pneumonia, otitis media, and hydrops of the gallbladder.
Figure 1. Racial distribution in percent for all patients with Kawasaki syndrome is shown in open bars together with percentage with aneurysm (dark bars) in that racial group. Asians and. to a lesser extent, Hispanics were disproportionately affected with aneurysms.
For the diagnosis of KS, the patient should present with fever, plus at least four of the five symptoms. Should coronary artery abnormalities be present, fever plus at least three of the five principal signs or symptoms are sufficient.8
In order to make the diagnosis of KS, other diseases that might mimic KS must be excluded, ie, scarlet fever, juvenile rheumatoid arthritis, Stevens-Johnson syndrome, rubella, leptospirosis, Epstein-Barr virus.
Laboratory studies show an increased white cell count, slight anemia, elevated erythrocyte sedimentation rate, and thrombocytosis. If a spinal tap is done, mononuclear cells may be present in the spinal fluid. Liver enzymes and bilirubin may be elevated, as well as amytase. Hydrops of the gallbladder might be documented on abdominal sonography.
COURSE OF ILLNESS
The clinical course of this illness is best described as triphasic with acute, subacute, and convalescent phases, but we believe there may be a chronic stage as well. The acute phase (one to two weeks from the onset) is characterized by fever, mucous membrane lesions, and exanthema. The rash may be quite fleeting. Myocarditis and pericarditis, sometimes with effusion, may be recognized. The subacute phase (three to six weeks from the onset) includes defervescence and peeling of fingertips and tips of toes. Thrombocytosis is characteristic of this phase. Coronary artery aneurysms and myocardial dysfunction, when they occur, usually appear in this period. The convalescent phase (six to eight weeks from onset) is characterized by the normalization of laboratory tests and of all signs of illness. Coronary arterial abnormalities may persist, however. Wide variation of each phase has been noted among patients, according to whether the illness is mild, moderate, or severe.
DETECTION OF CARDIAC INVOLVEMENT
During the acute and subacute phases of KS, arteries and veins undergo inflammatory changes. In approximately 20% of patients, coronary artery involvement with dilatation or aneurysms develops.9 Some resolve but in others, there may be the possible consequence of myocardial ischemia with angina or infarction and even sudden death (1% of patients). Postmortem studies in the acute stage show a pancardias with involvement of endo-, peri-, and myocardium. Cardiomyopathy with decreased ventricular function and clinical heart failure, as well as valvular insufficiency, may occur months or years later. 10
To detect cardiac involvement early in KS requires a high index of suspicion and a means of identifying coronary artery abnormalities.
Echocardiography has been an excellent technique to detect myocardial dysfunction and pericardial effusion, as well as to identify and follow the cou.se of coronary artery abnormalities. When myocarditis is clinically evident, the child has tachycardia out of proportion to fever and shows abnormalities of T waves in the electrocardiogram and abnormal function on echocardiography.
EXPERIENCE AT THE NEW YORK HOSPITAL
We compared epidemiologie and clinical features of KS in our experience in 106 children with 109 attacks from the referral area around m id- Manhattan11 and in large series reported from Japan. The racial distribution of our series (Figure 1) was 50% white, 18% black, 16% Hispanic, 16% Asian (eight were Chinese, six Japanese, two Indian, one South Korean).
We found similarities in the prevalence (greater among boys than girls) and in the age affected (chiefly below five years). Patients came almost entirely from urban and suburban dwellings. The recurrence rate was low (2%), as were the incidences of myocardial infarction (1%) and death (1%). Incidence of coronary aneurysms (18% to 20%) was associated in both areas with long duration of fever (14 days or more) and in Manhattan with Oriental race and height of platelet count (>l,000,000/mm3) and of the erythrocyte sedimentation rate (>100 mm/hr) (Figure 2). Yearly seasonai incidence was highest in the springtime, as in Japan during epidemics.
Figure 2. Relationship of highest platelet count and coronary aneurysms (dark bars) shows that those with platelet counts greater than or equal to 1,000,000/mm3 had a 46.1% incidence of aneurysms.
Dissimilarities noted were: heterogeneity in Manhattan (50% white, 18% black, 16% Hispanic, 16% Asian); mean age in Manhattan (three and one-half years) higher than in Japan (one and one-half years); 32% less than two years in Manhattan versus 50% to 60% in Japan; and higher incidence in upper middle class (73%) in Manhattan. The incidences of acute myocarditis (8%), late cardiac failure (1%), and valvular régurgitation (2%) were lower in Manhattan.
In our patient population, early evidence of cardiac involvement included pericardial effusion detected by echocardiography in 11 patients. This later disappeared in all of them. Five patients had clearcut myocarditis. Only one of them developed cardiac failure which responded to therapy. In follow-up, the patient has been well. Late manifestations included aortic and mitral régurgitation in one patient who also developed cardiac failure. One patient with myocardial infarction died.
The most common cardiac abnormality in KS patients is the development of coronary artery aneurysms. At one month from onset of KS, we found on two-dimensional echocardiography 38 aneurysms in 18 of 106 patients. In our series, Hispanic and Asian children tended to have a higher incidence of aneurysms than did the white or black children (Figure 1). The aneurysms had a tendency to regress spontaneously. In fact, by six months from the onset, 14 of 18 patients had 31 aneurysms, and by 12 months, 13 patients had 24 aneurysms. As yet, no others have regressed later than this, nor have any new changes appeared after the third month. The incidence of coronary artery involvement was 13% to 30% for each year of life of children below five years of age. We found no coronary abnormalities in children over five years of age. We observed a direct correlation between the duration of the fever and incidence of coronary artery aneurysm. Seventy-three percent of our patients with fever which lasted two weeks or longer had coronary artery aneurysms. This is in contrast to 17% of our patients with fever for less than two weeks. None who had fever that lasted only one week developed coronary artery involvement.
The height of the platelet count in the second and third week of the illness was a risk factor for coronary involvement. Among our patients with a platelet count of 1,000,000/mm3 or above, 46% had a coronary artery abnormality, whereas only 21% had aneurysms when the platelet count was 800,000 to 900,000/mm3 (Figure 2). None developed aneurysms if the highest recorded platelet count was less than 800,000/mm3 in the second or third week of the illness. The height of the sedimentation rate was also a significant factor, for 73% of children with a sedimentation rate greater than 100 mm/hr had coronary artery involvement.
In summary, risk factors for the development of coronary artery aneurysm were: age under five years, duration of fever for two weeks or longer, height of platelet count above 1,000,000/mm3, and height of erythrocyte sedimentation rate above 100 mm/hr.
MANAGEMENT OF CARDIAC INVOLVEMENT
Because etiology of KS is still unknown, although retroviruses are suspected to play a role,12 treatment is controversial. Acetylsalicylic acid (ASA) is the most widely used drug in KS. It has antipyretic and antiinflammatory effect and, in low doses, antiplatelet effect. There are many controversies about high- versus low-dose aspirin. Yokoyama et al compared the effectiveness of small-dose (30 mg/kg) and high-dose (150 mg/kg) ASA with platelet aggregation in KS during the acute phase.13 The small-dose group of patients showed a significant decrease in aggregation of platelets when compared with the control group. Therefore, they recommend low-dose ASA (30 mg/kg/ day) in the acute phase of KS. We found no difference in incidence of coronary abnormalities between children on high, medium, low, or no dosage of aspirin during the acute phase. At this time, we give highdose aspirin (100 mg/kg) in four doses each day of the acute phase until fever subsides. Thereafter, because of the risk of thrombosis during the period of high platelet count, we recommend low-dose aspirin in the form of one baby aspirin (80 mg) per day until the third month. If coronary abnormalities are present at that time, we continue this dose as long as coronary involvement is detected. If coronary arteries are normal at three months, we discontinue the aspirin.
Furusho14 in 1984 and Newburger15 and coworkers in 1986 reported that high-dose intravenous gamma globulin (IVGG) treatment significantly reduced the incidence of coronary artery aneurysms. These reports have given new hope that even though we do not know how to prevent KS, we may be able to favorably alter its course by preventing coronary arterial abnormality. If this treatment is to help, it should be given early, probably by day 6 to 10 of the illness. Early recognition of KS by the pediatrician is, therefore, very important for the appropriate treatment. Any child under age five years with persistent high fever for more than three days should be examined for the clinical and echocardiographic signs of KS.
1. Kawasaki T; MCLS- Clinical observation of 50 cases. ]fm} Allergy 1967; 16:178.
2. Kawasaki T, Kosaki F, Ofcawa S, et al: A new infenrile acute febrile mucocutaneous lymph node syndrome (MLNS) prevailing in Japan. Pediatrics 1974; 54(3):27l-276.
3. Melish ME. Hicks RM. Latson EJ: Mucocutaneous lymph node syndrome in the United States. Ami Dis CUJ 1976; 130:599-607.
4. Bell DM, Morene DM, Holman RC, et al: Kawasaki syndrome in the United States, 1976 to 19T?. Am J Dis OuU 1983; 137:211-224.
5. Bell DM, Brink EW, N ink in JL, et al: Kawasaki syndrome; Description of rwo outbreaks in the United States. N Eng. J Med 1981: 304?56T-1575.
6. Multiple outbreak: of Kawasaki syndrome. MMVCR 1985; 34:33-35.
7. Van der Hauwaett L, Takao A, RiiweRD, et al: Results of an international cooperative study on Kawasaki disease, in Doyle EF, Engle MA, Gersony WM, et at (eds): Pediatric Cardiology: Proceedings of lhe Second WmId Congress. New York, Springet- Verlag, 1986, p 1107.
8. Japan MCLS Research Committee: Kouusoki Oiseux, Diagnosis, Rahahgy, Treatment and Ejadfmiuiogy Department of Epidemiology. Institute of Public Health, Tokyo. Japan, May 1980.
9. Daniels SR, Specker B, Capannari TE, et al: Correlates of coronary artery aneurysm formation in patients with Kawasaki disease. ?t? ) Dis Child 1987; 141:205-207.
10. N altano H. NojimaK. Saito A, et al: High incidence of aortic régurgitation following Kawasaki disease. Pcdiatr 1985; 107:59-63.
11. Ichida F. Fatica NS, Engle MA, et al· Risk factors and role of aspirin in coronary involvement in Kawasaki syndrome in Manhattan. Pediatrici 1987; to be published.
12. Burns JC, Geha RS, Schneeberger EE, et al: ftilyrnerase activity in lymphocyte culture supematants from patients with Kawasaki disease. Nature 1986; 323:814-816.
13. Yokuyarna T, Kalo H, Ichinose E: Aspirin treatment and platelet function in Kawasaki disease. Kvnane Med) 1980; 27:57-61.
14. Furusho K, Nakano H, ShinomiyaK, et al: High-dose intravenous gamma globulin fot Kawasaki disease. Lanca 1984; 2:1055-1058.
15. Newburger JW. Takahashi M, Bums JC, et al: The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med 1986; 315:341-347.