Pediatric Annals

Management Strategies in Kawasaki Disease

Jerry C Jacobs, MD

Abstract

Every pediatrician can expect to see Kawasaki disease (KD) in the course of daily practice because it is becoming an important new cause of acquired heart disease in children. AU authorities agree that any treatment which might reduce sequelae must be introduced early in the course of the illness, perhaps in the first 8 days, before aneurysms form.1'3 Early diagnosis is the first essential of optimal care.

The clinical sextet of fever, rash, red eyes, red mouth, red, swollen hands and feet, and lymphadenopathy are rarely all simultaneously present in the first week of illness and in fact, fever, rash, and red eyes may be all that one should require for presumptive diagnosis to institute therapy; this triad is present in the first few days of illness in greater than 95% of cases. ' Early diagnosis is not essential if effective treatment is not possible, but presumptive diagnosis may be required if effective treatment is to be instituted early in the course of the disease.4 At present, the overwhelming majority of patients referred to us are not diagnosed within 1 week of onset, the optimal time for instituting treatment. Kawasaki has recently published an excellent review of the clinical features with color pictures worthy of study by all doctors who care for children.1

TREATMENT OF THE ACUTE PHASE

In 1977, we reported that the clinical manifestations of KD were responsive to aspirin; but because of salicylate malabsorption, unusually high doses of aspirin were often required for symptomatic control.5"7 These observations were subsequently confirmed by Koren8 and Melish.9 Recently, Koren has reported that patients in whom treatment with large doses of aspirin is instituted early developed significantly fewer aneurysms and other signs of coronary artery involvement than a population of patients in whom late diagnosis prevented the institution of vigorous salicylate therapy.4 Prospective studies of limited numbers of Japanese patients did not show this effect and high-dose aspirin treatment is not popular in Japan.1·2 Our continued recommendation, aspirin in sufficient dosage to control symptoms, is based on the following observations: 1) aspirin can shorten the duration of fever and lessen symptoms; 2) aneurysms and sequelae have been correlated with duration of fever and severity of symptoms; and 3) aspirin may reduce coronary artery involvement and sequelae if begun early.

If high-dose aspirin therapy is instituted in the first week of disease, one can anticipate that lowering to conventional doses (80 to 90 mg/kg/day) will be required as soon as control of fever is achieved.67 Daily monitoring of salicylate levels and liver enzymes with immediate retrieval of laboratory data and adjustment of dosage is essential for safety. Where daily monitoring with prompt reporting is not practical, high-dose aspirin therapy is dangerous. Some patients will not tolerate even conventional doses of aspirin. Other nonsteroidal anti-inflammatory drugs can be used in such cases to control the clinical manifestations of the disease, but the agents may not reduce aneurysm formation.1,3

Other therapeutic maneuvers are being evaluated in Japan and the United States.1,3 Benefit has been reported with intravenous pulse corticosteroids3 and with the intravenous administration of high doses of gamma globulin daily for 5 days3,10; both regimens were begun prior to the eighth day of illness. Both have the potential for significant toxicity and should be used only in controlled clinical trials. It appears most likely that evaluation of any regimen which has considerable risk will require a means of early (first week) identification of patients at high risk for sequelae of the disease itself.1,3,11,12

TREATMENT DURING THE SUBACUTE PHASE OF THE DISEASE

If acute rheumatic fever is considered a model for acute vasculitic disease,…

Every pediatrician can expect to see Kawasaki disease (KD) in the course of daily practice because it is becoming an important new cause of acquired heart disease in children. AU authorities agree that any treatment which might reduce sequelae must be introduced early in the course of the illness, perhaps in the first 8 days, before aneurysms form.1'3 Early diagnosis is the first essential of optimal care.

The clinical sextet of fever, rash, red eyes, red mouth, red, swollen hands and feet, and lymphadenopathy are rarely all simultaneously present in the first week of illness and in fact, fever, rash, and red eyes may be all that one should require for presumptive diagnosis to institute therapy; this triad is present in the first few days of illness in greater than 95% of cases. ' Early diagnosis is not essential if effective treatment is not possible, but presumptive diagnosis may be required if effective treatment is to be instituted early in the course of the disease.4 At present, the overwhelming majority of patients referred to us are not diagnosed within 1 week of onset, the optimal time for instituting treatment. Kawasaki has recently published an excellent review of the clinical features with color pictures worthy of study by all doctors who care for children.1

TREATMENT OF THE ACUTE PHASE

In 1977, we reported that the clinical manifestations of KD were responsive to aspirin; but because of salicylate malabsorption, unusually high doses of aspirin were often required for symptomatic control.5"7 These observations were subsequently confirmed by Koren8 and Melish.9 Recently, Koren has reported that patients in whom treatment with large doses of aspirin is instituted early developed significantly fewer aneurysms and other signs of coronary artery involvement than a population of patients in whom late diagnosis prevented the institution of vigorous salicylate therapy.4 Prospective studies of limited numbers of Japanese patients did not show this effect and high-dose aspirin treatment is not popular in Japan.1·2 Our continued recommendation, aspirin in sufficient dosage to control symptoms, is based on the following observations: 1) aspirin can shorten the duration of fever and lessen symptoms; 2) aneurysms and sequelae have been correlated with duration of fever and severity of symptoms; and 3) aspirin may reduce coronary artery involvement and sequelae if begun early.

If high-dose aspirin therapy is instituted in the first week of disease, one can anticipate that lowering to conventional doses (80 to 90 mg/kg/day) will be required as soon as control of fever is achieved.67 Daily monitoring of salicylate levels and liver enzymes with immediate retrieval of laboratory data and adjustment of dosage is essential for safety. Where daily monitoring with prompt reporting is not practical, high-dose aspirin therapy is dangerous. Some patients will not tolerate even conventional doses of aspirin. Other nonsteroidal anti-inflammatory drugs can be used in such cases to control the clinical manifestations of the disease, but the agents may not reduce aneurysm formation.1,3

Other therapeutic maneuvers are being evaluated in Japan and the United States.1,3 Benefit has been reported with intravenous pulse corticosteroids3 and with the intravenous administration of high doses of gamma globulin daily for 5 days3,10; both regimens were begun prior to the eighth day of illness. Both have the potential for significant toxicity and should be used only in controlled clinical trials. It appears most likely that evaluation of any regimen which has considerable risk will require a means of early (first week) identification of patients at high risk for sequelae of the disease itself.1,3,11,12

TREATMENT DURING THE SUBACUTE PHASE OF THE DISEASE

If acute rheumatic fever is considered a model for acute vasculitic disease, then rebound phenomena are to be anticipated and avoided. We do not know if this applies to KD, but authorities agree that patients with KD who have multiple fever spikes and/or prolonged fever are at higher risk for aneurysms.11,12 For this reason we advocate slow weaning of aspirin after the third week of illness; weaning from anti-inflammatory to anticoagulant doses of aspirin (8 mg/kg/day) may be accomplished within 3 weeks.

We believe every effort should be made to avoid thrombus formation.2 Therefore, in patients in whom platelet counts rise about 1 million we add dipyridamole, 1 to 2 mg/kg/day in three divided doses, to the regimen. We do not stop the platelet-inhibiting doses of aspirin or the dipyridamole until all of the following conditions of recovery are met: a) normal two-dimensional echocardiogram (2D ECHO) and electrocardiogram (EKG); b) normal platelet count; c) normal ESR; and d) normal physical examination. These parameters usually return to normal within 2 months in patients who do not have aneurysms.

REGIMENS AIMED AT INDUCING REGRESSION OF ANEURYSMS AND PREVENTION OF STENOTIC LESIONS

Sequelae of KD include dilation and/or aneurysms of the coronary arteries (and occasionally of peripheral vessels or the aorta), mitral and aortic valve insufficiency, and stenosis of the coronary arteries with the potential for ischemic sequelae.2 Prospective studies aimed at promoting healing of aneurysms or reducing the incidence of stenotic lesions which may evolve months to years after KD are just beginning.3 In the meantime, treatment is empiric. We have chosen to continue dipyridamole and tiny doses of aspirin in patients with aneurysms.

FOLLOW-UP PROCEDURES

Patients who have had undiagnosed KD and who were thought to be completely well have had sudden myocardial infarction,1316 rupture of a hepatic aneurysm,13 and sudden death from ischemic heart disease.1416 To our knowledge, however, patients who are normal at follow-up 1 year after KD are not at sufficient risk to require special care, and may be discharged to routine pediatric care if EKG and 2D ECHO done at that time are normal. The 2D ECHOs must be performed in pediatric centers capable of visualizing the coronary arteries of small children.17 The test is expensive and we find both families and pediatricians sometimes reluctant to obtain the necessary studies in apparently healthy children, especially where expert 2D ECHO facilities are not close at hand. Safety, however, requires such monitoring.

WHAT IS THE RISK OF SEQUELAE?

In prospective studies of KD the incidence of coronary artery lesions has been as low as 22% or as high as 58% transient dilatation and 33% aneurysm formation.2·3 One year later, the incidence of residual aneurysms/stenoses has varied from 1% to 12% of patients1"3; in our series, about 5% of patients have persistent aneurysms and 1% more possibly have other sequelae; one patient died in the acute phase. Manifestations of KD are not identical from year to year; in 1983, and again in 1985, 22% of our patients had persistent aneurysms, while in many years no children in our series developed aneurysms. We have no explanation for these variations, but they occur worldwide; the disease is generally more virulent during epidemics.1,7

MANAGING PATIENTS WITH SEQUELAE

In those patients with a potential for ischemic heart disease, monitoring with stress thalium is currently the procedure of choice; chemical stress (dipyridamole) rather than exercise is likely to be the best study for identifying patients who may need coronary bypass. Relatively few children have had bypass procedures, and many grafts have not been patent a year later.3 Nevertheless, bypass is the procedure of choice for some patients and can be life-saving. Some children will require heart transplantation.

REASSURING PARENTS

It is important not to make cardiac invalids out of the 88% to 94% of children with KD who recover completely without sequelae. These children should be reassured that they are normal and discharged from follow-up care in cardiac centers.

REFERENCES

1. Kawasaki T: Kawasaki disease: Comments on its history, clinical manifestations, etiology, and treatment, in Jacobs JC: New Frontiers m Pediatric Rheumatology. Motrisville, PA, Menley and James Laboratories, 1986, pp 6-13.

2. Kato H: Cardiovascular problems in Kawasaki disease, in Jacobs JC: New Frontiers m Pediatrie Rheumatology. Morrisville, PA, Menley and James Laboratories, 1986, pp 14-19.

3. Suzuki A, Kamiya T: Cardiac problems in Kawasaki disease: Evaluation and medical and surgical treatment, in Jacobs JC: New Frontiers in Pediaric Rheumatology Morrisville, PA, Menley and James Laboratories, 1986, pp 20-24.

4. Koren G. Rose V, Lavi S, et al·. Probable efficacy of high-dose salicylates in reducing coronary involvement in Kawasaki disease. JAMA 1985; 254:767-769.

5. Jacobs JC: Successful treatment of Kawasaki disease with high-dose aspirin. Pediatr Res 1978; 12:494.

6. Jacobs JC: Salicylate treatment of epidemic Kawasaki disease in New York City. Ther Drug Monit 1979; 1:123-130.

7. Jacobs JC: Pediatric Rheumatology for the Practitioner. New York, Springer-Verlag, 1982.

8. Koren G, Macleod SM: Difficulty in achieving therapeutic serum concentrations of salicylate in Kawasaki disease. J Pediatr 1984; 105:991-995.

9. Melish ME, Hicks RM, Dean AG: Kawasaki syndrome in Hawaii, abstracted. Pediatr Res 1979; 13:451.

10. Furusho K, Kamiya T, Nakano H, et ah High-dose intravenous gamma globulin for Kawasaki disease. Lancet 1984; 2:1055-1088.

11. Asai T: Evaluation method for the degree of seriousness in Kawasaki disease. Acta Pediatr Jap 1983; 25:170-175.

12. Koren G, Lavi S, Rose V, et al: Kawasaki disease: Review of risk factors for coronary aneurysms. J Pediatr 1986; 108:388-392.

13. Lipson MH, Ament ME, Fonkalsrud EW: Ruptured hepatic artery aneurysm and coronary artery aneurysms with myocardial infarction in a 14-year-old boy. New manifestation of mucocutaneous lymph node syndrome. J Pediatr 1981; 98:933-936.

14. Nakano H, Saito A, Ueda K, et al: Clinical characteristics of myocardial infarction following Kawasaki disease: Report of 11 cases. J Pediatr 1986; 108:198-203.

15. Kohr R: Progressive asymptomatic coronary artery disease as a late fetal sequelae of Kawasaki disease. J Pediatr 1986; 108:256259.

16. Pounder D: Coronary artery aneurysms presenting as sudden death 14 years after Kawasaki disease in infancy. Arch Pathol Lab Med 1985; 109:874-876.

17. Bierman FZ: Kawasaki disease: Cardiac ultrasound overview, in Jacobs JC: New Frontiers m Pediatric Rheumatology. Morrisville, PA, Menley and James Laboratories, 1986, p 36.

10.3928/0090-4481-19860901-10

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