Objective. Severe cardiac sequelae from Kawasaki disease include coronary ischemia and have been treated with a variety of coronary artery bypass procedures. There is only one published report of a child who underwent cardiac transplantation for severe Kawasaki disease-related cardiac complications. The purpose of this study was to gather the worldwide experience with cardiac transplantation for Kawasaki disease.
Methods. Data were obtained from the United Network for Organ Sharing Registry, the European transplant experience, and a phone survey of many Kawasaki disease investigators. Diagnostic and surgical reports as well as clinical records were reviewed.
Results. We identified 13 Kawasaki disease patients who underwent cardiac transplantation and obtained data on 10. In these 10 patients, the timing of transplantation was within 6 months after diagnosis of Kawasaki disease (4 patients), 1 to 5 years after diagnosis (3 patients), and 9 to 12 years after diagnosis (3 patients). Indications for transplantation included severe myocardial dysfunction, severe ventricular arrhythmias including cardiac arrest, and severe distal multivessel occlusive coronary artery disease. Nine of the 10 patients remain alive and healthy, with up to 6 years' posttransplant follow-up. One patient died 10 months posttransplant after severe refractory rejection. In addition, 1 patient required retransplantation at 4 years for severe rejection.
Conclusions. Cardiac transplantation for severe ischemic heart disease as a sequela of Kawasaki disease is feasible and can benefit the small subgroup of patients who are not candidates for revascularization because of distal coronary stenosis or aneurysms and/or those with severe irreversible myocardial dysfunction.
Coronary artery abnormalities are recognized as the most severe complications of Kawasaki disease.1 These lesions include coronary aneurysmal dilatation, stenosis, and occlusion, which may lead to myocardial infarction and dysfunction and even death.2,3 Serious coronary complications of Kawasaki disease have been treated with a variety of coronary interventions, including coronary artery bypass grafting procedures.4,5The Japanese national experience with myocardial revascularization procedures for Kawasaki disease, as reported by Kitamura et al6 in 1994, showed that the use of internal mammary artery grafts for bypass procedures yielded a patient survival rate of 98% at 7.5 years and is clearly superior to saphenous venous grafting. More recently, Ino et al7 reported a small series of Kawasaki patients who underwent successful balloon angioplasty for severe coronary stenosis.
However, there is a small population of patients for whom surgical or catheter revascularization procedures are not feasible because of the extent of their disease, with distal stenoses and/or extensive infarcted, nonviable myocardium. Such patients may be suitable candidates for cardiac transplantation.
There is only one published case report of a child who underwent cardiac transplantation for severe Kawasaki disease-related cardiac sequelae.8 The purpose of this report is to summarize the worldwide experience with cardiac transplantation for Kawasaki disease and review the indications for transplantation in this group and short-term follow-up data.
To identify patients with Kawasaki disease who underwent heart transplantation, we contacted the United Network for Organ Sharing Registry of the United States and large United States and European pediatric heart transplant centers. We also posted a request for data on the Pediheart Internet list server, solicited cases at an international Kawasaki disease symposium, and conducted a phone survey of large Kawasaki referral centers identified by their clinical and laboratory research activities and publications in the field. Clinical records for the patients who were identified were made available from eight transplant centers. (See “Acknowledgments”.)
Clinical records were reviewed for the following: 1) admission history and physical from the original hospitalization for acute Kawasaki disease; 2) laboratory data from the initial hospitalization; 3) history and physical examinations from subsequent cardiac admissions; 4) electrocardiographic, echocardiographic, and pretransplant cardiac catheterization and angiographic data; 5) coronary artery bypass grafting and transplant operative reports; 6) pathology reports for the explanted hearts; 7) discharge summaries; and 8) posttransplant follow-up records including cardiac catheterization and biopsy reports.
We identified 13 patients worldwide who had undergone cardiac transplantation for the sequelae of Kawasaki disease and were able to review data from 10 of these patients whose centers agreed to participate. The patient population consisted of 9 patients in the United States and 1 in France. We were unable to review clinical data for 3 patients in the United Kingdom. Cardiac transplantation is not performed for any indication in Japan.
The 10 patients included 7 boys and 3 girls (Table1). The mean age at the time of diagnosis of Kawasaki disease was 4.3 years (range, 3 months to 14 years), and mean age at transplantation was 8.5 years (range, 6 months to 14 years). The range of time from diagnosis of acute Kawasaki disease to transplant was within 6 months in 4 patients (with 1 patient undergoing transplantation 7 days after diagnosis), 1 to 5 years in 3 patients, and 9 to 12 years in 3, with the mean time of transplant being 4.2 years after acute Kawasaki disease.
The patients were diagnosed with Kawasaki disease using previously published clinical criteria9 and findings of coronary artery aneurysms by echocardiography and/or coronary angiography.10,11 Only 5 of the 10 patients had received intravenous immune globulin (IVIG) for acute Kawasaki disease. All five patients received the same dose of IVIG, 2 g/kg of body weight. Of those who had received IVIG, 3 patients were treated between days 7 and 10 of febrile illness (patients 2, 3, and 6) and 2 received IVIG treatment on days 11 and 14 of illness, respectively (patients 1 and 8).
Myocardial infarction was documented by the presence of laboratory and/or electrocardiographic changes in nine patients (all but patient 3). The exact timing of the infarctions are difficult to determine because of the limited availability of complete data. However, we were able to estimate that all occurred within 18 months after the onset of Kawasaki disease, and in eight of the nine patients, the infarction appeared to have occurred within 8 months after acute Kawasaki disease. The most common site for infarction was in the antero-septum, consistent with left anterior descending involvement, and was found in four patients (patients 4, 5, 7, and 10). Three patients actually had evidence of recurrent myocardial infarctions before transplantation (patients 2, 9, and 10).
Additional electrocardiographic or Holter findings in these patients included significant ventricular arrhythmias in five patients (patients 2, 3, 5, 7, and 9). These were ventricular tachycardias that progressed to ventricular fibrillation in four (patients 3, 5, 7, and 9) and wide complex supraventricular tachycardia in one (patient 2). Three patients were resuscitated after suffering cardiac arrest, two presumably related to ventricular dysrhythmias (patients 5 and 7) and one (patient 3) secondary to aneurysmal rupture and hemopericardium. The two patients who suffered dysrhythmias each received an implantable automatic cardiac defibrillator because of repeated syncopal episodes.
Severe myocardial dysfunction manifested by decreased shortening fraction, and left ventricular dilatation was present on echocardiography in all 10 patients. The shortening fraction documented on pretransplant echocardiography ranged from 5% to 24% (mean, 16%).
On measurement of coronary artery aneurysms by transthoracic echocardiography, four patients (patients 1, 2, 3, and 8) had giant aneurysms measuring >8 mm internal diameter with exact measurements available for patients 2, 3, and 8 measuring 15, 15, and 9 mm, respectively. The remaining six each had evidence of coronary stenosis with minimal to no distal flow by color Doppler interrogation.
Catheterization and Angiographic Data
Eight patients underwent coronary artery angiography before transplant, and all had evidence of severe stenosis (patients 1, 4, 5, 6, 7, 8, 9, and 10). Table 2 and Fig1 show the sites of aneurysmal dilatation and/or stenosis causing obstruction as identified by pretransplant coronary angiography, echocardiography, or pathologic data from the explanted heart. In seven patients (patients 1, 2, 5, 6, 7, 8, and 9), the sites of obstruction or dilatation predominantly involved the distal portions of the coronary arterial system. In the two patients with only proximal stenotic lesions (patients 4 and 10), severe (>90%) occlusion was present and was associated with severe left ventricular dysfunction related to previous infarctions.
Previous Coronary Bypass Surgery
Four patients had undergone coronary artery bypass grafting before transplantation (patients 3, 4, 9, and 10). In two patients, a single bypass using the left internal mammary artery was performed, one (patient 4) to the left anterior descending artery and the other (patient 10) to the left main coronary artery. The other two patients required the use of a saphenous vein graft to the circumflex artery as well as a graft to the left anterior descending artery (patients 3 and 9). Furthermore, one of these patients (patient 3) required a short course of extracorporeal membrane oxygenation and emergent bypass grafting after the acute rupture of a 15-mm aneurysm of the left main coronary artery 24 hours after the diagnosis of Kawasaki disease. The ventricular function did not improve after bypass in any of these four patients, and all were transplanted within 1 year postoperatively.
The pathologic examinations of seven of the explanted hearts were available for evaluation (patients 1, 2, 4, 5, 6, 8, and 9). On gross examination, each heart showed thickened epicardial coronary vessels with nodular surfaces. No atherosclerotic changes were noted, and the coronary ostia were found to be patent and in the normal position. Most coronary vessels were described as having a fibroproliferative intimal process. In these vessels, the lumens were slit-like and almost completely occluded.
Microscopic examination was available for four explanted hearts (patients 2, 4, 5, and 6). These microscopic sections were taken at 3 months (patient 2), 6 months (patient 6), 2 years (patient 4), and 11 years (patient 5) after their acute Kawasaki disease. Sections taken from patient 2 at 3 months postdisease showed destruction and fibrosis of the vessel walls associated with mononuclear cell and plasmacytic infiltration into the vessel walls with a mucoid basophilic substance surrounding the vessels. The microscopic examination of patient 6 (6 months postdisease) showed that the internal elastic membrane was fragmented and the medial tissues thinned with intimal proliferation and luminal narrowing and no ongoing inflammatory process.
Patients 4 and 5 (2 and 11 years, respectively, after acute Kawasaki disease) showed similar findings of fragmentation of the internal and external elastic lumina of the coronaries with severe fibrointimal proliferation. Sclerosis or fibrosis of the myocardium was present. However, no inflammatory cell infiltrates were seen within the myocardium or vessel walls.
On follow-up, 9 of the 10 patients are alive and functioning well 1 to 6 years after transplantation. They have been receiving conventional immunosuppression, either with a triple-therapy, cyclosporine-based protocol or with tacrolimus. No deviations were made from routine posttransplant immunosuppression, which was tailored to their clinical course. One patient (patient 6) died 10 months posttransplant after severe uncontrollable rejection episodes. One patient (patient 10) required a second heart transplant 2 years after his primary transplant because of severe rejection. He has survived 2 years after the second transplant and is reportedly healthy. This is a somewhat higher incidence of refractory rejection than is normally seen; however, our series is too small to make any conclusive statement.
To date, there has been no evidence of graft atherosclerosis in any of the transplanted hearts; however, the length of follow-up is short. In addition, there has been no recurrence of Kawasaki disease or coronary artery aneurysms in the transplanted hearts. One patient (patient 3), who was still in the acute stage of Kawasaki disease, empirically received additional IVIG after transplantation.
The prognosis of Kawasaki disease correlates with the severity of the coronary involvement. Serial angiographic follow-up of Kawasaki disease patients has indicated that ∼50% of the patients with coronary artery abnormalities showed resolution 5 to 18 months later, with giant aneurysms (defined as ≥8 mm in diameter) the least likely to regress and most likely to progress to stenosis.12-14
Japanese and US studies have shown the striking effectiveness of IVIG treatment in the prevention of coronary artery aneurysms.15,16 It has not been demonstrated that treatment with IVIG instituted later than 10 days after onset of acute Kawasaki disease is effective in preventing coronary abnormalities. In this series of transplanted patients, only 3 of 10 had received IVIG within 10 illness days. It is unclear why these 3 patients suffered such extensive coronary involvement despite receiving what would appear to be appropriate treatment for acute Kawasaki disease. However, it must be considered that these 3 are drawn from a very large population of IVIG-treated Kawasaki disease patients. We estimate that ∼3000 children in the United States are treated with IVIG for Kawasaki disease annually. This emphasizes that significant coronary artery disease still may develop in a tiny fraction of Kawasaki disease patients who are treated optimally.
Our echocardiographic findings of increased left ventricular end diastolic diameters and decreased shortening fraction are consistent with previous studies that have used these parameters to identify Kawasaki disease patients with severe cardiac dysfunction. Giant aneurysms were diagnosed by echocardiography in 4 (40%) of the 10 patients, and stenosis was present in 8 (80%). These findings clearly identify this population as having a high frequency of severe ventricular dysfunction and severe coronary abnormalities.
Surgical bypass procedures are effective when the stenotic lesions are proximal. However, the angiographic findings in our patient population showed a preponderance of distal stenotic and aneurysmal lesions (Fig1), making successful coronary artery bypass grafting procedures unfeasible. The predominance of distal sites of obstruction in the transplanted population contrasts with the sites of obstruction documented by Kitamura6 in his 1994 review of the Japanese national experience of patients treated with revascularization techniques (Fig 2). Most of those patients had sites of proximal obstruction. In addition, the transplanted patients suffered from severe ventricular dysfunction secondary to previous ischemic myocardial injury as well as from a high frequency of significant ventricular arrhythmias. These contributing factors made the viability of revascularized myocardium quite unlikely.
The pathologic findings of fragmentation of the internal and external elastic membranes with striking myointimal proliferation are consistent with those observed in previous autopsy studies.17Additionally, the findings of severe myocardial injury in these patients are consistent with the autopsy findings in children with Kawasaki disease reported by Fujiwara.17 Acute myocardial infarction was seen in 35% of those with healed coronary lesions and in 25% of those with acute coronary abnormalities. In that series, fibrous myocardial scars were noted in 80% of cases with healed coronary lesions and in no cases with acute changes.
US epidemiologic studies of Kawasaki disease demonstrate the peak incidence of disease to be 18 to 24 months of age, with children ≤5 years of age accounting for 80% to 85% of patients.18 In all surveys, the male-to-female ratio is 1.3 to 1.5:1, whereas the male-to-female ratio of those with coronary abnormalities is 2 to 4:1. Nakanishi at al14 reported a male-to-female ratio of 4:1 in their study of the hemodynamic and coronary angiographic findings in children with Kawasaki disease with obstructive coronary lesions. Our transplant patient population included seven boys and three girls, and the median age was 3 years. Two (20%) of the 10 were infants ≤4 months of age at onset of Kawasaki disease, a group that disproportionately develops serious coronary abnormalities.19
Two of our 10 transplanted patients (patients 5 and 9) were diagnosed with Kawasaki disease in retrospect after their presentations with acute life-threatening myocardial infarction and acute congestive heart failure, 5 and 9 years after a prolonged febrile illness. Several reports of myocardial infarction and sudden death attributable to coronary artery aneurysms have involved patients with a history of an illness that, in retrospect, was consistent with Kawasaki disease or who had no known previous illness.20-22
There are at least two potential indications for cardiac transplantation in Kawasaki disease. The first is the presence of severely impaired left ventricular function secondary to myocardial infarction. Successful revascularization may not restore function to such severely damaged myocardium. The second indication is extensive distal coronary disease that makes successful bypass grafting technically impossible in a patient at risk for severe myocardial infarction or sudden death from ventricular arrhythmias.
The overall rate of severe rejection episodes in our series (20%) may be consistent with rejection rates published previously for pediatric cardiac transplantation, but the severity of rejection appears greater than current experience at most centers.23,24 The immunosuppressive regimes used in these patients were not altered by the respective transplant centers because of the diagnosis of Kawasaki disease. Although the limited length of follow-up make specific recommendations impossible, there have been no reports of recurrence of Kawasaki disease in any transplanted patient; one patient received IVIG posttransplant as empiric treatment for possible recurrence of Kawasaki disease.
The limitations of the current study include the fact that it is a retrospective review of patients transplanted at institutions other than our own. We relied on the cooperation of recognized Kawasaki disease and cardiac transplant centers throughout the world to obtain reports of patients who underwent transplantation for this illness. However, it is possible that a small number of additional patients were not identified. We were unable to obtain sufficient information related to three patients who received cardiac transplants, all at one center in the United Kingdom, to include them in this series. Additionally, it is possible that some patients who were registered through United Network for Organ Sharing may have been listed only with the diagnosis of myocardial ischemia rather than referenced with their underlying condition of Kawasaki disease. The establishment of a worldwide database for gathering information on Kawasaki disease cardiac sequelae severe enough to require surgical intervention, either bypass or transplantation, would enable more accurate determination of the long-term success rates of these procedures.
In conclusion, cardiac transplantation for severe Kawasaki ischemic heart disease is technically feasible, and this intervention can benefit the small subgroup of patients with coronary lesions related to distal stenosis or aneurysm for which bypass is not feasible and/or with severe irreversible myocardial dysfunction.
Since the submission of this manuscript for publication, the patient in our series who suffered the rupture of a coronary artery aneurysm (patient 3) was presented in a case report in which the surgical aspects of the interventions performed were delineated.25
We thank the following individuals at each of the transplant centers for their assistance in providing us with patient information: F. Jay Fricker (Children's Hospital of Pittsburgh, Pittsburgh, PA), Richard E. Ringel (University of Maryland Medical Center, Baltimore, MD), Chris Bysani and Ernest Brookfield (Medical College of Ohio, Toledo, OH), Richard A. Meyer (Children's Hospital Medical Center, Cincinnati, OH), James Wiggins (Children's Hospital, Denver, CO), Daniel Tamisier (Laennec Hospital, Paris, France), and Gil Wernovsky (Children's Hospital of Philadelphia, Philadelphia, PA).
- Received December 6, 1996.
- Accepted March 20, 1997.
Some of the data in this work were published in preliminary form (Kato H, ed. Kawasaki disease. In: Proceedings of the Fifth International Kawasaki Disease Symposium; May 22–25; Amsterdam, The Netherlands: Elsevier; 1995:522–526).
Reprints not available.
- IVIG =
- intravenous immune globulin
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- Copyright © 1997 American Academy of Pediatrics