PEDIATRICS Vol. 114 No. 3 September 2004, pp. 751-754 (doi:10.1542/peds.2003-0118-F)
Older Age Is a Risk Factor for the Development of Cardiovascular Sequelae in Kawasaki Disease
* Department of Pediatrics, Kurume University School of Medicine, Kurume, Japan
Department of Public Health, Jichi Medical School, Tochigi, Japan
Saitama Prefectural University, Saitama, Japan
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Objectives. To clarify the characteristics of Kawasaki disease (KD) in children 6 years and older and to determine whether age is a risk factor for cardiovascular abnormalities.
Methods. Patients who had KD and were reported between 1999 and 2000 in the 16th nationwide survey of KD in Japan (n = 15 314) were analyzed. Patients who were aged 6 years or older (older group) were matched with patients who were aged 6 months to 3 years and were treated at the same hospital (younger groups). The total number of analyzed patients was 1498 (749 matched pairs).
Results. The proportion of complete KD in the older group was similar to that in the younger group. Recurrent cases in the older group were significantly more common than those in the younger group (9% vs 2%). The proportion of patients who were treated with intravenous 
-globulin in the older group was significantly lower than that in the younger group (82% vs 87%). The proportion of older group patients who were treated with intravenous -globulin at or after 7 days of illness was significantly higher than that in the younger group (35% vs 14%). There was a higher prevalence of cardiovascular abnormalities in the older group than in the younger group (20% vs 15%). Multivariate logistic regression analysis showed that older age was an independent risk factor for cardiovascular sequelae (odds ratio: 1.58; 95% confidence interval: 1.01–2.46).
Conclusions. In children older than 6 years, age is an independent risk factor for cardiovascular sequelae in KD.
Key Words: Kawasaki disease • cardiovascular sequelae • older children • intravenous -globulin
Abbreviations: KD, Kawasaki disease • IVGG, intravenous -globulin • OR, odds ratio • CI, confidence interval
Kawasaki disease (KD) is an acute febrile illness of unknown cause.1 Several epidemiologic studies have revealed that KD usually affects children younger than 3 years and is more common in boys.2,3 It is widely known that male gender and age <12 months are independent risk factors for cardiovascular sequelae.4 Our clinical impression was that KD in older children is uncommon but can contribute to cardiovascular sequelae. There have been a few descriptions of KD in older children.5,6 In these studies, older patients had a greater occurrence of additional symptoms and cardiovascular sequelae; however, the symptoms were less commonly associated with KD.5,6 It was not clear, however, whether older age was an independent risk factor for cardiovascular sequelae because too few patients had been studied. In the present study, we attempted to identify the clinical features and outcomes of KD in children 6 years and older.
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METHODS |
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Nationwide surveys of KD in Japan are conducted every 2 years.2 Participants in the surveys are patients whose KD was diagnosed at hospitals with 100 beds or more. In the most recent survey (the 16th, covering a 2-year period starting January 1, 1999, and ending December 31, 2000), 2619 hospitals participated. A questionnaire was sent to pediatricians along with a pamphlet describing the diagnostic criteria for the disease. The pamphlet included color pictures of typical lesions on the skin, eyes, hands, and feet. Pediatricians completed it. The total number of patients in the survey was 15 314.
Patients with KD were divided into 2 groups according to the diagnostic criteria. Diagnosis of complete KD in this survey was based on a patient's exhibiting at least 5 of the following 6 principal symptoms: 1) fever persisting for 5 or more days, 2) bilateral conjunctival congestion, 3) changes to the lips and oral cavity, 4) polymorphous exanthema, 5) changes to the peripheral extremities, and 6) acute nonpurulent cervical lymphadenopathy. Diagnosis of incomplete cases was defined as those with 4 or fewer of the symptoms listed above, with or without cardiovascular abnormalities.
Cardiovascular abnormalities were divided into 2 categories according to the duration of their conditions: 1) transient dilation, defined as a coronary artery dilation or aneurysm existing in an acute stage but showing no cardiovascular lesions within 1 month of onset, and 2) cardiovascular sequelae, defined as 1 of the following symptoms appearing 1 month after onset: coronary artery aneurysms, coronary stenosis, myocardial infarction, and valvular lesions. Criteria for defining a coronary artery aneurysm or artery abnormality in KD were defined by the Japanese Ministry of Health.7 These criteria, applicable to either angiographic or echocardiographic measurements, classify coronary arteries as abnormal when the internal lumen diameter is >3 mm in children younger than 5 years or >4 mm in children 5 years or older, when the internal diameter of any segment measures at least 1.5 times that of an adjacent segment, or when the coronary artery lumen is clearly irregular. A giant aneurysm was defined as the internal lumen diameter being >8 mm.
The following data were obtained: age, gender, diagnostic categories, family history, recurrence, the use of intravenous -globulin (IVGG) treatment, additional IVGG treatment, and cardiovascular sequelae. Other data (eg, severity of inflammation) were not obtained in the nationwide surveys.
From this database, we selected all patients who were 6 years of age or older at the time of illness. We selected the matched-pair younger cases only when the patient met the following criteria: same gender, 3 months to 3 years of age at the time of illness, and treated at the same hospital in the same calendar year. A total of 805 cases (5.3% of total reported cases) were reported as older cases. Among the 805 cases, 56 were excluded because appropriate younger cases did not exist. Therefore, a total of 749 older and 749 younger cases were studied.
Nominal data were analyzed using the 
2 test. Continuous variables were compared using the t test. P < .05 was considered statistically significant. The odds ratio (OR) with 95% confidence interval (CI) for the cardiovascular abnormalities was calculated by using Cox regression analysis after adjusting for gender, diagnostic categories, first day of IVGG treatment after onset, and total dose of IVGG therapy. Analyses were performed using SPSS 11.0 (SPSS Inc, Chicago, IL).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Profiles
The proportion of complete KD in the older group was similar to that in the younger group, as were sibling and patient histories. Recurrent cases (a second or more episode of the disease separate from the first) in the older group were significantly more common than in the younger group (9% vs 2%). The proportion of older children who first visited a doctor within 7 days of illness onset was significantly lower than that of the younger group (84% vs 91%; Table 1).
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IVGG Treatment
The proportion of patients who were treated with IVGG in the older group was significantly lower than that in the younger group (82% vs 87%). In patients who were not treated with IVGG, the proportion of complete KD patients in the older group was significantly higher than that in the younger group (54% vs 42%; P < .001). However, the complication rate of transient dilation (7% vs 7%; P = .94) and cardiovascular sequelae (4% vs 3%; P = 1.0) in the older group did not differ from those in the younger group. The complication rate of cardiovascular abnormalities in complete KD patients who were not treated with IVGG was lower than those who had complete KD and received initial IVGG treatment at a total dose of 2000 mg/kg within 9 days of illness onset (the dose and timing recommended by the American Heart Association8; 9% vs 18%; P = .01; Table 2).
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The proportion of patients who were treated with IVGG at or after 7 days of illness was significantly higher than that in the younger group (35% vs 14%). In addition, there was a tendency for fewer patients in the older group to be treated with single administration of high-dose IVGG than those in the younger group. Regarding IVGG retreatment, there was no significant difference between the 2 groups.
Cardiovascular Abnormalities
There was a higher prevalence of cardiovascular abnormalities in the older group than in the younger group. The complication rate of transient dilation in complete KD was lower than that in incomplete KD (12% vs 16%; P = .02). The complication rate of cardiovascular sequelae in complete KD did not differ than that in incomplete KD (6% vs 8%; P = .2; Table 3).
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To determine whether age >6 years was an independent risk factor for the development of cardiovascular abnormalities, we performed conditional logistic regression analysis after adjusting for other confounding variables. The confounding variables were determined by the results of univariate analysis. Multivariate logistic regression analysis showed that age >6 years was an independent risk factor for transient dilation (OR: 1.37; 95% CI: 1.03–1.82) and cardiovascular sequelae (OR: 1.58; 95% CI: 1.01–2.46; Table 4).
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Finally, to control for the other confounding variables such as total dose and timing of IVGG, we analyzed only the complete KD patients who received initial IVGG treatment at a total dose of 2000 mg/kg within 9 days of illness onset. The total number of analyzed patients was 618 (286 older and 332 younger cases). There were also higher prevalences of transient dilation (13% vs 11%) and cardiovascular sequelae (9% vs 3%) in the older group. The ORs with 95% CIs for the transient dilation and cardiovascular sequelae were 1.59 (1.04–2.45) and 3.11 (1.46–6.60), respectively.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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In this study, we observed a delay in IVGG treatment and a higher incidence of cardiovascular abnormalities in older children (6 years and older).
Clinical Features
Using the Japanese criteria for KD, there were no significant differences observed in the diagnostic categories between the 2 groups. However, the proportion of older group patients who first visited a doctor within 7 days of illness onset was significantly lower than that of the younger group. This result means that the older patients were delayed in being referred to a hospital for treatment. Momenah et al5 noted that the time interval for diagnosing in older children was more than twice that for the more typical age group. Unfortunately, we did not investigate the date of diagnosis, so we have no data regarding the time interval. However, in the cases with IVGG treatment, the date of diagnosis was nearly equal to the IVGG treatment starting date. In this study, the proportion of patients in the older group who were treated with IVGG after 7 days of illness was significantly higher than that of the younger group. We might conclude, therefore, that the diagnosis date for the older group was significantly later than that for the younger group.
Sibling and patient histories did not differ in the 2 groups. As such, we can speculate that there was no relationship between the age of KD onset and genetic factors. It was not surprising that the number of recurrent cases in the older group was higher than in the younger group, because the older group had more time to be affected by KD.
IVGG Treatment
The older KD patients in Japan tended to be treated at a later stage of disease and with less IVGG treatment. The older groups also tended not to receive IVGG treatment. We could not determine the treatment regimens for such patients. It may have been aspirin alone or no diagnosis before fever defervescence.
In patients who were not treated with IVGG, the proportion of complete KD patients in the older group was significantly higher than that in the younger group. In addition, the complication rate of cardiovascular abnormalities in the older group did not differ from that in the younger group. This result might mean that KD in older children is more difficult to diagnose and therefore children miss their chance of IVGG treatment.
It is interesting that the complication rate of cardiovascular abnormalities in complete KD patients who were not treated with IVGG was lower than that of patients who had complete KD and received recommended IVGG treatment. There are 2 possible explanations. First, approximately half of the patients who were not treated with IVGG in each group had incomplete KD; therefore, some of these patients might not have had KD at all. Second, patients who were not treated with IVGG were believed to be at low risk for the development of cardiovascular abnormalities and therefore did not receive IVGG. However, in patients who were not treated with IVGG, the complication rate of cardiovascular sequelae in the complete KD did not differ from that in incomplete KD (2% vs 5%; P = .5). Therefore, we believe that the latter hypothesis is true. Compared with the United States, in which almost all patients with KD or suspected KD receive IVGG, Harada's score is frequently used for the selection of IVGG treatment in Japan.4,9
Cardiovascular Sequelae
In this study, we found a higher prevalence of cardiovascular sequelae in the older group. Multivariate logistic regression analysis showed that older age was an independent risk factor for transient dilation and cardiovascular sequelae. In addition, there was a higher prevalence of cardiovascular abnormalities in the older group who had complete KD and received recommended IVGG treatment. This result means that even when the older group receives adequate treatment, the risk of cardiovascular abnormalities is higher. Stockheim et al6 noted that older age at the onset of illness might be an independent risk factor. This study supports such previous findings.
Clinical Implications
Older children with KD tend to have a delayed diagnosis. The primary pediatrician, therefore, should consider KD in cases in which older children have prolonged fever or other KD-like symptoms. In addition, older age should be recognized as an independent risk factor for the development of cardiovascular sequelae, and high-dose IVGG treatment should begin as soon as possible. Harada's score would be useful for the selection of IVGG treatment in older patients. It may also be necessary to formulate a new strategy for older KD patients.
Limitations
In the present study, we did not collect the following data: the presence of 6 major symptoms, other clinical features, the date of diagnosis, or laboratory data. Therefore, we did not compare the presence of individual symptoms. The study was limited by its retrospective design, so we could not conclude an accurate risk for cardiovascular abnormalities. In addition, we did not control the treatment regimens for KD at the various institutions, and we could not compare the precise risk of cardiovascular abnormalities because we could not control for the severity of the inflammation. The diagnostic methods of cardiovascular abnormalities might be biased. Despite these limitations, the sample size was large enough to permit the following conclusions to be made.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Older children with KD experience a delay in both diagnosis and treatment with IVGG. In addition, in children older than 6 years, age is an independent risk factor for the development of cardiovascular sequelae.
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ACKNOWLEDGMENTS |
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This work was supported in part by Grants-in-Aid 14570786 and 14770379 from the Ministry of Education, Science and Culture of Japan.
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FOOTNOTES |
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Accepted Dec 23, 2003.
Reprint requests to (H.M.) Department of Pediatrics, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan. E-mail: qze05346{at}nifty.com
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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- Research Committee on Kawasaki Disease. Report of Subcommittee on Standardization of Diagnostic Criteria and Reporting of Coronary Artery Lesions in Kawasaki Disease. Tokyo, Japan: Ministry of Health and Welfare; 1984
- Dajani AS, Taubert KA, Gerber MA, et al. Diagnosis and therapy of Kawasaki disease in children. Circulation. 1993;87 :1633 –1639
- Witt TM, Minich LL, Bohnsack JF, Young PC. Kawasaki disease: more patients are being diagnosed who do not meet American Heart Association criteria. Pediatrics. 1999;104(1) . Available at: www.pediatrics.org/cgi/content/full/104/1/e10
PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics
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