 |
|
Mortality Among Persons With a History of Kawasaki Disease in Japan
The Fifth Look
Yosikazu Nakamura, MD, MPH, FFPHM;
Hiroshi Yanagawa, MD, FFPHM;
Kensuke Harada, MD;
Hirohisa Kato, MD;
Tomisaku Kawasaki, MD
Arch Pediatr Adolesc Med. 2002;156:162-165.
ABSTRACT
| |
Objective To determine whether patients with Kawasaki disease have a higher death
rate than an age-matched healthy population after disease occurrence.
Study Design From July 1, 1982, to December 31, 1992, 52 collaborating hospitals
collected data on all patients with a new definite diagnosis of Kawasaki disease.
Patients were followed up until December 31, 1999, or death. The expected
number of deaths was calculated from Japanese vital statistics data and compared
with the observed number.
Results Of 6576 patients enrolled, 27 (19 male, 8 female) died. The standardized
mortality ratio (the observed number of deaths divided by the expected number
of deaths based on the vital statistics in Japan) was 1.25 (95% confidence
interval, 0.84-1.85). Despite the high standardized mortality ratios during
the acute disease phase, the mortality rate was not high after the acute phase
for the entire group of patients. Although the standardized mortality ratio
after the acute phase was 0.76 for those without cardiac sequelae, 6 male
patients (no female patients) with cardiac sequelae died during this period,
and the standardized mortality ratio for the male group with cardiac sequelae
was 2.35 (95% confidence interval, 0.96-5.19).
Conclusions Although it was not statistically significant, the mortality rate among
male patients with cardiac sequelae due to Kawasaki disease seemed higher
than that in the general population. On the other hand, mortality rates for
female patients with sequelae and both male and female patients without sequelae
were not elevated.
INTRODUCTION
SINCE 1991, the Kawasaki Disease Follow-up Group has been following
up a cohort of persons with a history of Kawasaki disease.1-4
The aim of this study was to determine whether the mortality among those persons
is higher than in the general population. Because Kawasaki disease as a kind
of vasculitis may be associated with rapidly accelerated atherosclerosis,5-7 the history may be a
risk factor of cardiovascular disease when patients become adults.
Differing from long-term follow-up data from hospitals,8-11
our data are unbiased because the cohort includes all patients who fulfill
the inclusion criteria from the nationwide survey's database. The latest follow-up
ended on December 31, 1997,4 and the current
study prolonged the observation period until December 31, 1999.
PATIENTS AND METHODS
The items and methods used in this study were similar to those in the
previous follow-up.1-4
The study was reviewed by the Jichi Medical School Institutional Review Board
and was exempt from review.
INCLUSION CRITERIA
In 5 nationwide surveys of Kawasaki disease in Japan, 8417 patients
at 52 collaborating hospitals from July 1, 1982, through December 31, 1992,
were considered for the study. From these potential cohort members, we excluded
652 patients because they did not have a definite diagnosis according to the
diagnostic guidelines established by the Japan Kawasaki Disease Research Committee,12 384 patients with recurrent disease, 786 patients
presenting on or after the 15th day of illness, and 19 non-Japanese patients.
Therefore, only patients with an initial episode of a definite diagnosis of
Kawasaki disease who were of Japanese nationality and who visited the hospital
less than 15 days after the onset of symptoms were included in this study.
A definite case means a patient with Kawasaki disease who has at least 5 of
6 major symptoms or 4 symptoms plus cardiac lesions.12
The condition placed on the date of the first visit was intended to avoid
bias caused by the inclusion of patients with late cardiac sequelae seen at
large referral hospitals. Non-Japanese patients were excluded because the
resident registration system for non-Japanese people is different from that
for Japanese people, and the system for non-Japanese patients is not available
for follow-up. Finally, we enrolled 6576 patients.
PROTOCOL
The cohort members had been followed up from the time they first came
to the hospitals until December 31, 1999, or time of death if it occurred
before that date. For all the members, excluding those whose deaths were known
through the previous observations, we checked resident registration records
or the Koseki system (permanent resident registration system)13
in municipal offices in 2000. The resident registration system, which is administrated
by a municipal government, lists residents and their Japanese addresses. The
permanent resident registration lists Japanese registrants in any place in
the country. It is easier to access the resident registration system than
the permanent system, but a Japanese person who lives abroad is registered
only in the permanent system because he or she does not have an address in
Japan. Therefore, we first checked the resident registration system; if the
patient was not registered in the resident registration system, we then checked
the permanent system. Registration in at least 1 of the 2 systems told us
that the patient was alive on or after January 1, 2000. If a patient died
before December 31, 1999, the systems also provided this information. In case
of death, copies of death certificates were obtained to determine the causes
of deaths from local officers of the District Legal Affairs Bureaus, Ministry
of Justice. Official approval by the Civil Affairs Bureau of the Ministry
of Justice of the Japanese government was obtained to use these records.
STATISTICAL ANALYSIS
The duration of observation was calculated according to sex, age, and
calendar year for each patient. The expected number of deaths was calculated
by multiplying the observation time for each patient by the death rate calculated
from Japanese vital statistics data for each group defined by sex, age, and
calendar year. Standardized mortality ratios, or the ratio of the observed
numbers of deaths to expected ones, were calculated by sex, phase of illness
(acute disease phase within 2 months after the first visit to the hospital
and after), and whether the patient experienced cardiac sequelae after the
acute disease phase. In the nationwide surveys of Kawasaki disease when the
follow-up started, the cardiac sequelae were defined as presence of dilation
(including aneurysms), stenosis, occlusion of coronary artery and/or myocardial
infarction, or valvular lesion 1 month after onset of Kawasaki disease.14 A 95% confidence interval was calculated for each
ratio based on Poisson distribution.15 A standardized
mortality ratio of which the 95% confidence interval did not include 1.0 was
considered to be statistically significant.
RESULTS
The sex and age distribution of the cohort members at the onset of Kawasaki
disease is given in Table 1. The
distribution was similar to the epidemiologic features of Kawasaki disease
in Japan.16 On December 31, 1999, the oldest
cohort member was 29 years and the youngest was 7 years. The age and sex distribution
on that day is given in Table 2.
Before that day, 27 patients had died. We could not certify whether 26 persons
were still alive after January 1, 2000, and they became lost to follow-up
in the current observation. Finally, the follow-up rate was 99.6% (6576-6526/6576).
Of these members, 1003 (15.3%, 649 male patients and 354 female patients)
were reported to nationwide surveys as having cardiac sequelae; the proportion
was also reasonable in comparison with the whole group of patients with Kawasaki
disease in Japan.16
|
|
|
|
Table 1. Age and Sex Distribution at Recruitment*
|
|
|
|
|
|
|
Table 2. Age Distribution at the End of Follow-up (December 31, 1999)*
|
|
|
The observed person-years were 83 162.3 for all members, 47 469.3
for male patients, and 35 693.0 for female patients; therefore, the average
observation periods were 12.6 years for both sexes (12.6 and 12.7 years for
male and female patients, respectively).
Table 3 gives the numbers
of deaths and standardized mortality ratios for the 5 subgroups by sex. Among
all the cohort members, 27 deaths occurred (19 male deaths and 8 female deaths).
The standardized mortality ratio for male patients was elevated slightly and
that for female patients was similar to unity; both were not significant.
The mortality was high during the acute phase of Kawasaki disease but not
high after the acute phase. However, the elevated mortality rate after the
acute phase was observed only among those with cardiac sequelae, especially
for male patients. Six cases with cardiac sequelae, all of whom were male
patients, died after the acute phase, and the standardized mortality ratio
was 2.35, which almost reached statistical significance.
|
|
|
|
Table 3. Numbers of Observed and Expected Deaths and Standardized Mortality
Ratios*
|
|
|
Detailed information of the fatal cases is given in Table 4. Of the 8 patients who died during the acute phase, 7 deaths
were owing to Kawasaki disease and 1 was owing to drowning in the bath at
home. After the acute phase, 19 patients died. Two patients died of coronary
artery insufficiency owing to Kawasaki disease; 1 death was 11 months after
the onset of Kawasaki disease, and 1 death was 6 years later. Kawasaki disease
was not mentioned on the death certificates of the other 2 patients, but the
disease was suspected to be related to the deaths. Because postmortem examinations
were not conducted for the 2 patients according to the death certificates,
no more detailed information was available. Because of the lack of necropsy,
it was not certain whether the patient who died suddenly during swimming in
a swimming pool had had a myocardial infarction or whether he simply drowned.
|
|
|
|
Table 4. Causes of Deaths for the 27 Fatal Cases*
|
|
|
COMMENT
This is the fifth look at the cohort consisting of all patients with
Kawasaki disease who were eligible for inclusion. The current follow-up data
show that persons with cardiac sequelae owing to Kawasaki disease were somewhat
more likely to die than the general population. This phenomenon was only true
for male patients; the mortality rate for male patients with the sequelae
was 2.35 times as high as in the general population and was not statistically
significant.
The aim of the study was to determine whether the mortality rate among
patients with a history of Kawasaki disease was higher than that of general
population. Several hypotheses should be considered regarding this study question.
One concerns the cardiac sequelae owing to the disease, which developed in
10% to 15% of the patients when the observation started. Indeed, 1003 patients
(15.3%) in this cohort had sequelae. This issue is revealed by the current
study. Six male patients with cardiac sequelae died after the acute phase,
whereas the expected number of deaths for this group was 2.6 (Table 3). This means that there were 3.4 (6 - 2.6) excess
deaths. Fortunately, no death was observed during the most recent 2-year period
(1998-1999) (the current observation). However, we should observe the cohort
longer to obtain definite conclusions.
The mortality rate for female patients with cardiac sequelae was not
elevated. Kawasaki disease is more prevalent among males than females, and
the proportion of patients with cardiac sequelae is higher in males.15 Therefore, the expected number of death was small
among female patients with cardiac sequelae, and the high mortality rate was
observed only for male patients in this study. Using Poisson distribution
with the expected number of 0.934 for female patients after the acute phase,
the probability that no patient died is 0.393. Thus, no fatal case among this
group might occur by chance. However, longer observation is required to reveal
whether females with cardiac sequelae have a high mortality rate.
Another issue is ischemic heart disease and cerebrovascular disease
owing to atherosclerosis induced by the systemic vasculitis in childhood.
Some pathologic observations reveals that atherosclerosis progressed in autopsy
cases with a history of Kawasaki disease more than those with similar age
but without the history.5, 17-18
Unfortunately, because the cohort was established in 1991, many of the members
were teens when the current observation was conducted (Table 2). The oldest person in the cohort was 29 years old on the
last day of observation. Thus, the risk of cardiovascular and cerebrovascular
diseases was still low. On the other hand, a recent study19
showed that coronary endothelial function was impaired from Kawasaki disease
onset after 1 to 12 years, even in cases with regression of coronary artery
aneurysms. If so, the mortality is expected to become close to that of persons
without a history of Kawasaki disease according to the passage of time. Further
long-term observation is required to discuss the issue.
The final issue is intravenous  -globulin therapy and the immune
system. Unusual immune system response of the disease is well known.20-21 In addition, many patients with Kawasaki
disease are treated with -globulin.22
Large amounts of external immunoglobulin for children may affect the immune
system, and the incidence of immunologic disease may increase after years.
Fortunately, such diseases or abnormalities are not reported to date. Two
persons have died of malignant neoplasm of the lymphatic or hematopoietic
tissue, but the mortality was not significantly high.3
Further observation is necessary regarding this issue.
Cause-specific mortality rates among the cohort are of interest. We
have shown them in the third observation.3
However, precision was low because the expected numbers of deaths were so
small owing to the size of the cohort, and there were wide 95% confidence
intervals of the standardized mortality rates. In the current study, we refrained
from observing these patients because the observation period after the fourth
observation was only 2 years. However, continuing to observe this cohort will
provide such data in the near future. A recent study23
showed that those with a history of Kawasaki disease had more cardiovascular
risk factors, such as obesity, hypertension, and hypercholesteremia, than
those without a history. Control of these risk factors is essential for the
health management of those with a history of the disease.
In conclusion, although the findings are not significant, the current
epidemiologic observation showed that mortality among persons with cardiac
sequelae owing to Kawasaki disease was high among male patients.
| What This Study Adds
Kawasaki disease is now the leading cause of acquired heart disease
in childhood, but its long-time prognosis is still unknown. In addition, following
up all patients with the disease, not just patients with cardiac sequelae
caused by the disease, is important to reveal the effects of the vasculitis
of the disease to the cardiovascular system, especially for atherosclerosis.
Such a cohort has been followed up in Japan. This study prolonged the follow-up
period (average follow-up, 12.6 years). In contrast to the high mortality
rate during the acute disease phase, the mortality rate was not elevated for
those without cardiac sequelae after the acute phase. On the other hand, high
but not significant mortality was observed for male patients with cardiac
sequelae after the acute phase of the disease.
|
|
AUTHOR INFORMATION
Accepted for publication October 8, 2001.
This study was conducted as a research project of the Japan Kawasaki
Disease Research Committee, sponsored by the Ministry of Health, Labor, and
Welfare of the Japanese government, Tokyo.
Corresponding author and reprints: Yosikazu Nakamura, MD, MPH, FFPHM,
Department of Public Health, Jichi Medical School, 3311-1 Yakushiji, Minamikawachi,
Tochigi 329-0498, Japan.
From the Department of Public Health, Jichi Medical School, Minamikawachi
(Dr Nakamura); Saitama Prefectural University, Koshigaya (Dr Yanagawa); Department
of Pediatrics, Nihon University School of Medicine, Tokyo (Dr Harada); Department
of Pediatrics and Child Health, Kurume University School of Medicine, Kurume
(Dr Kato); and Kawasaki Disease Research Center, Tokyo (Dr Kawasaki), Japan.
REFERENCES
| |
1. Nakamura Y, Yanagawa H, Kawasaki T. Mortality among children with Kawasaki disease in Japan. N Engl J Med. 1992;326:1246-1249.
ABSTRACT
2. Nakamura Y, Yanagawa H, Kato H, Kawasaki T for the Kawasaki Disease Follow-up Group. Mortality rates for patients with a history of Kawasaki disease in
Japan. J Pediatr. 1996;128:75-81.
FULL TEXT
|
ISI
| PUBMED
3. Nakamura Y, Yanagawa H, Kato H, Harada K, Kawasaki T for the Kawasaki Disease Follow-up Group. Mortality among patients with a history of Kawasaki disease: the third
look. Acta Paediatr Jpn. 1998;40:419-423.
PUBMED
4. Nakamura Y, Yanagawa H, Harada K, Kato H, Kawasaki T. Mortality among persons with a history of Kawasaki disease in Japan. J Epidemiol. 2000;10:372-375.
PUBMED
5. Sasaguri Y, Kato H. Regression of aneurysms in Kawasaki disease: a pathological study. J Pediatr. 1982;100:225-231.
FULL TEXT
|
ISI
| PUBMED
6. Tanaka N, Naoe S, Masuda H, Ueno T. Pathological study of sequelae of Kawasaki disease (MCLS). Acta Pathol Jpn. 1986;36:1513-1527.
PUBMED
7. Naoe S, Takahashi K, Masuda H, Tanaka N. Kawasaki disease: with particular emphasis on arterial lesions. Acta Pathol Jpn. 1991;41:785-797.
PUBMED
8. Suzuki A, Kamiya T, Ono Y, Kohata T, Kimura K, Takamiya M. Follow-up study of coronary artery lesions due to Kawasaki disease
by serial selective coronary arteriography in 200 patients. Heart Vessels. 1987;3:159-165.
FULL TEXT
| PUBMED
9. Kato H, Sugimura T, Akagi T, et al. Long-term consequences of Kawasaki disease. Circulation. 1996;94:1379-1385.
FREE FULL TEXT
10. Fukushige J, Takahashi N, Ueda K, Hijii T, Igarashi H, Ohshima A. Long-term outcome of coronary abnormalities in patients after Kawasaki
disease. Pediatr Cardiol. 1996;17:71-76.
ISI
| PUBMED
11. Iemura M, Ishii M, Sugimura T, Akagi T, Kato H. Long term consequences of regressed coronary aneurysms after Kawasaki
disease. Heart. 2000;83:307-311.
FREE FULL TEXT
12. Yanagawa H, Kawasaki T, Shigematsu I. Nationwide survey on Kawasaki disease in Japan. Pediatrics. 1987;80:58-62.
FREE FULL TEXT
13. MacMahon B, Pugh TF. Epidemiology: Principles and Methods. Boston, Mass: Little Brown & Co; 1970:99.
14. Yanagawa H, Nakamura Y, Yashiro M, Ojima T, Koyanagi H, Kawasaki T. Update of the epidemiology of Kawasaki disease in Japan. J Epidemiol. 1996;6:148-157.
PUBMED
15. Haenszel W, Loveland DB, Sirken MG. Lung-cancer mortality as related to residence and smoking histories. J Natl Cancer Inst. 1962;28:947-1001.
16. Yanagawa H, Nakamura Y, Yashiro M, et al. Results of the nationwide epidemiologic survey of Kawasaki disease
in 1995 and 1996 in Japan. Pediatrics. 1998;102:e65. Available at: http://www.pediatrics.org/cgi/content/full/102/6/e65. Accessibility verified November 17, 2001.
17. Sugimura T, Kato H, Inoue O, et al. Intravascular ultrasound of coronary arteries in children. Circulation. 1994;89:258-265.
FREE FULL TEXT
18. Takahashi K, Oharaseki T, Naoe S. Pathological study of postcoronary arteritis in adolescents and young
adults. Pediatr Cardiol. 2001;22:138-142.
FULL TEXT
|
ISI
| PUBMED
19. Yamakawa R, Ishii M, Sugimura T, et al. Coronary endothelial dysfunction after Kawasaki disease:
evaluation by intracoronary injection of acetylcholine. J Am Coll Cardiol. 1998;31:1074-1080.
FREE FULL TEXT
20. Jason J, Gregg L, Han A, et al. Immunoregulatory changes in Kawasaki disease. Clin Immunol Immunopathol. 1997;84:296-306.
FULL TEXT
|
ISI
| PUBMED
21. Leung DYM, Schlievert PM, Meissner HC. The immunopathogenesis and management of Kawasaki syndrome. Arthritis Rheum. 1998;41:1538-1547.
FULL TEXT
|
ISI
| PUBMED
22. Yanagawa H, Nakamura Y, Sakata K, Yashiro M. Use of intravenous -globulin for Kawasaki disease: effects on
cardiac sequelae. Pediatr Cardiol. 1997;18:19-23.
FULL TEXT
|
ISI
| PUBMED
23. Silva AAE, Maeno Y, Hashmi A, Smallborn JF, Silverman ED, McCrindle BW. Cardiovascular risk factors after Kawasaki disease: a case-control
study. J Pediatr. 2001;138:400-405.
FULL TEXT
|
ISI
| PUBMED
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter
What's this?
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
The adult after kawasaki disease the risks for late coronary events.
Gersony
J Am Coll Cardiol 2009;54:1921-1923.
FULL TEXT
Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Statement for Health Professionals From the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association
Newburger et al.
Pediatrics 2004;114:1708-1733.
ABSTRACT
| FULL TEXT
Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Statement for Health Professionals From the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association
Newburger et al.
Circulation 2004;110:2747-2771.
ABSTRACT
| FULL TEXT
Kawasaki Syndrome: Where Are the Answers?
Meissner and Leung
Pediatrics 2003;112:672-676.
FULL TEXT
|
