1. Background
Kawasaki disease is an acute vasculitis in children and affects medium sized arteries, especially coronary arteries. In 1970, a nationwide survey of KD in Japan documented 10 autopsies cases of sudden cardiac death after KD (1, 2). Occurrence of cardiac complications was 0.03 in 159 Iranian children (3). Its etiology remains unknown, but in accordance to clinical and epidemiologic features, infectious agents are strongly suspected as etiologic factors. The disease has various incidence rate among ethnic groups, with higher rates in Asians; therefore, genetic predisposition and familial pattern is also likely (2, 4, 5); there are reports of Kawasaki disease in children of parents who had Kawasaki disease in their childhood. In a 10-year study period from 1999 to 2008, 0.43% of the children with Kawasaki disease had a history of the disease in their parents (6). Among 14,163 parental pairs with Kawasaki disease, 33 parents had a history of the disease. The number of parents expected to have a history of Kawasaki disease was less than the observed cases. It was shown that children, whose parents had a history of Kawasaki disease, had a more severe course of their disease with a higher history of coronary abnormalities (2).
2. Objectives
The current study aimed to investigate the prevalence of Ischemic heart disease (IHD) in parents of children with severe and non-severe Kawasaki disease.
3. Patients and Methods
The current retrospective study was conducted on 61 subjects with Kawasaki disease admitted to Mofid Children hospital from December 21, 2004 to January 21, 2008. Inclusion criteria were normal children with no history of diseases such as diabetes, metabolic disorders, cerebral palsy, congenital anomalies, renal and hepatic and congenital heart diseases, with Kawasaki disease in accordance to American heart association (AHA) guideline (7).
Seven subjects because of being unavailable, one because of parents or child death, and three subjects because of refusal to enter the study were excluded, all subjects were contacted to be visited in cardiology clinic, and both of subjects’ parents had echocardiographic investigation by an expert cardiologist. Echocardiography was performed with no charge. All children had echocardiography on diagnosis, 2 - 3 and 6 - 8 weeks later by the same cardiologist, who was not aware of clinical and history information of the subjects. History taking and physical examination was performed on all parents.
The variables of epidemiologic, laboratory, clinical and echocardiographic results were transferred into a questionnaire for each subject. The 50 subjects were divided into two groups: severe (group 1) and non-severe (group 2). Subjects were defined as severe if they had at least one of the three following criteria:
1) Cardiac problems compatible with Kawasaki disease including internal coronary artery diameter more than 3 mm in patients under five years or less than 4 mm in older individuals, or diameter of one part of coronary artery ≥ 1.5 times larger than the normal width, and obvious irregularity of coronary artery lumen in each echocardiographic results (8).
2) No decrease of erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) after one week of treatment (9, 10).
3) Elevated alanine aminotransferase (ALT) > 80 IU/mL not related to other diseases (11). Therefore, more severe cases might have more cardiac and hepatic complications (12).
Criteria for presence of IHD in parents were one of the following:
1) History of acute myocardial infarction or unstable angina
2) History of abnormal physical stress test or heart scan
3) History of coronary artery bypass graft (CABG) or percutaneous transluminal coronary angioplasty (PTCA).
Clinical, laboratory and echocardiographic information of children and parents were collected on the questionnaire and analyzed by SPSS ver. 21 using exact and not exact logistic regression test. P value less than 5% was considered significant.
The research was approved by ethical committee of Shahid Beheshti University of Medical Sciences; all aspects of the world medical association declaration of Helsinki were considered.
4. Results
Thirty-two (64%) subjects of the study were male and 18 (36%) were female (male to female ratio about: 1.8/1). Mean age of children was 43 ± 33.1 months; 53.48 ± 37.26 months in the severe and 32.19 ± 25.76 months in the non-severe groups (CI = 2 - 38.2, P = 0.02). Duration of admission was statistically longer in the severe vs. non-severe group (8.27 ± 3.7 days vs. 2.24 ± 3, 54) (CI = 0.7 - 4.2, P = 0.006); 30% of the patients were admitted in spring and summer and 28% of them were admitted in fall and winter. Clinical signs such as oral cavity and mucosal changes were more common in non-severe subjects 18 (75%) vs. 23 (88.5%) in the severe ones, but it was not statistically significant (P > 0.05). There was one case of facial palsy in the severe group. Parental consanguinity and other clinical signs in the two groups are shown in Table 1. History of fathers IHD based on the study criteria (P = 0.001), History of cardiac drug usage (P = 0.009), and hypertension (P = 0.046) were more common in the severe Kawasaki disease group (Table 2); no significant difference was observed in the mean age of fathers between the two groups of severe and non-severe Kawasaki disease. The mean age of fathers in the severe and non-severe groups were 37.7 ± 6.7 years and 37.4 ± 6, respectively (P = 0.8).
Table 1. Frequency of Different Clinical and Laboratory Findings and Treatment Options in Severe Kawasaki Disease (n = 24)
| Clinical Findings | Severe Kawasaki | OR | Lower Limit of 95%CI | Upper Limit of 95%CI | P Value | |
|---|---|---|---|---|---|---|
| Yes | No | |||||
| Parent consanguinity | 2 (20.00) | 22 (55.00) | 0.21 | 0.02 | 1.24 | 0.10 |
| Oral and mucosal abnormality | 18 (43.90) | 6 (66.67) | 0.40 | 0.06 | 2.18 | 0.39 |
| Conjunctival injection | 20 (51.28) | 4 (36.36) | 1.84a | 0.46 | 7.32 | 0.38 |
| Rash | 18 (62.07) | 6 (28.57) | 4.09a | 1.22 | 13.69 | 0.02 |
| Adenopathy | 12 (60.00) | 12 (40.00) | 2.25a | 0.71 | 7.14 | 0.17 |
| Irritability | 3 (25.00) | 21 (55.26) | 0.27a | 0.06 | 1.16 | 0.07 |
| Finger desquamation | 10 (58.82) | 14 (42.42) | 1.94a | 0.59 | 6.36 | 0.27 |
| Anal desquamation | 7 (46.67) | 17 (48.57) | 0.93a | 0.28 | 3.11 | 0.90 |
| Erythema at BCG | 1 (20.00) | 23 (51.11) | 0.25 | 0.005 | 2.74 | 0.40 |
| Vomiting and diarrhea | 5 (71.43) | 19 (44.19) | 3.09 | 0.44 | 35.83 | 0.35 |
| Gallbladder hydrops | 1 (100) | 23 (46.94) | 1.08b | 0.03 | Infinity | 0.96 |
| Sterile pyuria | 7 (63.64) | 17 (43.59) | 2.26 | 0.57 | 9.02 | 0.24 |
| Arthritis | 2 (40.00) | 22 (48.89) | 0.70 | 0.05 | 6.75 | > 0.99 |
| Convulsion | 1 (33.33) | 23 (48.94) | 0.53 | 0.008 | 10.80 | > 0.99 |
| Facial palsy | 0 | 24 (48.98) | 1.08 | 0 | 42.25 | > 0.99 |
| Otitis media | 2 (40.00) | 22 (48.89) | 0.70 | 0.05 | 6.75 | > 0.99 |
| Pericardial effusion | 6 (31.58) | 18 (58.06) | 0.33a | 0.10 | 1.11 | 0.07 |
| (Coronary) aneurism | - | 24 (48.00) | - | - | - | - |
| (Other) Echo findings | 4 (57.14) | 20 (46.51) | 1.52 | 0.23 | 11.65 | 0.91 |
| Two times IVIG | 6 (100) | 18 (40.91) | 10.91a | 1.46 | +Infinity | 0.02 |
Abbreviations: BCG, bacilli Calmette-Guerin; IVIG, intravenous immunoglobulin; OR, odd ratios.
aLogistic regression (not exact).
bMedian unbiased estimates.
Table 2. Risk Factor in the Parents of Subjects With Severe Kawasaki Disease (n = 24) Group in Comparison With Those of the Non-severe Subjects
| Risk Factor | Severe Kawasaki | OR | Lower Limit of 95%CI | Upper Limit of 95%CI | P Value | |
|---|---|---|---|---|---|---|
| Yes | No | |||||
| Mothers’ Risk Factors | ||||||
| History of cardiac drugs usage | 3 (75.00) | 21 (45.65) | 3.49 | 0.26 | 194.84 | 0.34 |
| History of MIa and unstable angina | - | 24 (48.00) | - | - | - | - |
| HTNb | 1 (50.00) | 23 (47.92) | 1.09 | 0.01 | 88.69 | 1 |
| Chest pain | 2 (100) | 22 (45.83) | 2.70a | 0.21 | +Infinity | 0.23 |
| Exercise test abnormality | 1 (100) | 23 (46.94) | 1.08a | 0.03 | +Infinity | 0.48 |
| Ischemic heart disease | 3 (75.00) | 21 (45.65) | 3.49 | 0.26 | 194.84 | 0.34 |
| MRc | 1 (100) | 23 (46.94) | 1.08a | 0.03 | +Infinity | 0.48 |
| TRd | - | 24 (48.00) | - | - | - | - |
| MVPe | 9 (69.23) | 15 (40.54) | 3.22 | 0.73 | 17.06 | 0.11 |
| PSf | 0 | 24 (48.98) | 1.08a | 0 | 42.25 | 1 |
| HCMg | 0 | 24 (48.98) | 1.08 | 0 | 42.25 | 1 |
| Rheumatic fever | 0 | 24 (48.98) | 1.08 | 0 | 42.25 | 1 |
| Fathers’ Risk Factors | ||||||
| History of cardiac drugs usage | 6 (100) | 18 (40.91) | 10.91a | 1.46 | +Infinity | 0.009 |
| History of MI and unstable angina | 1 (100) | 23 (46.94) | 1.08a | 0.03 | +Infinity | 0.48 |
| HTN | 4 (100) | 20 (43.48) | 6.42a | 0.76 | +Infinity | 0.046 |
| Chest pain | 1 (100) | 23 (46.94) | 1.08a | 0.03 | +Infinity | 0.48 |
| Exercise test abnormality | 1 (100) | 23 (46.94) | 1.08a | 0.03 | +Infinity | 0.48 |
| Ischemic heart disease | 8 (100) | 16 (38.10) | 16.46a | 2.32 | +Infinity | 0.001 |
| MR | 1 (100) | 23 (46.94) | 1.08a | 0.03 | +Infinity | 0.48 |
| TR | 2 (100) | 22 (45.83) | 2.70a | 0.21 | +Infinity | 0.23 |
| MVP | 3 (50.00) | 21 (47.73) | 1.09 | 0.13 | 9.09 | 1 |
| PS | - | 24 (48.00) | - | - | - | - |
| HCM | - | 24 (48.00) | - | - | - | - |
| Rheumatic fever | 1 (100) | 23 (46.94) | 1.08a | 0.03 | +Infinity | 0.48 |
Abbreviations: HCMg, hypertrophic cardiomyopathy; HTNb, hypertension; MIa, myocardial infarction; MRc, mitral regurgitation; MVPe, mitral valve prolapse; OR, odd ratios; PSf, pulmonary stenosis; TRd, tricuspid regurgitation.
aMedian unbiased estimates.
5. Discussion
Incidence of Kawasaki disease is progressively increasing and the epidemics of this syndrome were studied in Japan (13). There was an increasing number of case reports of Kawasaki disease in parents and children in the literature (14, 15). In a study conducted in japan from 1999 - 2000 among 14163 children with Kawasaki, maternal incidence of Kawasaki disease was higher than expected cases in general population. Higher incidence of Kawasaki disease in mothers of children with Kawasaki disease than the statistically expected occurrence in general population shows the possible inherited risk factors in families. Among these children, the prevalence of coronary abnormalities one month after the onset of the disease was reported twice, and prevalence of a recurrence of Kawasaki disease and incidences involving their siblings were five and six times as high as that of all patients, respectively (2); data from 16th to 20th nationwide survey on patients with Kawasaki from 1999 to 2008 in Japan shows that history of Kawasaki disease in parents increased from 0.15% to 0.7%, the increasing pattern may be due to more concern on diagnosis (6). Although in North America, 0.7% of 424 subjects with Kawasaki syndrome (KS) had sibling cases and nine families were identified with KS in two generations (16). These results strengthen the genetic predisposition to cardiac sequel of KD in families.
Racial difference in incidence of KD, that is higher in Japanese (17), and higher occurrence of KD in siblings and parents than the general population (18) promoted investigators to find a specific locus of human leukocyte antigen (HLA) in children with Kawasaki or clarifying a genetic susceptibility to KD in children and their parents with a history of KD (19). Based on genetic predisposition, possible exposure to a common infectious agent (20) can be the proposed factors of KD occurrence in twins at the same time (21). The same genetic factors play the role of disease occurrence in two generations (18, 22). In this study more severe Kawasaki cases had higher incidence of fathers with IHD that may be related to previous history of Kawasaki in them, history of drug consumption and hypertension may be related to other cardiac conditions; accordingly, the significant difference between severe and non-severe subjects in the history of cardiac drug usage in fathers of the current study subjects may be unreliable; association between hypertension and coronary artery disease (CAD) is stated in epidemiologic studies but higher incidence of hypertension in fathers of children with severe KD is a matter of debate. This finding neither shows a causative relationship between hypertension and Kawasaki disease nor predicts more incidence of IHD in patients’ parents; further investigations are recommended (23). Koren et al. showed that duration of fever, as a factor to predict severity of ongoing vasculitis (24), was not different in the two groups of the current study. In a study by Sano T, patients who were non-responsive to intravenous immunoglobulin (IVIG) had higher CRP and aspartate aminotransferase (AST). Total bilirubin and Body surface area adjusted coronary dimensions were statistically more in diameter in non-responsive group (25). Kubayashi et al. proved that sodium ≤ 133 mM/L, neutrophils > 80%, days of illness at initial treatment ≤ four days, AST, age in months ≤ two, platelet count < 300,000/µL and CRP ≥ 10 mg/dL were independent predictors of non-responsive-IVIG, but not for coronary complications (26). The retrospective study which looked at risk factors for refractory KD in Japan resulted that in 20% of cases who did not respond to initial IVIG therapy, risk factors associated with the need for retreatment were initial treatment on/before the fifth day of illness, recurrent episodes of KD and male gender) (25). A scoring system by Nakano H. et al. used age, CRP and platelet count to predict and determine the patients with higher chance for coronary problems (27). In a study by sleeper LA et al. in eight centers in North America the most consistent variables as independent risk factors for IVIG retreatment model included male gender, lower albumin, and higher AST (c-statistic 0.83). However, the associations between Kubayashi score and coronary artery dimension were relatively weak (the largest Spearman correlation coefficient was 0.29) (12).
Therefore, the current study had a special focus on using the severity factors to investigate the parental ischemic heart disease. Choosing coronary artery lesion as a criterion of severity can select the genetically susceptible cases to tissue damage; other criteria of the study, such as no decrease of ESR and CRP after one week and elevation of ALT, are in accordance with further cardiac damage occurred in the current study patents. Higher CRP after one week is a factor of severity and ESR can be an additional helping indicator, although it may rise after IVIG treatment (9). Tremoulet et al. measured the laboratory values of 312 subjects with KD, which was statistically different between IVIG resistant and IVIG responsive subjects either in the subacute or convalescent phase. This is thought to occur as a consequence of the net positive charge of IgG molecule that neutralizes the net negative charge of the red blood cell (RBC) surface (zeta potential), leading enhanced rouleaux formation and accelerated RBC sedimentation. Tremoulet et al. stated no difference in comparison of convalescent ESR in IVIG-resistant vs. - subjects responsive to KD; in subjects with aneurysms suggested that the higher ESR was due to more inflammation rather than an effect of a second dose of IVIG (10). It is important to note that both groups of the current study used IVIG; therefore, the effect of IVIG on ESR rise affected both groups.
Although investigation of IHD on parents of the children with Kawasaki disease is prone to observation and recall bias, no other information about possible relationship with parents offered in the current study. Parents of the severe and non-severe groups were also in the same age range. With regard to the same results in other studies further studies on this important clinical issue are recommended.
5.1. Conclusions
Kawasaki disease is an important disease with unknown etiology and as described earlier, genetic factors may be related to its occurrence. The current study showed higher incidence of IHD in fathers of children with severe KD, which may be correlated with Kawasaki disease in their childhood; therefore, it is essential to take a careful family history from parents of the children with KD. Conducting a follow-up study on the children with this disease up to their adulthood and investigation of their children in prospective studies can provide more valuable information.
