Abstract
Background: Because of the different genetic backgrounds, living environments and economic conditions, the epidemiologic, clinical characteristics and risk factors for coronary artery abnormalities (CAAs) in the Chinese population may differ among different parts of China.
Methods: We did a retrospective study to explore the clinical characteristics and risk factors for CAAs in east China between 2006 and 2014.
Results: There were 1016 patients during the study period. Of the 1004 patients who completed echocardiographic studies, 23.9% had CAAs. Sex, serum albumin, erythrocyte sedimentation rate (ESR), Mycoplasma pneumoniae (MP) infection, intravenous immunoglobulin (IVIG) started after the 10th day of illness and IVIG non-responders were independent risk factors associated with CAA.
Conclusions: East China has a lower incidence of CAAs compared with southwest and northeast China, while similar to north China. Male gender, serum albumin, ESR, MP infection, IVIG started after the 10th day of illness and IVIG non-responders were predictive of CAA.
Keywords: Kawasaki disease, coronary artery abnormalities, factors, east China
INTRODUCTION
Kawasaki disease (KD) is an acute early childhood vasculitis of unknown etiology that most frequently occurs in children <5 years of age. A common KD complication is coronary artery abnormalities (CAAs), which is currently the leading cause of acquired heart disease in children.
Although KD occurs worldwide, the incidence of KD varies significantly by race: East Asian children have a 10–15 times higher risk of KD than Caucasian children [1]. Incidence of KD in Japan is the highest (264.8 per 100 000) [2], followed by Korea [3]. However, as a large country in East Asia, little has been studied on the epidemiologic and clinical characteristics of KD in China [4–8]. Because of the different genetic backgrounds, living environments and economic conditions, the epidemiologic, clinical characteristics and risk factors for CAAs in the Chinese population may differ among different parts of China. We sought to investigate the epidemiologic and clinical characteristics of KD and risk factors for CAAs in east China, which have never been thoroughly studied before.
In the present study, epidemiologic, clinical characteristics, radiographic findings and risk factors for CAAs were examined among children with KD onset in Suzhou during the 9 year period from 2006 to 2014.
MATERIALS AND METHODS
Patients enrolled
The study subjects were enrolled from Children’s Hospital of Soochow University with a diagnosis of complete KD (cKD) or incomplete KD (iKD) between January 2006 and December 2014. The clinical records of the patients who fulfilled the diagnostic criteria of KD according to the American Heart Association diagnostic guidelines were respectively reviewed. The study was approved by the Ethics Committee of Children’s Hospital of Soochow University.
Data collection
Data regarding epidemiologic, clinical, laboratory and radiographic characteristics were documented. Laboratory data included white blood cell (WBC) count, hemoglobin (Hb), platelet (PLT) count, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), serum albumin, serum sodium, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Serum Mycoplasma pneumoniae (MP)-specific antibody and Epstein Barr virus (EBV) DNA were also collected because there were cases reporting that MP and EBV might act as possible triggers to KD and play a pathogenic role in the development of CAAs [9–12].
Cardiovascular complications including congestive heart failure, myocarditis, pericarditis, valvular regurgitation and CAAs were recorded based on a written cardiologist’s evaluation and cardiac ultrasound reports.
Definition
cKD was defined by the presence of ≥5 days of fever and more than four clinical features of the five principal clinical features for KD [13]. These clinical features included (i) bilateral non-exudative conjunctival injection; (ii) oral mucosal changes, such as erythema of the lips or strawberry tongue; (iii) changes of the extremities, such as edema, erythema and desquamation; (iv) polymorphous rash; and (v) cervical lymphadenopathy. Patients with only two or three principal clinical features of KD in addition to fever are considered to have iKD when the other possible causes of fever have been excluded [13]. CAA was defined as an internal lumen diameter ≥3 mm in children <5 years of age or ≥4 mm in children >5 years of age. Coronary aneurysm was defined as a segmental internal diameter of any segment ≥1.5 times greater than that of an adjacent segment. An intravenous immunoglobulin (IVIG) non-responder was referred to persistent or recrudescent fever ≥36 h after the initial IVIG infusion. Reappearance of KD features at least 2 months after the initial presentation was considered as recurrence, while before 2 months was considered as recrudescence [14]. The redness at a Bacille Calmette-Guèrin (BCG) inoculation site, which was recorded precisely before and during hospitalization, was defined as any redness, induration or crust formation [7]. Detection of serum MP-specific antibody was performed using enzyme-linked immunosorbent assay (Virion-Serion, Germany). A significant rise in MP IgG titer or the presence of IgM antibodies were used as criteria of current MP infection [15].
Statistical analyses
Statistical analyses were conducted using SPSS 22.0. Data are expressed as mean ± standard deviation (SD), median with quartiles or number with percentage as appropriate. Descriptive statistics were performed on the demographic characteristics. Parametric and nonparametric comparative tests for continuous data and χ2 test for categorical data were used to compare variables between groups. Multivariate logistic regression analysis was performed to analyze risk factors for CAA development. p < 0.05 was considered statistically significant.
RESULTS
Patient diagnosis
A total of 1030 cases were identified during the study period. Eleven auto-discharged cases and three cases with incomplete data were excluded. In the remaining 1016 cases, 300 (29.5%) were iKD cases. The patient ages at diagnosis ranged from 2 months to 10.7 years, with a median age of 17 months. iKD patients had a younger median age (14.5 months; quartiles: 7, 29) than cKD patients (18 months; quartiles: 11, 36; p < 0.05). The age distribution of both cKD and iKD is shown in Fig. 1. There were 650 (64.0%) males and 366 (36.0%) females in this study population. The male-to-female ratio was 1.8 : 1.
Fig. 1.
The distribution of age at onset of cKD and iKD in Suzhou, from 2006 to 2014.
Seasonal distribution
The monthly distribution is shown in Fig. 2. The highest proportion of onset of cKD patients occurred during March through July (53.2%), with a peak in May. iKD patients occurred most frequently during March through July (55.3%), with a peak in April.
Fig. 2.
The seasonal distribution of cKD and iKD in Suzhou, from 2006 to 2014.
Clinical characteristics
The main clinical features of KD patients are described in Table 1. Except for redness at BCG inoculation site and perianal desquamation, significant differences (p < 0.05) in the frequency of clinical symptoms were demonstrated between cKD and iKD patients. Other clinical manifestations included coughing (44.0% of cases), gastrointestinal symptoms (26.2%) and sterile pyuria (6.7%). Clinical outcomes are summarized in Table 2. iKD patients tended to have a longer fever duration with a predisposition to recrudescence. No death was reported during the acute and subacute stage of the disease.
Table 1.
Clinical features and laboratory values of children with cKD and iKD
| Total (n = 1016) | Incomplete (n = 300) | Complete (n = 716) | p | |
|---|---|---|---|---|
| Gender | ||||
| Male, n (%) | 650 (64.0) | 188 (62.7) | 462 (64.5) | 0.57 |
| Age at disease onset | ||||
| Age in years, median (range) | 17 (2–129) | 14.5 (2–129) | 18 (2–120) | <0.01 |
| <1 year, n (%) | 382 (37.5) | 140 (46.7) | 242 (33.8) | <0.01 |
| <5 years, n (%) | 918 (90.4) | 273 (91.0) | 645 (90.1) | 0.65 |
| Clinical features | ||||
| Bulbar conjunctival injection, n (%) | 855 (84.2) | 196 (65.3) | 659 (92.0) | <0.01 |
| Reddening and cracking of the lips, n (%) | 846 (83.3) | 195 (65) | 651 (90.9) | <0.01 |
| Strawberry tongue, n (%) | 686 (67.5) | 136 (45.3) | 550 (76.8) | <0.01 |
| Rash, n (%) | 780 (76.8) | 133 (44.3) | 647 (90.4) | <0.01 |
| Edema of extremities, n (%) | 498 (49.0) | 68 (22.7) | 430 (60.1) | <0.01 |
| Desquamation of the fingertips, n (%) | 618 (60.8) | 129 (43.0) | 489 (68.3) | <0.01 |
| Perianal desquamation, n (%) | 428 (42.1) | 115 (38.3) | 313 (41.1) | 0.11 |
| Cervical lymphadenopathy, n (%) | 624 (61.4) | 101 (33.7) | 523 (73.0) | <0.01 |
| Redness at BCG inoculation site, n (%) | 137 (13.5) | 37 (12.3) | 100 (13.1) | 0.49 |
| Laboratory values | ||||
| WBC count, mean ± SD (median), × 109/l | 15.1 ± 5.9 (14.3) | 15.1 ± 6.3 (14.2) | 15.0 ± 5.8 (14.3) | 0.74 |
| Hb, mean ± SD (median), g/l | 108.3 ± 12.0 (108.0) | 106.3 ± 13.7 (107.0) | 109.2 ± 11.1 (108.0) | <0.01 |
| PLT count, mean ± SD (median), × 109/l | 391.2 ± 135.1 (380.0) | 380.2 ± 133.6 (368.5) | 416.3 ± 135.6 (407.5) | <0.01 |
| CRP, mean ± SD (median), mg/l | 66.9 ± 47.0 (59.4) | 61.4 ± 45.3 (56.2) | 69.2 ± 47.5 (60.5) | 0.01 |
| Serum albumin, mean ± SD (median), g/l | 39.3 ± 4.3 (39.3) | 39.8 ± 4.1 (39.8) | 39.1 ± 4.3 (39.1) | 0.02 |
| ESR, mean ± SD (median), mm/h | 38.9 ± 26.1 (35.0) | 38.3 ± 24.8 (35.0) | 39.1 ± 26.6 (35.0) | 0.96 |
| ALT, mean ± SD (median), U/l | 60.9 ± 101.2 (23.2) | 47.6 ± 91.3 (19.8) | 66.4 ± 104.6 (26.3) | <0.01 |
| AST, mean ± SD (median), U/l | 57.0 ± 100.5 (33.6) | 48.7 ± 60.5 (32.9) | 60.4 ± 112.8 (33.7) | 0.71 |
| Serum sodium, mean ± SD (median), mmol/l | 134.7 ± 2.7 (134.8) | 135.3 ± 2.5 (135.3) | 134.4 ± 2.8 (134.4) | <0.01 |
Table 2.
Summary of clinical outcomes
| Clinical outcomes | Incomplete (n = 300) | Complete (n = 716) | p |
|---|---|---|---|
| Total fever duration, mean ± SD (median), d | 8.3 ± 3.1 (8.0) | 7.4 ± 2.2 (7.0) | <0.01 |
| Length of hospitalization, mean ± SD (median), d | 10.1 ± 3.2 (10.0) | 10.5 ± 3.5 (10.0) | 0.14 |
| Recurrence, n (%) | 1 (0.3) | 2 (0.3) | 1.00 |
| Recrudescence, n (%) | 4 (1.3) | 1 (0.1) | 0.03 |
| Number of patients with CAAs | 93 (31.0) | 189 (26.4) | 0.14 |
Laboratory findings
The laboratory values of both cKD and iKD patients at admission are given in Table 1. The most common abnormal laboratory findings were elevated CRP (996 children, 95.7%) and elevated ESR (777 children, 82.8%). The levels of Hb, PLT, CRP and ALT were significantly higher in cKD patients, while serum albumin and serum sodium were significantly higher in iKD patients.
Radiographic evaluation
Of the 1016 patients, 763 (75.1%) received chest X-ray films at the acute stage. The radiological evaluation was performed by a radiologist blinded to the diagnosis. Of the 763 patients receiving chest X-ray films, abnormal findings were seen in 162 (21.2%) patients, including 124 cases (16.3%) of reticulogranular patterns, 31 (4.1%) of peribronchial cuffing, 29 (3.8%) of pleural effusion and 14 (1.8%) of atelectasis. Different radiographic abnormities could be observed in one patient simultaneously.
Treatment
Of the 1016 patients, 1005 (98.9%) received IVIG treatment (2 g/kg). Of the 11 patients who did not receive IVIG treatment, 8 in whom the diagnosis was initially missed and 2 of whose level of IgA was < 0.01 mg/l, one patient refused to receive IVIG treatment. Forty-eight patients (4.7%) received a second dose of IVIG because of non-response to IVIG. Additional treatment with steroids was administrated in 29 IVIG non-responders. No side effect of IVIG was found in our study. All patients received a high dose of aspirin (30–50 mg/kg/d) during the febrile period until afebrile for 3–4 days and thereafter were given low-dose aspirin (3–5 mg/kg/d).
Echocardiographic findings of KD and risk factors of CAA
Results of echocardiography during the acute phase and 6–8 weeks later were available in all patients except for 12 patients. Of these 1004 patients with echocardiographic data, 240 (23.9%) had CAAs; 235 (23.4%) of whom had coronary artery dilation and 5 (0.5%) had coronary artery aneurysms. Other cardiac complications include pericardial effusion (18 cases, 1.8%), valvular regurgitation (12 cases, 1.2%), cardiac dysfunction (11 cases, 1.1%) and ventricular enlargement (7 cases, 0.7%). Different lesions could occur in one case simultaneously.
A univariate analysis for 16 influence factors associated with CAA was performed. It identified nine variables (gender, Hb, CRP, serum albumin, ESR, MP infection, abnormal radiographic findings, IVIG non-responders and IVIG started after the 10th day of illness) as significant CAA risk factors (p < 0.05, Table 3). Multivariate logistic regression identified sex, serum albumin, ESR, MP infection, IVIG started after the 10th day of illness and IVIG non-responders as independent risk factors for CAAs (p < 0.05, Fig. 3).
Table 3.
Univariate analysis for risk factors associated with CAA
| Variables | With CAA | Without CAA | χ2 value | u or z value | p value |
|---|---|---|---|---|---|
| N (%) | 240 (23.9) | 764 (76.1) | |||
| Male, n (%) | 176 (27.3) | 469 (72.7) | 11.300 | 0.001 | |
| Age, n (%) | |||||
| <1 year | 102 (26.9) | 277 (73.1) | 3.000 | 0.082 | |
| >5 years | 23 (24.2) | 72 (75.8) | 0.005 | 0.941 | |
| Laboratory parameters, mean ± SD (median), | |||||
| WBC count, × 109/l | 15.2 ± 5.9 (14.5) | 15.0 ± 5.9 (14.2) | 0.277 | 0.782 | |
| Hb, g/l | 106.7 ± 12.1 (106.0) | 108.9 ± 11.4 (109.0) | −2.530 | 0.012 | |
| PLT count, × 109/l | 404.4 ± 141.7 (389.0) | 387.0 ± 132.8 (378.5) | 1.728 | 0.084 | |
| CRP, mg/l | 73.6 ± 48.8 (65.6) | 64.0 ± 46.6 (56.4) | 2.724 | 0.007 | |
| Serum albumin, g/l | 38.0 ± 4.5 (38.3) | 39.7 ± 4.1 (39.7) | −5.274 | <0.001 | |
| ESR, mm/h | 42.6 ± 27.7 (37.0) | 37.9 ± 25.4 (34.0) | −2.112 | 0.006 | |
| ALT, U/l | 47.1 ± 55.3 (32.1) | 60.3 ± 111.3 (33.8) | 0.501 | 0.617 | |
| AST, U/l | 64.2 ± 111.5 (26.8) | 60.3 ± 98.6 (21.9) | −1.337 | 0.181 | |
| Serum sodium, mmol/l | 134.5 ± 2.7 (134.9) | 134.7 ± 2.8 (134.8) | −0.915 | 0.361 | |
| MP infection, n (%) | 82 (30.5) | 187 (69.5) | 8.743 | 0.003 | |
| EBV infection, n (%) | 10 (18.9) | 43 (81.1) | 0.780 | 0.377 | |
| Abnormal radiographic findingsa | 56 (34.6) | 106 (65.4) | 12.075 | 0.001 | |
| IVIG non-responders, n (%) | 22 (45.8) | 26 (54.2) | 13.326 | <0.001 | |
| IVIG started after the 10th day of illness, n (%) | 42 (44.2) | 53 (55.8) | 23.785 | <0.001 |
Note. aSeven hundred thirty-six of the 1014 patients received chest X-ray films at the acute stage.
Fig. 3.
Odds ratios for risk factors associated with CAAs in patients with KD. According to multiple logistic regression analyses, the independent significant risk factors associated with CAAs are those with a p-value of < 0.05. The reference for male patients is female patients and for disease group MP infection is non-MP infection. NS indicates not significant.
DISCUSSION
This is by far the largest scale study of KD in Suzhou covering a 9 year period. Using the clinical data of the 1016 patients, we found epidemiologic features of KD in this area: an age distribution with ∼90% <5 years of age, a male-to-female ratio of 1.8 : 1, a younger median age in iKD patients and higher occurrence in spring and summer. The seasonal and monthly distributions differed among different areas: Japan peaked in January and summer months [2]; Korea in summer (June and July), followed by winter (December and January) months [16]; Athens in March and February [17]; Netherlands in December and January [18]; California in March [19]; and Shanghai in summer months [20]. The reason for seasonal discrepancy remains unknown. Environmental factors or infectious agents may be a trigger for the disease [21].
A high proportion of patients experienced CAAs (23.9%) in the present study, which is comparable with 19–63% of KD patients with CAAs reported in recent studies [7, 8, 17, 19, 20, 22]. The discrepancy in CAA detection rate of different areas may partly be explained by the difference of races, the detection time and diagnostic criteria. As a major city in east China, the incidence of CAAs (17.2% from 2006 to 2008) in Suzhou was similar to that of Shanghai (19.6% from 2003 to 2007) [20] and Beijing (20.6%, from 2004 to 2006) [5], two major cities of east and north China. On the other hand, it was lower than that reported in Chongqing (36.1% from 2003 to 2009) [7], a major southwest city, and Jilin, a northwest province (63.3%, from 1999 to 2008) [8]. Although this could be partly explained by the methods used, regional differences of CAA occurrence could not be neglected.
The role of MP infection in cardiovascular complications in KD has not been adequately assessed. Recently, MP has been reported to cause KD in several studies, suggesting that the processes of superantigens may be important in the pathophysiology of KD [9, 10]. Our study also identified the importance of MP in KD and suggested MP infection as a predictor of CAA. Lee et al. [9] found that there was no significant difference in the incidence of coronary aneurysm between the MP group and the non-MP group in patients with KD. However, this study was probably too small (12 KD patients with MP infection) to show a significant effect on cardiovascular complications. Further prospective studies are necessary to confirm our results.
IVIG non-responders, which presumably reflect the severity of ongoing vasculitis, have been confirmed as important predictors of CAAs in various studies [23–25]. We also identified IVIG non-responders as a risk factor for CAA in KD patients. In this case, early identification of IVIG non-responders and active therapeutic intervention for fever in KD cases were of great importance and might decrease the incidence of CAAs.
The role of administration of IVIG in the acute phase of KD had been adequately assessed. But no consensus has been reached on the time window of IVIG treatment. It is generally recognized that IVIG treatment within 10 days, especially within 7 days of illness, was optimal [13]. Some researchers pointed out that IVIG treatment as soon as the disease was recognized could reduce CAAs in KD patients [19, 26]. We were unable to show if it was beneficial for the treatment before the fifth day of illness because most patients (90.5%) received IVIG treatment within the 5–9 days of illness. Our result was in agreement with the view of Muta et al. [27]. They proposed that IVIG treatment after 10 days of illness was less effective in preventing CAAs.
We described the epidemiological and clinical features of KD in Suzhou using the clinical data from 2006 to 2014. However, this retrospective study may have some limitations. Overdiagnosis and underdiagnosis may exist for the lack of golden diagnostic criteria for KD. There were some variables with missing laboratory data in the study cases. CAAs usually begin on 7–10 days of illness but may be progressive at any stage, so a long-term follow-up of CAA should be carried out.
Funding
This work was financially supported by the Chinese Natural Science Foundation (No. 81370217, No. 81400222, No. 81570455), and the Jiangsu Province Science Foundation (No. BE2013632, BRA2015489, and No. BK20150291), and Suzhou Science and Technology Bureau (No. SZS201411).
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