Introduction
Kawasaki disease is an acute, self-limiting systemic vasculitis with an unknown aetiology, marked by the involvement of multiple organs and predominantly affecting the cardiovascular system, particularly the coronary arteries. Kawasaki disease, also referred to as mucocutaneous lymph node syndrome, ranks among the most prevalent vasculitides in childhood, involving small- and medium-sized vessels. Reference Saguil, Fargo and Grogan1,Reference Kil, Yu, Lee, Rhim and Lee2 Without a diagnostic test, Kawasaki disease is identified through clinical criteria. Patients who meet the case definition based on principal clinical findings are classified as having complete Kawasaki disease. Patients who do not fully meet these criteria but whose clinical presentation is suggestive of Kawasaki disease are considered to have incomplete Kawasaki disease, in whom laboratory and echocardiographic findings serve as important supportive diagnostic information. Reference McCrindle, Rowley and Newburger3,Reference Son and Newburger4
The prognosis of Kawasaki disease is primarily determined by the presence and severity of coronary artery involvement. Coronary artery lesions are observed to occur in about 15–25% of patients who do not receive treatment, whereas timely initiation of intravenous immunoglobulin therapy has been demonstrated to lower the occurrence of coronary artery involvement to less than 5%. Reference Son and Newburger4–Reference Lo and Newburger6
In this study, the demographic, clinical, and laboratory characteristics of children diagnosed with Kawasaki disease were evaluated, and patients were compared between complete and incomplete Kawasaki disease, as well as according to the presence or absence of coronary artery involvement. In addition, laboratory findings before and after treatment were compared between patients with the presence or absence of coronary artery involvement.
Materials and Methods
This retrospective study included 35 patients diagnosed with Kawasaki disease at a tertiary care centre. The diagnosis of Kawasaki disease was made based on the clinical criteria specified in the guidelines of the American Heart Association. Reference McCrindle, Rowley and Newburger3 Complete Kawasaki disease was defined as the presence of at least five days of fever together with four or more of the five principal clinical features, including bilateral non-purulent conjunctivitis, oral mucosal changes, cervical lymphadenopathy, skin rash, and extremity changes. Patients presenting with two or three principal clinical features in addition to fever lasting at least five days were classified as having incomplete Kawasaki disease. In addition, patients with unexplained fever lasting ≥7 days were diagnosed with incomplete Kawasaki disease if elevated acute phase reactants (C-reactive protein ≥3 mg/dL and/or erythrocyte sedimentation rate ≥ 40 mm/h) were accompanied by three or more supplementary laboratory findings (anaemia for age, platelet count of ≥450,000 after the seventh day of fever, white blood cell count of ≥15,000/mm Reference McCrindle, Rowley and Newburger3 , albumin ≤3 g/dl, elevated alanine aminotransferase or urine ≥10 white blood cell/hpf) or if coronary artery involvement was detected on echocardiography. Reference McCrindle, Rowley and Newburger3 All paediatric patients diagnosed with Kawasaki disease were evaluated in a consecutive manner. Patients with complete clinical, laboratory, and echocardiographic data were included in this study. Patients with incomplete records or those referred to another institution before completion of follow-up or those who declined treatment were excluded from the analysis.
All data were obtained from medical records. Demographic and clinical variables included gender, age at diagnosis, season of diagnosis, hospitalisation duration, duration of fever before the first intravenous immunoglobulin administration (days), time to defervescence after intravenous immunoglobulin treatment (hours), and clinical findings such as fever, conjunctivitis, oral mucosal changes, cervical lymphadenopathy, rash, sterile pyuria, gallbladder hydrops, and erythema at the Bacillus Calmette-Guérin inoculation site. Laboratory evaluation included complete blood count parameters (white blood cell, neutrophil, lymphocyte, haemoglobin, and platelet counts), inflammatory markers (C-reactive protein and erythrocyte sedimentation rate), liver enzymes (alanine aminotransferase and aspartate aminotransferase), serum albumin, and serum sodium.
All patients received first-line treatment consisting of intravenous immunoglobulin (2 g/kg) combined with acetylsalicylic acid (80–100 mg/kg/day). In cases of persistent fever at 48 hours following the initial intravenous immunoglobulin infusion, a second dose of intravenous immunoglobulin was administered.
All patients were evaluated by a paediatric cardiologist using two-dimensional transthoracic echocardiography at least twice, at the time of diagnosis and during the subacute phase, approximately two weeks after intravenous immunoglobulin therapy. Echocardiographic examinations were performed using the Vivid 7 Pro® (GE Medical Systems, Vigmed Ultrasound AS, N-3190 Horten, Norway). Echocardiographic findings were interpreted according to American Heart Association guidelines. Reference McCrindle, Rowley and Newburger3 Coronary artery involvement was defined as the presence of perivascular brightness, ectasia/dilatation, or aneurysm. Coronary arteries were evaluated and classified using Z-scores calculated from coronary artery segment diameters normalised to body surface area, in accordance with the American Heart Association recommendations. Reference McCrindle, Rowley and Newburger3
Patients were categorised according to age at symptom onset (≤12 months, 13–60 months, and ≥61 months). Patients were additionally stratified as having complete Kawasaki disease or incomplete Kawasaki disease and with or without coronary artery involvement and were compared in terms of demographic, clinical, and laboratory features. Furthermore, laboratory parameters were compared between patients with and without coronary artery involvement at two time points: at admission (before intravenous immunoglobulin treatment) and one week after intravenous immunoglobulin administration (after intravenous immunoglobulin treatment).
Statistical analysis
SPSS for Windows, version 26.0, was utilised to carry out the statistical analyses (SPSS Inc., Chicago, IL, USA). The Kolmogorov–Smirnov test was utilised to evaluate the normal distribution of continuous variables. These variables were represented as either mean ± standard deviation or median (range from minimum to maximum). For variables demonstrating a normal distribution, differences between independent study groups were assessed using the Student’s t-test. Categorical data were summarised as frequencies and percentages and analysed with the chi-square test. When statistical significance was observed in comparisons including more than two groups, additional post hoc analyses were conducted to determine which groups accounted for the observed differences. Statistical significance was defined as p < 0.05 in all analyses. Graphical representations of the data were created using Prism software (version 8, GraphPad Software, San Diego, California).
Results
Baseline demographic, clinical, and laboratory findings of the total cohort
The mean age at the onset of the disease among the 35 patients diagnosed with Kawasaki disease was 33.8 ± 26.1 months, and 71.43% (n = 25) of the patients were male. Regarding age distribution, 20% (n = 7) of the patients were aged 12 months or younger, 62.86% (n = 22) were between 13 and 60 months, and 17.14% (n = 6) were aged 61 months or older. In terms of seasonal distribution, the majority of diagnoses were made during the summer (31.43%, n = 11), followed by winter (28.57%, n = 10), while 20% (n = 7) of the cases were diagnosed in both spring and autumn. The mean duration of fever before the first intravenous immunoglobulin treatment was 10.37 ± 5.8 days, and the mean time to defervescence following intravenous immunoglobulin administration was 19.29 ± 13.36 hours. Clinical findings included fever (n = 35, 100%), oral mucosal changes (n = 35, 100%), bilateral non-purulent conjunctivitis (n = 30, 85.7%), rash (n = 29, 82.9%), cervical lymphadenopathy (n = 22, 62.9%), extremity changes (n = 19, 54.3%), erythema at the Bacillus Calmette-Guérin inoculation site (n = 3, 8.6%), sterile pyuria (n = 2, 5.7%), and gallbladder hydrops (n = 2, 5.7%).
The mean white blood cell count was 15.35 ± 7.71 × 103/µL, mean neutrophil count was 9.95 ± 6.08 × 103/µL, mean lymphocyte count was 3.62 ± 1.88 × 103/µL, mean haemoglobin level was 10.17 ± 1.51 g/dL, mean platelet count was 461.42 ± 271.88 ×103/µL, mean C-reactive protein level was 9.74 ± 8.80 mg/dL, mean erythrocyte sedimentation rate was 46.68 ± 21.80 mm/h, mean alanine aminotransferase level was 44.53 ± 64.84 U/L, mean aspartate aminotransferase level was 46.31 ± 41.47 U/L, mean albumin was 2.92 ± 0.57 g/dl, and mean sodium level was 134.39 ± 2.58 mmol/L at the admission. Second-dose intravenous immunoglobulin treatment was administered to 2.85% of the patients (n = 1). Among the patients, 24 (68.6%) had complete Kawasaki disease, and 11 (31.4%) had incomplete Kawasaki disease.
In the echocardiographic assessment, coronary artery involvement was detected in 37.1% (n = 13) of the patients. Among these patients, coronary ectasia was observed in 8.5% (n = 3), coronary aneurysm in 25.7% (n = 9), and the coexistence of both ectasia and aneurysm in 2.8% (n = 1). Among the 10 patients with coronary aneurysms, 7 had small aneurysms, and 3 had medium aneurysms. During follow-up, regression of coronary abnormalities was observed in all patients, and no persistent severe cardiac complication was documented.
Comparisons between patients with complete and incomplete Kawasaki disease
Extremity changes were significantly more frequent in patients with complete Kawasaki disease than in those with incomplete Kawasaki disease (n = 17, 70.8% vs. n = 2, 18.2%; p = 0.011). C-reactive protein levels were significantly higher in patients with complete Kawasaki disease compared to those with incomplete Kawasaki disease (11.58 ± 9.73 mg/dL vs. 5.73 ± 4.46 mg/dL; p = 0.014), whereas alanine aminotransferase levels were significantly lower in patients with complete Kawasaki disease (33.04 ± 26.09 U/L vs. 61.55 ± 105.37 U/L; p = 0.014). No statistically significant differences were identified in the demographic, clinical, or laboratory characteristics when comparing the two groups (Table 1).
Comparison of demographic, clinical, and laboratory data between complete and incomplete Kawasaki disease
Table 1. Long description
The table compares demographic, clinical, and laboratory data between patients with complete Kawasaki disease (cKD) and incomplete Kawasaki disease (iKD). It has 24 rows and 6 columns. The columns are labeled Patients with cKD (n=24), Patients with iKD (n=11), and p. The rows include various parameters such as male gender, age, age of onset of symptoms, hospitalization duration, season of diagnosis, clinical findings, and laboratory findings at admission. Each row provides specific data points for both groups and a p-value indicating statistical significance. Notable trends include higher frequency of extremity changes in cKD patients (70.8%) compared to iKD patients (18.2%) with a p-value of 0.011, higher C-reactive protein levels in cKD patients (11.58 mg/dL) compared to iKD patients (5.73 mg/dL) with a p-value of 0.014, and lower alanine aminotransferase levels in cKD patients (33.04 U/L) compared to iKD patients (61.55 U/L) with a p-value of 0.014.
BCG: Bacillus Calmette-Guérin, cKD: complete Kawasaki disease, iKD: incomplete Kawasaki disease. IVIG: intravenous immunoglobulin.
Comparisons between patients with and without coronary artery involvement
A statistically significant association was observed between coronary artery involvement and age at symptom onset, with coronary artery involvement being significantly more frequent in patients whose symptoms began at ≤12 months of age compared to others (p = 0.011). Patients with coronary artery involvement had a significantly lower mean age (17.46 ± 15.8 vs. 43.45 ± 26.52 months; p = 0.001), whereas hospitalisation duration (9.23 ± 6.32 vs. 7.68 ± 2.37 days; p = 0.020), duration of fever before the first intravenous immunoglobulin administration (12.0 ± 8.73 vs. 9.41 ± 2.87 days; p = 0.003), and time to defervescence after intravenous immunoglobulin treatment (22.15 ± 18.22 vs. 17.59 ± 9.54 hours; p = 0.028) were significantly longer compared with patients without coronary artery involvement. In addition, cervical lymphadenopathy was significantly more frequent in patients without coronary artery involvement than in those with coronary artery involvement (n = 17, 77.3% vs. n = 5, 38.5%; p = 0.033) (Table 2).
Comparison of patients with and without coronary artery involvement
BCG: Bacillus Calmette-Guérin, CAI: coronary artery involvement, IVIG: intravenous immunoglobulin.
aCoronary artery involvement was significantly more frequent in patients with symptom onset at ≤12 months of age compared to others.
Before intravenous immunoglobulin treatment, patients with coronary artery involvement had significantly higher erythrocyte sedimentation rate values (52.77 ± 25.44 vs. 47 ± 14.89 mm/h; p = 0.033), lymphocyte counts (4.74 ± 2.24 vs. 3.15 ± 1.65 × 103/µL; p = 0.022), and platelet counts (572.23 ± 389.9 vs. 425.45 ±173.4 × 103/µL; p = 0.001) compared to patients without coronary artery involvement. No significant differences were observed in C-reactive protein levels (8.19 ± 9.9 vs. 10.66 ± 8.19 mg/dL; p = 0.433), white blood cell counts (15.69 ± 8.63 vs. 15.44 ± 6.99 ×103/µL; p = 0.288), or haemoglobin levels (9.55 ± 1.57 vs. 10.49 ± 1.32 g/dL; p = 0.068) between patients with and without coronary artery involvement. After intravenous immunoglobulin treatment, no statistically significant differences were observed between patients with and without coronary artery involvement in terms of C-reactive protein levels (1.06 ± 1.24 vs. 2.62 ± 5.43 mg/dL; p = 0.319), erythrocyte sedimentation rate values (47.88 ± 19.45 vs. 52 ± 23.82 mm/h; p = 0.674), white blood cell counts (9.24 ± 3.98 vs. 11.28 ± 3.28 × 103/µL; p = 0.122), lymphocyte counts (5.26 ± 2.16 vs. 5.27 ± 2.37 × 103/µL; p = 0.990), platelet counts (617.75 ± 298.2 vs. 635.86 ± 229 × 103/µL; p = 0.846), or haemoglobin levels (9.86 ± 1.41 vs. 10.5 ± 1.11 g/dL; p = 0.116). These comparisons are summarised in Figure 1.
Comparison of laboratory parameters between patients with and without coronary artery involvement before (a) and after (b) intravenous immunoglobulin treatment (CAI: coronary artery involvement; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate, WBC: white blood cell).
Discussion
In this study, we evaluated the demographic, clinical, and laboratory characteristics of children diagnosed with Kawasaki disease, and patients were compared according to complete Kawasaki disease and incomplete Kawasaki disease classification as well as the presence or absence of coronary artery involvement. While the demographic and clinical characteristics were largely similar between patients with complete Kawasaki disease and incomplete Kawasaki disease, extremity changes were observed significantly more frequently in complete Kawasaki disease, and significant differences were identified in C-reactive protein and alanine aminotransferase levels between the two groups. Patients with coronary artery involvement exhibited significantly different clinical characteristics compared with those without involvement, including a younger age at symptom onset, longer duration of hospitalisation, prolonged fever before intravenous immunoglobulin treatment, and a longer time to defervescence after treatment. In addition, significant differences in several laboratory parameters, including platelet count, lymphocyte count, and erythrocyte sedimentation rate, were observed between patients with and without coronary artery involvement before treatment; however, these differences disappeared following intravenous immunoglobulin therapy.
Kawasaki disease predominantly affects children under five years of age and is approximately 1.5 times more common in boys than in girls. Reference Agarwal and Agrawal7,Reference Nakamura8 Studies have shown that the seasonal distribution of Kawasaki disease varies. While some studies have reported a higher frequency of diagnoses during the winter and spring months, others have documented an increased incidence during the summer months. Reference Makino, Nakamura and Yashiro9–Reference Xie, Yan and Huang13 In our study, consistent with the literature, the majority of patients were younger than five years of age, and the disease was observed more frequently in boys. In addition, the predominance of diagnoses during the summer months was consistent with findings reported in some previous studies.
In the literature, oral mucosal changes, rash, and bilateral non-purulent conjunctivitis are generally reported as the most common clinical findings accompanying fever in Kawasaki disease, whereas extremity changes and cervical lymphadenopathy are observed less frequently. Consistent with the literature, in our study, the most common clinical findings other than fever were, in order of frequency, oral mucosal changes, bilateral non-purulent conjunctivitis, rash, cervical lymphadenopathy, and extremity changes. Reference Chbeir, Gaschignard and Bonnefoy14–Reference Fernandez-Cooke, Barrios Tascón and Sánchez-Manubens16 In addition, extra-criteria findings such as sterile pyuria, gastrointestinal symptoms, gallbladder hydrops, and erythema at the Bacillus Calmette-Guérin inoculation site, although less frequently observed, may occur in patients with Kawasaki disease; similarly, erythema at the Bacillus Calmette-Guérin inoculation site, sterile pyuria, and gallbladder hydrops were identified in a limited number of patients in our study. Reference McCrindle, Rowley and Newburger3,Reference Uehara, Igarashi, Yashiro, Nakamura and Yanagawa17,Reference Egritas, Nacar, Hanioglu, Soyer and Tezic18
Without a definitive diagnostic test, Kawasaki disease is diagnosed according to clinical criteria. In our study, no significant differences were identified between the complete Kawasaki disease and incomplete Kawasaki disease groups concerning demographic and clinical characteristics, except for extremity changes. This finding may be related to the relatively limited sample size of our cohort, as well as to the high level of awareness of incomplete Kawasaki disease associated with being a tertiary referral centre. Nevertheless, extremity changes were found to be significantly more frequent in patients diagnosed with complete Kawasaki disease. Considering that extremity changes, although included among the diagnostic criteria for Kawasaki disease, may be observed less frequently compared with other clinical manifestations, the higher frequency of this finding in patients fulfilling complete diagnostic criteria can be regarded as an expected observation. With respect to laboratory findings, C-reactive protein levels were higher in the complete Kawasaki disease group, whereas alanine aminotransferase levels were higher in the incomplete Kawasaki disease group. Higher C-reactive protein levels in patients with complete Kawasaki disease may reflect a more pronounced systemic inflammatory response. In contrast, there were no significant differences between the two groups regarding other laboratory parameters or the involvement of coronary arteries. These findings suggest that patients with incomplete Kawasaki disease may present with clinical and laboratory features comparable to those of complete Kawasaki disease.
In our study, patients with coronary artery involvement were significantly younger than those without coronary artery involvement, with coronary involvement observed more frequently in patients aged ≤12 months, consistent with the literature. Reference Cameron, Carr, Pahl, DeMarais, Shulman and Rowley19,Reference Sudo, Monobe, Yashiro, Sadakane, Uehara and Nakamura20 In addition, patients with coronary artery involvement had significantly longer hospital stays, longer duration of fever before intravenous immunoglobulin treatment, and longer time to defervescence after intravenous immunoglobulin compared with patients without coronary artery involvement. These findings suggest that a more prolonged inflammatory process may be present in patients who develop coronary artery involvement. In line with our observations, previous studies have demonstrated an association between longer duration of fever before intravenous immunoglobulin treatment, as well as total fever duration, and coronary artery involvement in Kawasaki disease. Reference Türkuçar, Yıldız, Acarı, Dundar, Kır and Ünsal21–Reference Fabi, Andreozzi and Frabboni23 When clinical findings were evaluated, cervical lymphadenopathy was the only finding observed significantly more frequently in patients without coronary artery involvement. This could be related to the observation that patients without coronary artery involvement were in a significantly older age group. Indeed, a previous study reported that Kawasaki disease patients with cervical lymphadenopathy were significantly older than those without this finding. Reference April, Burns, Newburger and Healy24
Limited studies evaluating laboratory parameters before and after treatment in Kawasaki disease patients with and without coronary artery involvement have reported different results. Reference Türkuçar, Yıldız, Acarı, Dundar, Kır and Ünsal21,Reference Liu, Ye, Su, Qin, Zhao and Pang25 In one study, it was reported that lymphocyte counts were higher and haemoglobin levels were lower before treatment in Kawasaki disease patients with coronary artery involvement, and these differences were shown to remain significant in evaluations performed 48 hours after intravenous immunoglobulin therapy. Reference Türkuçar, Yıldız, Acarı, Dundar, Kır and Ünsal21 In another study, no significant laboratory differences were observed between patients with and without coronary artery involvement either before treatment or 24–36 hours after intravenous immunoglobulin therapy. Reference Liu, Ye, Su, Qin, Zhao and Pang25 In our study, erythrocyte sedimentation rate, lymphocyte count, and platelet count before intravenous immunoglobulin treatment were significantly higher in patients with coronary artery involvement compared with those without coronary artery involvement. However, these laboratory differences were no longer observed after treatment. This finding suggests that patients who develop coronary artery involvement may have a more pronounced inflammatory and immune activation process before treatment, which may be effectively suppressed following intravenous immunoglobulin therapy. The difference between our findings and previous studies may partly be explained by the fact that post-treatment laboratory evaluations in our cohort were performed at a later time point, namely one week after intravenous immunoglobulin therapy. In addition, another study reported temporal variations in laboratory parameters during long-term follow-up before and after intravenous immunoglobulin therapy in Kawasaki disease patients with coronary artery lesions. Reference Zhao, Ma, Xin, Wang and Gao26 In contrast to this study, which primarily focused on laboratory findings, our study also evaluated demographic and clinical characteristics in addition to laboratory parameters and further included analyses of complete Kawasaki disease and incomplete Kawasaki disease subgroups.
The retrospective design, relatively small cohort size, and single-centre nature of the study represent important limitations that may restrict the generalisability of the findings. In addition, due to the low number of patients requiring second-line therapy, the association between treatment resistance and coronary artery involvement could not be evaluated in detail. Nevertheless, our study demonstrated that inflammatory differences observed before intravenous immunoglobulin treatment in Kawasaki disease patients with coronary artery involvement were no longer present after treatment, while also providing a broader evaluation through the inclusion of demographic and clinical characteristics and analyses of complete Kawasaki disease and incomplete Kawasaki disease subgroups.
In conclusion, this study demonstrates that coronary artery involvement in Kawasaki disease is associated with younger age at disease onset, longer duration of fever before intravenous immunoglobulin treatment, prolonged hospitalisation, and delayed defervescence after treatment. In addition, inflammatory markers were higher before treatment in patients with coronary artery involvement compared with those without coronary artery involvement; however, these differences resolved after treatment.
Acknowledgements
Paperpal, an AI language model, was employed for language editing.
Financial support
The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.
Competing interests
The authors declare that they have no conflicts of interest.
Ethical standard
Ethical committee approval was received from the Ethics Committee of the Dicle University Faculty of Medicine (07/01/2021–230). This research adhered to the Helsinki Declaration and was also in accordance with local laws and regulations.
Data sharing statement
All data relevant to the study are included in the article.
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