Kawasaki disease (KD), an acute systemic vasculitis that has a high rate of incidence in Asian population, occurs primarily in infants and children under the age of 5.1 KD is characterized by prolonged fever, diffuse mucosal inflammation, edema of hands and feet, skin rash, and nonsuppurative lymphadenopathy.1 The disease is liable to be complicated by development of coronary artery lesions (CALs), which develop in approximately 15–25% of untreated KD children2 and in approximately 5% of those after intravenous immunoglobulin (IVIG) therapy.3–5 Although the etiology of KD remains unknown, it may be attributed to the combined effects of infection, immune response, and genetic susceptibility.1
Many studies have suggested that immune activation and the secretion of cytokines may contribute to the pathogenesis of KD. Activation of the immune system, including neutrophils and monocytes/macrophages, etc., plays an important role in the development of CALs in patients with KD.1,6,7 The immune response is characterized by increased amounts of several cytokines, such as interleukin-1 (IL-1), tumor necrosis factor (TNF)-α, interferon-γ (IFN-γ), IL-4, IL-6, IL-8, IL-10, IL-18, and a variety of other cytokines.8–13 IL-18, a proinflammatory member of the IL-1 cytokine superfamily, can induce the production of IFN-γ in the presence of IL-12 and co-stimulants.14 Furthermore, IL-18 activates T cells to synthesize IL-2 and TNF-α, enhances the differentiation of T cells into the Th1 phenotype, and suppresses the production of the anti-inflammatory cytokine IL-10.15–17
IL-18 had been reported to be associated with development of multiple diseases, such as autoimmune diseases, inflammation, infection, and coronary artery disease (CAD).18–22 However, the literature regarding the association between IL-18 and KD is limited.13,23 Nomura et al demonstrated that patients with KD showed normal IL-18 values in the acute phase and increased values in the subacute phase.13 They concluded that IL-18 pathways were activated in the subacute phase of KD, and that subacute IL-18 values might be reflected in the severity of KD.13 Chen et al indicated that 105A/C polymorphism and the haplotypes in the IL-18 gene are associated with the risk of KD in Taiwanese population.23 Although IL-18 is a nonspecific biomarker for inflammation, it may be a key factor that is associated with cytokine storm in conditions of acute KD. The clinical implication of IL-18 in KD may contribute to the scoring system for KD severity and provide additional anti-inflammatory therapy in IVIG-resistant patients. In this study, we aimed to evaluate the correlations between IL-18 and CALs in KD.
We recruited 14 children with KD, who were treated with IVIG (2 g/kg) in the acute stage at the Department of Pediatrics, Kaohsiung Veterans General Hospital (KVGH), Taiwan, between October 2008 and March 2011. Medical records were reviewed for age, gender, presenting symptoms, doses of IVIG treatment, complications, and laboratory data including baseline white blood cell (WBC), platelet count, hemoglobin level, alanine aminotransferase (ALT) (glutamic-pyruvic transaminase) level, aspartate aminotransferase (AST) (glutamic-oxaloacetic transaminase) level, lipid profile, and C-reactive protein (CRP) level. The average time from fever onset to IVIG therapy is 6.29 ± 1.98 days, ranging from 4 to 10 days. Resistance to IVIG is defined as persistent fever for 3 days after initial IVIG administration. All children with KD underwent two-dimensional echocardiography during diagnosis and again at weeks 2, 4, 8, and 12 following the treatment, the 6th month, and annually during follow-up. CALs in the acute stage and chronic stage are defined as CALs within 2 weeks of illness and beyond 1 year, separately. The internal diameter of the coronary arteries was measured and CALs were defined as follows: coronary arteries were classified as abnormal if the internal lumen diameter was ≥3 mm in children younger than 5 or ≥4 mm in children older than 5 years of age, if the internal diameter of a segment measured 1.5 times that of an adjacent segment, or if the coronary lumen was clearly irregular.24 Febrile controls included 18 children who had viral infection and were previously healthy. This study was carried out after obtaining approval from the Institutional Review Board of the KVGH.
2.2. Sample collection
Blood samples (approximately 3 mL) were collected in the pre-IVIG acute phase (5.1 ± 1.9 days from fever onset), post-IVIG acute phase (8.4 ± 2.1 days from fever onset), subacute phase (44.1 ± 22.2 days from fever onset), and convalescent stage (199.9 ± 108.1 days from fever onset) after obtaining informed consent from the parents. Blood samples (approximately 3 mL) were collected once in the acute stage (4.7 ± 1.6 days from fever) after obtaining informed consent from febrile control patients with viral infection. The samples were processed, separated into aliquots of 1 mL, and then frozen to −80 °C until IL-18 analysis.
2.3. Detection of IL-18
The IL-18 standards and samples were measured in duplicate with a Bio-Plex Pro Human Cytokine Assay (Bio-Rad Laboratories, Hercules, CA, USA). In brief, the IL-18 standards (n = 16) and samples diluted in serum diluent were added to two 96-well filter plates and incubated with the antibody-coupled beads for 1 hour with continuous shaking. The beads were washed three times with wash buffer to remove unbound protein and incubated with biotinylated detection antibodies for 30 minutes with continuous shaking. Following three washes, premixed streptavidin phycoerythrin was added to each well and incubated for 30 minutes. After incubation, the beads were washed and re-suspended in an assay buffer. The reaction mixture was quantified using the Bio-Plex protein array reader. The IL-18 level was automatically calculated by Bio-Plex Manager software using the appropriate standard curve. The detection limit of IL-18 was 1.8 pg/mL.
2.4. Statistical analysis
Data are presented as mean ± standard deviation. Student t test, Chi-square test, Wilcoxon signed-rank test, and Mann–Whitney U test were used to determine differences in age, gender, and laboratory data between patients and controls. The correlation between IL-18 and laboratory data was analyzed by Spearman rank correlation test. A p value <0.05 was taken to be significant.
3.1. Patient characteristics
There were 14 KD patients (2.90 ± 3.44 years, M/F 11/3) and 18 febrile controls with viral infection (2.51 ± 1.56 years, M/F 9/9). Seven KD patients had CALs in the acute stage, which regressed in the chronic stage. The remaining seven KD patients had no CALs, and no KD patients had IVIG resistance. There was no significant difference between the two groups in terms of age and gender (Table 1).
3.2. Comparison of IL-18 and CRP levels between febrile controls and KD patients in various phases
There was no significant difference between KD patients before IVIG treatment and febrile controls in terms of IL-18 level (76.2 ± 47.6 vs 56.0 ± 35.0 pg/mL, p = 0.214) (Table 2). In an acute phase of KD, the IL-18 level was not significantly lower in the post-IVIG period than that in the pre-IVIG period (72.0 ± 38.4 vs 76.2 ± 47.6 pg/mL, p = 0.499) (Fig. 1), but the CRP level was significantly lower in the post-IVIG period than that in the pre-IVIG period (10.9 ± 7.1 vs 4.1 ± 3.0 mg/dL, p = 0.004) (Fig. 2). In KD patients, both IL-18 and CRP levels were significantly lower in the subacute and convalescent phases than that in the acute phases (pre-IVIG or post-IVIG period) (all p < 0.01) (Table 2).
3.3. Comparison of IL-18 and CRP levels between febrile controls and KD patients with/without CALs in various phases
Table 3 shows a comparison of IL-18 and CRP levels between febrile controls and KD patients with/without CALs in various phases. Compared with febrile controls, patients with CALs in the acute stage (post-IVIG period) had a significantly higher IL-18 level (88.4 ± 20.7 vs 56.0 ± 35.0 pg/mL, p = 0.006), but those without CALs in the acute stage (post-IVIG period) did not have a similarly higher level (62.0 ± 40.6 vs 56.0 ± 35.0 pg/mL, p = 0.762). In patients with acute-stage CALs, the IL-18 level in acute stage did not decrease significantly until the convalescent phase (97.4 ± 55.8 vs 38.7 ± 22.6 pg/mL, p = 0.018), but CRP level significantly decreased in the acute phase (10.67 ± 8.10 vs 3.80 ± 2.62 mg/dL, p = 0.011). In patients without CALs, the IL-18 level in acute stage did not decrease significantly until the subacute phase (60.2 ± 37.4 vs 23.6 ± 13.8 pg/mL, p = 0.018), but the CRP level significantly decreased in the acute phase (11.1 ± 6.5 vs 4.4 ± 3.5 mg/dL, p = 0.018). In the subacute stage, there was a significant difference of IL-18 level between patients with and without acute CALs (p = 0.048) (Fig. 3).
3.4. Correlation between IL-18 and laboratory data of KD patients in pre-IVIG acute phase
Table 4 shows the correlation between IL-18 and laboratory data values in the pre-IVIG acute phase. The IL-18 level negatively correlated to hemoglobin level, but the significance was borderline (r = −0.514, p = 0.060). There is no significant correlation between the IL-18 and other laboratory data values.
3.5. Correlation between IL-18 and CRP at various phases of KD
Table 5 showed the correlation between IL-18 and CRP at various phases of KD. There was no significant correlation between the levels of IL-18 and CRP in different phases of KD.
Our study showed elevated values of IL-18 in the acute phase of KD, which gradually decreased. Compared with the febrile controls, patients with CALs in the acute stage had a significantly higher IL-18 level, but those without CALs in the acute stage had not. In an acute phase of KD, the IL-18 level after IVIG treatment was not significantly lower than that before IVIG treatment, but the CRP level after IVIG was significantly lower than that before IVIG treatment. CRP is not correlated to IL-18 in various phases of KD. The IL-18 level in patients without CALs decreased significantly in the subacute phase, but in those with acute CALs it did not decrease significantly until the convalescent phase. In the subacute stage, there was a significant difference of IL-18 level between patients with and without acute CALs. In this study, longitudinal measurement of IL-18 suggests that IL-18 pathway is activated in acute-stage KD and there might be an association between IL-18 and risk of CALs.
The literature regarding the effect of IL-18 in KD is scant.13,23 In contrast to our findings, Nomura et al demonstrated that patients with KD showed normal IL-18 values in the acute phase.13 They speculated that the idea of transient infiltration of activated IFN-γ-producing cells in the study by Hahn and co-workers25 could not be applied to explain the normal IL-18 values in acute KD.13 According to them, normal IL-18 values in the acute phase of KD might be a result of a kind of negative feedback mechanism of IL-18 pathways.13 Three factors may partially explain the discrepancy between the study results of Nomura and co-workers13 and ours. First, the measurement of IL-18 is different in terms of the method used (enzyme-linked immunosorbent assay vs Bio-Plex) and stored sample temperature (−30°C vs. −80°C) in two studies. Stored temperature can affect the stability of cytokines.26 Most cytokines are recommended to be stored at −80°C.27 Consequently, storage at −80°C may be the superior method to best and most accurately determine IL-18. Second, the sampling time between the two studies is also different. Their sampling time in the acute phase is earlier than ours (4.3 ± 1.7 vs. 5.1 ± 1.9 days). The subacute phase in the study by Nomura and co-workers occurred much earlier than that in this series (13.3 ± 3.4 vs 44.1 ± 22.2 days), and similar to our post-IVIG period in the acute stage (13.3 ± 3.4 vs. 8.43 ± 2.1 days). Third, the patients in their study were Japanese,13 whereas those patients in our study were all Taiwanese. Cytokines such as IL-1, TNF-α, IFN-γ, IL-4, IL-6, IL-8, IL-10, and a variety of other cytokines have been shown to increase significantly during acute KD.8–12 They are believed to play important roles in the onset of KD. The IL-18, a member of the IL-1 family, might be theoretically elevated in the acute phase of KD. Elevated IL-18 levels were found in the acute phase of other diseases and considered as an indicator of disease activity.19,20 Further studies are needed to demonstrate IL-18 levels in various phases of KD.
In this series, acute-phase patients with CALs showed a higher mean IL-18 value than that of febrile controls. The specificity of IL-18 in terms of etiologic distinction of KD patients and febrile controls remains cumbersome, and further studies are required to elucidate the mechanism. The IL-18 level of patients with CALs did not decrease significantly until the convalescent stage, but for those without CALs it significantly decreased in the subacute phase. There was a significant difference in levels of IL-18 between patients with and without acute CALs only in the subacute stage. The small cohort size and large standard deviation might be a cause for no statistically significant difference in other stages. However, the mechanism of IL-18 in the formation of CALs is unclear. Hahn et al demonstrated that IFN-γ levels increased in acute KD and might play an important role in KD-related vasculitis.25 We speculate that the effect of IL-18 on the coronary artery may be mediated by the induction of IFN-γ production and suppression of IL-10. Furthermore, the IL-18 level is not correlated to the CRP level in various phases of KD. Our results suggest that activation of IL-18 pathway may be related to the formation of CALs in the acute stage and independent of the risk factor of CRP. In contrast to our findings, Nomura et al reported IL-18 values after IVIG in the subacute phase to be elevated, and to be significantly correlated with the values of WBC and CRP.13 It is difficult to explain the discrepancy between the study results of Nomura and co-workers13 and this study. The relation between IL-18 and CAD had been studied previously.21,22 Animal studies in atherosclerosis support the proatherogenic role of IL-1828 and the beneficial effect of inhibiting IL-18 on plaque progression and composition.29 Blankenberg et al reported that the IL-18 level was a strong independent risk factor in patients with CAD and remained unaffected by various markers of inflammation such as CRP.21 By contrast, IL-18 suppresses the production of the anti-inflammatory cytokine IL-10.17 Anguera et al showed lower levels of IL-10 in patients with unstable angina who subsequently had cardiovascular events.30 Weng et al reported that the ACC haplotype of IL-10 polymorphism (high production of IL-10) may be a genetic marker related to reduced risk of acute CALs in KD.31 These previous studies may support the hypothesis that a pathway for signaling in CALs in acute KD involves IL-18 to mediate the inflammation by stimulating or suppressing other cytokines. Further study including measurement of other cytokines is necessary to elucidate the role of IL-18 in acute CALs in KD.
CRP is a powerful marker of acute KD. The increment of CRP is related to the rise of plasma IL-6, which is produced predominantly by macrophages.32 CRP has been incorporated in some scoring systems for predicting IVIG resistance in KD treatment. Fukunishi et al reported that patients with a CRP > 10 mg/dL, lactate dehydrogenase >590 IU/L, and/or hemoglobin level <10 g/dL are considered resistant to IVIG.33 Kobayashi et al designed a seven-variable logistic model with high sensitivity and specificity, including day of illness at initial treatment, age in months, neutrophil count, platelet count, AST, sodium, and CRP.34 Sano et al showed that patients with at least two of the three predictors (CRP ≥ 7.0 mg, total bilirubin ≥ 0.9 mg, or AST ≥ 200 IU/L) are considered to be resistant to IVIG for acute KD.35 Egami et al demonstrated that resistance to IVIG treatment can be predicted using age, illness days, platelet count, ALT, and CRP.36 The predictive value of these scoring systems is variable, especially in different ethnic populations.37 Our results showed that CRP is not correlated to IL-18 in various stages of KD. In the acute stage, the IL-18 level after IVIG was not significantly lower than that before IVIG treatment, but the CRP level after IVIG was significantly lower than that before IVIG treatment. The IL-18 belongs to the IL-1 superfamily and can induce the production of IFN-γ in the presence of IL-12 and co-stimulants.14 The function of IL-18 is different from that of CRP in the pathogenesis of KD. This may partially account for the lack of significant correlation between IL-18 and CRP levels in this series. The correlation between IL-18 and IVIG resistance is another interesting issue, but merits further investigation.
This study demonstrated a correlation between anemia and IL-18 level in acute KD, but the correlation was borderline statistically significant. Anemia may develop, usually with normal red blood cell indexes, particularly with an extended duration of active inflammation.1 Severe anemia is rare and may be related to macrophage-activation syndrome or IVIG infusion.38,39 Although anemia is an important laboratory finding in acute KD, the exact mechanism of anemia remains unclear. Macrophages have been shown to have a negative regulation of the growth and development of mature erythroid progenitors [erythrocyte colony-forming unit (CFU-E)] in normal and erythroleukemic mice.40 In animal models, administration of IL-1 induces anemia by suppressing the activity of CFU-E.40 The activity of IL-18, a member of the IL-1 family, has also been implicated in hematopoietic progenitor cell growth,41 but its role in erythropoiesis is unclear. The IL-18 receptors are expressed constitutively in macrophages, and/or its lineage,42 and may be involved in the activity of macrophage. It is therefore possible that a regulatory axis related to IL-18 plays a role in the control of erythropoiesis and provides a mechanism for the hematopoietic response to acute inflammation in KD, and the pathogenesis of the anemia.
Some limitations in this study need to be specified. This is a single-center investigation with a limited number of patients. The discrepancy between the results of the study by Nomura and co-workers13 and this study cannot be well explained because of inconsistency in the populations studied and the methods chosen. The difference in IL-18 levels between KD patients and febrile controls is not elucidated clearly. Because there was no IVIG-resistant patient in this series, we could not define the relationship between IL-18 and IVIG resistance. Measurement of IL-18 was performed on samples that were stored at −80°C. However, the possibility of protein degradation in the stored samples cannot be excluded. A multicenter study with a large cohort is suggested.
In conclusion, the results of this study show that IL-18 levels were elevated in the acute phase of KD and might be related to the formation of CALs.
This research was supported in part by grants from the Kaohsiung Veterans General Hospital (Grant Nos. VGHKS101-46, VGHKS101-G01-1, and VGHKS101-G01-2), and the Zuoying Armed Forces Hospital (Grant Nos. 100-10, 100-13, and 101-13).
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