Kawasaki Disease and Vaccination: Prospective Case-Control and Case-Crossover Studies among Infants in Japan.

The causal effects of vaccines on Kawasaki disease (KD) remain elusive. We aimed to examine the association between vaccines administered during infancy and the development of KD in Japan. We conducted a multicenter prospective case-control study using questionnaires and compared the vaccination status of infants (age: 6 weeks to 9 months) who developed KD (KD group; n = 102) and those who did not develop KD (non-KD group; n = 139). Next, we performed a case-crossover study of 98 cases in the KD group and compared the status of vaccinations between the case and control periods. We also compared the incidence of KD in children for each 5-year period before and after the addition of new vaccines (2012-2013) using data from the Nationwide Survey of KD. In the case-control study, the vaccination status of the KD and control groups did not differ to a statistically significant extent. Multivariable analysis of the vaccination status and patient backgrounds showed no significant association between vaccination and KD development. In the case-crossover study, the status of vaccinations during the case and control periods did not differ to a statistically significant extent. In the analysis of data from the Nationwide Survey of KD, the incidence of KD in children of ages subject to frequent vaccination showed no significant increases in the latter five years, 2014-2018. Based on these prospective analyses, we confirmed that vaccination in early infancy did not affect the risk of KD.

Treatment change and coronary artery abnormality in incomplete Kawasaki disease.

BACKGROUND: Incomplete Kawasaki disease (iKD) showed a higher incidence of coronary artery abnormalities (CAAs) than complete KD. However, the incidence of CAAs among iKD patients may have changed recently. METHODS: We examined KD patients from recent nationwide surveys conducted between 2013 and 2016 and compared them with the results of a previous survey (2001-2002). RESULTS: Of 63 270 KD patients, 13 770 patients (22%) had iKD. They showed a higher incidence of convalescent-phase CAAs (cCAAs, 2.8%) than complete KD (2.1%). The incidence of cCAAs in patients with one or two symptoms (6.7%) was significantly higher than those with three or four symptoms (2.6%) (P < 0.0001). Intravenous immunoglobulin (IVIG) treatment was administered to 80% of iKD patients; 30% of them received IVIG before the fifth illness day (early treatment) and 12% of patients received IVIG after the seventh illness day (late treatment). In the previous survey, the incidence of cCAAs was higher in both iKD (5.9%) and cKD (4.4%). Intravenous immunoglobulin was administered to 62% of iKD patients; 26% of them received early treatment, and 16% received late treatment. CONCLUSIONS: The incidence of cCAAs remained higher among iKD patients than cKD patients but this difference was reduced by the increased proportion of iKD patients treated with IVIG and those at an earlier time point. It is important to recognize the possibility that patients may have iKD and perform echocardiography even if they present with a few principal symptoms.

Risk factors for development of ventricular tachycardia in patients with ventricular premature contraction with a structurally normal heart.

BACKGROUND: We examined risk factors for development of ventricular tachycardia (VT) in pediatric patients with ventricular premature contractions (VPCs) and a structurally normal heart. METHODS: The subjects were 81 844 first graders and 88 244 seventh graders of Kagoshima City School-based cardiovascular screening (SCV-screening) between 2001 and 2015. We retrospectively reviewed the clinical data of students who were diagnosed as having VPC. RESULTS: Ventricular premature contractions were observed in 134 first graders (0.16%) and 270 seventh graders (0.31%). On the screening electrocardiograms (ECGs), 43 patients (11%) showed bi-/trigemini, three patients (0.7%) showed a couplet, and one patient showed VT. We obtained 166 patients' follow-up information and evaluated 59 patients (36%) as improved, 97 patients (58%) as no change, and 10 patients (6%) as worsened (couplets, five; triplets, two; VT, three). We assumed that these worsened patients have risk factors for development of VT. Comparing the findings of SCV-screening ECGs of risk patients with the others, a significant difference was observed only in the number of VPCs (per 10 seconds) (mean ± SD; 4.3 ± 2.6 vs 1.8 ± 1.4, P < .0001). A logistic regression analysis revealed that the number of VPCs was significant (P < .001, odds ratio; 2.01, 95% confidence intervals; 1.46-2.93). Receiver operating characteristics analysis showed an adequate cut-off number of three VPCs for the risk, the sensitivity was 89% and the specificity was 77%. CONCLUSIONS: Of the patients with VPC and a structurally normal heart, a few patients developed VT. Careful observation is important in patients who had three or more VPCs on SCV-screening ECG.

Disruption of Endothelial Cell Homeostasis Plays a Key Role in the Early Pathogenesis of Coronary Artery Abnormalities in Kawasaki Disease.

Disruption of endothelial cell homeostasis may be associated with the pathogenesis of coronary artery abnormalities (CAA) in Kawasaki disease (KD). We sought to clarify the poorly understood pathogenic role of endothelial cell survival and death in KD vasculitis. Human umbilical vein endothelial cells (HUVECs) stimulated with sera from KD patients, compared with sera from patients with bacterial infections, exhibited significant increases in cytotoxicity, high mobility group box protein 1 (HMGB-1), and caspase-3/7 and a decrease in phosphorylated Akt/Akt (pAkt/Akt) ratios. HUVECs stimulated with sera from KD patients treated with immunoglobulin (IG) showed significantly decreased cytotoxicity, HMGB-1, and caspase-3/7 levels and increased pAkt/Akt ratios, as compared with results for untreated HUVECs (P < 0.001, P = 0.008, P = 0.040, and P < 0.001, respectively). In HUVECs stimulated with sera from KD patients, the increased cytotoxicity levels and the suppression of increased pAkt/Akt ratios after subsequent IG treatment were closely related to the development of CAA (P = 0.002 and P = 0.035). Our data reveal that shifting the balance toward cell death rather than survival appears to perturb endothelial cell homeostasis and is closely related to the development of CAA. The cytoprotective effects of IG treatment appear to ameliorate endothelial cell homeostasis.

Circulating platelet-neutrophil aggregates play a significant role in Kawasaki disease.

BACKGROUND: Circulating platelet-neutrophil aggregates play a crucial role in amplifying acute inflammation and could promote adverse effects involving vascular injury. The aim of this study was to evaluate the role of platelet-neutrophil aggregates in Kawasaki disease (KD). METHODS AND RESULTS: Forty patients with KD (30 intravenous immunoglobulin [IVIG] responders and 10 IVIG non-responders), 7 febrile patients with bacterial infections, and 9 normal volunteers were analyzed. Thirty-three patients with KD were treated with IVIG, and 7 were treated with IVIG plus prednisolone. We evaluated the rate of platelet-neutrophil aggregates and measured the platelet factor 4 (PF4) and ß-thromboglobulin (ß-TG) levels. The rate of platelet-neutrophil aggregates was significantly higher in patients with KD than those with bacterial infection and normal volunteers. The rate of platelet-neutrophil aggregates was significantly higher in patients with coronary artery abnormalities (CAA) than in those without CAA, and was correlated with PF4 and ß-TG levels in patients with KD. Comparing time-course analysis, the rate of platelet-neutrophil aggregates was significantly decreased in patients treated with IVIG plus prednisolone than in those treated with IVIG alone. CONCLUSIONS: The findings demonstrate that platelet-neutrophil aggregates are significantly present in higher rates and are closely related to pathological developments of CAA in KD. Additional prednisolone treatment for patients in the acute phase of KD could suppress platelet-neutrophil aggregates, indicating that platelet-neutrophil aggregates would inhibit amplified reciprocal vascular inflammatory activation.

Immunoglobulin G values before treatment are correlated with the responsiveness to initial intravenous immunoglobulin therapy for Kawasaki disease.

BACKGROUND: Low levels of serum immunoglobulin G (IgG) before intravenous immunoglobulin (IVIG) therapy for Kawasaki disease (KD) have been reported as one of the risk factors for coronary artery abnormalities (CAAs). This risk factor needs to be re-evaluated because the dosage of IVIG has changed from 0.2-0.4 g/kg/day for 5 days to a single high dose of 2 g/kg. METHODS: We reviewed the clinical records of KD patients admitted to our hospital from January 2001 to August 2011. Patients who were given a single high dose of IVIG within 7 days of illness, and who had blood collected for serum immunoglobulin values before treatment, were selected. The serum immunoglobulin levels and coronary artery diameters measured by echocardiogram were transformed to z-scores. RESULTS: The subjects were 197 KD patients, including 22 IVIG nonresponders and 16 patients with CAAs. Of these, 150 (76%) had a z-score for IgG (IgGz) of ≤0. There were no differences in IgGz values between patients with CAAs and those without CAAs. However, nonresponders had higher IgGz values than responders (median, 25th percentile and 75th percentile: -0.26, -0.83 and 0.34 vs. -0.79, -1.40 and -0.03; p = 0.020). Logistic regression analysis showed that the IgGz value was an independent risk factor for resistance to IVIG (OR 1.36, 95% CI 1.002-1.849; p = 0.048). CONCLUSIONS: Low IgGz values were not a risk factor for CAAs in this study. However, KD patients with relatively high IgGz values before treatment may have an increased risk of resistance to initial IVIG therapy. © 2014 S. Karger AG, Basel.

Kawasaki disease patients with six principal symptoms have a high risk of being a non-responder.

BACKGROUND: A diagnosis of Kawasaki disease (KD) is established using six principal symptoms. Because the principal symptoms are deeply connected with KD, it is thus important to investigate the usefulness of the principal symptoms for evaluating the disease severity of KD. METHODS: Patients with definite KD or suspicion of KD were retrospectively examined. Blood test data and the incidence of patients who failed to respond to the initial i.v. immunoglobulin treatment (non-responders) were compared between patients with six principal symptoms, including fever of ≤ 4 days, before treatment of KD (six-symptom patients), and those with five or fewer symptoms (five-symptom patients). RESULTS: The study group of 207 patients who were treated with immunoglobulin consisted of 121 six-symptom patients and 86 five-symptom patients. The six-symptom patients were older and had higher neutrophil proportion and total bilirubin, and lower serum sodium at diagnosis than the five-symptom patients. Although the treatments did not differ between the groups, the six-symptom patients had a higher incidence of non-responders than the five-symptom patients (17% vs 5%; P= 0.008). Logistic regression analysis showed that six-symptom status was related to the risk of being a non-responder (odds ratio [OR], 5.3; 95% confidence interval [95%CI]: 1.6-17.4). This association was still significant after adjustment for the effect of age, neutrophil proportion, and total bilirubin and sodium (OR, 4.4; 95%CI: 1.4-17.3). CONCLUSIONS: The number of principal symptoms before treatment is a useful guide to KD disease severity. Six-symptom patients have a higher risk of being a non-responder than five-symptom patients.

Serum procalcitonin value is useful for predicting severity of Kawasaki disease.

We measured serum procalcitonin concentrations in 160 patients suffering from Kawasaki disease. Serum procalcitonin was significantly higher in nonresponders to an initial intravenous immunoglobulin treatment than in responders. A cutoff value of procalcitonin (0.5 ng/mL) for nonresponders showed that the sensitivity was 85% and the accuracy was 64%. Multivariate logistic regression analysis revealed that procalcitonin-positive cases showed the highest risk for nonresponders.

An elevated value on drug-induced lymphocyte stimulation test for immunoglobulin is an immunological abnormality of Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is an acute febrile vasculitis in childhood. Currently, treatment with 2 g/kg of intravenous immunoglobulin (IVIG) is recommended. Previously we had encountered a patient with KD who showed persistent fever and a severe eruption after IVIG treatment. Using a drug-induced lymphocyte stimulation test (DLST), he was positive for an immunoglobulin product. The aim of this study was to clarify the importance of a positive value for the DLST for immunoglobulin products in KD patients. METHODS: Subjects were 30 confirmed KD patients treated with IVIG at the Kagoshima Medical Association Hospital. DLST values were compared between patients with additional events and those without additional events using the stimulation index (SI = value of (3)H-thymidine absorption with antigen/without antigen). Additional events were defined as symptoms observed after IVIG that were considered unexplainable by the symptoms of KD alone. RESULTS: DLST results were evaluated in 13 patients with additional events and 17 patients without additional events. Elevated DLST values were observed not only in patients with additional events but also in those without additional events. Elevated SI values were observed in the initial 14 days after IVIG and the SI values in this period were significantly higher than those after day 14 (initial 14 days, n = 20, 194 +/- 112%; after day 14, n = 10, 117 +/- 66%, p = 0.010). CONCLUSIONS: Elevated SI values of DLST for immunoglobulin products are not related with additional events. Our results show they may represent one of the immunological abnormalities of KD.

A severe form of Kawasaki disease presenting with only fever and cervical lymphadenopathy at admission.

OBJECTIVE: To examine the characteristics of patients with Kawasaki disease (KD) presenting with only fever and cervical lymphadenopathy at admission. STUDY DESIGN: The laboratory and clinical findings of patients with definite KD presenting with only fever and cervical lymphadenopathy at admission (KDiL) were compared with those of all other patients with KD. RESULTS: Sixteen patients with KDiL (8.6%) and 171 patients without KDiL were examined. The patients with KDiL were significantly older (KDiL/non-KDiL: 4.9+/-2.5/2.2+/-1.9 years) and admitted earlier (3.0+/-1.2/3.9+/-1.3 days of illness) than the patients without KDiL. They also showed significantly elevated white blood cell counts and C-reactive protein levels. Patients with KDiL were treated with the same dose of intravenous immunoglobulin as the patients without KDiL but were treated slightly later and had significantly higher frequency of additional intravenous immunoglobulin treatment (38%/10%) and coronary artery abnormalities (25%/5%). After adjustment for age, white blood cell count, and day of illness at admission or first intravenous immunoglobulin administration, the presence of KDiL significantly increased the risk of being a nonresponder to IVIG treatment or development of a coronary artery abnormality. CONCLUSIONS: KDiL indicates a severe form of KD associated with increased risks of additional intravenous immunoglobulin treatment and coronary artery abnormalities. Patients with KDiL may require heightened surveillance and more aggressive treatment.

Platelet vascular endothelial growth factor is a useful predictor for prognosis in Kawasaki syndrome.

Kawasaki syndrome (KS) is an acute febrile vasculitis of childhood. Coronary artery abnormalities (CAA) are a significant problem in KS patients. High dose intravenous immunoglobulin (IVIG) is effective for reducing the occurrence of CAA. Clinical and histopathological findings suggest that vascular endothelial growth factor (VEGF) is involved in CAA. In circulating blood, newly activated platelets are the major source of VEGF, which is released in large amounts in vascular inflammation. The present study analysed 80 KS patients (69 IVIG responders and 11 IVIG non-responders) and evaluated the role of platelet VEGF in KS vasculitis. Serum VEGF and platelet VEGF levels were significantly higher in KS patients than controls (P < 0.001). Platelet VEGF reflected the reactivity of IVIG treatment and was decreased in responders (P < 0.001), but remained increased in non-responders (P = 0.01). Platelet VEGF levels, but not serum VEGF levels, before IVIG were significantly correlated with the maximum CAA z-score (r = 0.524, P = 0.02). Our findings demonstrate that platelet VEGF may reflect the severity of vasculitis related to the pathological development of CAA in KS. Platelet VEGF may be an important feature of KS pathophysiology.

An elevated value of high mobility group box 1 is a potential marker for poor response to high-dose of intravenous immunoglobulin treatment in patients with Kawasaki syndrome.

We examined the serum values of high mobility group box 1 (HMGB1) in 36 patients with Kawasaki syndrome (KS) (29 responders and 7 poor-responders to initial intravenous immunoglobulin treatment). A mean value of HMGB1 of poor-responders was significantly elevated compared with those of responders (P = 0.0042). Among the 6 factors showing significant differences between responders and poor-responders including HMGB1 (admission illness day, white blood cell counts, C-reactive protein, aspartate aminotransferase, lactate dehydrogenase), values of HMGB1 showed the widest area under the receiver operating characteristic curve. In conclusion, an elevated HMGB1 value could be a potential marker for poor-responders.

Early diagnosis of Kawasaki disease in patients with cervical lymphadenopathy.

BACKGROUND: Among typical patients with Kawasaki disease (KD), a few KD patients present with only fever and cervical lymphadenopathy at admission (KDL). These patients have a significant risk for misdiagnosis, delay in treatment for KD, and development of coronary artery abnormalities. Therefore, the development of an easy tool for early diagnosis in these patients is desirable. METHODS AND RESULTS: Patients who presented with only fever and cervical lymphadenopathy at admission were studied. Of these, 14 patients were eventually diagnosed with KD (KDL) and 24 patients were successfully treated using antibiotics (control). KDL patients were significantly older than control patients (P > 0.022). Among the laboratory findings, neutrophil counts (P > 0.003), C-reactive protein (CRP; P < 0.001), and aspartate aminotransferase (AST; P > 0.018) were significantly different between the groups. To discriminate KDL patients from controls, cut-off points of the aforementioned parameters (KDL indices) were determined using the receiver operating characteristic curves in order to maximize sensitivity and accuracy (age, 5.0 years; neutrophil counts, 10,000 /microL; CRP, 7.0 mg/dL; AST, 30 IU/L). One point was assigned if a subject exceeded the cut-off point in a KDL index. If a patient with three or four KDL indices was considered to have KD, the sensitivity was 78% and the specificity 100%. None of the patients with one or zero KDL index developed KD. CONCLUSIONS: KDL indices may be helpful in discriminating KDL from lymphadenitis at admission. It is important to monitor the symptoms of KD in a patient with three or four KDL indices at admission.

Four cases of Kawasaki syndrome complicated with myocarditis.

BACKGROUND: Myocarditis frequently occurs in the acute phase of Kawasaki syndrome (KS), and a few severe cases have been reported. Four cases of myocarditis in KS required additional catecholamine treatment because of severe left ventricular dysfunction (LVD). CASE REPORTS: Three cases were relatively older children and 2 cases were complicated with encephalopathy. All 4 developed coronary artery abnormalities during convalescence. There was 1 case of LVD because of prolonged severe inflammation prior to administration of intravenous immunoglobulin (IVIG). The remaining 3 patients had normal values for ejection fraction before the administration of IVIG but decreased values (42-51%) and increased C-reactive protein levels after IVIG administration. These cases demonstrate an association between myocarditis in KS and severe or worsened inflammation. CONCLUSIONS: Even with prior normal echocardiography, careful observation of cardiac function may be necessary for patients with KS, especially older children, when inflammation deteriorates after administration of IVIG.

Serum levels of interleukin-18 are elevated in the subacute phase of kawasaki syndrome.

BACKGROUND: Elevations of various cytokines, including Th1 and Th2 cytokines, have been reported in the acute phase of Kawasaki syndrome (KS). As interleukin (IL)-18 plays an important role in the Th1 cell response, investigating the relevance of IL-18 in KS should be helpful in determining the pathophysiology of KS. Therefore, we examined the IL-18 values in KS. METHODS: Serum IL-18 values were measured by an enzyme-linked immunosorbent assay. Samples were obtained from 41 patients in the acute and subacute phase of KS, 35 age-matched febrile controls and 13 afebrile controls. RESULTS: No difference was observed in the values of white blood cell counts or C-reactive protein between acute-phase KS patients and febrile controls. On the contrary, acute-phase KS patients showed a significantly lower mean IL-18 value (398 +/- 206 pg/ml) than that of febrile controls (584 +/- 307 pg/ml) (p = 0.006). Subacute-phase KS patients showed a significantly elevated level of IL-18 (517 +/- 276 pg/ml) compared to acute-phase patients (p = 0.0008). The IL-18 values in the subacute-phase patients showed a significant positive correlation with the duration of fever (r = 0.427, p = 0.0055) and also with the presence of coronary artery abnormalities (r = 0.332, p = 0.0340). The incidence of elevated IL-18 values in the subacute-phase patients was significantly higher than that in the afebrile controls (p = 0.048). CONCLUSIONS: Patients with KS showed normal IL-18 values in the acute phase and elevated values in the subacute phase. IL-18 pathways were activated in the subacute phase of KS, and subacute IL-18 values might be reflected in the severity of KS.

Possible relationship between streptococcal pyrogenic exotoxin A and Kawasaki syndrome in patients older than six months of age.

BACKGROUND: We previously investigated antibody titers against four kinds of superantigens [streptococcal pyrogenic exotoxin A (SPEA), streptococcal pyrogenic exotoxin C, toxic shock syndrome toxin-1 and staphylococcal enterotoxin B] in patients with Kawasaki syndrome (KS) younger than 6 months of age and reported a relationship between toxic shock syndrome toxin-1 and KS patients. In this study we have investigated antibody titers in KS patients older than 6 months of age. METHODS: Serum of 81 patients with KS older than 6 months of age, before intravenous gamma-globulin therapy, and 88 normal age-matched children were used in this study. The IgG antibody titers against four kinds of superantigens were measured with an enzyme-linked immunosorbent assay. RESULTS: The KS patients showed significantly elevated mean SPEA titer (P = 0.006) and significantly higher incidence of high SPEA (P = 0.0024) compared with the controls. The SPEA titer in KS patients showed a significant positive correlation with the number of days from onset of illness (P = 0.0002). CONCLUSIONS: The elevated antibody titer against superantigens of KS patients older than 6 months of age was different from that of KS patients younger than 6 months of age. Our results suggest that KS patients' exposure to SPEA occurred a few weeks before the onset of KS. SPEA may be one of the possible etiologic agents of KS among patients older than 6 months of age in Kagoshima, Japan.

Patients diagnosed with Kawasaki disease before the fifth day of illness have a higher risk of coronary artery aneurysm.

BACKGROUND: A fever lasting for at least 5 days is an essential characteristic of the original diagnostic criteria of Kawasaki disease (KD). However, it is not difficult for an experienced physician to confirm the diagnosis of KD before the fifth day of fever. The aim of this study is to investigate the effect of intravenous gamma globulin therapy (IVGG) in KD initiated before the fifth day of illness. METHODS: A total of 125 patients treated with IVGGwere divided into group A (IVGG was initiated before the fifth day of illness, n= 46) and group B (IVGG was initiated at the fifth day or after, n= 79). Patients' characteristics,laboratory findings, treatments and outcomes were compared between the groups. RESULTS: White blood cell count value, C-reactive protein and Harada's score showed no difference between the groups. A significantly higher average value of alanine aminotransferase(ALT) was observed in group A. Although the treatments were identical in both groups, the average duration of fever from the initial day of IVGG in group A was significantly longer than in group B. The incidence of aneurysm in group A was significantly higher than that in group B. Stepwise regression analysis using aneurysm as a dependent variable revealed that group A and ALT were significant. CONCLUSIONS: Patients diagnosed with KD before the fifth day of illness showed a poor response to IVGG. This observation might be related to high ALT values. Further examination concerning the modification of treatment in such patients is necessary.

Maternal antibody against toxic shock syndrome toxin-1 may protect infants younger than 6 months of age from developing Kawasaki syndrome.

The symptoms of Kawasaki syndrome (KS) suggest a possible relationship between KS and superantigen(s). The infrequent occurrence of KS among young infants may be due to a passive maternal antibody. We investigated the antibody titers for superantigens (toxic shock syndrome toxin [TSST]-1, staphylococcal exotoxin B, and streptococcal pyrogenic exotoxins C and A) in 15 patients with KS who were <6 months of age prior to gamma globulin therapy and in 10 mothers of patients with KS <6 months of age. Significant findings were observed for only TSST-1 among the 4 anti-superantigens. The proportion of patients with KS who had high anti-TSST-1 titers was significantly higher than that among infant control subjects (33% vs. 5%, respectively; P=.031). The mean anti-TSST-1 titer for the mothers was significantly lower than that of adult control subjects (P=.021). Among infants <6 months of age, TSST-1 may be related to KS, and a maternal antibody may protect infants from developing KS.