Clinical Outcomes of Low-Dose Methotrexate Therapy as a Second-Line Drug for Intravenous Immunoglobulin-Resistant Kawasaki Disease

PURPOSE: Intravenous immunoglobulin (IVIG) is the standard treatment for Kawasaki disease (KD). However, there is still no standard treatment for IVIG-resistant KD. This study aimed to evaluate the efficacy of low-dose methotrexate (MTX) as a treatment for IVIG-resistant KD. MATERIALS AND METHODS: We retrospectively analyzed 10-year data for patients with IVIG-resistant KD who were administered MTX at Severance Children's Hospital. RESULTS: The subjects included 75 patients with KD aged 5 months to 9.2 years who had been administered MTX. Their maximum body temperatures decreased significantly within 24 h of therapy. The patients' C-reactive protein levels were significantly lower 1 week after administering the first dose of MTX than those before treatment. No adverse effect for MTX was observed. CONCLUSION: MTX treatment of IVIG-resistant KD resulted in rapid defervescence, improvement of clinical symptoms, and normalization of acute-phase reactants in all patients. Thus, MTX could be a candidate treatment for IVIG-resistant KD.

Riesgo de afectación coronaria en la enfermedad de Kawasaki / Risk of coronary artery involvement in Kawasaki disease

Introducción: La enfermedad de Kawasaki es una vasculitis sistémica con riesgo de afectación coronaria. Nuestro objetivo es identificar los factores de riesgo asociados a la afectación coronaria en pacientes con enfermedad de Kawasaki completa e incompleta. Material y métodos: Estudio descriptivo retrospectivo de los pacientes diagnosticados con enfermedad de Kawasaki en un hospital terciario entre 2008 y 2014. Se utilizaron los criterios diagnósticos de la Asociación Americana de Cardiología para definir la enfermedad de Kawasaki en su forma completa e incompleta. Resultados: Treinta y un niños fueron diagnosticados con enfermedad de Kawasaki; 24 cumplían criterios para la forma completa y 7, para la incompleta. Cinco presentaron afectación coronaria. Uno de ellos presentaba enfermedad de Kawasaki incompleta (1/7= 14,3%), y los 4 restantes, enfermedad de Kawasaki completa (4/24= 16,7%). No se encontraron diferencias significativas en el riesgo de afectación coronaria entre ambos grupos (p= 1,0). Los pacientes con afectación coronaria tenían una proteína C reactiva mayor (mediana: 16,2 mg/dl vs. 8,4 mg/dl; p= 0,047) y una menor albuminemia (mediana: 3,2 mg/dl vs. 3,99 mg/dl; p= 0,002). Conclusiones: El riesgo de afectación coronaria de la enfermedad de Kawasaki incompleta es similar al de la enfermedad de Kawasaki completa, por lo que, en pacientes con la forma incompleta de la enfermedad, no se debería demorar el tratamiento con inmunoglobulina. En nuestra población, los valores de proteína C reactiva y de albúmina se relacionan con un mayor riesgo de afectación coronaria.

Introduction: Kawasaki disease refers to systemic vasculitis with risk of coronary artery disease. Our objective is to identify risk factors associated with coronary artery disease in patients with complete and incomplete Kawasaki disease. Material and methods: Descriptive, retrospective study conducted in patients diagnosed with Kawasaki disease in a tertiary-care hospital between 2008 and 2014. The American Heart Association diagnostic criteria were used to define complete and incomplete Kawasaki disease. Results: Thirty-one children were diagnosed with Kawasaki disease; 24 met the criteria for the complete form, and 7, for the incomplete form of this condition. Five had coronary artery disease. One of them had incomplete Kawasaki disease (1/7= 14.3%), and the remaining four had the complete form (4/24= 16.7%). No significant differences were found between both groups (p= 1.0). Patients with coronary artery involvement had a higher C-reactive protein level (median: 16.2 mg/dL versus 8.4 mg/dL, p= 0.047) and lower albuminemia (median: 3.2 mg/dL versus 3.99 mg/dL, p= 0.002). Conclusions: The risk of coronary artery involvement in incomplete Kawasaki disease is similar to that in complete Kawasaki disease; therefore, in patients with the incomplete form, immunoglobulin therapy should not be delayed. In our population, C-reactive protein and albumin levels were related to a higher risk of coronary artery involvement.

Association between Adipokines and Coronary Artery Lesions in Children with Kawasaki Disease

Body fat is an important source of adipokine, which is associated with energy balance and inflammatory and immune responses. However, the role of adipokines in coronary artery complications in Kawasaki disease (KD) has not yet been fully explained. We investigated whether serum adipokine level can be a useful marker for patients with KD who are at higher risk of developing coronary artery lesion (CAL). We measured adipokine levels and other inflammatory parameters in 40 patients with KD, 32 febrile controls, and 15 afebrile controls. Interleukin (IL)-6, tumor necrosis factor (TNF)-alpha and other laboratory parameters were also measured before and after intravenous immunoglobulin therapy, and in the convalescent phase. At admission, the serum resistin levels in KD children were significantly higher than those in controls (177.56 ng/mL in KD children, 76.48 ng/mL in febrile controls, and 17.95 ng/mL in afebrile controls). In patients with KD, resistin levels were significantly associated with decreased hemoglobin levels (P=0.049) and increased IL-6 levels (P=0.014). The serum IL-6 levels were significantly higher and body mass index was significantly lower in the group of KD with CALs than those without CALs (228.26 ng/mL vs. 39.18 ng/mL and 15.09 vs. 16.60, respectively). In conclusion, resistin is significantly elevated in KD patients, although it has no prognostic value of predicting coronary artery lesion in the acute stage.

Clinical characteristics of kawasaki disease according to age at diagnosis.

Objective: We compared the clinical, laboratory and diagnostic features of Kawasaki disease (KD) in children £6 mo and ³5 y of age to those in the more typical age range at diagnosis (6 mo-5 y of age). Study design: Retrospective analysis. Setting: Severeance Children Hospital attached to a Medical School, Korea. Methods: All children with a discharge diagnosis of KD at Severance Children’s Hospital (2006-2007) were retro-spectively reviewed and grouped according to age at presentation in 3 groups: <6 mo, 6 mo-5 y and ³5 years. Clinical, hematological, and biochemical features and involvement of coronary artery and proportion of Classic vs. Incomplete KD were compared between the 3 groups. Results: A total of 185 children were identified. Complete KD was found in 63 (34%) children and Incomplete KD in 122 (66%). There was 22(12%) children below 6 months of age, 131 (71%) between 6 months to 5 years) and 32 (17%) above 5 years of age. Clinical, hematological and biochemical features were comparable between the three age groups. Overall, coronary artery lesions occurred in 9% children without any preference for age. The proportion of Classical vs. Incomplete KD was also similar in the three age categories. Conclusion: The clinical and laboratory phenotype of KD does not vary significantly with age.

Cardiovascular involvement in Kawasaki disease.

We report 72 patients with Kawasaki disease seen at this Centre over 7 years. Cardiac involvement in the form of mild pancarditis was seen in 28 % patients, but disappeared subsequently. Thirteen (18.5 percent) children developed coronary artery disease, out of which 4 resolved by the end of two months and another 6 after one year; 3 patients continued to show coronary artery dilatation and aneurysm formation. Children who received IV gammaglobulin in full dose within 10 days of onset of illness, showed no evidence of coronary artery disease during follow up.

Inflammatory Processes in Kawasaki Disease Reach their Peak at the Sixth Day of Fever Onset: Laboratory Profiles According to Duration of Fever

We evaluated the inflammatory indices according to the fever duration in children with Kawasaki disease (KD), and determined duration when the inflammatory processes in KD reach their peak. Children with KD (n=152) were classified into 7 groups according to fever duration: at the third day or earlier (n=20), fourth (n=33), fifth (n=46), sixth (n=15), seventh (n=15), eighth (n=9), and at the ninth day or later after fever onset (n= 14). The levels of various laboratory indices were determined 3 times: before, 24 hr and 7 days after intravenous immunoglobulin administration (2 g/kg). WBC and neutrophil counts, and C-reactive protein level were the highest at the sixth day. Levels of hemoglobin, albumin, and high density lipoprotein cholestrol were the lowest at the sixth day. Although these indices were not significant statistically between groups, the indices showed either bell-shaped or U-shaped distribution of which peak or trench were at the sixth day. These findiugs showed that the inflammatory processes in KD reach peak on the sixth day of fever onset. This finding is important because a higher single-dose intravenous immunoglobulin treatment before the peak day may help reduce the coronary artery lesions in KD.

Production of Chemokines in Kawasaki Disease, Henoch-Schonlein Purpura and Acute Febrile Illness

We compared the production of three chemokines; interferon-gamma-inducible protein-10 (IP-10), monocyte chemoattractant protein-1 (MCP-1) and growth-related onco-gene-alpha(Gro-alpha) that attracts monocytes or neutrophils, or both, in peripheral blood at acute stage of Kawasaki disease (n=29), Henoch-Schonlein purpura (n=15) and acute febrile illnesses (n=12). The production of the chemokines was assayed by ELISA. The plasma levels of IP-10 were markedly elevated in Kawasaki disease (538.6 +/-336.4 pg/mL) and acute febrile illnesses (417.1 +/-262.2 pg/mL) compared with in Henoch-Schonlein purpura (58.7 +/-95.7 pg/mL) (p<0.05). The MCP-1 levels were elevated in Kawasaki disease (443.0 +/-473.1 pg/mL) and acute febrile illnesses (328.6 +/-261.1 pg/mL) compared with in Henoch-Schonlein purpura (82.9 +/-79.0 pg/mL) (p<0.05). The Gro- levels were elevated only in acute febrile illnesses (134.3 +/-153.6 pg/mL) compared with in Kawasaki disease (31.8 +/-22.1 pg/mL) or Henoch-Schonlein purpura (29.4 +/-53.3 pg/mL) (p<0.05). According to these results, monocytes may play an important role in Kawasaki disease. In acute febrile illness-es, both monocytes and neutrophils may play an important role. By contrast, Henoch-Schonlein purpura may not be associated with the role of monocytes and neutrophils. Further studies using a larger number of cases are needed.

Chemokines in Kawasaki disease: measurement of CCL2, CCL22 and CXCL10.

Kawasaki disease (KD) is a childhood-onset vascular disease. In order to determine whether KD is associated with altered chemokine production, we measured CCL2, CCL22, and CXCL10 levels in the serum of KD patients and healthy control subjects. The mean serum concentration of CCL2 in KD subjects was 829.0 +/- 388.2 pg/ml, significantly higher than that seen in healthy controls (223.4 +/- 92.6 pg/ml; p < 0.001). In addition, the mean serum CXCL10 level in KD subjects was 2,469.4 +/- 998.8 pg/ml, again significantly higher than that in healthy controls (127.7 +/- 64.2 pg/ml; p < 0.001). No difference was observed in serum concentrations of CCL22 between KD and healthy controls (1,685 +/- 1,985 microg/ml and 1,539 +/- 380 microg/ml, respectively). Thus, we observed the selective induction of a TH1-associated (CXCL10) and a TH2-associated chemokine (CCL2) in the serum of individuals with KD, suggesting a mixed TH1/TH2 response at the level of chemokine production and subsequent cell recruitment and thus pointing at a potential role for these chemokines in the pathology of KD.

Tumor Necrosis Factor-alpha Levels and Promoter Polymorphism in Patients with Kawasaki Disease in Korea

Tumor necrosis factor (TNF) -alpha plays a major role in the pathogenesis of Kawasaki disease (KD), a systemic vasculitis primarily affecting young children. We performed this study to examine the serum levels of TNF-alpha and to investigate a possible relation to promoter polymorphism at positions -238 and -308 in KD patients in Korea. We obtained 48 paired serum samples from 24 patients in the acute and subacute stages of KD, and control sera from 12 age-matched children who were having routine blood samples taken before elective surgical procedures. Our studies showed a significant increase in serum levels of TNF-alpha measured in the acute stage of KD (24.1+/-9.4 pg/mL) compared to those in the subacute stage (11.8+/-5.8 pg/mL; p < 0.01) and normal controls (10.4+/-4.9 pg/mL; p < 0.01). Previous studies report that the presence of the A allele at positions -308 and -238 may be associated with higher TNF-alpha levels. However, our results showed that the frequency of the A allele at position -308 in the KD patients was the same as the controls (2 out of 24, 8.3% vs. 8.3%, odds ratio (OR) = 1.00), while the frequency of the A allele at position -238 in the KD patients was lower than the controls (0/24, 0% vs. 8.3%, OR=0.00) ; this difference though was not statistically significant. We concluded that although TNF-alpha levels were significantly elevated in the acute stage of KD, there was no significant difference in the frequency of the A allele at positions -238 and -308 between the KD and control groups in Korean patients.

Inverse correlation between macrophage-colony stimulating factor, cholesterol and high density lipoprotein cholesterol in Kawasaki disease.

Kawasaki disease (KD) is a childhood-onset vascular disease. We assessed the concentrations of macrophage-colony stimulating factor (M-CSF) and those of lipids in sera from patients with KD. The M-CSF concentration in patients with acute-phase KD was 2,914+/-159 U/ml, significantly higher than that in control subjects with Infectious diseases (1,241+/-96 U/ml). The elevated levels of this cytokine in the acute phase fell to 1,319+/-138 U/ml in the convalescent phase. Total and high-density lipoprotein cholesterol concentrations in acute phase KD (113.8+/-8.4 and 21.5+/-2.3 mg/dl, respectively) were lower than in the infectious disease controls (195.8+/-7.0 and 62.5+/-1.8 mg/dl). The elevation of M-CSF correlated with the decrease of total and high-density lipoprotein cholesterol. Overproduction of macrophage-colony stimulating factor activates macrophages and monocytes and may disturb the lipid metabolism. Both effects could contribute to vasculitis in KD.

Increased serum interleukin-10 level in Kawasaki disease

Serum IL-10 level in Kawasaki disease(KD) was tested. In the KD patients' sera during the acute phase, the levels of IL-10 were markedly elevated (122.0 +/- 39.1 pg/ml) compared to 3.7 +/- 1.7 pg/ml in the control subjects (p< 0.001). The serum IL-10 levels remained elevated in the subacute phase (16. 7 +/- 9.7 pg/ml, p< 0.001) and were restored to the normal levels(7.9 +/- 3.9 pg/ml) during the convalescent phase. In the patients with acute febrile disease, the serum IL-10 level increased significantly (34.4 +/- 14.1 pg/ml, p< 0.001) compared to that of the age-matched control subjects, but were not as high as in acute phase of KD(p< 0.005). This increase in serum IL-10 levels in KD may contribute to the up-regulation of humoral immunity and to the down-regulation of acute inflammation due to an increase in proinflammatory cytokines.

Doença de kawasaki em Pernanbuco: consideraçöes sobre um caso visto em hospital geral / Kawasaki disease in Pernambuco: a case report in a general hospital

Descreve-se o primeiro caso de doença de Kawasaki registrado em Recife, PE. Menimo de 1 ano e 6 meses de idade, com quadro de adenomegalia febril e acometimento de pele e mucosas, teve detectadas, ao ecocardiograma bidimensional, dilataçäo e formaçöes aneurismáticas em artérias coronárias direita e esquerda. Submetido à terapêutica com aspirina em dose alta, apresenta-se assintomático, em acompanhamento de sete meses, com involuçäo das lesöes coronarianas

Serum interleukin-6 in Kawasaki disease

Kawasaki disease (KD) is an acute febrile illness of infancy and early childhood. In spite of extensive studies, the cause of KD is not known. Interleukin 6 (IL-6) has manyfold biological functions involved in the immune or inflammatory responses of the host to various stimuli. Here the author investigated whether IL-6 might be responsible for manifestations of KD, such as immunoglobulin hypersecretion, lymphocyte activation and systemic vasculitis. Serum IL-6 levels in KD were determined by ELISA. Usually sera from healthy children contained only negligible levels of IL-6. Serum IL-6 was markedly elevated in all patients with acute KD, which gradually decreased during the course of the disease. Serum IL-6 correlated with serum concentration of C-reactive protein and with serum soluble interleukin-2 receptor level, but did not show any correlation with peak platelet count during subacute phase of the disease. Increased serum IL-6 level did not show any relation to development of coronary aneurysms and dilatation. Further studies will be needed to examine the source and the pathogenetic roles of increased serum IL-6 in KD.