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    Iron deficiency anemia as a predictor of coronary artery abnormalities in Kawasaki disease. Kim Sohyun,Eun Lucy Youngmin Korean journal of pediatrics PURPOSE:Coronary artery abnormalities (CAA) are the most important complications of Kawasaki disease (KD). Iron deficiency anemia (IDA) is a prevalent micronutrient deficiency and its association with KD remains unknown. We hypothesized that presence of IDA could be a predictor of CAA. METHODS:This retrospective study included 173 KD patients, divided into 2 groups according to absence (group 1) and presence (group 2) of CAA. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a logistic regression model to estimate the association between CAA and other indicators. Due to collinearity between indicators of IDA, each indicator was paired with anemia in 3 models. RESULTS:Serum iron, iron saturation, and ferritin concentration, the 3 indicators of IDA, were significantly higher in group 1 than in group 2. Three sets of models including anemia with iron indicators produced the OR of CAA of 3.513, 3.171, and 2.256, respectively. The 3 indicators of IDA were negatively associated with CAA, by OR of 0.965, 0.914, and 0.944, respectively. The areas under the curve (AUCs) of ferritin concentration, iron saturation, serum iron, anemia, and Kobayashi score were 0.907 (95% CI, 0.851-0.963), 0.729 (95% CI, 0.648-0.810), 0.711 (95% CI, 0.629-0.793), 0.638 (95% CI, 0.545-0.731), and 0.563 (95% CI, 0.489-0.636), respectively. CONCLUSION:Indicators of IDA, especially ferritin, were highly associated with CAA; therefore, they were stronger predictors of CAA than Kobayashi scores. IDA indicators can be used to predict CAA development and to suggest requirements for early interventions. 10.3345/kjp.2018.06905
    A 2-month-old boy with hemolytic anemia and reticulocytopenia following intravenous immunoglobulin therapy for Kawasaki disease: a case report and literature review. Kim Na Yeon,Kim Joon Hwan,Park Jin Suk,Kim Soo Hyun,Cho Yeon Kyung,Cha Dong Hyun,Kim Ki Eun,Kang Myung Suh,Lim Kyung Ah,Sheen Youn Ho Korean journal of pediatrics Herein, we report a rare case of hemolytic anemia with reticulocytopenia following intravenous immunoglobulin therapy in a young infant treated for Kawasaki disease. A 2-month-old boy presented with fever lasting 3 days, conjunctival injection, strawberry tongue, erythematous edema of the hands, and macular rash, symptoms and signs suggestive of incomplete Kawasaki disease. His fever resolved 8 days after treatment with aspirin and high dose infusion of intravenous immunoglobulin. The hemoglobin and hematocrit decreased from 9.7 g/dL and 27.1% to 7.4 g/dL and 21.3%, respectively. The patient had normocytic hypochromic anemia with anisocytosis, poikilocytosis, immature neutrophils, and nucleated red blood cells. The direct antiglobulin test result was positive, and the reticulocyte count was 1.39%. The patient had an uneventful recovery. However, reticulocytopenia persisted 1 month after discharge. 10.3345/kjp.2016.59.11.S60
    High-Dose Aspirin is Associated with Anemia and Does Not Confer Benefit to Disease Outcomes in Kawasaki Disease. Kuo Ho-Chang,Lo Mao-Hung,Hsieh Kai-Sheng,Guo Mindy Ming-Huey,Huang Ying-Hsien PloS one BACKGROUND:Kawasaki disease (KD) is also known as multiple mucocutaneous lymph node syndrome of systemic vasculitis and is a leading cause of coronary artery lesions (CAL) in childhood. Intravenous immunoglobulin (IVIG) has been proven to effectively reduce the incidence of CAL, but the role and effect dose of aspirin in KD is still unclear. Moreover, overt bleeding and anemia are associated with the use of aspirin, and anemia is common in patients with KD. Thus, the aim of this study was conducted to compare the treatment efficacy, degree of anemia and inflammation, and changes in serum hepcidin in children who received a combination of high-dose aspirin and IVIG in the acute stage of KD, and those who received IVIG alone. MATERIALS AND METHODS:KD patients from two medical centers were retrospectively analyzed from 1999-2009. All patients were initially treated with a single dose of IVIG (2 g/kg) as the standard care of treatment. In group 1, high-dose aspirin was prescribed (> 30 mg/kg/day) until the fever subsided, and then low-dose aspirin (3-5 mg/kg/day) was prescribed until all the inflammation signs had resolved. In group 2, low-dose aspirin was prescribed without high-dose aspirin. Laboratory data were collected for analysis in both groups. RESULTS:A total of 851 KD patients (group 1, N = 305, group 2, N = 546) were enrolled in this study. There were no significant differences between group 1 and group 2 in terms of gender (p = 0.51), IVIG resistance rate (31/305 vs. 38/546, p = 0.07), CAL formation (52/305 vs. 84/546, p = 0.67), and duration of hospitalization (6.3 ± 0.2 vs. 6.7 ± 0.2 days, p = 0.13). There were also initially no significant differences in total white blood cell count, hemoglobin level, platelet count, and CRP before IVIG treatment between groups (all p>0.1). After IVIG treatment, group 1 had significantly lower levels of hemoglobin (p = 0.006) and higher CRP (p<0.001) as well as a smaller decrease in CRP level (p = 0.012). Furthermore, there was also a higher serum level of hepcidin and a delayed decrease in hepcidin level after receiving IVIG in group 1 (p = 0.04 and 0.02, respectively). CONCLUSIONS:These results provide evidence demonstrating that high-dose aspirin in the acute phase of KD does not confer any benefit with regards to inflammation and it does not appear to improve treatment outcomes. Therefore, high-dose aspirin is unnecessary in acute phase KD. 10.1371/journal.pone.0144603
    Hepcidin-Induced Iron Deficiency Is Related to Transient Anemia and Hypoferremia in Kawasaki Disease Patients. Huang Ying-Hsien,Kuo Ho-Chang,Huang Fu-Chen,Yu Hong-Ren,Hsieh Kai-Sheng,Yang Ya-Ling,Sheen Jiunn-Ming,Li Sung-Chou,Kuo Hsing-Chun International journal of molecular sciences Kawasaki disease (KD) is a type of systemic vasculitis that primarily affects children under the age of five years old. For sufferers of KD, intravenous immunoglobulin (IVIG) has been found to successfully diminish the occurrence of coronary artery lesions. Anemia is commonly found in KD patients, and we have shown that in appropriately elevated hepcidin levels are related to decreased hemoglobin levels in these patients. In this study, we investigated the time period of anemia and iron metabolism during different stages of KD. A total of 100 patients with KD and 20 control subjects were enrolled in this study for red blood cell and hemoglobin analysis. Furthermore, plasma, urine hepcidin, and plasma IL-6 levels were evaluated using enzyme-linked immunosorbent assay in 20 KD patients and controls. Changes in hemoglobin, plasma iron levels, and total iron binding capacity (TIBC) were also measured in patients with KD. Hemoglobin, iron levels, and TIBC were lower (p < 0.001, p = 0.009, and p < 0.001, respectively) while plasma IL-6 and hepcidin levels (both p < 0.001) were higher in patients with KD than in the controls prior to IVIG administration. Moreover, plasma hepcidin levels were positively and significantly correlated with urine hepcidin levels (p < 0.001) prior to IVIG administration. After IVIG treatment, plasma hepcidin and hemoglobin levels significantly decreased (both p < 0.001). Of particular note was a subsequent gradual increase in hemoglobin levels during the three weeks after IVIG treatment; nevertheless, the hemoglobin levels stayed lower in KD patients than in the controls (p = 0.045). These findings provide a longitudinal study of hemoglobin changes and among the first evidence that hepcidin induces transient anemia and hypoferremia during KD's acute inflammatory phase. 10.3390/ijms17050715
    Hemolytic anemia following intravenous immunoglobulin therapy in patients treated for Kawasaki disease: a report of 4 cases. Berard Roberta,Whittemore Blair,Scuccimarri Rosie Pediatric rheumatology online journal BACKGROUND:Hemolytic anemia is a rare but reported side effect of intravenous immunoglobulin (IVIG) therapy. The risk of significant hemolysis appears greater in those patients who receive high dose IVIG. The etiology is multifactorial but may relate to the quantity of blood group antibodies administered via the IVIG product. FINDINGS:We describe 4 patients with significant hemolytic anemia following treatment with IVIG for Kawasaki disease (KD). Direct antibody mediated attack as one of the mechanisms for hemolysis, in this population, is supported by the demonstration of specific blood group antibodies in addition to a positive direct antiglobulin test in our patients. CONCLUSIONS:Clinicians should be aware of this complication and hemoglobin should be closely monitored following high dose IVIG therapy. 10.1186/1546-0096-10-10
    Para-aortic Lymphadenopathy Associated with Kawasaki Disease. Kashef Sara,Momen Tooba,Heidari Behzad,Amin Reza Iranian journal of pediatrics BACKGROUND:Kawasaki disease is an acute vasculitis that occurs mainly in children. Cervical lymphadenopathy is one of the major presenting manifestations of Kawasaki disease. We report a case of Kawasaki disease with para aortic lymphadenopathy, as an unusual feature in this disease. CASE PRESENTATION:This 2.5 year old girl presented with persistent high grade fever, erythematous rash, bilateral non purulent conjunctivitis, red lips, and edema of extremities. Laboratory results included an elevated erythrocyte sedimentation rate, leukocytosis, anemia, and positive C-reactive protein. On second day after admission she developed abdominal pain. Ultrasonography of abdomen revealed multiple lymph nodes around para aortic area, the largest measuring 12mm×6mm. Treatment consisted of aspirin and high dose intravenous γ-globulin. Ultrasonography and CT scan of abdomen performed one week later showed disappearance of the lymph nodes. CONCLUSION:There are few previous reports of lymphadenopathy in unusual sites such as mediastinum in Kawasaki disease. Para aortic lymph nodes enlargement might be an associated finding with acute phase of Kawasaki disease. In these patients a close observation and ultrasonographic follow up will prevent unnecessary further investigation.
    Significance of Differential Characteristics in Infantile Kawasaki Disease. Kwak Ji Hee,Lee JungHwa,Ha Kee Soo Korean circulation journal BACKGROUND AND OBJECTIVES:Immunological variability in Kawasaki disease (KD) shows age-specific differences; however, specific differences in laboratory values have not been compared between infants and non-infants with KD. We compared age-adjusted Z-values (Z) of white and red blood cells in infants with KD with those in non-infants with KD. METHODS:This study retrospectively investigated 192 infants and 667 non-infants recruited between 2003 and 2015 at the Korea University Hospital. Laboratory values for infants with KD and non-infants with KD were analyzed and age-unadjusted raw values (R) and age-adjusted Z for blood cells counts were determined. RESULTS:Z in infants with KD during pre-intravenous immunoglobulin (IVIG), post-IVIG, and chronic phases showed increased lymphopenia and eosinophilia, low neutrophil:lymphocyte and neutrophil:eosinophil ratios, worse anemia, increased thrombocytosis, and reduced erythrocyte sedimentation rates compared with those in non-infants with KD. The optimal cut-off value for pre-IVIG Z-hemoglobin for prediction of KD in all patients was <-0.01 (area under the curve [AUC], 0.914; sensitivity/specificity, 0.999/0.886; p=0.04). The optimal cut-off value for pre-IVIG C-reactive protein (CRP) for prediction of KD in infants compared to that in febrile control infants was >40 mg/L (AUC, 0.811; sensitivity/specificity, 0.712/0.700; p=0.04). CONCLUSIONS:Laboratory characteristics enable differentiation between infants and non-infants with KD and contribute to a better understanding of changes in blood cell counts. Infants with incomplete KD can be more easily differentiated from infants with simple febrile illness using pre-IVIG Z-hemoglobin and pre-IVIG CRP values. 10.4070/kcj.2018.0434
    Prospective study of Kawasaki disease complications: review of 115 cases. Alves Natália Ribeiro de M,Magalhães Cristina Medeiros R de,Almeida Roseane de Fátima R,Santos Regina Cândido R Dos,Gandolfi Lenora,Pratesi Riccardo Revista da Associacao Medica Brasileira (1992) OBJECTIVE:To draw attention to complications that might arise in any Kawasaki disease (KD) stage, risk factors contributing to the onset of complications and possible transient or permanent disease sequelae. METHODS:Prospective study (clinical cohort) conducted between April 2002 and April 2009 of 115 patients with KD admitted to the Pediatric Rheumatology Clinic of the General Hospital of the Federal District, Brazil. All patients were sequentially assessed with clinical and laboratory examinations, Doppler echocardiography, imitanciometry, auditory evoked potentials, psychological evaluation, ophthalmologic examination and, in one patient with chorea, cerebral magnetic resonance angiography. In all patients, a questionnaire assessing the possible presence of cognitive, emotional, behavioral and social disorders was applied. RESULTS:Twenty-five patients (21.7%) had coronary aneurisms. Thirty eight patients (33%) had a sensorineural auditory loss during the acute and subacute phases of the disease and 13 patients (11.3%) maintained the auditory loss six months after the first assessment. Other complications observed were as follows: facial palsy in one patient (0.9%), ataxia in acute and subacute phases in 11 (9.5%); 15 patients had ophthalmologic complications (13.2%), with uveitis in 13, papilledema in one patient, and conjunctival hemorrhage in another patient. One patient experienced chorea (0.9%), with a magnetic resonance angiography showing changes consistent with cerebral ischemia. In one patient, a thoracic aorta aneurism was found (0.9%) and another patient had a necrotizing vasculitis progressing to peripheral gangrene and tongue tip loss (0.9%). Behavioral changes over convalescence were observed in 23 children. CONCLUSION:KD may progress with several complications even within months of the disease acute phase, eventually resulting in permanent sequelae. The earlier the diagnosis and therapeutic intervention with IV IgG administration are, the lower will be the occurrence of complications; the presence of thrombocytosis, anemia and elevated and extended inflammatory activity are risk factors for complication arising.
    Incomplete Kawasaki disease in a 12-month-old girl presenting with cardiac murmur and iron deficiency anemia. Choi Yunjung,Eun Lucy Youngmin,Oh Seung Hwan Pediatrics international : official journal of the Japan Pediatric Society Kawasaki disease (KD) is an acute necrotizing vasculitis that occurs in children <5 years of age. The cause of KD remains unknown, but various complications, including dilatation of the coronary arteries, can occur. Coronary artery aneurysm or ectasia are the most important complications of KD. Children with suspected KD who do not fulfill the diagnostic criteria may have incomplete KD. Given that incomplete KD is associated with delayed diagnosis and treatment, children with incomplete KD have a high risk of cardiovascular complications. Meanwhile, iron deficiency anemia (IDA) is one of the most prevalent micronutrient deficiencies in the world. Children with IDA are prone to infection and inflammation. We report the case of a 12-month-old girl with incomplete KD who presented with cardiac murmur and severe IDA. 10.1111/ped.12789
    Kawasaki disease triggered by parvovirus infection: an atypical case report of two siblings. Maggio M C,Cimaz R,Alaimo A,Comparato C,Di Lisi D,Corsello G Journal of medical case reports BACKGROUND:There are reports of the familial occurrence of Kawasaki disease but only a few reports described Kawasaki disease in siblings. However, the familial cases were not simultaneous. In these patients the idea of infective agents as trigger must be considered. CASE PRESENTATION:We describe two siblings with atypical presentations of Kawasaki disease; the sister was first diagnosed as having parvovirus infection with anemia and the brother was diagnosed as having myocarditis. The first patient was a 9-month-old Caucasian girl with fever, conjunctivitis, rash, and pharyngitis, and later she had cervical adenopathy, diarrhea and vomiting, leukocytosis, and anemia, which were explained by positive immunoglobulin M against parvovirus. However, coronary artery lesions with aneurysms were documented at day 26 after fever onset. An infusion of intravenous immunoglobulin and high doses of steroids were not efficacious to resolve the coronary lesions. She was treated with anakinra, despite a laboratory test not showing inflammation, with prompt and progressive improvement of coronary lesions. Her 7-year-old Caucasian brother presented vomiting and fever at the same time as she was unwell, which spontaneously resolved after 4 days. Four days later, he again presented with fever with abdominal pain, associated with tachypnea, stasis at the pulmonary bases, tachycardia, gallop rhythm, hypotension, secondary anuria, and hepatomegaly. An echocardiogram revealed a severe hypokinesia, with a severe reduction of the ejection fraction (20%). He had an increase of immunoglobulin M anti-parvovirus, tested for the index case of his sister, confirming the suspicion of viral myocarditis. He received dopamine, dobutamine, furosemide plus steroids, with a progressive increase of the ejection fraction to 50%. However, evaluating his sister's history, the brother showed a myocardial dysfunction secondary to Kawasaki shock syndrome. CONCLUSIONS:We report on familial Kawasaki disease in two siblings which had the same infectious trigger (a documented parvovirus infection). The brother was diagnosed as having post-viral myocarditis. However, in view of the two different and simultaneous evolutions, the girl showed Kawasaki disease with late coronary artery lesions and aneurysms, whereas the brother showed Kawasaki shock syndrome with myocardial dysfunction. We stress the effectiveness of anakinra in non-responder Kawasaki disease and the efficacy on coronary aneurysms. 10.1186/s13256-019-2028-5
    Kawasaki disease with autoimmune hemolytic anemia. Thakkar Dhwanee,Radhakrishnan Nita,Pruthi P K,Sachdeva Anupam Indian pediatrics BACKGROUND:Association of autoimmune haemolytic anaemia has been seldom reported with Kawasaki disease. CASE CHARACTERISTICS:A 7-month-old boy, presented with prolonged fever, erythematous rash, severe pallor and hepatosplenomegaly. OBSERVATIONS:Positive Direct Coombs test and coronary artery aneurysm on echocardiography. He was managed with steroids along with intravenous immunoglobulins and aspirin. OUTCOME:Early identification of the condition helped in the management. MESSAGE:Patients of autoimmune hemolytic anemia with unusual features such as prolonged fever, skin rash, and mixed antibody response in Coombs test should be evaluated for underlying Kawasaki disease as a possible etiology.
    High dose Anakinra for treatment of severe neonatal Kawasaki disease: a case report. Shafferman Ashley,Birmingham James D,Cron Randy Q Pediatric rheumatology online journal We report an 11-week-old female who presented with Kawasaki disease (KD) complicated by macrophage activation syndrome (MAS). The infant presented to the hospital with persistent fever, cough, diarrhea, and emesis, among other symptoms. Her condition quickly began to decompensate, and she developed classic features (conjunctivitis, rash, cracked lips, distal extremity edema) prompting a diagnosis of acute KD. The patient was treated with standard therapy for KD including three doses of intravenous immunoglobulin (IVIG), aspirin, and high dose glucocorticoids with no change in her condition. Due to a high suspicion for MAS, high dose anakinra therapy was initiated resulting in dramatic clinical improvements. She also received one dose of infliximab for concern for coronary artery changes, and over the course of several months, anakinra and high dose glucocorticoids were tapered. Nearly complete reversal of echocardiogram changes were observed after 8 months, and the infant is now off all immunosuppressive therapy. In this case report, we briefly review the importance of early recognition of MAS in pediatric patient populations with rheumatic diseases, and we suggest early initiation of anakinra therapy as a rapid and effective treatment option. 10.1186/1546-0096-12-26
    Kawasaki disease in adults: Observations in France and literature review. Fraison Jean-Baptiste,Sève Pascal,Dauphin Claire,Mahr Alfred,Gomard-Mennesson Emeline,Varron Loig,Pugnet Gregory,Landron Cédric,Roblot Pascal,Oziol Eric,Chalhoub Gihane,Galempoix Jean-Marc,Humbert Sébastien,Humbert Philippe,Sbidian Emilie,Grange Florent,Bayrou Olivier,Cathebras Pascal,Morlat Philippe,Epaulard Olivier,Pavese Patricia,Huong Du Le Thi,Zoulim Abdelkader,Stankovic Katia,Bachelez Hervé,Smail Amar,Bachmeyer C,Granel Brigitte,Serratrice Jacques,Brinchault Graziella,Mekinian Arsène,Costedoat-Chalumeau Nathalie,Bourgarit-Durand Anne,Puéchal Xavier,Guillevin Loïc,Piram Maryam,Koné-Paut Isabelle,Fain Olivier, Autoimmunity reviews OBJECTIVE:Kawasaki disease (KD) is a vasculitis that mostly occurs in young children and rarely in adults. We analyzed the characteristics of adult-onset KD (AKD) in France. METHODS:We collected retrospective and prospective data for patients with a diagnosis of KD occurring after the age of 18 years. Cases were obtained via various French medical networks and identified from the international literature. RESULTS:We included 43 patients of AKD at 26 institution from 1992 to 2015, with mean (SD) age 30 (11) years (range 18-68) and sex ratio (M/F) 1.2; 34 patients met the American Heart Association criteria and 9 were incomplete AKD. The median time to diagnosis was 13 days (interquartile range 8-21). The main symptoms were fever (100%), exanthema (98%), changes in the extremities (91%), conjunctivitis (77%), oral cavity changes (89%), cervical adenitis (55%) and cardiac abnormalities (45%). Overall, 35% of patients showed large-vessel vasculitis: coronary vasculitis (26%) and coronary aneurysm (19%). Treatment was mostly intravenous immunoglobulins (79%) and aspirin (81%). Four patients showed myocardial infarction due to coronary vasculitis, but none were treated with IVIg because of late diagnosis. After a median follow-up of 5 months (range 1-117), persistent aneurysm was noted in 9% of cases. Damage was significantly lower with early treatment than late or no treatment (p=0.01). CONCLUSION:Given the high frequency of cardiac involvement and complications in this series of AKD, diagnosis and treatment should not be delayed, and early IVIg treatment seems to improve the outcome. 10.1016/j.autrev.2015.11.010
    Kawasaki disease in Sicily: clinical description and markers of disease severity. Maggio Maria Cristina,Corsello Giovanni,Prinzi Eugenia,Cimaz Rolando Italian journal of pediatrics BACKGROUND:Kawasaki disease (KD) is an acute systemic vasculitis of small and middle size arteries; 15-25 % of untreated patients and 5 % of patients treated with intravenous immunoglobulin (IVIG) develop coronary artery lesions (CAL). Many studies tried to find the most effective treatment in the management of resistant KD and to select the risk factors for CAL. Our data are assessed on children from west Sicily, characterized by a genetic heterogeneity. METHODS:We studied the clinical data of 70 KD Sicilian children (36 males: 51 %; 34 females: 49 %), analysed retrospectively, including: demographic and laboratory parameters; echocardiographic findings at diagnosis, at 2, 6 and 8 weeks, and at 1 year after the onset of the illness. RESULTS:Forty-seven had Typical KD, three Atypical KD and twenty Incomplete KD. Age at the disease onset ranged from 0.1 to 8.9 years. IVIG were administered 5 ± 2 days after the fever started. Defervescence occurred 39 ± 26 hours after the first IVIG infusion. Fifty-six patients (80 %) received 1 dose of IVIG (responders); 14 patients (20 %) had a resistant KD, with persistent fever after the first IVIG dose (non responders). Ten (14 %) non responders responded to the second dose, 4 (5 %) responded to three doses; one needed treatment with high doses of steroids and Infliximab. Cardiac involvement was documented in twenty-two cases (eighteen with transient dilatation/ectasia, fifteen with aneurysms). Pericardial effusion, documented in eleven, was associated with coronaritis and aneurysms, and was present earlier than coronary involvement in seven. Hypoalbuminemia, D-dimer pre-IVIG, gamma-GT pre-IVIG showed a statistically significant direct correlation with IVIG doses, highlighting the role of these parameters as predictor markers of refractory disease. The persistence of elevated CRP, AST, ALT levels, a persistent hyponatremia and hypoalbuminemia after IVIG therapy, also had a statistical significant correlation with IVIG doses. Non responders showed higher levels of D-dimer and gamma-GT pre-IVIG, persistent high levels of D-dimer, CRP, AST, ALT, hypoalbuminemia and hyponatremia after IVIG. CONCLUSIONS:This is the first study on KD in Sicily. We suggest some laboratory parameters as predictive criteria for resistant KD. Patients who show early pericarditis need careful surveillance for coronary lesions. 10.1186/s13052-016-0306-z
    Soy isoflavone intake is associated with risk of Kawasaki disease. Portman Michael A,Navarro Sandi L,Bruce Margaret E,Lampe Johanna W Nutrition research (New York, N.Y.) Kawasaki disease (KD) is an acute vasculitis affecting children. Incidence of KD varies according to ethnicity and is highest in Asian populations. Although genetic differences may explain this variation, dietary or environmental factors could also be responsible. The objectives of this study were to determine dietary soy and isoflavone consumption in a cohort of KD children just before disease onset and their mothers' intake during pregnancy and nursing. We tested the hypothesis that soy isoflavone consumption is associated with risk of KD in US children, potentially explaining some of the ethnic-cultural variation in incidence. We evaluated soy food intake and isoflavone consumption in nearly 200 US KD cases and 200 age-matched controls using a food frequency questionnaire for children and in their mothers. We used a logistic regression model to test the association of isoflavones and KD. Maternal surveys on soy intake during pregnancy and nursing showed no significant differences in isoflavone consumption between groups. However, we identified significantly increased KD risk in children for total isoflavone (odds ratio [OR], 2.33; 95% confidence interval [CI], 1.37-3.96) and genistein (OR, 2.46; 95% CI, 1.46-4.16) intakes, when comparing high soy consumers vs nonconsumers. In addition, significantly increased KD risk occurred in Asian-American children with the highest consumption (total isoflavones: OR, 7.29; 95% CI, 1.73-30.75; genistein: OR, 8.33; 95% CI, 1.92-36.24) compared to whites. These findings indicate that childhood dietary isoflavone consumption, but not maternal isoflavone intake during pregnancy and nursing, relates to KD risk in an ethnically diverse US population. 10.1016/j.nutres.2016.04.002
    Kawasaki disease and immunisation: A systematic review. Phuong Linny Kimly,Bonetto Caterina,Buttery Jim,Pernus Yolanda Brauchli,Chandler Rebecca,Felicetti Patrizia,Goldenthal Karen L,Kucuku Merita,Monaco Giuseppe,Pahud Barbara,Shulman Stanford T,Top Karina A,Trotta Francesco,Ulloa-Gutierrez Rolando,Varricchio Frederick,de Ferranti Sarah,Newburger Jane W,Dahdah Nagib,Singh Surjit,Bonhoeffer Jan,Burgner David, Vaccine BACKGROUND:Kawasaki disease is a complex and potentially serious condition. It has been observed in temporal relation to immunisation. METHODS:We conducted a systematic literature review using various reference sources to review the available evidence published in the literature. RESULTS:We identified twenty seven publications reporting a temporal association between immunisation and Kawasaki disease. We present a systematic review of data drawn from randomised controlled trials, observational studies, case series and reports, and reviews. Overall there was a lack of standardised case definitions, making data interpretation and comparability challenging. CONCLUSIONS:Although a temporal relationship between immunisation and Kawasaki disease is suggested, evidence for an increased risk or a causal association is lacking. Implementation of a standardised Kawasaki disease case definition would increase confidence in the findings and add value to future studies of pre- or post-licensure vaccine safety studies. 10.1016/j.vaccine.2016.09.033
    Pathogenetic determinants in Kawasaki disease: the haematological point of view. Del Principe Domenico,Pietraforte Donatella,Gambardella Lucrezia,Marchesi Alessandra,Tarissi de Jacobis Isabella,Villani Alberto,Malorni Walter,Straface Elisabetta Journal of cellular and molecular medicine Kawasaki disease is a multisystemic vasculitis that can result in coronary artery lesions. It predominantly affects young children and is characterized by prolonged fever, diffuse mucosal inflammation, indurative oedema of the hands and feet, a polymorphous skin rash and non-suppurative lymphadenopathy. Coronary artery involvement is the most important complication of Kawasaki disease and may cause significant coronary stenosis resulting in ischemic heart disease. The introduction of intravenous immunoglobulin decreases the incidence of coronary artery lesions to less than 5%. The etiopathogenesis of this disease remains unclear. Several lines of evidence suggest that an interplay between a microbial infection and a genetic predisposition could take place in the development of the disease. In this review, we summarize the state of the art of pathogenetic mechanisms of Kawasaki disease underscoring the relevance of haematological features as a novel field of investigation. 10.1111/jcmm.12992
    Clarithromycin Plus Intravenous Immunoglobulin Therapy Can Reduce the Relapse Rate of Kawasaki Disease: A Phase 2, Open-Label, Randomized Control Study. Nanishi Etsuro,Nishio Hisanori,Takada Hidetoshi,Yamamura Kenichiro,Fukazawa Mitsuharu,Furuno Kenji,Mizuno Yumi,Saigo Kenjiro,Kadoya Ryo,Ohbuchi Noriko,Onoe Yasuhiro,Yamashita Hironori,Nakayama Hideki,Hara Takuya,Ohno Takuro,Takahashi Yasuhiko,Hatae Ken,Harada Tatsuo,Shimose Takayuki,Kishimoto Junji,Ohga Shouichi,Hara Toshiro Journal of the American Heart Association BACKGROUND:We previously reported that biofilms and innate immunity contribute to the pathogenesis of Kawasaki disease. Therefore, we aimed to assess the efficacy of clarithromycin, an antibiofilm agent, in patients with Kawasaki disease. METHODS AND RESULTS:We conducted an open-label, multicenter, randomized, phase 2 trial at 8 hospitals in Japan. Eligible patients included children aged between 4 months and 5 years who were enrolled between days 4 and 8 of illness. Participants were randomly allocated to receive either intravenous immunoglobulin (IVIG) or IVIG plus clarithromycin. The primary end point was the duration of fever after the initiation of IVIG treatment. Eighty-one eligible patients were randomized. The duration of the fever did not differ between the 2 groups (mean±SD, 34.3±32.4 and 31.1±31.1 hours in the IVIG plus clarithromycin group and the IVIG group, respectively [=0.66]). The relapse rate of patients in the IVIG plus clarithromycin group was significantly lower than that in the IVIG group (12.5% versus 30.8%, =0.046). No serious adverse events occurred during the study period. In a post hoc analysis, the patients in the IVIG plus clarithromycin group required significantly shorter mean lengths of hospital stays than those in the IVIG group (8.9 days versus 10.3 days, =0.049). CONCLUSIONS:Although IVIG plus clarithromycin therapy failed to shorten the duration of fever, it reduced the relapse rate and shortened the duration of hospitalization in patients with Kawasaki disease. CLINICAL TRIAL REGISTRATION:URL: http://www.umin.ac.jp/ctr/index.htm. Unique identifier: UMIN000015437. 10.1161/JAHA.116.005370
    Discrimination between incomplete and atypical Kawasaki syndrome versus other febrile diseases in childhood: results from an international registry-based study. Falcini Fernanda,Ozen Seza,Magni-Manzoni Silvia,Candelli Marco,Ricci Laura,Martini Giorgia,Cuttica Ruben J,Oliveira Sheila,Calabri Giovanni Battista,Zulian Francesco,Pistorio Angela,La Torre Francesco,Rigante Donato Clinical and experimental rheumatology OBJECTIVES:Kawasaki syndrome (KS) is an acute systemic vasculitis of unknown origin predominantly affecting young children. Early diagnosis is crucial to prevent cardiac complications. However, the differential diagnosis of patients with the incomplete or atypical form of the disease poses a heavy challenge for the paediatrician. Our aim was to evaluate the prevalence of incomplete and atypical cases among children with KS and to identify clinical and laboratory variables that may help differentiate incomplete and atypical KS from other febrile diseases at this age. METHODS:We established an international registry to recruit patients with KS, including those with incomplete and atypical forms. The control group included age-matched febrile children admitted to the hospital with a variety of diseases mimicking KS. The aim was to define clinical or laboratory clues to help in the discrimination of incomplete and atypical KS patients from others. RESULTS:Two hundred and twenty-eight patients with incomplete KS (78%) and atypical KS (22%) were compared to 71 children with other febrile diseases. Patients with incomplete and atypical KS presented a statistically significant higher frequency of mucosal changes, conjunctivitis, extremity abnormalities and perineal desquamation compared to the group of other febrile diseases. In addition, C-reactive protein and platelet counts were significantly higher in incomplete and atypical KS compared to the other group. CONCLUSIONS:This is the largest series of incomplete and atypical KS patients of non East-Asian ancestry: we suggest that in patients with the aforementioned clinical features and laboratory evidence of systemic inflammation in terms of increased C-reactive protein and platelet counts an echocardiogram should be performed and diagnosis of KS considered.
    Dissecting Kawasaki disease: a state-of-the-art review. Dietz S M,van Stijn D,Burgner D,Levin M,Kuipers I M,Hutten B A,Kuijpers T W European journal of pediatrics Kawasaki disease (KD) is a pediatric vasculitis with coronary artery aneurysms (CAA) as its main complication. The diagnosis is based on the presence of persistent fever and clinical features including exanthema, lymphadenopathy, conjunctival injection, and changes to the mucosae and extremities. Although the etiology remains unknown, the current consensus is that it is likely caused by an (infectious) trigger initiating an abnormal immune response in genetically predisposed children. Treatment consists of high dose intravenous immunoglobulin (IVIG) and is directed at preventing the development of CAA. Unfortunately, 10-20% of all patients fail to respond to IVIG and these children need additional anti-inflammatory treatment. Coronary artery lesions are diagnosed by echocardiography in the acute and subacute phases. Both absolute arterial diameters and z-scores, adjusted for height and weight, are used as criteria for CAA. Close monitoring of CAA is important as ischemic symptoms or myocardial infarction due to thrombosis or stenosis can occur. These complications are most likely to arise in the largest, so-called giant CAA. Apart from the presence of CAA, it is unclear whether KD causes an increased cardiovascular risk due to the vasculitis itself. CONCLUSION:Many aspects of KD remain unknown, although there is growing knowledge on the etiology, treatment, and development and classification of CAA. Since children with previous KD are entering adulthood, long-term follow-up is increasingly important. What is known: • Kawasaki disease (KD) is a pediatric vasculitis with coronary artery damage as its main complication. • Although KD approaches its 50th birthday since its first description, many aspects of the disease remain poorly understood. What is new: • In recent years, multiple genetic candidate pathways involved in KD have been identified, with recently promising information about the ITPKC pathway. • As increasing numbers of KD patients are reaching adulthood, increasing information is available about the long-term consequences of coronary artery damage and broader cardiovascular risk. 10.1007/s00431-017-2937-5
    Complete Kawasaki disease (KD) with peculiar skin manifestations. Poddighe Dimitri BMJ case reports 10.1136/bcr-2017-222724
    Arterial immune protein expression demonstrates the complexity of immune responses in Kawasaki disease arteritis. Cameron S A,White S M,Arrollo D,Shulman S T,Rowley A H Clinical and experimental immunology A more complete understanding of immune-mediated damage to the coronary arteries in children with Kawasaki disease (KD) is required for improvements in patient treatment and outcomes. We recently reported the transcriptional profile of KD coronary arteritis, and in this study sought to determine protein expression of transcriptionally up-regulated immune genes in KD coronary arteries from the first 2 months after disease onset. We examined the coronary arteries of 12 fatal KD cases and 13 childhood controls for expression of a set of proteins whose genes were highly up-regulated in the KD coronary artery transcriptome: allograft inflammatory factor 1 (AIF1), interleukin 18 (IL-18), CD74, CD1c, CD20 (MS4A1), Toll-like receptor 7 (TLR-7) and Z-DNA binding protein 1 (ZBP1). Immunohistochemistry and immunofluorescence studies were performed to evaluate protein expression and co-localization, respectively. AIF1 was expressed transmurally in KD arteritis and localized to macrophages and myeloid dendritic cells. CD74, which interacts with major histocompatibility complex (MHC) class II on antigen-presenting cells, localized to the intima-media. CD1c, a marker of myeloid dendritic cells, was expressed in a transmural pattern, as were IL-18 and CD20. ZBP1 and TLR-7 were up-regulated compared to controls, but less highly compared to the other proteins. These findings provide evidence of antigen presentation and interferon response in KD arteritis. In combination with prior studies demonstrating T lymphocyte activation, these results demonstrate the complexity of the KD arterial immune response. 10.1111/cei.13010
    Safety netting versus overtreatment in paediatrics: viral infection or incomplete Kawasaki disease? Charlesworth Jennifer Michelle,Power Bernadette,Moylett Edina BMJ case reports Kawasaki disease (KD) is the most common systemic vasculitis of childhood. The following presentation of a 4-year-old Irish boy referred to a secondary care paediatric service from the community with prolonged fever, oral mucous membrane changes and painless blistering lesions of the hands and feet in the presence of elevated inflammatory markers serves as an opportunity to discuss the diagnostic criteria and treatment for KD and incomplete KD, an often missed diagnosis with significant paediatric morbidity outside an academic paediatric centre. 10.1136/bcr-2017-222323
    Rare case of pulmonary involvement in an adult with Kawasaki disease. Escalon Joanna G,Wu Xiaoping,Drexler Ian R,Lief Lindsay,Plataki Maria,Bender Michael,Gruden James F Clinical imaging Kawasaki disease is an acute, self-limited, febrile vasculitis typically seen in early childhood. Pulmonary involvement is uncommon and is not part of the conventional diagnostic criteria. We add to the literature a unique case of a 22year-old male with Kawasaki disease and pulmonary involvement. It illustrates the importance of recognizing unusual presentations of Kawasaki disease and highlights the possibility of pulmonary abnormalities on physical and imaging examination. Awareness of such presentations can help avoid delayed diagnosis, prevent the development of coronary aneurysms, and allow careful observation for imaging resolution. 10.1016/j.clinimag.2017.08.001
    Is Kawasaki disease an infectious disorder? Rowley Anne H International journal of rheumatic diseases Although the etiology of Kawasaki disease (KD) is largely unknown, a large body of clinical, epidemiologic, immunologic, pathologic and ultrastructural evidence suggests that an infectious agent triggers a cascade that causes the illness. However, this elusive infectious agent remains unidentified at present. Increasingly sensitive molecular methods for identifying microbial nucleic acids and proteins in tissue samples continue to rapidly emerge, and these methods should be utilized in studies on KD etiology as they become available. Identifying the etiology of this enigmatic disease remains the single most important research goal in the field, and accomplishing this goal is the best means to improve diagnosis, treatment and prevention of this potentially fatal childhood disease. 10.1111/1756-185X.13213
    Diagnosis of Kawasaki disease. Singh Surjit,Jindal Ankur Kumar,Pilania Rakesh Kumar International journal of rheumatic diseases Kawasaki disease (KD) is a medium vessel vasculitis with predilection for coronary arteries. Due to lack of a reliable confirmatory laboratory test, the diagnosis of KD is based on a constellation of clinical findings that appear in a typical temporal sequence. These diagnostic criteria have been modified from time to time and the most recent guidelines have been proposed by the American Heart Association (AHA) in 2017. However, several children may have incomplete or atypical forms of KD and the diagnosis can often be difficult, especially in infants and young children. In this review, we have detailed the steps involved in arriving at a diagnosis of KD and also highlight the important role of echocardiography in diagnosis and management of children with KD. 10.1111/1756-185X.13224
    Anemia in Kawasaki Disease: Hepcidin as a Potential Biomarker. Huang Ying-Hsien,Kuo Ho-Chang International journal of molecular sciences Kawasaki disease (KD) is an autoimmune-like disease and acute childhood vasculitis syndrome that affects various systems but has unknown etiology. In addition to the standard diagnostic criteria, anemia is among the most common clinical features of KD patients and is thought to have a more prolonged duration of active inflammation. In 2001, the discovery of a liver-derived peptide hormone known as hepcidin began revolutionizing our understanding of anemia's relation to a number of inflammatory diseases, including KD. This review focuses on hepcidin-induced iron deficiency's relation to transient hyposideremia, anemia, and disease outcomes in KD patients, and goes on to suggest possible routes of further study. 10.3390/ijms18040820
    Critical Overview of the Risk Scoring Systems to Predict Non-Responsiveness to Intravenous Immunoglobulin in Kawasaki Syndrome. Rigante Donato,Andreozzi Laura,Fastiggi Michele,Bracci Benedetta,Natale Marco Francesco,Esposito Susanna International journal of molecular sciences Kawasaki syndrome (KS) is the most relevant cause of heart disease in children living in developed countries. Intravenous immunoglobulin (IVIG) has a preventive function in the formation of coronary artery abnormalities and a poor strictly-curative action in established coronary damage. More than two decades ago, the Harada score was set to assess which children with KS should be subject to administration of IVIG, evaluating retrospectively a large cohort of patients with regard to age, sex and laboratory data. Nowadays, high dose IVIG is administered to all children with a confirmed diagnosis of KS, but a tool for predicting non-responsiveness to the initial infusion of IVIG has not been found. The prediction of IVIG resistance is a crucial issue, as recognising these high-risk patients should consent the administration of an intensified initial treatment in combination with IVIG in order to prevent coronary injuries. Few reports have focused on factors, referring to both clinical parameters and laboratory data at the onset of KS, in order to predict which patients might be IVIG non-responsive. We have analysed three different risk scores which were formulated to predict IVIG resistance in Japanese children with typical KS, but their application in non-Japanese patients or in those with incomplete and atypical patterns of the disease has been studied in a fragmentary way. Overall, our analysis showed that early and definite ascertainment of likely IVIG non-responders who require additional therapies reducing the development of coronary artery involvement in children with KS is still a challenge. 10.3390/ijms17030278
    Epidemiologic features of Kawasaki disease: Winter versus summer. Ozeki Yukie,Yamada Fumiya,Kishimoto Tsuyoshi,Yashiro Mayumi,Nakamura Yosikazu Pediatrics international : official journal of the Japan Pediatric Society BACKGROUND:The epidemiology of Kawasaki disease (KD) shows seasonal variations, although the etiology of KD is unknown. In this study, we compared the clinical epidemiology of KD onset in winter versus that in summer to identify its etiology, that is, infectious agents. METHODS:Epidemiologic features of KD were compared between two seasons with high incidence (January [winter] and July [summer]) using a dataset of the 22nd nationwide survey in Japan. Data on patients who visited hospital during 2011-2012 in Japan were analyzed after adjusting for age differences. Subgroup analysis was carried out for day of illness at the day of first hospital visit. RESULTS:The total number of KD patients reported in the survey was 26 691. The number of patients who visited hospital with KD for the first time in January and July was 2,812 and 2,302, respectively. The proportion of patients in the age group 15 months-3 years was 38.8% in January and 33.5% in July. Mean serum albumin was significantly lower in January than in July (at days 2-5 of illness, P < 0.05). There were no between-group differences with respect to treatment, incidence of cardiac lesions, recurrence, or history of KD among the patients' siblings and parents. CONCLUSION:No significant differences were observed between KD with onset in January and July, although minor differences with respect to age distribution and serum albumin were observed. 10.1111/ped.13293
    A master role for neutrophils in Kawasaki syndrome. Andreozzi Laura,Bracci Benedetta,D'Errico Francesca,Rigante Donato Immunology letters 10.1016/j.imlet.2017.02.011
    Whole blood transcriptional profiles as a prognostic tool in complete and incomplete Kawasaki Disease. Jaggi Preeti,Mejias Asuncion,Xu Zhaohui,Yin Han,Moore-Clingenpeel Melissa,Smith Bennett,Burns Jane C,Tremoulet Adriana H,Jordan-Villegas Alejandro,Chaussabel Damien,Texter Karen,Pascual Virginia,Ramilo Octavio PloS one BACKGROUND:Early identification of children with Kawasaki Disease (KD) is key for timely initiation of intravenous immunoglobulin (IVIG) therapy. However, the diagnosis of the disease remains challenging, especially in children with an incomplete presentation (inKD). Moreover, we currently lack objective tools for identification of non-response (NR) to IVIG. METHODS:Children with KD were enrolled and samples obtained before IVIG treatment and sequentially at 24 h and 4-6 weeks post-IVIG in a subset of patients. We also enrolled children with other febrile illnesses [adenovirus (AdV); group A streptococcus (GAS)] and healthy controls (HC) for comparative analyses. Blood transcriptional profiles were analyzed to define: a) the cKD and inKD biosignature, b) compare the KD signature with other febrile illnesses and, c) identify biomarkers predictive of clinical outcomes. RESULTS:We identified a cKD biosignature (n = 39; HC, n = 16) that was validated in two additional cohorts of children with cKD (n = 37; HC, n = 20) and inKD (n = 13; HC, n = 8) and was characterized by overexpression of inflammation, platelets, apoptosis and neutrophil genes, and underexpression of T and NK cell genes. Classifier genes discriminated KD from adenovirus with higher sensitivity and specificity (92% and 100%, respectively) than for GAS (75% and 87%, respectively). We identified a genomic score (MDTH) that was higher at baseline in IVIG-NR [median 12,290 vs. 5,572 in responders, p = 0.009] and independently predicted IVIG-NR. CONCLUSION:A reproducible biosignature from KD patients was identified, and was similar in children with cKD and inKD. A genomic score allowed early identification of children at higher risk for non-response to IVIG. 10.1371/journal.pone.0197858
    Kawasaki disease: a case report and overview of symptoms, signs, investigations and treatment. Almeida Beverley,Gleeson Pauline,Chawla Kavita,Brogan Paul British journal of hospital medicine (London, England : 2005) Kawasaki disease was initially described by a Japanese paediatrician, Dr Tomisaku Kawasaki, in 1967. He reported an acute mucocutaneous lymph node syndrome affecting the skin, mucosa and lymph nodes. This initial description has since been expanded and is now recognized as Kawasaki disease, an acute systemic selflimiting vasculitis complicated by coronary arterial aneurysms, and even myocardial infarction in some patients (Shulman et al, 1995; Kato et al, 1996; Brogan et al, 2002).
    [Research advances in the pathogenesis of familial Kawasaki disease]. Cai Ke,Wang Feng,Gui Yong-Hao Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics Kawasaki disease has become the leading cause of acquired heart disease in children in North America and Japan. The incidence rate of Kawasaki disease varies significantly across regions and races. The first-degree relatives of patients with Kawasaki disease have a significantly higher risk of this disease than the general population. This article reviews the onset of familial Kawasaki disease and possible pathogenesis.
    Transient subcortical high-signal lesions in Kawasaki syndrome. Okanishi Tohru,Enoki Hideo Pediatric neurology Kawasaki syndrome is an acute systemic vasculitis in children. The pathophysiology of Kawasaki syndrome presumably involves vascular inflammation, causing plasma leakage from systemic microvessels. From 1-30% of patients with Kawasaki syndrome exhibit central nervous system involvement, e.g., aseptic meningitis, epileptic seizures, transient hemiplegia, facial palsy, ataxia, chorea, ischemia, hearing loss, abnormal vision, disturbed consciousness, and behavioral changes. Neuroradiologically, Kawasaki syndrome demonstrates subdural effusion, infarction, atrophy, and reversible splenial lesions on magnetic resonance imaging. A 25-month-old boy developed transient hypertension with generalized seizure in the subacute phase of Kawasaki syndrome. Fluid-attenuated inversion recovery imaging, performed 5 hours and 2 days postseizure, indicated subtle, subcortical, high-signal-intensity lesions. Acute transient hypertension in this patient may have triggered the onset of lesions because of the increased permeability of brain microvessels, attributable to systemic vasculitis in Kawasaki syndrome. To our knowledge, subcortical lesions in Kawasaki syndrome were not previously reported. 10.1016/j.pediatrneurol.2012.05.022
    Kawasaki Disease: A Condition of Many Guises. Yeo Wee Song Annals of the Academy of Medicine, Singapore
    Intrauterine and Early Postnatal Exposure to Particulate Air Pollution and Kawasaki Disease: A Nationwide Longitudinal Survey in Japan. Yorifuji Takashi,Tsukahara Hirokazu,Kashima Saori,Doi Hiroyuki The Journal of pediatrics OBJECTIVES:To examine the effects of prenatal and postnatal exposure to particulate matter on Kawasaki disease (KD) occurrence, using data from a nationwide population-based longitudinal survey in Japan that began in 2010. STUDY DESIGN:Prenatal and postnatal suspended particulate matter concentrations were obtained at municipality level and assigned to participants based on their municipality of birth. We analyzed data from 30 367 participants with data on either exposure period. We used hospital admission for KD from 6 to 30 months of age as the main outcome of interest. We conducted a multilevel logistic regression analysis, adjusting for individual and municipality-level variables. RESULTS:Children who were exposed to higher levels of suspended particulate matter, in particular during pregnancy, were more likely to be hospitalized for KD. The ORs for ≥25 µg/m exposure compared with <20 µg/m exposure were 1.59 (95% CI 1.06, 2.38) for prenatal exposure and 1.41 (0.82, 2.41) for postnatal exposure. Prenatal exposure during mid-to-late gestation seemed to be more relevant for the increased risk. CONCLUSIONS:Early life exposure to particulate air pollution, in particular during pregnancy, is associated with an increased risk of KD hospital admission in early childhood in a nationally representative sample in Japan. 10.1016/j.jpeds.2017.10.012
    Kawasaki disease shock syndrome: a rare and severe complication of Kawasaki disease. Çakan Mustafa,Gemici Hakan,Aktay-Ayaz Nuray,Keskindemirci Gonca,Bornaun Helen,İkizoğlu Tarkan,Çeliker Alpay The Turkish journal of pediatrics Kawasaki disease is an acute systemic vasculitis that occurs most commonly in young children. It affects medium-sized muscular arteries and the coronary arteries are the predominant site of involvement. Morbidity and mortality is generally due to coronary artery aneurysms that develop during the chronic phase. Although it is well known that Kawasaki disease can cause myocarditis, tachycardia and heart failure during acute stage, Kawasaki disease shock syndrome has been recently described. It is characterized by hypotension, signs and symptoms of poor perfusion and a shock-like state. Herein we describe two cases of Kawasaki disease shock syndrome that were treated in the pediatric intensive care unit and followed a course without morbidity or mortality. 10.24953/turkjped.2016.04.012
    Dengue-Triggered Kawasaki Disease: A Report of 2 Cases. Guleria Sandesh,Jindal Ankur Kumar,Pandiarajan Vignesh,Singh Mini P,Singh Surjit Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases 10.1097/RHU.0000000000000704
    Profile of resistance to IVIG treatment in patients with Kawasaki disease and concomitant infection. Dionne Audrey,Le Cathie-Kim,Poupart Steffany,Autmizguine Julie,Meloche-Dumas Léamarie,Turgeon Jean,Fournier Anne,Dahdah Nagib PloS one INTRODUCTION:Kawasaki disease (KD) can be associated with concomitant viral or bacterial infections. Children with persistent or recurrent fever 36 hours after the end of intravenous immunoglobulin (IVIG) are considered to be resistant to treatment and are at increased risk for coronary complications. Although concomitant infection does not affect coronary outcome, it is unknown how it influences the response to IVIG treatment. METHODOLOGY:Retrospective cohort study between 2008 and 2016 in a tertiary pediatric university hospital, including 154 children, of which 59 (38%) had concomitant infection. RESULTS:Children with concomitant infection were more likely to have fever 48 hours after initial IVIG treatment (36% vs 20%, p = 0.05) and to be treated with a second dose (33% vs 18%, p = 0.04). Children with infection had higher C-reactive protein at the time of diagnosis (148 vs 112 mg/L, p = 0.04), and 48 hours after IVIG administration (111 vs 59 mg/L, p = 0.003). Nevertheless, there was no statistically significant difference in the prevalence of coronary complications (Z-score > 2.5) between children with and without concomitant infection (36% vs 39%, p = 0.68). CONCLUSION:Children with KD and concomitant infection are more likely to have persistent fever and elevated inflammatory markers after treatment. This association increases the likelihood of receiving a second dose of IVIG but not the risk of coronary complication. Accordingly, prospective studies to distinguish true IVIG resistance from infection induced persistent fever is warranted. 10.1371/journal.pone.0206001
    Clinical characteristics of Kawasaki syndrome and the risk factors for coronary artery lesions in China. Ruan Yu,Ye Bei,Zhao Xiaodong The Pediatric infectious disease journal BACKGROUND:Kawasaki syndrome (KS) is the leading cause of acquired heart disease in childhood in developed countries. This study was designed to identify the clinical characteristics of a large cohort of KS in China and explore the risk factors for coronary artery lesions. METHODS:Clinical records of 1370 patients with acute KS were retrospectively reviewed. The clinical features of different age groups were analyzed, and a multivariate logistic regression analysis was performed to identify the risk factors for coronary artery lesions caused by KS. RESULTS:The prevalence of redness at a Bacille Calmette-Guèrin inoculation site was greatest in infants younger than 6 months (18.4%), whereas cervical lymphadenopathy was more frequent in patients older than 60 months (61.5%). Age, sex, therapeutic time, intravenous immunoglobulin dose, platelet count and erythrocyte sedimentation rate were risk factors for coronary artery lesions (P < 0.05). A total fever duration >10 days was a risk factor for coronary artery aneurysms in patients with coronary artery lesions (P < 0.05). CONCLUSIONS:KS occurs more frequently in children younger than 5 years, in boys and during the summer months. Redness at a Bacille Calmette-Guèrin inoculation site signals the diagnosis of incomplete KS in infants and young children. Male gender, younger age, intravenous immunoglobulin dose, delayed administration (>10 days), high platelet level and elevated erythrocyte sedimentation rate are predictive for coronary artery lesions, and total fever duration (>10 days) is predictive for coronary artery aneurysms in patients with coronary artery lesions. 10.1097/INF.0b013e31829dd45e
    Diagnosis and management of kawasaki disease. Saguil Aaron,Fargo Matthew,Grogan Scott American family physician Kawasaki disease is an acute, systemic vasculitis that predominantly affects patients younger than five years. It represents the most prominent cause of acquired coronary artery disease in childhood. In the United States, 19 per 100,000 children younger than five years are hospitalized with Kawasaki disease annually. According to U.S. and Japanese guidelines, Kawasaki disease is a clinical diagnosis. Classic (typical) Kawasaki disease is diagnosed based on the presence of a fever lasting five or more days, accompanied by four out of five findings: bilateral conjunctival injection, oral changes such as cracked and erythematous lips and strawberry tongue, cervical lymphadenopathy, extremity changes such as erythema or palm and sole desquamation, and polymorphous rash. Incomplete (atypical) Kawasaki disease occurs in persons with fever lasting five or more days and with two or three of these findings. Transthoracic echocardiography is the diagnostic imaging modality of choice to screen for coronary aneurysms, although other techniques are being evaluated for diagnosis and management. Treatment for acute disease is intravenous immunoglobulin and aspirin. If there is no response to treatment, patients are given a second dose of intravenous immunoglobulin with or without corticosteroids or other adjunctive treatments. The presence and severity of coronary aneurysms and obstruction at diagnosis determine treatment options and the need, periodicity, and intensity of long-term cardiovascular monitoring for potential atherosclerosis.
    B Cells and Antibodies in Kawasaki Disease. Lindquist Michael E,Hicar Mark D International journal of molecular sciences The etiology of Kawasaki disease (KD), the leading cause of acquired heart disease in children, is currently unknown. Epidemiology supports a relationship of KD to an infectious disease. Several pathological mechanisms are being considered, including a superantigen response, direct invasion by an infectious etiology or an autoimmune phenomenon. Treating affected patients with intravenous immunoglobulin is effective at reducing the rates of coronary aneurysms. However, the role of B cells and antibodies in KD pathogenesis remains unclear. Murine models are not clear on the role for B cells and antibodies in pathogenesis. Studies on rare aneurysm specimens reveal plasma cell infiltrates. Antibodies generated from these aneurysmal plasma cell infiltrates showed cross-reaction to intracellular inclusions in the bronchial epithelium of a number of pathologic specimens from children with KD. These antibodies have not defined an etiology. Notably, a number of autoantibody responses have been reported in children with KD. Recent studies show acute B cell responses are similar in children with KD compared to children with infections, lending further support of an infectious disease cause of KD. Here, we will review and discuss the inconsistencies in the literature in relation to B cell responses, specific antibodies, and a potential role for humoral immunity in KD pathogenesis or diagnosis. 10.3390/ijms20081834
    Interleukin-6 is prone to be a candidate biomarker for predicting incomplete and IVIG nonresponsive Kawasaki disease rather than coronary artery aneurysm. Wu Yue,Liu Fei Fei,Xu Yao,Wang Jing Jing,Samadli Sama,Wu Yang Fang,Liu Hui Hui,Chen Wei Xia,Luo Huang Huang,Zhang Dong Dong,Wei Wei,Hu Peng Clinical and experimental medicine Kawasaki disease (KD) is an acute, systemic vasculitis and occurs mainly in childhood. Interleukin-6 (IL-6) is a pleiotropic cytokine synthesized predominantly by neutrophils and monocytes/macrophages and plays an important role in systemic inflammatory disease. However, a little information is currently available on the relationship of serum IL-6 with conventional inflammatory mediators, clinical classification, IVIG response and coronary artery aneurysm (CAA). 165 Chinese children with KD were enrolled and divided into six subgroups, including complete KD, incomplete KD, IVIG-responsive KD, IVIG-nonresponsive KD, coronary artery noninvolvement KD and coronary artery involvement KD. Blood samples were collected from all subjects within 24-h pre- and 48-h post-IVIG therapy, respectively. Serum IL-6 and conventional inflammatory mediators were detected. (1) Serum IL-6 markedly increased in the acute phase of KD, whereas declined to normal after IVIG therapy; it was positively correlated with C-reactive protein and erythrocyte sedimentation rate. (2) Serum IL-6 was significantly elevated in patients with incomplete KD when compared with their complete counterparts. The area under receiver operating characteristic curve (AUC) value for serum IL-6 in prediction of incomplete KD was 0.596, and the estimated sensitivity and specificity were 77.80% and 54.40% with a cutoff of IL-6 > 13.25 pg/ml, respectively. (3) Serum IL-6 was significantly elevated in patients with IVIG-nonresponsive KD when compared with their IVIG-responsive counterparts; the AUC value for serum IL-6 in prediction of IVIG-nonresponsive KD was 0.580, and the estimated sensitivity and specificity were 60.00% and 66.30% with a cutoff of IL-6 > 26.40 pg/ml, respectively. (4) No significant differences in IL-6 were found between KD patients with and without CAA. IL-6 is prone to be a candidate biomarker for predicting incomplete and IVIG nonresponsive KD rather than CAA. 10.1007/s10238-018-00544-5
    Autoimmune Aspects of Kawasaki Disease. Sakurai Y Journal of investigational allergology & clinical immunology Kawasaki disease (KD) is a vasculitis that is part of systemic vasculitis syndrome. It affects medium-sized vessels and is characterized by hypercytokinemia. Although the etiology of KD remains unidentified, epidemiological features point to the role of infection and genetic predisposition. Recent studies on KD revealed endothelial damage and resultant thrombin generation, as well as B-cell activation during the acute phase. Several antiendothelial cell autoantibodies (AECAs) have been identified in KD patients. Analysis of this phenomenon together with the recently developed concept of immunothrombosis reveals a potential pathogenic mechanism for KD. First, polyclonal antibodies generated against invading microorganisms would exhibit cross-reactivity toward endothelial cell components and become dominant during affinity maturation. Binding of AECAs to endothelial cells would cause endothelial activation or damage, with proinflammatory cytokine release, thus fostering a hypercoagulable state resulting from leukocyte activation by proinflammatory cytokines. This, in turn, would lead to coronary artery lesions. KD vasculitis might be initiated upon binding of AECAs to the vasa vasorum and progress to panvasculitis and a vulnerable vessel wall, resulting in an aneurysm. The aneurysm would cause flow recirculation and alteration of wall shear stress. Consequently, platelets activated by shear stress, along with ultralarge von Willebrand factor (VWF) released by endothelial cells, would cause platelet-driven arterial thrombosis. Autoimmunity-associated thrombosis initiated by binding of AECAs to endothelial cells might play a major role in the pathogenesis of certain subtypes of KD. The notion of KD consisting of subtypes, the major one of which is AECA-associated vasculitis, will help improve our understanding of KD and further promote early and accurate diagnosis, which remains challenging. 10.18176/jiaci.0300
    Kawasaki Disease. Newburger Jane W,Takahashi Masato,Burns Jane C Journal of the American College of Cardiology Kawasaki disease is an acute, self-limited vasculitis of unknown etiology that occurs predominantly in infants and children. If not treated early with high-dose intravenous immunoglobulin, 1 in 5 children develop coronary artery aneurysms; this risk is reduced 5-fold if intravenous immunoglobulin is administered within 10 days of fever onset. Coronary artery aneurysms evolve dynamically over time, usually reaching a peak dimension by 6 weeks after illness onset. Almost all the morbidity and mortality occur in patients with giant aneurysms. Risk of myocardial infarction from coronary artery thrombosis is greatest in the first 2 years after illness onset. However, stenosis and occlusion progress over years. Indeed, Kawasaki disease is no longer a rare cause of acute coronary syndrome presenting in young adults. Both coronary artery bypass surgery and percutaneous intervention have been used to treat Kawasaki disease patients who develop myocardial ischemia as a consequence of coronary artery aneurysms and stenosis. 10.1016/j.jacc.2015.12.073
    Kawasaki disease: part II. Complications and treatment. Bayers Stephanie,Shulman Stanford T,Paller Amy S Journal of the American Academy of Dermatology Kawasaki disease, or mucocutaneous lymph node syndrome, is the leading cause of acquired heart disease in children in the United States and other developed countries. Coronary artery lesions are the most significant cause of morbidity and mortality. Treatment should ideally be provided within 10 days of symptom onset to reduce the risk of coronary artery complications. The standard of care for treatment is intravenous immunoglobulin plus aspirin, but adding corticosteroids may provide additional benefit for high-risk patients. Some patients do not respond to intravenous immunoglobulin and require additional therapy. Part II of this continuing medical education article will focus on the complications of Kawasaki disease and potential treatment options. 10.1016/j.jaad.2013.06.040
    Diagnosis and classification of Kawasaki disease. Sánchez-Manubens Judith,Bou Rosa,Anton Jordi Journal of autoimmunity Kawasaki disease is an acute systemic vasculitis of unknown etiology. Diagnosis is based on clinical criteria that include fever, exanthema, conjunctivitis, changes in the extremities, erythema of oral mucosa and lips and cervical lymphadenopathy. However, these criteria have low sensitivity and specificity and therefore, other clinical and laboratory features may be helpful in establishing the diagnosis, especially for cases of atypical or incomplete Kawasaki disease. Prognosis depends on the extent of cardiac involvement; coronary aneurysms develop in 20-25% of untreated patients and these may lead to myocardial infarction and sudden death. Treatment with high-dose intravenous immunoglobulin is effective in reducing the risk of coronary aneurysms in most cases and is the treatment of choice for initial Kawasaki disease. 10.1016/j.jaut.2014.01.010
    Kawasaki disease: epidemiology and the lessons from it. Nakamura Yosikazu International journal of rheumatic diseases A half of century has passed since Dr. Tomisaku Kawasaki reported his 50 cases with Kawasaki disease (KD) in 1967. Since then, more than 300 000 cases have been reported to the nationwide epidemiologic surveys in Japan. However, the etiology and risk factors of the disease are still unknown. In this paper, the author emphasizes that the epidemiology of KD may indicate an infectious agent to be a potential trigger of disease in susceptible children. 10.1111/1756-185X.13211
    [National consensus on the cardiological treatment and follow-up of Kawasaki disease]. Barrios Tascón Ana,Centeno Malfaz Fernando,Rojo Sombrero Henar,Fernández-Cooke Elisa,Sánchez-Manubens Judith,Pérez-Lescure Picarzo Javier, Anales de pediatria (Barcelona, Spain : 2003) Kawasaki disease is a self-limiting acute vasculitis that affects small and medium-sized vessels, and is the most common cause of acquired heart disease in children in our environment. Up to 25% of untreated patients develop coronary aneurysms. It is suspected that an infectious agent may be the trigger of the disease, but the causative agent is still unknown. Based on the previous evidence, recommendations are proposed for the diagnosis, treatment of acute disease, and the long-term management of these patients, in order to unify criteria. The diagnosis must be quick, based on easy-to-use algorithms and with the support of complementary tests. This document includes the indication of available imaging techniques, as well as the planning of cardiological examinations based on the initial involvement. Intravenous immunoglobulin is the basis of the initial treatment. The role of corticosteroids is still controversial, but there are studies that support its use as adjuvant treatment. A multidisciplinary working group has developed a scheme with different treatment guidelines depending on the risk factors at diagnosis, the patient's clinical situation, and response to previous treatment, including indications for thromboprophylaxis in patients with coronary involvement. The stratification of risk for long-term treatment is essential, as well as the recommendations on the procedures based on the initial cardiological involvement and its progression. Patients with coronary aneurysms require continuous and uninterrupted cardiological monitoring for life. 10.1016/j.anpedi.2018.04.003
    The effects of early intravenous immunoglobulin therapy for Kawasaki disease: The 22nd nationwide survey in Japan. Kuwabara Masanari,Yashiro Mayumi,Ae Ryusuke,Yanagawa Hiroshi,Nakamura Yosikazu International journal of cardiology BACKGROUND:Although intravenous immunoglobulin (IVIG) therapy is the standard therapy for Kawasaki disease (KD) to prevent coronary aneurysms including dilatations, it is unclear whether early IVIG therapy is more efficient in the acute stage of KD. METHODS:We conducted a cohort study using data from the 22nd nationwide survey of KD in Japan from January 2011 to December 2012. We excluded patients with recurrent KD and whose first admission day was later than seven days from the onset of symptoms. Finally, 20,933 patients with echocardiography assessment and IVIG therapy were divided into three groups according to the start of the IVIG therapy: 1) early: ≤4 days, 2) conventional: 5-7 days, and 3) late: 8-10 days. Then we investigated whether the early IVIG therapy prevented coronary dilatation or aneurysm after multiple adjustments for age, sex, total amount of IVIG, use of steroids, infliximab, other immunosuppressive agents, and plasma exchange. RESULTS:After multiple adjustments, conventional therapy had similar risks for coronary dilatation or aneurysm compared with early therapy (odds ratio [OR]:0.95; 95% confidence interval [CI], 0.78-1.16), whereas late therapy had a higher risk (OR:1.66; 95% CI, 1.03-2.68). Other risk factors for coronary dilatation or aneurysm were young male, older age, use of steroids, infliximab, other immunosuppressive agents, and a larger amount of total IVIG. CONCLUSIONS:Early IVIG therapy for KD did not reduce the risk for coronary dilatation or aneurysm compared with conventional therapy. It is recommended to start IVIG therapy within 7 days from the onset of symptoms. 10.1016/j.ijcard.2018.07.092
    Nationwide epidemiologic survey of Kawasaki disease in Japan, 2015-2016. Makino Nobuko,Nakamura Yosikazu,Yashiro Mayumi,Kosami Koki,Matsubara Yuri,Ae Ryusuke,Aoyama Yasuko,Yanagawa Hiroshi Pediatrics international : official journal of the Japan Pediatric Society BACKGROUND:Approximately 50 years have passed since Kawasaki disease (KD) was first reported. The KD nationwide survey began in 1970. Although >360 000 cases have already been reported in Japan, the cause is still unknown. In Japan, the number of patients and incidence rate of KD has continued to increase. It is necessary to examine the trend of the occurrence in the surveillance of KD. METHODS:The nationwide survey of patient incidence in 2015 and 2016 was conducted in 2017, as the 24th nationwide survey of KD. A questionnaire was sent to pediatric departments in hospitals with >100 beds and specialized pediatric hospitals, and was responded to by the attending pediatricians. RESULTS:The total number of patients in 2 years was 31 595, and the sex ratio (male/female) was 1.34. The incidence rate (/100 000 children aged 0-4 years/year) was 330.2 (371.2 in boys, 287.3 in girls) in 2015, and 309.0 (343.2 in boys, 273.2 in girls) in 2016. The number of patients by month peaked in January. The age-specific incidence rate according to sex was highest in children between 9 and 11 months of age, after which the incidence rate gradually decreased with advancing age. CONCLUSIONS:We summarize the most recent nationwide survey of KD and consider the change in the epidemiologic picture. 10.1111/ped.13809
    Evidence-based management of Kawasaki disease in the emergency department. Seaton Kara K,Kharbanda Anupam Pediatric emergency medicine practice Kawasaki disease, also known as mucocutaneous lymph node syndrome, was first described in Japan in 1967. It is currently the leading cause of acquired heart disease in children in the United States. Untreated Kawasaki disease may lead to the formation of coronary artery aneurysms and sudden cardiac death in children. This vasculitis presents with fever for ≥ 5 days, plus a combination of key criteria. Because each of the symptoms commonly occurs in other childhood illnesses, the disease can be difficult to diagnose, especially in children who present with an incomplete form of the disease. At this time, the etiology of the disease remains unknown, and there is no single diagnostic test to confirm the diagnosis. This issue reviews the presentation, diagnostic criteria, and management of Kawasaki disease in the emergency department. Emergency clinicians should consider Kawasaki disease as a diagnosis in pediatric patients presenting with prolonged fever, as prompt evaluation and management can significantly decrease the risk of serious cardiac sequelae.