Sialylated Immunoglobulins for the Treatment of Immuno-Inflammatory Diseases. Markina Yuliya V,Gerasimova Elena V,Markin Alexander M,Glanz Victor Y,Wu Wei-Kai,Sobenin Igor A,Orekhov Alexander N International journal of molecular sciences Immunoglobulins are the potent effector proteins of the humoral immune response. In the course of evolution, immunoglobulins have formed extremely diverse types of molecular structures with antigen-recognizing, antigen-binding, and effector functions embedded in a single molecule. Polysaccharide moiety of immunoglobulins plays the essential role in immunoglobulin functioning. There is growing evidence that the carbohydrate composition of immunoglobulin-linked glycans, and especially their terminal sialic acid residues, provide a key effect on the effector functions of immunoglobulins. Possibly, sialylation of Fc glycan is a common mechanism of IgG anti-inflammatory action in vivo. Thus, the post-translational modification (glycosylation) of immunoglobulins opens up significant possibilities in the diagnosis of both immunological and inflammatory disorders and in their therapies. This review is focused on the analysis of glycosylation of immunoglobulins, which can be a promising addition to improve existing strategies for the diagnosis and treatment of various immuno-inflammatory diseases. 10.3390/ijms21155472
    Impact of oral immunoglobulins on animal health-A review. Balan Prabhu,Sik-Han Kyoung,Moughan Paul J Animal science journal = Nihon chikusan Gakkaiho Immunoglobulin (Ig) is the one of the main anti-infective components of blood, colostrum and breast milk. It is the unique glycoprotein that defends the body from harmful bacteria, viruses and other environmental pathogens by either binding to them or by forming an encapsulating barrier. The expansion of antimicrobial and immunomodulatory products from natural sources for dietary supplementation in both animals and humans is an ever growing and thriving area of research. Purified Ig from sheep serum (ovine serum Ig) is one such candidate product. Recent work has shown the various biological effects of oral Ig in different animal models including its effect on growth, immunity, intestinal growth and gut barrier function. The objective of this paper is to review the results of recent studies demonstrating the effects of oral Ig in both pathogenic and non-pathogenic animal models and to suggest a possible mechanism of its action. Overall, purified oral Ig improves growth of healthy (and challenged) rats and defends against enteric infection by immunomodulation, mucin protein and/or modification of commensal microbial composition. The findings contribute to knowledge of how orally administered ovine Ig can influence and enhance key indicators of gut function and overall growth performance in an animal model. 10.1111/asj.13258
    The time option of IVIG treatment is associated with therapeutic responsiveness and coronary artery abnormalities but not with clinical classification in the acute episode of Kawasaki disease. Samadli Sama,Liu Fei Fei,Mammadov Goshgar,Wang Jing Jing,Liu Hui Hui,Wu Yang Fang,Luo Huang Huang,Wu Yue,Chen Wei Xia,Zhang Dong Dong,Wei Wei,Hu Peng Pediatric rheumatology online journal BACKGROUND:In the last decade, incomplete Kawasaki disease (KD), intravenous immunoglobulin (IVIG) non-response and coronary artery abnormalities (CAA) have experienced the increasing trends in China. In addition, the enhancement of pediatricians' awareness may also raise the diagnostic rate of incomplete KD and stimulate more aggressive initial therapy in the acute episode of KD. Given this background, we hypothesize that the time option of IVIG treatment should be in parallel with peak time of systemic inflammation; either earlier or later IVIG treatment may affect the clinical classification, therapeutic responsiveness and CAA occurrence in KD patients. Therefore, the major objective of the present study is to identify whether the time option of IVIG treatment could be associated with the clinical classification, therapeutic responsiveness and CAA occurrence in the acute episode of KD. MATERIALS AND METHODS:A total of 153 children with KD were recruited between July 2015 and May 2018. All patients received the standard therapy of KD, including a single infusion of IVIG (2 g/kg) and aspirin (30-50 mg/kg/d). Blood samples were collected from all subjects within 24 h pre-IVIG treatment, respectively. Echocardiography was performed during the period from 2 days to 14 days after IVIG treatment. RESULTS:(1) The clinical classification presented no significant heterogenicity among different treatment time (x = 1.59, p > 0.05) (2) Eleven KD patients resisted to IVIG treatment and 7 of them (63.60%) received the initial IVIG dose on day 5 and 6. (3) The distribution of CAA onset was subjected to a significant difference according to timing option of IVIG treatment (x = 11.94, p < 0.05). CONCLUSIONS:The time option of IVIG treatment is associated with therapeutic responsiveness and CAA but not with clinical classification in the acute episode of KD. 10.1186/s12969-019-0352-3
    Acute and late coronary outcomes in 1073 patients with Kawasaki disease with and without intravenous γ-immunoglobulin therapy. Lin Ming-Tai,Sun Li-Chuan,Wu En-Ting,Wang Jou-Kou,Lue Hung-Chi,Wu Mei-Hwan Archives of disease in childhood OBJECTIVE:To explore acute and late coronary outcomes and their risk/modifiers in patients with Kawasaki disease (KD). DESIGN:Retrospective study. SETTING AND PATIENTS:1073 patients with KD identified from a tertiary care medical centre (1980-2012; 8677 patient-years). MAIN OUTCOME MEASURES:The acute coronary severities and late outcomes (survival free of coronary aneurysm persistence and ischaemia) were assessed. RESULTS:Coronary arterial lesions occurred in 40.6% of cases at their acute febrile stages, and persisted beyond 1 month in 196 (18.3%, M/F=138/58) patients: 125 (11.6%) had small aneurysms, 44 (4.1%) had medium aneurysms, and 27 (2.5%) had giant aneurysms. At follow-up (1-46 years), coronary aneurysms persisted in all with giant aneurysms, in 55% of those with medium aneurysms (18% with stenosis), and in 9% of those with small aneurysms. Ischaemia events occurred in 14 patients (M/F=13/1) and caused four deaths. Among the patients with KD with coronary aneurysms, 10-year ischaemia event-free and aneurysm persistence probability was 87.5% and 20.6%, respectively. The only independent risk for aneurysm persistence was the aneurysm severity 1 month after KD onset (χ(2)=80.73, p<10(-3)). Male patients and intravenous γ-immunoglobulin (IVIG) therapy were independent risk factors of initial coronary severity but were not associated with the late coronary outcomes, even in severity stratified subgroups. CONCLUSIONS:The coronary severity 1 month after KD onset is most crucial to the late coronary outcomes. Although IVIG use improves the initial severity of coronary lesions, it does not further modify the long-term fate of coronary aneurysms. 10.1136/archdischild-2014-306427
    Altered immunoglobulin A and M levels associated with changes in BAFF and APRIL after administration of intravenous immunoglobulin to treat Kawasaki disease. Doi M,Takeda T,Sakurai Y,Kato J,Hayashi T,Fukuda K,Takase T,Shima M Journal of investigational allergology & clinical immunology BACKGROUND:Kawasaki disease (KD) is an acute vasculitis of unknown etiology. Immunoregulatory abnormalities have been thought to contribute to its pathogenesis. Although treatment with intravenous immunoglobulin (IVIG) effectively prevents significant cardiac morbidity, the mechanism by which IVIG produces an effect in KD has yet to be fully elucidated. OBJECTIVE:To investigate the effects of IVIG on the immune system of patients with KD. PATIENTS AND METHODS:Eleven patients with KD (mean [SD] age, 2.2 [1.5] years) were enrolled in this prospective study and treated with high-dose IVIG therapy (2 g/kg in 1 or 2 infusions) during the acute phase of the disease. We examined immunological changes, with special reference to Ig levels and 2 previously unassessed cytokines: B cell-activating factor belonging to the tumor necrosis factor family (BAFF), and a proliferation-inducing ligand (APRIL). RESULTS:Clinical symptoms disappeared quickly in all cases, with no coronary artery abnormalities. IgA and IgM levels responded more rapidly than previously reported and reached a peak between the 3rd and 10th day after the start of IVIG treatment. The mean (SD) BAFF level was high before IVIG treatment (3234 [1904] pg/mL) and decreased significantly (1085 [257] pg/mL) after IVIG treatment, whereas the mean (SD) APRIL level before IVIG treatment (18.0 [10.0] ng/mL) rose significantly (120.6 [41.2] ng/mL). A significant inverse correlation between BAFF and APRIL was observed in patients with KD. CONCLUSIONS:These results suggest that IVIG may affect the pathogenesis of KD through alteration of BAFF/APRIL.
    A randomized prospective study on the use of 2 g-IVIG or 1 g-IVIG as therapy for Kawasaki disease. Sakata Koichi,Hamaoka Kenji,Ozawa Sei-Ichiro,Niboshi Ayumi,Yoshihara Takao,Nishiki Tesuo,Nakagawa Yumi,Kazuta Kikuko,Morimoto Yoshiko,Kamiya Yasutaka,Yamamoto Toru,Horii Yoshihiro,Kido Sachiko European journal of pediatrics A single, 2 g/kg dose of immune globulin (IG), denoted 2 g-intravenous (IV)IG, has become a standard regimen for treating Kawasaki disease (KD) because of its highly preventive effect on coronary arterial lesions (CAL). However, IG is obtained from blood specimens, a drawback to many patients, and is also very expensive. This randomized prospective study reported here was carried out with the aim of developing a treatment regimen that would reduce the total dose of IG. The study tested two protocols (A: 2 g-IVIG; B: 1 g-IVIG) that included the strategy of administering additional IVIG to IVIG-resistant patients based on the criteria we described previously. In protocol A, an additional 2 g-IVIG was administered only once; in protocol B, the first additional IVIG was 1 g-IVIG and the second was 2 g-IVIG. One hundred and nine patients who were admitted before the seventh day of illness and had no CAL at the time of admission were enrolled in the study (protocol A: 54 patients; B: 55 patients). In the protocol A group, 7.4% (4/54) of the patients received 4 g/kg IG. In protocol B, 41.8% (23/55) were treated only with 1 g/kg IG, and 10.9% (6/55) received 4 g/kg IG. No significant differences were observed between the patients of the two subgroups receiving 4 g/kg IG in each protocol group. Discriminate analysis also suggested that 52.4% of the patients in the protocol A group could be treated only with 1 g/kg IG. On the other hand, no significant difference was observed in the incidence of aneurysms between patients in the protocol A group (1/54) and those in the protocol B group (4/55). Our protocol based on 1 g-IVIG, including additional IVIG, was assessed to be an effective treatment and to provide a considerably useful means to reduce the total dose of IG. 10.1007/s00431-006-0280-3
    Indicators of unresponsiveness after initial i.v. immunoglobulin treatment in acute Kawasaki disease. Hashimoto Ikuo Pediatrics international : official journal of the Japan Pediatric Society BACKGROUND:The aim of this study was to identify the indicators of unresponsiveness to initial i.v. immunoglobulin (IVIG) treatment for Kawasaki disease (KD). METHODS:One hundred and forty-five patients with KD, who had received initial treatment consisting of a single IVIG dose (1 g/kg or 2 g/kg) and oral aspirin (30 mg/kg), were studied. Laboratory parameters, including C-reactive protein (CRP) and serum sodium (Na), were measured before and after IVIG treatment, and during the convalescent phase, and the laboratory data compared with regards to IVIG response. Multiple logistic regression models, which included laboratory data obtained immediately after the IVIG treatment, were constructed to determine the indicators of IVIG unresponsiveness immediately after the completion of the initial treatment. RESULTS:On logistic regression analysis, serum Na after IVIG treatment was the only independent factor related to initial IVIG unresponsiveness (β = 0.53, P < 0.01; OR, 1.69; 95%CI: 1.15-2.49). On receiver operating characteristic curve analysis, the optimal serum Na cut-off immediately after IVIG treatment was 135.5 mEq/L with a sensitivity of 0.75, and a specificity of 0.79. CONCLUSIONS:Prolonged hyponatremia after completion of the initial IVIG therapy was an indicator of the need for subsequent IVIG therapy. Treatment plans should be established for patients with acute KD that pay particular attention to prolonged hyponatremia. 10.1111/ped.13898
    Intravenous immunoglobulin preparation type: association with outcomes for patients with acute Kawasaki disease. Manlhiot Cedric,Yeung Rae S M,Chahal Nita,McCrindle Brian W Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology To determine whether two different intravenous immunoglobulin (IVIG) preparations were equally efficacious in the treatment of Kawasaki disease (KD). Single centre retrospective review of all patients treated with IVIG for KD between January 1990 and April 2007. Comparison of IVIG (dose 2 g/kg) from two commercial preparations; Iveegam stabilized with sugar (lyophilized, 5 g/ml glucose, pH 6.4-7.2, IgA 10 microg/ml, 5% IgG/ml) and Gamimune stabilized through acidification (no sugar, pH 4.0-4.5, IgA 270 microg/ml, 5% 1990-1999, 10% 1999-2007 IgG/ml). Propensity-adjusted differences in duration of fever after treatment initiation, frequency of retreatment with IVIG, hospital stay and maximum coronary artery z-score. A total of 954 patients were included, 862 (90%) were treated with Iveegam and 92 (10%) were treated with Gamimune. Patients' demographic, clinical and laboratory characteristics were similar between the two groups. In propensity-adjusted models, Iveegam was found to be associated with higher probability of non-response to IVIG (12% vs. 5%, p = 0.05) and longer median duration of fever after IVIG [1 (1-27) vs. 1 (1-8) days, p = 0.02] than Gamimune. Nevertheless, Gamimune was found to be associated with longer median duration of hospital stay [5 (2-49) vs. 4 (2-76) days, p < 0.0001] and higher median maximum coronary artery z-score both at the end of the acute phase (+1.4 vs. +0.8, p < 0.0001) and 6-8 weeks after the acute phase (+0.7 vs. +0.4, p < 0.0001). IVIG preparations with lower IgA content and stabilized with glucose appear to be associated with improved coronary artery outcomes for patients with KD. 10.1111/j.1399-3038.2010.00987.x
    Intravenous Immunoglobulin for the Treatment of Kawasaki Disease. Shulman Stanford T Pediatric annals Standard first-line therapy for Kawasaki disease (KD) consists of intravenous immunoglobulin (IVIG) and aspirin. Current guidelines recommend 2 g/kg of IVIG and 80 to 100 mg/kg of aspirin administered within the first 10 days of illness. This regimen has marked efficacy in preventing the development of coronary artery aneurysms. Approximately 15% to 20% of treated patients require a second dose of IVIG to control the inflammatory process. The role of adjunctive corticosteroid therapy with IVIG and aspirin is evolving, with Japanese studies showing a clear benefit in those patients at highest risk for development of coronary disease. The challenge in North America has been reliable identification of the highest-risk patients, which still eludes us because the Japanese scoring systems are ineffective in multiethnic populations. Despite its efficacy, the precise mechanism of IVIG's effect in KD is unclear but probably relates to its ability to down-regulate aspects of the up-regulated inflammatory response in patients with KD. [Pediatr Ann. 2017;46(1):e25-e28.]. 10.3928/19382359-20161212-01
    Neutropenia after intravenous immunoglobulin therapy is associated with coronary artery lesions in children with Kawasaki disease: a case control study. Wang Zhenquan,Weng Fengfeng,Li Chen,Shi Hongying,Tang Zhangke,Qiu Huixian,He Yue'e,Wu Rongzhou,Chu Maoping BMC pediatrics BACKGROUND:To evaluate differences in laboratory parameters, clinical presentation, and incidence of coronary artery lesions (CAL) between children with neutropenic and non-neutropenic Kawasaki disease (KD). METHODS:All consecutive KD patients that presented to the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University in Wenzhou, China between January 2005 and December 2015 were included in this study. Patients were divided into two groups (KD with neutropenia (NKD) and KD without neutropenia (NNKD)) based on whether or not they developed neutropenia during the course of treatment. We compared differences in clinical manifestations, laboratory parameters, and treatment protocols between groups. We also evaluated the relationship between neutropenia with immunoglobulin dosage and incidence of CAL. RESULTS:An IVIG treatment regimen of 2 g/kg*1d was associated with a lower incidence of neutropenia compared to the 1 g/kg*2d protocol. The incidence of CAL was higher in KD patients with neutropenia than in those without. Subgroup analysis showed no difference in the incidence of CAL among the different age groups between KD patients with and without neutropenia. CONCLUSIONS:Follow up ultrasonic echocardiography should be performed in KD patients with neutropenia in order to allow for early detection of CAL and timely intervention. 10.1186/s12887-018-1032-z
    Impact of intravenous immunoglobulin infusion on longitudinal left ventricular performance in patients with acute Kawasaki disease of usual course. Koteda Yusuke,Suda Kenji,Kishimoto Shintaro,Ito Shinichi,Kudo Yoshiyuki,Nishino Hiroshi,Ishii Haruka,Iemura Motofumi,Matuishi Toyojiro Journal of cardiology PURPOSE:To determine the acute change in cardiac performance after intravenous immunoglobulin infusion (IVIG) in patients with acute Kawasaki disease (KD). MATERIALS AND METHODS:Subjects were 33 patients with KD who were treated with IVIG 2 g/kg and recovered without coronary artery lesion and 27 controls. Subjects underwent combined two-dimensional, Doppler, and tissue Doppler echocardiographic (TDI) studies. In KD, these echocardiographic studies were performed before IVIG, 48 h after IVIG, and in convalescence. Echocardiographic variables were compared between KD and controls as well as among 3 time points in KD. RESULTS:Before IVIG, KD showed significantly higher peak aortic velocity and shorter aortic ejection time as results of tachycardia and significantly lower E' (p<0.04) but significantly higher E/E' (p<0.02). After IVIG, patients with KD became afebrile and showed significantly lower TDI indices such as S', E', and, A' and isovolumic acceleration (IVA) (163+/-56 vs. 208+/-70 cm/s(2), p<0.01) with higher TDI-derived Tei index (0.50+/-0.10 vs. 0.44+/-0.06, p<0.02) than controls. These differences tended to disappear in convalescence. In analysis of repeated measurements, except for hemodynamic changes associated with tachycardia, S' (7.9+/-1.3 vs. 7.0+/-1.1 vs. 7.4+/-0.9 cm/s, p<0.001), IVA (227+/-72 vs. 163+/-56 vs. 180+/-63, p<0.05), and A' (7.7+/-3.0 vs. 5.6+/-1.3 vs. 6.7+/-2.3 cm/s, p<0.001) were significantly different among these time points. CONCLUSIONS:In patients with acute KD with usual course, IVIG induced transient sub-clinical longitudinal left ventricular dysfunction. 10.1016/j.jjcc.2009.03.005
    Prediction of nonresponsiveness to medium-dose intravenous immunoglobulin (1 g/kg) treatment: an effective and safe schedule of acute treatment for Kawasaki disease. Moon Kyung Pil,Kim Beom Joon,Lee Kyu Jin,Oh Jin Hee,Han Ji Whan,Lee Kyung Yil,Lee Soon Ju Korean journal of pediatrics PURPOSE:Medium-dose (1 g/kg) intravenous immunoglobulin (IVIG) is effective in the majority of patients with Kawasaki disease (KD) but some patients who do not respond to medium-dose IVIG are at high risk for the development of coronary artery lesions (CALs). The purpose of this study was to identify the clinical predictors associated with unresponsiveness to medium-dose IVIG and the development of CALs. METHODS:A retrospective study was performed in 91 children with KD who were treated with medium-dose IVIG at our institution from January 2004 to December 2013. We classified the patients into responders (group 1; n=68) and nonresponders (group 2; n=23). We compared demographic, laboratory, and echocardiographic data between the 2 groups. RESULTS:Multivariate logistic regression analysis identified 6 variables as predictors for resistance to medium-dose IVIG. We generated a predictive scoring system assigning 1 point each for percentage of neutrophils ≥65%, C-reactive protein≥100 mg/L, aspartate aminotransferase≥100 IU/L, and alanine aminotransferase≥100 IU/L, as well as 2 points for less than 5 days of illness, and serum sodium level≤136 mmol/L. Using a cutoff point of ≥4 with this scoring system, we could predict nonresponsiveness to medium-dose IVIG with 74% sensitivity and 71% specificity. CONCLUSION:If a patient has a low-risk score in this system, medium-dose IVIG can be recommended as the initial treatment. Through this process, we can minimize the adverse effects of high-dose IVIG and incidence of CALs. 10.3345/kjp.2016.59.4.178
    Recurrence of Fever After Initial Intravenous Immunoglobulin Treatment in Children With Kawasaki Disease. Yoshida Masanori,Oana Shinji,Masuda Hiroshi,Ishiguro Akira,Kato Hitoshi,Ito Shuichi,Kobayashi Tohru,Abe Jun Clinical pediatrics The standard treatment for Kawasaki disease (KD) is high-dose intravenous immunoglobulin (IVIG). Some patients experienced recurrent fever after IVIG following defervescence. However, little is known about the frequency of such episodes and the clinical outcome for such patients. We classified 195 KD patients into 4 groups based on their fever patterns after initial IVIG treatment: group NR (no response), group EF (early recurrent fever within 72 hours after defervescence), group LF (late recurrent fever >72 hours after defervescence), and group GR (good response). We compared the clinical characteristics and laboratory data among these groups retrospectively. Nearly a third of patients had recurrent fever (group EF, n = 45; group LF, n = 11). In two-thirds of these patients, the fever had subsided spontaneously without retreatment; 2 patients in Group LF with smoldering KD symptoms had developed coronary artery lesions (CALs) even after additional IVIG. Recurrent fever and smoldering symptoms might be risk factors for CAL. 10.1177/0009922817694459
    Role of intravenous immunoglobulin in the treatment of Kawasaki disease. Lo Mindy S,Newburger Jane W International journal of rheumatic diseases Intravenous immunoglobulin (IVIg) is a purified plasma product that is used for many immune-deficient conditions and autoimmune conditions. Use of IVIg for treatment for Kawasaki disease (KD) is critical for control of inflammation. The American Heart Association (AHA) recommends a single infusion of 2 g/kg preferably given during the first 10 days of illness. In this review, we have discussed the possible mechanisms of action of IVIg in KD and its clinical usage in this condition. 10.1111/1756-185X.13220
    IVIG reduced vascular oxidative stress in patients with Kawasaki disease. Takatsuki Shinichi,Ito Yuka,Takeuchi Daiji,Hoshida Hiroshi,Nakayama Tomotaka,Matsuura Hiroyuki,Saji Tsutomu Circulation journal : official journal of the Japanese Circulation Society BACKGROUND:Oxidative stress (OS) contributes to the acute phase of Kawasaki disease (KD) in a manner that is as yet unknown. In the present study OS in the acute phase of KD was investigated by measuring urinary 8-iso-prostaglandin F2alpha (8-iso-PG) and evaluating its correlation to the efficacy of intravenous immunoglobulin (IVIG) administration. METHODS AND RESULTS:The 62 patients with acute phase of KD were enrolled, as well as 20 healthy children (HC) and 20 with acute febrile illness (FI). Urinary samples were obtained before and after administration of IVIG. The HC and FI groups also had inflammatory markers evaluated at the same time. The 8-iso-PG was significantly elevated in the 62 KD patients (719 +/-335 pg/mg Cr) without IVIG administration compared with those with FI (583 +/-213 pg/mg Cr) as well as HC (443 +/-288 pg/mg Cr) (P<0.01). 40 patients were given 3 different regimens of IVIG: 16 received 2 g/kg for 1 day; 17 received 1 g/kg for 1 day; 7 received 400 mg . kg(-1) . day(-1) for 5 days. All regimens of IVIG reduced the 8-iso-PG level at 7 days after initiation. CONCLUSIONS:OS provokes vasculitis in KD, the activation of which was reduced by IVIG. The urinary level of 8-iso-PG is a useful marker of the effectiveness of IVIG in the acute phase of KD.
    Relationship between post-IVIG IgG levels and clinical outcomes in Kawasaki disease patients: new insight into the mechanism of action of IVIG. Goto Ryunosuke,Inuzuka Ryo,Shindo Takahiro,Namai Yoshiyuki,Oda Yoichiro,Harita Yutaka,Oka Akira Clinical rheumatology INTRODUCTION/OBJECTIVES:The dosing of intravenous immunoglobulin (IVIG) therapy for Kawasaki disease (KD) has been a matter of debate for decades, with recent studies implicating that larger doses lead to better outcomes. Despite this, few have investigated post-IVIG infusion immunoglobulin G (IgG) levels in relation to outcomes of KD such as response to IVIG and development of coronary artery abnormalities (CAAs). The present study investigated how varying levels of post-infusion IgG affected these outcomes. METHOD:We collected demographic and laboratory data, including post-infusion IgG, from children with KD who were admitted to six hospitals in Japan between 2006 and 2012. We conducted multivariate analyses to examine the relationship between independent variables and non-response to IVIG and development of CAAs. We used random forest, a decision tree-based machine learning tool, to investigate the marginal effect of varying post-infusion IgG levels on non-response to IVIG and development of CAAs. RESULTS:Of 456 patients included in the study, 130 (28.5%) were non-responders and 38 (8.3%) developed CAAs. Sodium, post-infusion IgG, and AST were significantly associated with non-response. Post-infusion IgG and sodium were significantly associated with CAA development. The random forest plots revealed a decrease in non-response and CAA rates with increasing post-infusion IgG until post-infusion IgG was near the median (2821 mg/dL), after which the non-response and CAA rates leveled off. CONCLUSIONS:Greater post-infusion IgG is associated with better response to IVIG and decreased CAA development in KD patients, but this effect levels off at post-infusion IgG levels greater than the median. Key points • Though previous studies have shown that post-intravenous immunoglobulin (IVIG) infusion immunoglobulin G (IgG) is associated with non-response to IVIG therapy and coronary artery abnormality (CAA) development in Kawasaki disease (KD) patients, no study has investigated the relationship between varying levels of post-infusion IgG and these clinical outcomes. • Our study showed that non-response to IVIG therapy and CAA development in Kawasaki disease patients follow a decreasing trend with increasing post-infusion IgG at post-infusion IgG levels below the median. • At values of post-infusion IgG greater than the median, non-response and CAA development rates remain relatively constant with increasing post-infusion IgG. • Our study suggests that when post-infusion IgG is greater than the median, IgG may have fully bound to the therapeutic targets of KD, and in these patients, there may be limited benefit in administering additional IVIG. 10.1007/s10067-020-05153-w
    Immunoglobulin profiling identifies unique signatures in patients with Kawasaki disease during intravenous immunoglobulin treatment. Ko Tai-Ming,Kiyotani Kazuma,Chang Jeng-Sheng,Park Jae-Hyun,Yin Yew Poh,Chen Yuan-Tsong,Wu Jer-Yuarn,Nakamura Yusuke Human molecular genetics Identifying the causes of high fever syndromes such as Kawasaki disease (KD) remains challenging. To investigate pathogen exposure signatures in suspected pathogen-mediated diseases such as KD, we performed immunoglobulin (Ig) profiling using a next-generation sequencing method. After intravenous Ig (IVIG) treatment, we observed disappearance of clonally expanded IgM clonotypes, which were dominantly observed in acute-phase patients. The complementary-determining region 3 (CDR3) sequences of dominant IgM clonotypes in acute-phase patients were commonly observed in other Ig isotypes. In acute-phase KD patients, we identified 32 unique IgM CDR3 clonotypes shared in three or more cases. Furthermore, before the IVIG treatment, the sums of dominant IgM clonotypes in IVIG-resistant KD patients were significantly higher than those of IVIG-sensitive KD patients. Collectively, we demonstrate a novel approach for identifying certain Ig clonotypes for potentially interacting with pathogens involved in KD; this approach could be applied for a wide variety of fever-causing diseases of unknown origin. 10.1093/hmg/ddy176
    IgG levels in Kawasaki disease and its association with clinical outcomes. Yamazaki-Nakashimada Marco Antonio,Gámez-González Luisa Berenise,Murata Chiharu,Honda Takafumi,Yasukawa Kumi,Hamada Hiromichi Clinical rheumatology Previous studies have suggested an association of IgG levels (before and after IVIG infusion) with clinical outcomes in Kawasaki disease. A retrospective analysis was performed that included 418 patients with KD admitted to Tokyo Women's Medical University Yachiyo Medical Center to evaluate pre- and post-IVIG IgG levels and its relation to outcomes. All patients received an initial IVIG infusion and aspirin; IgG levels were measured in 350 patients before IVIG (pre-IVIG IgG levels) and in 373 patients 48 h after starting IVIG infusion (post-IVIG IgG levels). Media and standard deviation of the pre- and post-IVIG IgG levels were reported and classified according to age. Also, IgG z-scores were calculated according to normal values of IgG by age. The number of cases and corresponding percentage of non-responders were reported by age and total patients. The association of pre-IVIG, post-IVIG IgG levels and post-IVIG IgG level/pre-IVIG IgG level ratio with no-response was evaluated by simple logistic regression model based on the IgG z-score, and regression coefficient, X value, p, and R of Nagelkerke were reported. Pre-IVIG and post-IVIG IgG levels presented an association with non-responders with statistical significance. This association was more evident between post-IVIG IgG levels and non-responders. Regarding coronary alterations, it was not possible to perform an adequate statistical analysis due the small number of patients. Pre- and post-IVIG infusion IgG levels could be an important biomarker in KD as well as in other inflammatory conditions. Higher IgG levels could be associated with a more effective immunomodulatory action and associated with better clinical outcomes. 10.1007/s10067-018-4339-0
    Decreased Steroid Hormone Receptor Expression in Kawasaki Disease Before IVIG Treatment. Huang Ying-Hsien,Chen Kuang-Den,Lo Mao-Hung,Cai Xin-Yuan,Kuo Ho-Chang Frontiers in pediatrics Kawasaki disease (KD) is anacute febrile coronary vasculitis disease in children. In general, this disease can be treated with a single dose of 2 g/kg intravenous immunoglobulin (IVIG). However, the best timing for administering steroid treatment in acute-stage KD is still under debate. In this study, we recruited 174 participants to survey the transcript levels of steroid hormone receptors in KD patients. The chip studies consisted of 18 KD patients that were analyzed before IVIG treatment and at least 3 weeks after IVIG administration, as well as 36 control subjects, using GeneChip® HTA 2.0. Another cohort consisting of 120 subjects was analyzed to validate qRT-PCR. Our microarray study demonstrated significant downregulated expressions of the mRNA levels of NR1A2, RORA, NR4A1-3, THRA, and PPARD in KD patients in comparision to the controls. However, these genes increased considerably in KD patients after IVIG administration. After PCR validation, our data only revealed decreased NR4A2 mRNA expression in the KD patients compared to those of the controls, which increased after they received IVIG treatment. Our study is the first to report the potential effective utilization of steroid treatment in KD. Prior to IVIG treatment, decreased steroid receptors allowed for the reduced treatment role of steroids. However, after IVIG treatment, increased steroid receptors indicate that steroids are effective as a supplementary treatment for KD. 10.3389/fped.2019.00007
    Effectiveness of intravenous immunoglobulin alone and intravenous immunoglobulin combined with high-dose aspirin in the acute stage of Kawasaki disease: study protocol for a randomized controlled trial. Kuo Ho-Chang,Guo Mindy Ming-Huey,Lo Mao-Hung,Hsieh Kai-Sheng,Huang Ying-Hsien BMC pediatrics BACKGROUND:Kawasaki disease (KD) is an acute febrile systemic vasculitis most commonly seen in children under 5 years old. High-dose aspirin is often administered, but the duration of such treatment varies. Many centers reduce the aspirin dose once the patient is afebrile, even before treating said patient with intravenous immunoglobulin (IVIG). However, a randomized controlled trial regarding high-dose aspirin in the acute stage of KD has not previously been carried out. METHODS/DESIGN:This trial has been designed as a multi-center, prospective, randomized controlled, evaluator-blinded trial with two parallel groups to determine whether IVIG alone as the primary therapy in acute-stage KD is as effective as IVIG combined with high-dose aspirin therapy. The primary endpoint is defined as coronary artery lesion (CAL) formation at 6-8 weeks. Patients meeting the eligibility criteria are randomly assigned (1:1) to a test group (that receives only IVIG) or a standard group (that receives IVIG plus high-dose aspirin). This clinical trial is conducted at three medical centers in Taiwan. DISCUSSION:Since high-dose aspirin has significant anti-inflammatory and anti-platelet functions, it does not appear to affect disease outcomes. Furthermore, it can decrease hemoglobin levels. Therefore, we have initiated this randomized controlled trial to evaluate the necessity of high-dose aspirin in the acute stage of KD. TRIAL REGISTRATION:Kawasaki Disease Center, Kaohsiung Chang Gung Memorial Hospital, Taiwan. ClinicalTrials.gov Identifier: NCT02951234. Release Date: November 3, 2016. 10.1186/s12887-018-1180-1
    Delayed intravenous immunoglobulin treatment increased the risk of coronary artery lesions in children with Kawasaki disease at different status. Qiu Huixian,He Yuee,Rong Xing,Ren Yue,Pan Lulu,Chu Maoping,Wu Rongzhou,Shi Hongying Postgraduate medicine OBJECTIVE:Kawasaki disease (KD) is a systemic vasculitis with serious complications, especially the development of coronary artery lesions (CALs). The aim of this study was to identify the risk for the development of CALs with IVIG treatment of KD >10 days after illness onset in patients with different KD status, and explore potential moderators of the association between delayed treatment and CALs. METHODS:We performed a retrospective review of the medical records of KD patients. All patients were divided into two groups (conventional therapy group and delayed therapy group, IVIG treatment ≤10 days vs >10 days). We compared the demographic and clinical characteristics, laboratory data, and analyzed risk factors for CALs in patients who received IVIG treatment >10 days, and determined whether different status of KD modified the effects of delayed IVIG treatment on CALs. RESULTS:In the delayed IVIG treatment group, children were more likely to develop CALs and the proportion of incomplete KD was higher, compared with the conventional therapy group. The number of children younger than 12 months or older than 61 months was higher and children had higher BMI and were more likely to receive steroids before diagnosis in the delayed IVIG treatment group compared with the conventional therapy group. Delayed IVIG treatment was an independent risk factor for the development of CALs (adjusted OR = 2.90, 95%CI = 1.42, 5.91). Delayed therapy children with higher levels of C-reactive protein (>79 mg/L) and erythrocyte sedimentation rate (>34 mm/h) had the highest risk for developing CALs (OR = 5.68, 95%CI: 1.17, 27.59; OR = 4.11, 95%CI: 1.62, 10.46, respectively). CONCLUSION:Delayed IVIG treatment was an independent risk factor for the development of CALs. Children in the delayed IVIG treatment group with higher levels of CRP and ESR (CRP >79 mg/L, ESR >34 mm/h) had the greatest likelihood of developing CALs. 10.1080/00325481.2018.1468712
    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