Genetic variants in the inhibiting FcγRIIB mediate anti-inflammatory responses and influence IVIG refractoriness (IVIG-R). However, these variants are rare in Asian and Hispanic populations so other genes in the pathway could be potentially involved. IVIG is ineffective in mice lacking SIGN-R1, a related molecule to human DC-SIGN. Further, DC-SIGN is a known receptor for sialylated Fc, the component responsible for the anti-inflammatory action of IVIG. Thus, we hypothesized that DC-SIGN would also be involved in the pathway of IVIG response in Kawasaki Disease (KD) patients.
A case-control approach was performed to examine the differential distribution of five single nucleotide polymorphisms (SNPs) in DC-SIGN promoter with IVIG-R among White (158 vs. 62), Asian (64 vs. 12) and Hispanic (55 vs. 20) KD patients. Distinct differences in allele frequency distributions of several variants in the DC-SIGN promoter were observed in the three ethnic groups. Further, Asians with the major allele “A” in rs2287886 were more likely (OR = 1.76, p = 0.04) to be IVIG non-responder, but this allele is a minor allele in other two ethnic groups, where the association was not apparent.
DC-SIGN can potentially complement the role of FcγRIIB in the anti-inflammatory cascade involved in the IVIG response mechanism.
Kawasaki disease; IVIG treatment response; FcγR; Coronary artery disease; DC-SIGN
A functional polymorphism in the inhibitory IgG-Fc receptor FcγRIIB influences intravenous immunoglobulin (IVIG) response in Kawasaki Disease (KD) a vasculitis preferentially affecting the coronary arteries in children. We tested the hypothesis that the polymorphisms in the activating receptors (Fcγ RIIA, Fcγ RIIIA and Fcγ RIIIB) also influence susceptibility, IVIG treatment response, and coronary artery disease (CAD) in KD patients.
Methods and Results
We genotyped polymorphisms in the activating FcγRIIA, FcγRIIIA and FcγRIIIB genes using pyrosequencing in 443 KD patients, including 266 trios and 150 single parent-child pairs, in northwest US and genetically determined race with 155 ancestry information markers. We used the FBAT program to test for transmission disequilibrium and further generated pseudo-sibling controls for comparisons to the cases. The FcγRIIA-131H variant showed an association with KD (p = 0.001) with ORadditive = 1.51 [1.16–1.96], p = 0.002) for the primary combined population, which persisted in both Caucasian (p = .04) and Asian (p = .01) subgroups and is consistent with the recent genome-wide association study. We also identified over-transmission of FcγRIIIB-NA1 among IVIG non-responders (p = 0.0002), and specifically to Caucasian IVIG non-responders (p = 0.007). Odds ratios for overall and Caucasian non-responders were respectively 3.67 [1.75–7.66], p = 0.0006 and 3.60 [1.34–9.70], p = 0.01. Excess NA1 transmission also occurred to KD with CAD (ORadditive = 2.13 [1.11–4.0], p = 0.02).
A common variation in FcγRIIA is associated with increased KD susceptibility. The FcγRIIIB-NA1, which confers higher affinity for IgG compared to NA2, is a determining factor for treatment response. These activating FcγRs play an important role in KD pathogenesis and mechanism of IVIG anti-inflammatory.
coronary disease; pediatrics; Kawasaki disease; IVIG treatment response; FcγR
Intravascular neutrophil recruitment and activation are a key pathogenic factor that contributes to vascular injury. Intravenous immunoglobulin (IVIG) has been shown to have a beneficial effect in systemic inflammatory disorders; however, the mechanisms underlying IVIG’s inhibitory effect on neutrophil recruitment and activation are not understood.
We studied the mechanisms by which IVIG exerts protection from neutrophil-mediated acute vascular injury.
Methods and Results
We examined neutrophil behavior in response to IVIG in vivo using real time intravital microscopy. We found that an antibody that blocks both FcγRIII and its inhibitory receptor counterpart, FcγRIIB, abrogated the inhibitory effect of IVIG on leukocyte recruitment and heterotypic RBC interactions with adherent leukocytes in wild-type mice. In the context of sickle cell disease, the blockade of both FcγRIIB and III abrogated the protective effect of IVIG on acute vaso-occlusive crisis caused by neutrophil recruitment and activation. Analysis of FcγRIIB- and FcγRIII-deficient mice revealed the predominant expression of FcγRIII on circulating neutrophils. FcγRIII mediated IVIG-triggered inhibition of leukocyte recruitment, circulating RBC capture, and enhanced Mac-1 activity, whereas FcγRIIB was dispensable. In addition, FcγRIII-induced IVIG anti-inflammatory activity in neutrophils was mediated by recruitment of Src homology 2 (SH2)-containing tyrosine phosphatase-1 (SHP-1). Indeed, the protective effect of IVIG on leukocyte recruitment and activation was abrogated in SHP-1-mutant mice.
FcγRIII, a classical activating receptor, has an unexpected inhibitory role on neutrophil adhesion and activation via recruitment of SHP-1 in response to IVIG. Our results identify SHP-1 as a therapeutic target in neutrophil-mediated vascular injury.
neutrophils; vascular injury; FcγRIII; IVIG; SHP-1
Background and Objectives
We sought to determine whether high-dose aspirin is necessary for the acute therapy of Kawasaki disease (KD) in the intravenous immunoglobulin (IVIG) era.
Subjects and Methods
Two groups of KD patients treated during the different periods were included. Study group (n=51, treated with IVIG without concomitant use of aspirin in the acute phase) was compared with control group (n=129, treated with IVIG plus high-dose aspirin) with regard to the response to IVIG, duration of fever after IVIG completion, time to C-reactive protein (CRP) <3 mg/dL, and the incidence of coronary artery lesions (CALs).
There was no difference between the groups in age, sex, and duration of fever before treatment. Pre-IVIG laboratory measures also did not differ from each other. IVIG-resistant cases were 8 (15.7%) in study group and 22 (17.1%) in control group (p=1.000). Mean duration of fever after IVIG completion in IVIG-responsive patients was 13.3±13.5 hours in study group compared to 6.2±8.3 hours in control group (p=0.000). The mean time to decrease in CRP was 4.0±1.7 days in study group and 4.1±2.2 days in control group (p=0.828). There were 2 (3.9%) patients with CALs in study group and 10 (7.8%) in control group (p=0.514).
Although high-dose aspirin shortens the duration of fever, treatment without aspirin in the acute phase has no influence on the response to IVIG, resolution of inflammation, or the development of CALs. In the IVIG era, high-dose aspirin may provide little benefit to the treatment in the acute phase of KD.
Kawasaki disease; Aspirin; Therapeutics
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.
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.
Clinicians should be aware of this complication and hemoglobin should be closely monitored following high dose IVIG therapy.
Direct antiglobulin test; Isohemagglutinins; Retreatment
Background and Objectives
We sought to determine parameters to guide the decision of retreatment in patients with Kawasaki disease (KD) who remained febrile after initial intravenous immunoglobulin (IVIG).
Subjects and Methods
A total of 129 children with KD were studied prospectively. Patients were treated with IVIG 2 to 9 days after the onset of disease. Laboratory measures, such as white blood cell (WBC), percentage of neutrophils, C-reactive protein (CRP), and N-terminal pro-brain natriuretic peptide (NT-proBNP), were determined before and 48 to 72 hours after IVIG treatment. Patients were classified into IVIG-responsive and IVIG-resistant groups, based on the response to IVIG.
Of a total of 129 patients, 107 patients (83%) completely responded to a single IVIG therapy and only 22 patients (17%) required retreatment: 14 had persistent fever and 8 had recrudescent fever. There was no significant difference between the groups in age, gender distribution, and duration of fever to IVIG initiation, but coronary artery lesions developed significantly more often in the resistant group than in the responsive group (31.8% vs. 2.8%, p=0.000). Compared with pre-IVIG data, post-IVIG levels of WBC, percentage of neutrophils, CRP, and NT-proBNP decreased to within the normal range in the responsive group, whereas they remained high in the resistant group. Multivariate logistic regression indicated that neutrophil counts, CRP, and NT-proBNP were independent parameters of retreatment.
Additional therapy at an early stage of the disease should be administered for febrile patients who have high values of CRP, NT-proBNP, and/or neutrophil counts after IVIG therapy.
Kawasaki disease; Intravenous immunoglobulins; Retreatment
Background and Objectives
About 10-15% of Kawasaki disease (KD) is refractory to intravenous immunoglobulin (IVIG) therapy. This study was designed to investigate the predicting factors for refractory KD.
Subjects and Methods
We reviewed retrospectively the clinical records of 77 patients with typical KD admitted at Wonju Christian Hospital from January, 2005, to December, 2008. The variance of laboratory and demographic parameters between the IVIG-responsive group and IVIG-resistant group were analyzed. Thirteen patients with urinary tract infections were randomly collected as a febrile control group.
Among 77 patients diagnosed with complete KD, 13 patients (16.9%) were IVIG-resistant. The febrile period and hospital days were significantly longer in the IVIG-resistant group than IVIG-responsive group (p<0.001, p=0.002). Serum levels of albumin and sodium were significantly lower in the IVIG-resistant group (p=0.025). The Kobayashi score could differentiate these two groups (p=0.015). Fewer lymphocytes was observed during the subacute phase in the IVIG-resistant group (p=0.032). Coronary arterial dilatations (CADs) were observed in 10.9% (7/64) of IVIG-responders and 38.5% (5/13) of IVIG-resistant patients (p=0.038).
The percentage of neutrophils and lymphocytes in patients with KD, in addition to known risk factors for refractory KD, may help predict IVIG-resistance in patients with KD.
Mucocutaneous Lymph Node Syndrome; Risk factors; Coronary arteries
The optimal management of Kawasaki disease (KD) unresponsive to intravenous immunoglobulin (IVIG) therapy remains unclear.
To prospectively evaluate the efficacy and safety of intravenous methylprednisolone pulse (IVMP) therapy in KD cases unresponsive to additional IVIG.
KD patients who initially received IVIG (2 g/kg/24 h) and acetylsalicylic acid within nine days after disease onset were studied. Patients who did not respond received additional IVIG (2 g/kg/24 h), and those who still did not respond were given IVMP (30 mg/kg/day) for three days, followed by oral prednisolone. The response to treatment, echocardiographic findings and adverse effects were evaluated.
Among 412 KD cases, 74 (18.0%) were treated with additional IVIG; 21 (28.4%) of the latter cases subsequently received IVMP followed by prednisolone. All cases became afebrile soon after IVMP infusion and did not have a high-grade fever during treatment with prednisolone for two to six weeks. Four weeks after disease onset, coronary artery lesions (CAL) were diagnosed according to the Japanese Ministry of Health and Welfare or the American Heart Association criteria in two of the 21 cases treated with IVMP plus prednisolone; among all 412 cases, three (0.7%) and eight (1.9%) had CAL according to each criteria, respectively. All CAL regressed completely one year after disease onset. Adverse effects of IVMP, such as hypothermia and sinus bradycardia, resolved spontaneously.
In KD patients unresponsive to additional IVIG, IVMP promptly induced defervescence, and subsequent oral prednisolone suppressed recurrence of fever. IVMP followed by prednisolone therapy may prevent CAL, without severe adverse effects.
Coronary artery lesions; Kawasaki disease; Nonresponders to intravenous immunoglobulin; Prednisolone; Steroid pulse
Intravenous immunoglobulin (IVIG)-resistant Kawasaki disease (KD) patients comprise at least 20% of treated patients and are at higher risk of coronary artery abnormalities. If identified early in the course of the disease, such patients may benefit from additional anti-inflammatory therapy. The aim of this study was to compare the transcript abundance between IVIG-resistant and – responsive KD patients to identify biomarkers that might differentiate between these two groups and to generate new targets for therapies in IVIG-resistant KD patients. We compared the transcript abundance profiles of whole blood RNA on Agilent arrays from acute and convalescent KD subjects and age-similar, healthy controls. KD subjects were stratified as IVIG-resistant or – responsive based on response to initial IVIG therapy. Transcript abundance was higher for IL-1 pathway genes (IL-1 receptor, interleukin receptor associated kinase, p38 mitogen-activated protein kinase), and MMP-8. These findings point to candidate biomarkers that may predict IVIG-resistance in acute KD patients. The results also underscore the importance of the IL-1 pathway as a mediator of inflammation in KD and suggest that IL-1 or its receptor may be reasonable targets for therapy, particularly for IVIG-resistant patients.
Kawasaki disease; gene expression; intravenous immunoglobulin
To assess the performance of three risk scores from Japan that were developed to predict, in children with Kawasaki disease, resistance to intravenous immunoglobulin (IVIG) treatment.
We used data from a randomized trial of pulsed steroids for primary treatment of Kawasaki disease to assess operating characteristics of the three risk scores, and we examined whether steroid therapy lowers the risk of coronary artery abnormalities in patients prospectively classified as IVIG resistant.
For comparability with published cohorts, we analyzed the data of 99 patients not treated with steroids (16% IVIG-retreated), and identified male sex, lower albumin and higher AST as independent risk factors for IVIG resistance. The Kobayashi score was similar in IVIG-resistant and responsive patients, yielding sensitivity=33% and specificity=87%. There was no interaction of high vs. low risk status by treatment received (steroid vs. placebo) using any of the three risk score algorithms.
Risk scoring systems from Japan have good specificity but low sensitivity for predicting IVIG resistance in a North American cohort. Primary steroid therapy did not improve coronary outcomes among patients prospectively classified as high risk for IVIG resistance.
Kawasaki; pediatrics; inflammation; therapy
Kawasaki disease (KD) is an acute febrile vasculitic syndrome of early childhood often complicated by coronary artery lesion that drastically reduces the quality of life. The study aimed to identify a reliable marker for predicting nonresponsiveness to the first course of intravenous immunoglobulin (IVIG) in KD patients. A total of 63 patients with KD were enrolled in the study (IVIG response, 58; IVIG resistance, 5). Plasma samples were collected before and after IVIG infusion for measurement of biomarkers. Patients' clinical characteristics and laboratory data were also analyzed. A receiver operating characteristic curve was generated to identify a cut-off value for predicting IVIG resistance. Among the biomarkers, the difference in plasma clusterin concentrations before and after IVIG infusion (CLUSTER 12) was significantly related to IVIG resistance (P = 0.040; 95% confidence interval (CI): −25.8% to −6.0%). Using a CLUSTER 12 cut-off value of <8.52 mg/L, the odds ratio for IVIG resistance was 11.467 (95% CI: 1.186 to 110.853). Patients with plasma CLUSTER 12 concentrations >8.52 mg/L had a much higher risk of IVIG resistance than those with CLUSTER 12 concentrations <8.52 mg/L. Plasma clusterin concentration shows promise as a candidate biomarker for predicting IVIG resistance in patients with KD.
Crosslinking of FcγRIIB and the BCR by immune complexes (ICs) can downregulate antigen-specific B cell responses. Accordingly, FcγRIIB deficiencies have been associated with B cell hyperactivity in patients with SLE and mouse models of lupus. However, we have previously shown that murine IgG2a-autoreactive AM14 B cells respond robustly to chromatin- associated ICs through a mechanism dependent on both the BCR and endosomal TLR9, despite FcγRIIB coexpression. To further evaluate the potential contribution of FcγRIIB to the regulation of autoreactive B cells, we have now compared the IC-triggered responses of FcγRIIB-deficient and FcγRIIB-sufficient AM14 B cells. We find that FcγRIIB-deficient cells respond significantly better than FcγRIIB-sufficient cells when stimulated with DNA ICs that incorporate low affinity TLR9 ligand (CG-poor dsDNA fragments). AM14 B cells also respond to RNA-associated ICs through BCR/TLR7 coengagement, but such BCR/TLR7 dependent responses are normally highly dependent on IFNα costimulation. However, we now show that AM14 FcγRIIB-/- B cells are very effectively activated by RNA ICs without supplemental IFNα priming. These results demonstrate that FcγRIIB can effectively modulate both BCR/TLR9 and BCR/TLR7 endosomal-dependent activation of autoreactive B cells.
Autorective B cells; endogenous TLR ligands; inhibitory Fc receptor
Polymorphous skin rashes are one of the major presentations in children with Kawasaki disease. This report describes an unusual presentation of a skin rash (non-Langerhans cell histiocytosis) in a 4-month-old baby with resistance to intravenous immunoglobulin (IVIG) treatment and coronary artery dilatation. Though refractory to repeat dosages of IVIG treatment, the patient had a favourable response to methylprednisolone pulse therapy.
Kawasaki disease (KD) is characterized by systemic vasculitis of unknown etiology. High-dose intravenous immunoglobulin (IVIG) is the most effective therapy for KD to reduce the prevalence of coronary artery lesion (CAL) formation. Recently, the α2, 6 sialylated IgG was reported to interact with a lectin receptor, specific intracellular adhesion molecule-3 grabbing nonintegrin homolog-related 1 (SIGN-R1) in mice and dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN) in human, and to trigger an anti-inflammatory cascade. This study was conducted to investigate whether the polymorphism of DC-SIGN (CD209) promoter −336 A/G (rs4804803) is responsible for susceptibility and CAL formation in KD patients using Custom TaqMan SNP Genotyping Assays. A total of 521 subjects (278 KD patients and 243 controls) were investigated to identify an SNP of rs4804803, and they were studied and showed a significant association between the genotypes and allele frequency of rs4804803 in control subjects and KD patients (P = 0.004 under the dominant model). However, the promoter variant of DC-SIGN gene was not associated with the occurrence of IVIG resistance, CAL formation in KD. The G allele of DC-SIGN promoter −336 (rs4804803) is a risk allele in the development of KD.
The aim of this study was to evaluate the efficacy of low-dose oral methotrexate (MTX) as a treatment for patients with Kawasaki disease (KD) which was resistant to intravenous immunoglobulin (IVIG).
Patients and Methods
The patients who had persistent or recrudescent fever after treatment with IVIG were subsequently treated with low-dose oral MTX [10 mg/body surface area (BSA)] once weekly.
Seventeen patients developed persistent or recrudescent fever after treatment of KD with IVIG and were consequently given MTX. The proportion of children with coronary artery lesions (CALs) was 76%. The median value of maximum body temperatures decreased significantly within 24 hours of MTX therapy (38.6℃ vs. 37.0℃, p < 0.001). The median CRP (C-reactive protein) level was found to be significantly lower 1 week after administering the first dose of MTX (8.9 mg/dL vs. 1.2 mg/dL, p < 0.001). The median duration of fever before MTX treatment was shorter in CALs (-) group than in CALs (+) group (7 days vs. 10 days, p = 0.023). No adverse effects of MTX were observed.
MTX treatment for
IVIG-resistant KD resulted in quick resolution of fever and rapid improvement of inflammation markers without causing any adverse effects. MTX therapy should further be assessed in a multicenter, placebo-blinded trial to evaluate whether it also improves coronary artery outcome.
Kawasaki disease; methotrexate; resistance to immunoglobulin
Aseptic meningitis is a serious adverse reaction to intravenous immunoglobulin (IVIG) therapy. We studied the clinical characteristics of patients with acute Kawasaki disease (KD) who developed IVIG-induced aseptic meningitis.
A retrospective analysis of the medical records of patients with KD who developed aseptic meningitis after IVIG treatment was performed.
During the 10-year period from 2000 through 2009, among a total of 384 patients with Kawasaki disease, 4 (3 females and 1 male; age range, 19-120 months) developed aseptic meningitis after IVIG. All 4 developed aseptic meningitis within 48 hours (range, 25-40 hours) of initiation of IVIG. The analyses of cerebrospinal fluid (CSF) revealed elevated white blood cell counts (22-1,248/μL) in all 4 patients; a predominance of polynuclear cells (65%-89%) was noted in 3. The CSF protein level was elevated in only 1 patient (59 mg/dL), and the glucose levels were normal in all 4 patients. Two patients were treated with intravenous methylprednisolone; the other 2 children were observed carefully without any special therapy. All patients recovered without neurological complications.
In our patients with Kawasaki disease, aseptic meningitis induced by IVIG occurred within 48 hours after initiation of IVIG, resolved within a few days, and resulted in no neurological complications, even in patients who did not receive medical treatment.
Kawasaki disease; intravenous immunoglobulin; aseptic meningitis
The aims of this study were to determine the occurrence and variables associated with the initial intravenous immunoglobulin (IVIG) treatment failure in Kawasaki disease (KD) and to categorize differences in clinical characteristics between responders and nonresponders to initial IVIG treatment. Patients were classified into two groups. Group A included 33 patients who received a single dose of IVIG treatment and responded. Group B included 18 patients who received more than two doses of IVIG due to failure of the initial treatment. The mean duration of fever after initial treatment in group B was significantly longer than it was in group A. In group B, we found that higher bilirubin, aspartate aminotransferase (AST), polymorphonuclear cells (PMN) (%), and lower platelet values at baseline were independent predictors of persistent or recurrent fever in patients with KD. Coronary artery abnormalities were found in 8 patients (44.4%) in group B and in two patients (6.1%) in group A. We found that abnormal liver function tests and a lower platelet count at baseline were possible predictors of nonresponders to IVIG in patients with KD. There is a need for a prospective study focused on baseline hepatobiliary parameters.
Coronary Aneurysm; Immunoglobulins, Intravenous; Mucocutaneous Lymph Node Syndrome; Treatment Failure
The etiology of Kawasaki Disease (KD) is enigmatic, although an infectious cause is suspected. Polymorphisms in CC chemokine receptor 5 (CCR5) and/or its potent ligand CCL3L1 influence KD susceptibility in US, European and Korean populations. However, the influence of these variations on KD susceptibility, coronary artery lesions (CAL) and response to intravenous immunoglobulin (IVIG) in Japanese children, who have the highest incidence of KD, is unknown.
We used unconditional logistic regression analyses to determine the associations of the copy number of the CCL3L1 gene-containing duplication and CCR2-CCR5 haplotypes in 133 Japanese KD cases [33 with CAL and 25 with resistance to IVIG] and 312 Japanese controls without a history of KD. We observed that the deviation from the population average of four CCL3L1 copies (i.e., < or > four copies) was associated with an increased risk of KD and IVIG resistance (adjusted odds ratio (OR) = 2.25, p = 0.004 and OR = 6.26, p = 0.089, respectively). Heterozygosity for the CCR5 HHF*2 haplotype was associated with a reduced risk of both IVIG resistance (OR = 0.21, p = 0.026) and CAL development (OR = 0.44, p = 0.071).
The CCL3L1-CCR5 axis may play an important role in KD pathogenesis. In addition to clinical and laboratory parameters, genetic markers may also predict risk of CAL and resistance to IVIG.
Although intravenous immunoglobulin (IVIG) is highly effective in Kawasaki disease (KD), mechanisms are not understood and 10-20% of patients are treatment-resistant, manifesting a higher rate of coronary artery aneurysms. Murine models suggest that α2-6-linked sialic acid (α2-6Sia) content of IVIG is critical for suppressing inflammation. However, pro-inflammatory states also up-regulate endogenous levels of β-galactoside:α2-6 sialyltransferase-I (ST6Gal-I), the enzyme that catalyzes addition of α2-6Sias to N-glycans. We asked whether IVIG failures correlated with levels of α2-6Sia on infused IVIG or on the patient’s own endogenous IgG.
We quantified levels of α2-6Sia in infused IVIG and endogenous IgG from 10 IVIG-responsive and 10 resistant KD subjects using multiple approaches. Transcript levels of ST6GAL1, in patient whole blood and B cell lines were evaluated by RT-PCR. Plasma soluble (s)ST6Gal-I levels were measured by ELISA.
There was no consistent difference in median sialylation levels of infused IVIG between groups. However, α2-6Sia levels in endogenous IgG, ST6GAL1 transcript levels, and ST6Gal-I protein in serum from IVIG-resistant KD subjects were lower than in responsive subjects at both pre-treatment and one-year time points (p <0.001, respectively).
Our data indicate sialylation levels of therapeutic IVIG are unrelated to treatment response in KD. Rather, lower sialylation of endogenous IgG and lower blood levels of ST6GALI mRNA and ST6Gal-I enzyme predict therapy resistance. These differences were stable over time, suggesting a genetic basis. Because IVIG-resistance increases risk of coronary artery aneurysms, our findings have important implications for the identification and treatment of such individuals.
The 2004 American Heart Association (AHA) statement included a clinical case definition and an algorithm for diagnosing and treating suspected incomplete Kawasaki disease (KD). We explored the performance of these recommendations in a multicenter series of US patients with KD with coronary artery aneurysms (CAAs).
We reviewed retrospectively records of patients with KD with CAAs at 4 US centers from 1981 to 2006. CAAs were defined on the basis of z scores of >3 or Japanese Ministry of Health and Welfare criteria. Our primary outcome was the proportion of patients presenting at illness day ≤21 who would have received intravenous immunoglobulin (IVIG) treatment by following the AHA guidelines at the time of their initial presentation to the clinical center.
Of 195 patients who met entry criteria, 137 (70%) met the case definition and would have received IVIG treatment at presentation. Fifty-three patients (27%) had suspected incomplete KD and were eligible for algorithm application; all would have received IVIG treatment at presentation. Of the remaining 5 patients, 3 were excluded from the algorithm because of fever for <5 days at presentation and 2 because of <2 clinical criteria at >6 months of age. Two of these 5 patients would have entered the algorithm and received IVIG treatment after follow-up monitoring. Overall, application of the AHA algorithm would have referred ≥190 patients (97%) for IVIG treatment.
Application of the 2004 AHA recommendations, compared with the classic criteria alone, improves the rate of IVIG treatment for patients with KD who develop CAAs. Future multicenter prospective studies are needed to assess the performance characteristics of the AHA algorithm in febrile children with incomplete criterion findings and to refine the algorithm further.
Kawasaki disease; guidelines; diagnostic recommendations; cardiac disease; coronary aneurysm
Introduction of heterologous anti–glomerular basement membrane antiserum (nephrotoxic serum, NTS) into presensitized mice triggers the production of IgG anti-NTS antibodies that are predominantly IgG2b and the glomerular deposition of pathogenic immune complexes, leading to accelerated renal disease. The pathology observed in this model is determined by the effector cell activation threshold that is established by the coexpression on infiltrating macrophages of the IgG2a/2b restricted activation receptor FcγRIV and its inhibitory receptor counterpart, FcγRIIB. Blocking FcγRIV with a specific monoclonal antibody thereby preventing IgG2b engagement or treatment with high dose intravenous γ-globulin (IVIG) to down-regulate FcγRIV while up-regulating FcγRIIB, protects mice from fatal disease. In the absence of FcγRIIB, IVIG is not protective; this indicates that reduced FcγRIV expression alone is insufficient to protect animals from pathogenic IgG2b immune complexes. These results establish the significance of specific IgG subclasses and their cognate FcγRs in renal disease.
FcγRIIb is an inhibitory Fc receptor expressed on B cells and myeloid cells. It is important in controlling responses to infection, and reduced expression or function predisposes to autoimmunity. To determine if increased expression of FcγRIIb can modulate these processes, we created transgenic mice overexpressing FcγRIIb on B cells or macrophages. Overexpression of FcγRIIb on B cells reduced the immunoglobulin G component of T-dependent immune responses, led to early resolution of collagen-induced arthritis (CIA), and reduced spontaneous systemic lupus erythematosus (SLE). In contrast, overexpression on macrophages had no effect on immune responses, CIA, or SLE but increased mortality after Streptococcus pneumoniae infection. These results help define the role of FcγRIIb in immune responses, demonstrate the contrasting roles played by FcγRIIb on B cells and macrophages in the control of infection and autoimmunity, and emphasize the therapeutic potential for modulation of FcγRIIb expression on B cells in inflammatory and autoimmune disease.
To explore the increased incidence of intravenous immunoglobulin (IVIG) resistance among San Diego County Kawasaki disease (KD) patients in 2006 and to evaluate a scoring system to predict IVIG-resistant patients with KD.
We performed a retrospective review of patients with KD treated within 10 days of fever onset. Using multivariate analysis, independent predictors of IVIG-resistance were combined into a scoring system.
In 2006, 38.3 % of patients with KD in San Diego County were IVIG-resistant, a significant increase over previous years. IVIG-resistance was not associated with a particular brand or lot of IVIG. Resistant patients were diagnosed earlier, had higher % bands, and higher concentrations of C-reactive protein, alanine aminotransferase, and γ-glutamyl transferase (GGT). They also had lower platelet counts and age-adjusted hemoglobin (zHgb) concentrations and were more likely to have aneurysms (p=0.0008). A scoring system developed to predict IVIG-resistant patients using illness day, % bands, GGT, and zHgb, had a sensitivity of 73.3% and specificity of 61.9%.
An unexplained increase in IVIG-resistance was noted among patients with KD in San Diego County in 2006. Scoring systems based on demographic and laboratory data were insufficiently accurate to be clinically useful in our ethnically diverse population.
coronary artery aneurysm; vasculitis; pediatrics
As outlined in the 2004 American Heart Association guidelines, the diagnosis of Kawasaki disease (KD) is supported by results of clinical laboratory studies. However, detailed information regarding the evolution of these results during illness has not been previously reported. The goals of this project were to characterize the evolution of clinical laboratory values in KD before and after treatment with intravenous immunoglobulin (IVIG).
Laboratory values from 380 unselected, consecutive KD patients were analyzed at 3 times: acute (illness day 2-10, illness day 1= first day of fever and before IVIG), subacute (illness day 11-21) and convalescent (illness day 22-60). Results were stratified by IVIG response and coronary artery outcome.
While white blood cell count, percentage bands, erythrocyte sedimentation rate (ESR), and CRP values were highest and age-adjusted hemoglobin was lowest in the acute phase before IVIG, platelet count was highest in the subacute phase and percentage lymphocytes and eosinophils were highest in the convalescent phase after IVIG. KD patients with coronary artery aneurysms had a higher WBC count in the subacute phase and higher ESR in the subacute and convalescent phases compared with those with dilated or normal coronary arteries.
A consistent evolution of laboratory values is associated with KD before and after treatment. Understanding the dynamic changes in laboratory values can assist physicians in using laboratory criteria to diagnose KD following the American Heart Association guidelines.
Kawasaki disease; laboratory values
Background and Objectives
High-dose intravenous immunoglobulin (IVIG) (2 g/kg) is usually given in the treatment of Kawasaki disease (KD). According to the authors' experience, however, medium-dose immunoglobulin (1 g/kg) was also effective in the majority of patients. We performed a retrospective clinical study to validate effectiveness of the medium-dose regimen in treatment of KD.
Subjects and Methods
A total of 274 patients with KD who were treated with medium-dose immunoglobulin at Bundang Jesaeng General Hospital from July 1998 to October 2007 were enrolled.
Medium-dose immunoglobulin was given once in 220 patients (group A; 80.3%) and twice or more in 54 patients (group B; 19.7%). Age and gender distributions, duration of fever before treatment, hemoglobin concentrations, and white blood cell and platelet counts did not differ significantly between the two groups (p>0.05). Concentrations of C-reactive protein, aspartate aminotransferase, alanine aminotransferase, and bilirubin were significantly higher in group B (p<0.005). Coronary arterial lesions (CAL) were found in 51 patients (23.2%) in group A and in 26 patients (48.1%) in group B during the acute stage, and in 14 patients (6.4%) in group A and in 11 patients (20.4%) in group B during the convalescent stage (p<0.005, respectively). A giant aneurysm was found in one patient in each group (0.5% in group A and 1.9% in group B; p<0.005) during the follow-up period.
A single infusion of medium-dose immunoglobulin was effective in 80% of patients with KD. About 20% of patients required two or more infusions of medium-dose immunoglobulin, who had higher concentrations of C-reactive protein, aspartate aminotransferase, alanine aminotransferase and bilirubin. The authors think that the medium-dose regimen proffers an advantage over the high-dose regimen in view of cost-effectiveness.
Kawasaki disease; Immunoglobulin; Intravenous infusions