Intravenous Immunoglobulin Response Research Articles

Elevated Serum IL-17A in Kawasaki Disease Patients Predicts Responsiveness to Intravenous Immunoglobulin Therapy

Introduction: This study aimed to investigate the correlation between serum interleukin (IL)-17A levels and responsiveness to intravenous immunoglobulin (IVIG) therapy in Kawasaki disease (KD) patients. Methods: A retrospective analysis on data from 192 KD patients admitted to the Anqing Municipal Hospital between January 2021 and January 2024 was conducted. Patients were categorized into IVIG-nonresponsive and IVIG-sensitive groups as per the treatment outcomes. Outcome measures included serum IL-17A levels, left coronary artery (LCA) Z scores, and relevant laboratory parameters. Logistic regression analysis was performed to identify predictive factors for IVIG responsiveness, and diagnostic performance was assessed using receiver operating characteristic (ROC) curves and calculation of the area under the curve (AUC). Results: A total of 40 IVIG-nonresponsive cases and 152 IVIG-sensitive cases were included. Prior to intervention, IVIG-nonresponsive patients had significantly higher serum IL-17A levels compared to IVIG-sensitive patients, with a statistically significant difference. After intervention, serum IL-17A levels significantly decreased in IVIG-sensitive patients while remaining elevated in IVIG-nonresponsive patients. IVIG-nonresponsive patients exhibited significantly higher levels of C-reactive protein (CRP), white blood cell count (WBC), NE, and ALT compared to IVIG-sensitive patients, whereas no significant differences in LCA Z scores between the two groups existed. Multivariable logistic regression analysis identified pre-IL-17A, CRP, WBC, and ALT as independent predictors of IVIG-nonresponsiveness in KD. When pre-IL-17A was ≥39.96 pg/mL, the specificity and sensitivity for predicting IVIG-nonresponsive KD were 63.9% and 71.9%, respectively, with an AUC of 0.637. The combined diagnosis of IL-17A, CRP, WBC, and ALT yielded an AUC of 0.780. Conclusion: Serum IL-17A levels were remarkably elevated in IVIG-nonresponsive KD patients both before and after intervention. A serum IL-17A level (≥39.96 pg/mL) demonstrated good predictive profile for IVIG-nonresponsive KD, and combining IL-17A with CRP, WBC, and ALT improved diagnostic performance.

The changes of coagulation profiles in Kawasaki disease and its associations with clinical classification, intravenous immunoglobulin responsiveness and coronary artery involvement

Coagulation disorders are common in Kawasaki disease (KD). The main objectives of the present study were to probe the associations of coagulation profiles with clinical classification, IVIG responsiveness, coronary artery abnormalities (CAAs) in the acute episode of KD. A total of 313 KD children were recruited and divided into six subgroups, including complete KD (n = 217), incomplete KD (n = 96), IVIG-responsive KD (n = 293), IVIG-nonresponsive KD (n = 20), coronary artery noninvolvement KD (n = 284) and coronary artery involvement KD (n = 29). Blood samples were collected within 24-h pre-IVIG therapy and 48-h post-IVIG therapy. Coagulation profiles, conventional inflammatory mediators and blood cell counts were detected. Echocardiography was performed during the period from 2- to 14-day post-IVIG infusion. In addition, 315 sex- and age-matched healthy children were enrolled as the controls. (1) Before IVIG therapy, coagulation disorders were more prone to appear in KD patients than in healthy controls, and could be overcome by IVIG therapy. FIB and DD significantly increased in the acute phase of KD, whereas reduced to normal levels after IVIG therapy. (2) PT and APTT were significantly longer in patients with complete KD when compared with their incomplete counterparts after IVIG therapy. (3) The larger δDD, δFDP and the smaller δPT, δINR predicted IVIG nonresponsiveness. (4) The higher δDD and δFDP correlated with a higher risk for CAAs (DD: r = −0.72, FDP: r = −0.54). Coagulation disorders are correlated with complete phenotype, IVIG nonresponsiveness and CAA occurrence in the acute episode of KD, and can be rectified by synergistic effects of IVIG and aspirin.

Pharmacogenomics of intravenous immunoglobulin response in Kawasaki disease.

Kawasaki disease (KD) is a diffuse vasculitis in children. Response to high dose intravenous gamma globulin (IVIG), the primary treatment, varies according to genetic background. We sought to identify genetic loci, which associate with treatment response using whole genome sequencing (WGS). We performed WGS in 472 KD patients with 305 IVIG responders and 167 non-responders defined by AHA clinical criteria. We conducted logistic regression models to test additive genetic effect in the entire cohort and in four subgroups defined by ancestry information markers (Whites, African Americans, Asians, and Hispanics). We performed functional mapping and annotation using FUMA to examine genetic variants that are potentially involved IVIG non-response. Further, we conducted SNP-set [Sequence] Kernel Association Test (SKAT) for all rare and common variants. Of the 43,288,336 SNPs (23,660,970 in intergenic regions, 16,764,594 in introns and 556,814 in the exons) identified, the top ten hits associated with IVIG non-response were in FANK1, MAP2K3:KCNJ12, CA10, FRG1DP, CWH43 regions. When analyzed separately in ancestry-based racial subgroups, SNPs in several novel genes were associated. A total of 23 possible causal genes were pinpointed by positional and chromatin mapping. SKAT analysis demonstrated association in the entire MANIA2, EDN1, SFMBT2, and PPP2R5E genes and segments of CSMD2, LINC01317, HIVEPI, HSP90AB1, and TTLL11 genes. This WGS study identified multiple predominantly novel understudied genes associated with IVIG response. These data can serve to inform regarding pathogenesis of KD, as well as lay ground work for developing treatment response predictors.

Effectiveness of two same-manufacturer intravenous immunoglobulin for Kawasaki disease

BackgroundTo investigate whether two brands of intravenous immunoglobulin (IVIG) from the same manufacturer lead to varied effects when administered to patients with Kawasaki disease. (KD) MethodsClinical characteristics, laboratory data, IVIG response, and coronary arteries change were analyzed between two groups. ResultsWe included 158 KD cases. The mean age at KD diagnosis was 23 ± 1.39 (range, 2–95) months. In the first IVIG course, 18 (11.4 %) patients were unresponsive. TBSF (brand T) and Privigen (brand P) were administered to 94 and 64 patients, respectively. The brand P group had a significantly longer fever (P < 0.001) and hospitalization (P = 0.007) durations after the therapy and a higher number of IVIG unresponsiveness (P = 0.016) than the brand T group. In the multivariate logistic regression analysis, a high Formosa score (≥3, Odds ratio [OR], 4.939; 95 % confidence interval [CI], 1.199–20.337; P = 0.027), high levels of CRP (≥12 mg/L, OR: 4.257,95 % CI,1.265–14.322; P = 0.019), and treatment with brand P (OR, 3.621; 95 % CI, 1.029–12.677; P = 0.045) were independent risk factors for IVIG unresponsiveness. ConclusionsCompared with brand T, brand P prolonged the fever and hospitalization durations after IVIG treatment and increased the proportion of IVIG treatment unresponsiveness, but it did not infer the coronary arteries sequelae.

Platelet Count Response to Obstetrical Use of IVIG for Maternal Thrombocytopenia: A 14-Year Retrospective Study

Introduction: Thrombocytopenia affects approximately 10% of pregnant individuals with Gestational Thrombocytopenia (GT) accounting for 80% of cases and Immune Thrombocytopenia (ITP) representing 3% of cases. Distinguishing between GT and ITP is challenging, leading to many pregnant individuals with moderate thrombocytopenia receiving treatment for ‘possible ITP’ with Intravenous Immunoglobulin (IVIG) in attempt to raise platelet counts (PLT) for safe labor and delivery and to potentially allow for neuraxial anesthesia. However, evidence on the impact of IVIG on PLT during pregnancy remains limited, and predictive factors for IVIG response are lacking. We aim to investigate the effect of IVIG on PLT in pregnant individuals with moderate thrombocytopenia (PLT &amp;lt; 100 x 10 9/L). The specific objectives are to assess the incremental response in maternal PLT following IVIG administration, the proportion of PLT exceeding 80 x 10 9/L after IVIG administration, the proportion of incremental increase in PLT by more than 20 x 10 9/L following IVIG administration, and to identify factors associated with these outcomes. Methods: We conducted a retrospective cohort study using administrative and chart review data between 2007-2020. We included all pregnant individuals who received IVIG for moderate thrombocytopenia. Data collected encompassed parameters such as age, gestational age at delivery, platelet counts at various timepoints, highest immature platelet fraction (IPF) during pregnancy, IVIG dose and frequency, hemoglobin levels, transfusions, and corticosteroid use. Data were analyzed using descriptive statistics. Paired t-test was used to compare means of PLT pre- and post-IVIG administration. Simple logistic regression was used to assess predictors of PLT ≥ 80 x10 9/L and PLT increment ≥ 20 x10 9/L post-IVIG. Results: Out of 651 deliveries with moderate thrombocytopenia, 79 (12.1%) received IVIG for a total of 4,527.50 grams and a median dose of 60 g (IQR: 30 - 77.5). Excluding 22 pregnancies due to other interventions such as platelet transfusions (n=12), corticosteroids (n=7), or both (n=3), 57 remained for analysis. The median incremental response in PLT following IVIG administration was 27 x10 9/L (IQR: 3-94). Pre-IVIG PLT median was 65 x10 9/L (IQR: 48-73), and post-IVIG PLT median was 98 x10 9/L (IQR: 69-142). PLT increment ≥ 20 x 10 9/L following IVIG was observed in 54.4% (31/57) of deliveries, and 57.9% (33/57) of deliveries achieved PLT ≥ 80 x 10 9/L following IVIG administration. Mean PLT post-IVIG (M = 112.51 x10 9/L, SD 55.88) were significantly greater than pre-IVIG PLT (M = 59 x10 9/L, SD = 19.71) by 53.51 points, p = &amp;lt; .001. Nadir PLT &amp;lt; 30 in pregnancy was associated with a statistically significant increase in PLT ≥ 80 x10 9/L following IVIG (odds ratio (OR) = 6.29, 95% confidence interval (CI) = 1.25-31.51, p &amp;lt; 0.05) and PLT increment ≥ 20 x10 9/L (OR = 7.58, 95% CI = 1.51-38.05, p &amp;lt; 0.05). An IPF &amp;lt; 16% was also associated with a statistically significant increase in PLT ≥ 80 x10 9/L (OR = 4.85, 95% CI = 1.08-21.76, p &amp;lt; 0.05) and PLT increment ≥ 20 x10 9/L (OR = 4.85, 95% CI = 1.08 - 21.76, p &amp;lt; 0.05). Moreover, a post-IVIG PLT increment ≥ 20 x10 9/L was positively associated with pre-IVIG PLT below 50 x10 9/L (OR = 8.67, 95% CI = 1.73 - 43.33, p &amp;lt; 0.05), but negatively associated with PLT 70-100 x10 9/L (OR = 0.18, 95% CI = 0.05 - 0.57, p &amp;lt; 0.05). For post-IVIG PLT ≥ 80 x10 9/L, there were no statistically significant relationships with gestational age, maternal age, pre-pregnant PLT or pre-IVIG PLT. Similarly, for post-IVIG PLT increment ≥ 20 x10 9/L, there were no statistically significant relationships with GA, maternal age, pre-pregnant PLT, or a pre-IVIG PLT between 50-69 x10 9/L. Conclusions: IVIG administration shows promising results for pregnant individuals with moderate thrombocytopenia. The study highlights the importance of nadir PLT in pregnancy, IPF levels, and pre-IVIG PLT as potential factors influencing the response to IVIG treatment. Our study is limited by its retrospective and single-centered design, and small sample size. Nevertheless, these findings generate hypotheses and could inform future prospective multicenter studies to optimize IVIG administration in this setting, considering its effectiveness and potential risks while minimizing costs.

Serum amyloid A as a biomarker for immunoglobulin resistance in Kawasaki disease

Background Intravenous immunoglobulin (IVIG) resistance is of prime importance in Kawasaki disease (KD). In this study, we examined the value and mechanism of serum amyloid A (SAA) level in predicting IVIG resistance in patients with KD. Methods SAA levels were measured in 497 consecutive patients with KD before IVIG therapy in the training set. The patients were divided into two groups (IVIG-responsive and IVIG-resistant) according to the American Heart Association (AHA) definition of IVIG resistance. Demographic, echocardiographic, and laboratory data were also retrospectively analyzed and tabulated to predict IVIG resistance. The predictive value of SAA was validated on test sets of prospective data. Cytokine microarrays were analyzed from 4 patients with resistant to IVIG, 4 patients with responsive to IVIG and 4 healthy volunteers. Results During the training set, 409 patients with KD were enrolled, of whom 43 (10.5%) were resistant to initial IVIG treatment and 47 (11.49%) had coronary artery lesions (CALs). Serum levels of SAA were higher in the IVIG resistant group compared to the IVIG responsive group, (380.00 [204.40–547.25] vs 230.85 [105.40–490.00] mg/L; p = .008). The values of total bilirubin, C-reactive protein, neutrophils, alanine aminotransferase, aspartate aminotransferase, interleukin-6(IL-6), and procalcitonin were significantly higher in the IVIG-resistant group than in the IVIG-responsive group (p < .05); however, the lymphocytes, platelets, serum sodium levels, and duration of fever before IVIG therapy were significantly lower (p < .05). There was no significant difference in SAA levels between patients with KD with and without CALs. Binary logistic regression analysis showed that SAA (p = .008), neutrophils (p < .001), total bilirubin (p = .001), platelet count (p = .004), and serum sodium level (p = .019) were independent factors influencing IVIG resistance. The optimal cutoff value of SAA for IVIG resistance prediction was 252.45 mg/L, with a corresponding clinical sensitivity of 69.8% and specificity of 54.4%. Based on receiver operating characteristic (ROC) curve analyses, the area under the curve (AUC) of combined detection with these five indicators was 0.800, clinical sensitivity was 69.8%, and specificity was 76.2%. In the prospective data, the sensitivity, specificity, and accuracy of SAA for identifying IVIG resistance KD were 77.8%,69.0%, and 70.0%, respectively. Compared with IVIG- responsive group and healthy children, the levels of IL-6 was upregulated significantly in IVIG-resistant group through cytokine microarrays. Conclusions SAA may be a potential biomarker for predicting IVIG responsiveness to KD, Combined detection of SAA levels, total bilirubin, neutrophil count, platelet count, and serum sodium levels is superior to that of any other single indicator for predicting IVIG resistance in KD. And elevated SAA may accompany with IL-6 in KD patients, its use in clinical practice may be helpful for treatment management.

Association between Rab31/rs9965664 polymorphism and immunoglobulin therapy resistance in patients with Kawasaki disease.

Kawasaki disease (KD) is an acute febrile systemic vasculitis affecting infants and young children. A high dose of intravenous immunoglobulin (IVIG) is the first-line strategy for patients with KD to reduce persistent inflammation and the risk of coronary artery aneurysm (CAA) formation. Unfortunately, 10-20% of the patients showed no response to the treatment and were defined as resistant to IVIG. Rab31 has been reported to regulate innate immunity in several human diseases. However, whether single nucleotide polymorphism (SNP) in Rab31 gene could predispose to IVIG therapy response in KD was uncovered. Rab31/rs9965664 polymorphism was genotyped in 1,024 Chinese patients with KD through TaqMan assay. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of association between Rab31/rs9965664 polymorphism and IVIG therapeutic effects. Our results showed that Rab31/rs9965664 AA/GA genotype was significantly associated with an increased risk of IVIG resistance compared to GG genotype (GA vs. GG: p = 0.0249; AA vs. GG: p = 0.0016; AA/GA vs. GG: p = 0.0039; and AA vs. GG/GA: p = 0.0072). Moreover, the KD individuals carrying the rs9965664 A allele displayed lower Rab31 protein levels, and the expression level of Rab31 in the IVIG-resistant group was decreased significantly when compared to that observed in the response group. A mechanical study demonstrated that Rab31 modulated IVIG response through NLRP3 and p38 pathways. These results suggested that Rab31/rs9965664 polymorphism might be associated with an increased risk of IVIG resistance in southern Chinese patients with KD. The possible mechanism is that Rab31 regulates the NLRP3 pathway negatively to inhibit IVIG response.

Systems biology and artificial intelligence analysis highlights the pleiotropic effect of IVIg therapy in autoimmune diseases with a predominant role on B cells and complement system.

Intravenous immunoglobulin (IVIg) is used as treatment for several autoimmune and inflammatory conditions, but its specific mechanisms are not fully understood. Herein, we aimed to evaluate, using systems biology and artificial intelligence techniques, the differences in the pathophysiological pathways of autoimmune and inflammatory conditions that show diverse responses to IVIg treatment. We also intended to determine the targets of IVIg involved in the best treatment response of the evaluated diseases. Our selection and classification of diseases was based on a previously published systematic review, and we performed the disease characterization through manual curation of the literature. Furthermore, we undertook the mechanistic evaluation with artificial neural networks and pathway enrichment analyses. A set of 26 diseases was selected, classified, and compared. Our results indicated that diseases clearly benefiting from IVIg treatment were mainly characterized by deregulated processes in B cells and the complement system. Indeed, our results show that proteins related to B-cell and complement system pathways, which are targeted by IVIg, are involved in the clinical response. In addition, targets related to other immune processes may also play an important role in the IVIg response, supporting its wide range of actions through several mechanisms. Although B-cell responses and complement system have a key role in diseases benefiting from IVIg, protein targets involved in such processes are not necessarily the same in those diseases. Therefore, IVIg appeared to have a pleiotropic effect that may involve the collaborative participation of several proteins. This broad spectrum of targets and ‘non-specificity’ of IVIg could be key to its efficacy in very different diseases.

Autoimmune nodopathies, an emerging diagnostic category.

In the last decade, antibodies targeting cell adhesion molecules of the node of Ranvier were described in patients with autoimmune neuropathies. These nodal/paranodal antibodies associate with specific clinicopathological features that are different from classical chronic inflammatory demyelinating polyneuropathy (CIDP). In this review, we will summarize recent findings establishing autoimmune nodopathies (AN) as a new category of autoimmune neuropathies. AN include anti-contactin 1, anti-contactin-associated protein 1, anti-neurofascin 155 and anti-pan-neurofascin antibody-mediated neuropathies. Their clinical spectrum includes acute, subacute or chronic onset sensory-motor neuropathies mimicking Guillain-Barré syndrome (GBS) and CIDP, although they differ in their response to standard therapy with intravenous immunoglobulin (IVIG). Neurophysiologically they overlap with acquired demyelinating neuropathies, but ultrastructural studies and animal models demonstrated antibody-mediated pathology restricted to the node of Ranvier. Anti-contactin1 and anti-pan-neurofascin also associate with nephrotic syndrome. Nodal/paranodal antibodies are predominantly of the immunoglobulin (IgG)4 subclass during the chronic phase of the disease, but complement-fixing IgG3 antibodies are detected during the early phase and associate with aggressive onset and IVIG response. Nodal/paranodal antibodies testing is key in the diagnosis of AN. AN have emerged as a new diagnostic category pathologically different from acquired demyelinating neuropathies. Clinically they overlap with GBS and CIDP although they associate with specific clinical features that should lead to clinical suspicion. Nodal/paranodal antibodies are key effector mechanisms of disease and good diagnostic and disease-monitoring biomarkers in AN.

Association of Genetic Polymorphisms in Kawasaki Disease with the Response to Intravenous Immunoglobulin Therapy.

Kawasaki disease (KD) is an acute febrile and systemic vasculitis disease mainly affecting children < 5years old. Although the first case of KD was reported in 1967 and despite extensive research on KD since then, the cause of the disease remains largely unknown. The most common complications of KD are coronary artery lesions (CAL), which significantly increase the risk of coronary heart disease. The standard treatment for KD is high-dose intravenous immunoglobulin (IVIG) plus aspirin within 10days from symptoms' appearance, which has been shown to decrease the incidence of CAL to 5-7%. Despite the benefits of IVIG, about 25% of the patients treated with IVIG develop resistance or are unresponsive to the therapy, which represents an important risk factor for CAL development. The cause of IVIG unresponsiveness has not been fully elucidated. However, the role of gene polymorphisms in IVIG response has been suggested. Herein, we comprehensively review genetic polymorphisms in KD that have been associated with IVIG resistance/unresponsiveness and further discuss available models to predict IVIG unresponsiveness.Kindly check and confirm inserted city in affiliation [1] is correctly identified.confirm.

Serum alanine aminotransferase level and intravenous immunoglobulin resistance in patients with kawasaki disease.

Serum alanine aminotransferase (ALT) elevation is considered a risk factor for resistance to initial intravenous immunoglobulin (IVIG) treatment in patients with Kawasaki disease (KD). However, serum ALT levels change dramatically during acute KD illness. We tested the hypothesis that risk assessment for initial IVIG resistance based on serum ALT elevation may differ by examination day after KD onset. We analyzed 18,492 population-based patients who developed KD throughout Japan. First, we epidemiologically evaluated the serum ALT variation at 1‒10days after disease onset. Second, we conducted multivariable logistic regression to determine the association between serum ALT level and initial IVIG resistance according to timing of initial hospital visit by stratifying the patients into an early group (1‒5days after onset) and a late group (6‒10days after onset). Serum ALT rapidly increased after KD onset, peaked at day 4 of illness, and then declined regardless of IVIG responsiveness. The adjusted odds ratio (OR) increased with increasing serum ALT in the early group (adjusted OR [95% CI]: 1.44 [1.25-1.66], 1.94 [1.65-2.28], and 2.22 [1.99-2.48] for serum ALT 50-99, 100-199, and ≥ 200IU/L, respectively; reference ALT level: 1-49IU/L). No significant association was observed in the late group. The findings indicate that risk assessment for initial IVIG resistance based on serum ALT level may only be reliable for patients with KD who visit hospitals during early illness, specifically 1-5days after disease onset. Key Points Serum alanine aminotransferase level differed markedly according to examination days after Kawasaki disease onset. Serum alanine aminotransferase level declined toward normal range after day 5 of illness regardless of intravenous immunoglobulin responsiveness. Elevated serum alanine aminotransferase level was no longer a significant risk factor for initial intravenous immunoglobulin resistance when measured on delayed hospital visits. Risk assessment for initial intravenous immunoglobulin resistance based on serum alanine aminotransferase level may only be reliable for patients who visit hospitals during early illness, specifically 1-5days after disease onset.

The EIF2AK4/rs4594236 AG/GG Genotype Is a Hazard Factor of Immunoglobulin Therapy Resistance in Southern Chinese Kawasaki Disease Patients.

Background: Kawasaki disease (KD) is an acute, self-limited vasculitis disorder of unknown etiology in children. Immunologic abnormalities were detected during the acute phase of KD, which reflected that the effect cells of the activated immune system markedly increased cytokine production. High-dose intravenous immunoglobulin (IVIG) therapy is effective in resolving inflammation from KD and reducing occurrence of coronary artery abnormalities. However, 10%–20% of KD patients have no response to IVIG therapy, who were defined as IVIG resistance. Furthermore, these patients have persistent inflammation and increased risk of developing coronary artery aneurysm (CAA). EIF2AK4 is a stress sensor gene and can be activated by pathogen infection. In addition, the polymorphisms of EIF2AK4 were associated with various blood vessel disorders. However, it remains unclear whether the EIF2AK4 gene polymorphisms were related to IVIG therapy outcome in KD patients. Methods: EIF2AK4/rs4594236 polymorphism was genotyped in 795 IVIG response KD patients and 234 IVIG resistant KD patients through TaqMan, a real-time polymerase chain reaction. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of association between EIF2AK4/rs4594236 polymorphism and IVIG therapeutic effects. Results: Our results showed that the EIF2AK4/rs4594236 AG/GG genotype was significantly associated with increased risk to IVIG resistance compared to the AA genotype (AG vs. AA: adjusted ORs = 1.71, 95% CIs = 1.17–2.51, and p = 0.0061; GG vs. AA: adjusted ORs = 2.09, 95% CIs = 1.36–3.23, and p = 0.0009; AG/GG vs. AA: adjusted ORs = 1.82, 95% CIs = 1.27–2.63, and p = 0.0013; and GG vs. AA/AG: adjusted ORs = 1.45, 95% CI = 1.04–2.02, and p = 0.0306). Furthermore, the stratified analysis of age and gender in the KD cohort indicated that male patients carrying the rs4594236 AG/GG genotype tends to be more resistant to IVIG therapy than female patients. Conclusion: These results suggested that EIF2AK4/rs4594236 polymorphism might be associated with increased risk of IVIG resistance in southern Chinese KD patients.

Immunoglobulin use in childhood epilepsy

Background: Epilepsy's aetiology is well-known to include an immune component. Several clinical and laboratory research have discovered abnormalities in epileptic patients' immune system branches when compared to the general population. Such anomalies include immunoglobulin deficiencies (mainly immunoglobulin A and immunoglobulin G2), an increased prevalence of specific human leukocyte antigen types, and alterations in cytokine and interleukin profiles. In people with epilepsy, autoantibodies were discovered against glutamic acid decarboxylase, components of the voltage-gated potassium channel complex, and the N-methyl-D-aspartate, gamma-aminobutyric acid, a-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid, and glutamate receptor three receptors. Immune modulating drugs like corticosteroids and corticotrophin have also been demonstrated to help with seizures. In view of these findings, immunosuppressive medicine has potential as an add-on therapy for refractory epilepsy. Aim: We aimed to evaluate the efficacy of immunoglobulin in childhood epilepsy. Conclusion: Despite the fact that new medications are constantly being developed to treat intractable infantile epilepsy, the refractory rate remains high. Despite several investigations on the subject, predictive variables for a good intravenous immunoglobulin response have yet to be identified. In some epileptic disorders, such as idiopathic West syndrome and electrical status epilepticus during sleep, intravenous immunoglobulin appears to be beneficial.

Circulating Immune Cell Profile and Changes in Intravenous Immunoglobulin Responsiveness Over the Disease Course in Children With Kawasaki Disease.

Kawasaki disease (KD) is an acute, self-limited febrile illness of young children. The etiology of KD remains to be poorly understood. There has been limited research on longitudinal examination of peripheral blood leukocytes for immune profiling particularly in relation to treatment response with intravenous immunoglobulin (IVIG). This study profiles immune cells at the time of diagnosis and over the disease course. In addition, we identified the characteristics of the immune cells in IVIG-responsive patients with KD. We enrolled patients diagnosed with KD between May 1, 2017, and January 1, 2020. Blood was taken at least three times from all enrolled patients: at diagnosis (before IVIG infusion) and immediately and 2 weeks after IVIG infusion. We evaluated the laboratory findings and results of flow cytometry analysis of immune cells at all stages, focusing on CD4+ T lymphocytes, CD8+ T lymphocytes, CD19+ B lymphocytes, granulocytes, classical monocytes, and natural killer (NK) cells. Non-febrile healthy controls (NFCs) and other febrile controls (OFCs) were also enrolled. A total of 68 patients were enrolled and divided into two groups according to IVIG resistance status: IVIG-responsive (n = 55) and IVIG-resistant (n = 13). The total fever duration was significantly longer in the IVIG-resistant group (9.7 ± 5.3 days) than in the IVIG-responsive group (6.7 ± 3.0 days; P = 0.02). There was a significant difference in intermediate CD14+CD16+ monocytes between KD patients and both NFC and OFCs; they were significantly higher and lower in KD patients than NFC and OFCs, respectively (P < 0.001). The levels of all three subtypes of NK cells were significantly lower in KD patients than in both NFC and OFCs (P < 0.001). Regarding IVIG responsiveness, CD14+CD16+ intermediate monocyte levels were significantly lower in the IVIG-resistant group (P < 0.001). In addition, CD56−CD16+ NK cell expression was significantly lower in the IVIG-resistant group than in the IVIG-responsive group (P = 0.002). In conclusion, our results suggest CD56−CD16+N NK cells and CD14+CD16+ intermediate monocytes might play an essential role in immunopathogenesis of KD. Further studies are warranted to explore the role of these subpopulations particularly for the observed association with coronary artery lesions (CAL) and treatment response.

Splenectomy Outcomes in Relapsed or Refractory Immune Thrombocytopenia according to First-Line Intravenous Immunoglobulin Response

Objectives: Although splenectomy has long been second-line option for immune thrombocytopenia (ITP) patients, an indicator that reliably predicts the efficacy of splenectomy is still being explored. We investigated the treatment outcomes of splenectomy as a second-line therapy for relapsed/refractory ITP according to first-line intravenous immunoglobulin (IVIG) responses. Methods: Fifty-two adult patients treated with splenectomy as second-line therapy for ITP between 2009 and 2019 were included, and they were classified according to first-line IVIG responses (no response to IVIG: nonresponders; only transient IVIG response shorter than 4 weeks: poor responders; IVIG response for a longer period; stable responders). The efficacy of splenectomy was analyzed in the three subgroups. Results: Of the 52 patients, 10 were IVIG nonresponders, 34 were poor responders, and the remaining 8 were stable responders. Response to splenectomy was observed in 50.0% of IVIG nonresponders, 94.1% of poor responders, and 100% of stable responders (p = 0.0030). Among the 45 patients who responded to splenectomy, 51.1% relapsed subsequently, and a significantly lower relapse rate was noted in the stable IVIG responders (12.5%, p = 0.0220) than in nonresponders (60.0%) and poor responders (59.4%). Conclusions: First-line IVIG response is indicated as a useful predictive factor for response to splenectomy.

Baseline Characteristics and Predictive Factors of Intravenous Immunoglobulin Response in Drug and Device Refractory Gastroparesis Symptoms.

Intravenous immunoglobulin (IVIG) has been shown in a small pilot series to be helpful for some patients with gastroparesis that is refractory to drugs, devices, and surgical therapies. Many but not all patients have serologic neuromuscular markers. We hypothesize that those patients with serologic markers and/or longer duration of therapy would have better responses to IVIG. We studied 47 patients with a diagnosis of gastroparesis and gastroparesis-like syndrome that had all failed previous therapies including available and investigational drugs, devices, and/or pyloric therapies. Patients had a standardized 12-week course of IVIG, dosed as 400 mg/kg per week intravenously. Symptom assessment was done with Food and Drug Administration (FDA) compliant traditional patient-reported outcomes. Success to IVIG was defined as 20% or greater reduction in average symptom scores from baseline to the latest evaluation. Fourteen patients (30%) had a response, and 33 (70%) had no response per our definition. Patients responding had a higher glutamic acid decarboxylase 65 positivity (64% vs. 30%, P =0.049, missing=3) and longer duration of therapy (>12 wk/continuous: 86% vs. 48%, P =0.09). In this moderately sized open-label series of refractory patients with gastroparesis symptoms treated with IVIG, 30% of patients responded. While serologic markers and extended therapies show a trend to greater response, neither was statistically significant, except for glutamic acid decarboxylase 65 which showed a higher positivity rate in responders. We conclude that a clinical trial of IVIG may be warranted in severely refractory patients with gastroparesis symptoms.

S1398 Should IVIG Be Used Alone or With Other Gastroparesis Therapies?

Introduction: Intravenous Immunoglobulin (IVIG) has been shown to be helpful for some patients with gastroparesis, many of whom have neuromuscular markers, that are refractory to available drugs, devices, and surgical therapies. We evaluated the effectiveness of IVIG therapy by itself compared with IVIG and Gastric Electrical Stimulation (GES) and/or pyloric therapy. Methods: We studied 112 patients with diagnosis of gastroparesis and gastroparesis-like syndrome (GLS) that had all failed previous therapies including available and investigational drugs, devices and/or pyloric therapies. Seventy-one patients had full thickness GI biopsies. Patients received standardized 12-week courses of IVIG, dosed as 400mg/kg per week IV. Symptom assessment was done with FDA compliant traditional patient reported outcomes including both upper and lower GI symptoms. Patients were categorized in a non-randomized fashion into three sub-groups: IVIG only; IVIG and GES; IVIG, GES with pyloric therapy. Success to IVIG was defined as 20% or greater reduction in average symptom scores from baseline to post-IVIG evaluation. Descriptive analysis was performed. Results: Overall, 28.6% of patients responded to IVIG therapy with or without other therapies. In these patients, the average duration of therapy was 39 weeks. IVIG solo therapy had higher response rates compared to IVIG along with GES and pyloric therapies (36.4% vs. 27.9% and 24.1%). IVIG combined with other therapies such as GES and pyloric therapy reduced the total duration of IVIG required (47.0 vs. 40.0 and 36.1 weeks). Conclusion: In this moderately-sized open label series of patients with gastroparesis symptoms treated with IVIG conjunction with other therapies for gastroparesis, 28.6% of patients responded. Use of other therapies for gastroparesis such as GES and pyloric therapies along with IVIG help reduce the duration of IVIG infusions. We conclude that a clinical trial of IVIG may be warranted in severely refractory patients with gastroparesis symptoms.Table 1.: Comparison of IVIG Response Amongst Various Sub-Groups.

Overlapping Features in Kawasaki Disease-Related Arthritis and Systemic-Onset Juvenile Idiopathic Arthritis: A Nationwide Study in Japan.

Background: Arthritis may occur after the diagnosis of Kawasaki disease (KD). Most cases are self-limiting; however, some patients require prolonged treatment.Method: To characterize KD-related arthritis, 14 patients who required arthritis treatment within 30 days after the diagnosis of KD were recruited from the 23rd KD survey in Japan. Twenty-six additional patients were included from our tertiary center and literature review cohorts.Results: The estimated prevalence of KD-related arthritis in Japan was 48 per 100,000 KD patients. Patients with KD-related arthritis had an older age at onset (52 vs. 28 months, P = 0.002) and higher rate of intravenous immunoglobulin (IVIG) resistance in comparison to those without arthritis (86 vs. 17%, P < 0.001). Among 40 patients, 18 had arthritis in the acute phase KD (continued fever-onset type) and 22 did in the convalescent phase (interval fever-onset type). Both showed a similar rate of complete KD or IVIG response. Interval-type patients required biologics for arthritis control less frequently (5 vs. 39%, P = 0.02) and had a higher 2-year off-treatment rate (100 vs. 43%, P = 0.009) than continued-type ones. Interval-types showed lower serum ferritin and interleukin-18 levels than continued-types. When continued-types were grouped according to whether or not they required biologics (n = 7 and n = 11, respectively), the former subgroup had higher ferritin and interleukin-18 levels (P = 0.01 and 0.02, respectively). A canonical discriminant analysis differentiated interval-type from continued-type with the combination of age, time to arthritis, and the ferritin and matrix metalloproteinase-3 levels.Conclusion: Arthritis requiring treatment is a rare complication of KD. KD-associated arthritis includes interval-type (KD-reactive) and continued-type (true systemic-onset juvenile idiopathic arthritis [JIA] requiring biologics), and overlapping arthritis, suggesting the pathophysiological continuity of autoinflammation between KD and JIA.

The \u201cIntermediate\u201d CD14\u2009+\u2009CD16\u2009+\u2009monocyte subpopulation plays a role in IVIG responsiveness of children with Kawasaki disease

BackgroundKawasaki disease (KD) is an acute, self-limited febrile illness of unknown cause. Intravenous immunoglobulin (IVIG)-resistance are related to greater risk for permanent cardiac complications. We aimed to determine the correlation between monocytes and the phenotype of KD in relation to IVIG responsiveness in children.Materials and methods The study cohort included 62 patients who were diagnosed with KD, 20 non febrile healthy controls (NFC), and 15 other febrile controls (OFC). In all enrolled patients, blood was taken at least 4 times and laboratory tests were performed. In addition, subtypes of monocytes were characterized via flow cytometry.ResultsThe numbers of intermediate monocytes were significantly lower in IVIG-resistant group compared to IVIG-responsive group before IVIG infusion (p < 0.0001). After infusion, intermediate monocytes decreased in the responsive group, while a trend of increase was observed in the resistant group. Only intermediate monocytes were significant in logistic regression with adjusted OR of 0.001 and p value of 0.03.ConclusionsCD14 + CD16 + intermediate monocyte may play an important role in IVIG responsiveness among KD children. Low starting levels of intermediate monocytes, followed by a dramatic increase post-IVIG infusion during acute phase of KD are associated with IVIG-resistance. Functional studies on intermediate monocyte may help to reveal the pathophysiology.

Increased Pentraxin 3 Levels Correlate With IVIG Responsiveness and Coronary Artery Aneurysm Formation in Kawasaki Disease.

Kawasaki disease (KD) is a febrile disease of childhood characterized by systemic vasculitis that can lead to coronary artery lesions (CAL). This was a prospective cohort study to determine the levels of the pentraxin 3 (PTX3), soluble CD24-Subtype (Presepsin) and N-terminal pro-brain natriuretic peptide (NT-pro BNP) in consecutive KD patients. From January 2013 to March 2015, all patients with KD admitted to Aichi Medical University Hospital who provided consent had their plasma saved before IVIG administration. In total, 97 cases were registered. 22 cases of incomplete KD were excluded from the outcome analysis. The total 75 cases were used for statistical analyses. A PTX3 threshold of >7.92 ng/ml provided a specificity of 88.5 %, a sensitivity of 94.4 %, and a likelihood ratio as high as 15.92 for the diagnosis of KD compared with febrile non-KD controls. Although an echocardiographic diagnosis of CAL in the early course of the disease was confirmed in 24 cases, it was not in the remaining 51 cases. Neither NT-proBNP nor Presepsin had statistical significance for the prediction of the echocardiographic CAL diagnosis. Only PTX3 was significantly predictive of the echocardiographic CAL diagnosis (p=0.01). The PTX3 level was significantly higher in the intravenous immunoglobulin (IVIG) non-responders (45.9±7.45) than in the IVIG responders (17.0 ± 1.46 ng/ml) (p< 0.001). The PTX3 level also correlated with the number of IVIG treatment courses needed to resolve fever (R² =0.64). Persistent CAL (pCAL) formation was observed in three cases; one of aneurysm only and two aneurysms with dilatations. The patients with pCAL had significantly higher PTX3 levels (85 ± 8.4 ng/ml) than patients without pCAL (22 ± 2.2 ng/ml) (p< 0.0001). In terms of pCAL prediction, the area under the curve (AUC) of receiver operating characteristic ROC curve of PTX3 was 0.99, and it was significantly greater than that of Presepsin (0.67) or NT-proBNP (0.75). PTX3 is a soluble pattern recognition molecule that acts as a main component of the innate immune system. These data suggest that PTX3 can be utilized as a definitive biomarker for the prediction of IVIG resistance and subsequent CAL formation in patients with KD.