Effect Of Intravenous Immunoglobulin Research Articles

P-386 The effect of intravenous immunoglobulin versus placebo in patients with recurrent pregnancy loss: a systematic review and meta-analysis of randomized trials

Abstract Study question In women with recurrent pregnancy loss (RPL), how does intravenous immunoglobulin (IVIg) compared with placebo affect live birth rate (LBR) in the first subsequent pregnancy? Summary answer IVIg significantly improved LBR in the per protocol (PP), but not the intention to treat (ITT) analysis. LBR increased significantly with number of pregnancy losses. What is known already RPL is defined as two or more pregnancy losses before 24 weeks of gestation, impacting 1-2% of fertile couples. It results from diverse causes, and immunological factors are increasingly implicated in unexplained RPL cases. IVIg has been studied as a treatment with various proposed mechanisms. Existing research on IVIg in RPL has shown conflicting results, but a recent Japanese randomized controlled trial (RCT) reported a significantly increased LBR when IVIg was administered early and in high-dose. Study design, size, duration We conducted a systematic review and meta-analysis of relevant (RCTs, incorporating individual patient data (IPD) to evaluate IVIg’s impact on LBR in RPL patients. Participants/materials, setting, methods This study adhered to PRISMA guidelines and was registered in PROSPERO (ID CRD42023375788). We searched PubMed, Embase, and Cochrane libraries for relevant RCTs up to March 20, 2023. We conducted a meta-analysis with predefined primary (live birth and clinical pregnancy rates) and secondary outcomes. Risk ratios with 95% confidence intervals were calculated for dichotomous outcomes, and mean and standard deviation for continuous variables. We contacted the original authors to perform subgroup analyses based on IPD. Main results and the role of chance A total of 10 RCTs comprising 594 women were included in the meta-analysis, and IPD were retrieved from six RCTs including 354 women. No statistically significant results in LBR between IVIg and placebo treated women were found in the ITT analysis (RR: 1.02 [95% CI 0.86-1.22] p = 0.78). In the PP analysis, LBR was increased in the IVIg group compared with placebo (RR: 1.23 [1.00-1-50]). A statistically significant increase in clinical pregnancy rate was found in the IVIg group compared with placebo among women receiving high dose (median ³ 77.5 g) IVIg (RR: 1.79, [95% CI 1.21-2.65], p = 0.004). Furthermore, a statistically significant decrease in pregnancy loss rate was found in patients receiving high doses of IVIg (RR: 0.76 [95% CI 0.60-0.96], p = 0.02) compared to placebo. In the IPD analysis, RRs for live birth in the IVIg group compared with placebo increased steadily with the number of previous pregnancy losses. RRs for live birth in patients receiving IVIg compared with placebo were 5.26 (1.58-17.53) and 7.50 [1.20-47.05) in patients with ≥6 and ≥7 consecutive pregnancy losses, respectively. In analyses of IPD data adjusted for maternal age, the RRs for live birth were almost similar. Limitations, reasons for caution Limitations in the systematic review include potential bias due to financial support from pharmaceutical companies in half of the studies; potential confounding in subgroup analysis, missing individual patient data; and clinical and methodological heterogeneity among the included RCTs, which all may impact the overall reliability of results. Wider implications of the findings The findings highlight the importance of patient selection and personalized treatment. The PP analysis favored IVIg, emphasizing importance of protocol adherence. Secondly, the effectiveness of IVIg seems to increase with number of previous consecutive pregnancy losses. Thirdly, the dose of IVIg seem to impact its effectiveness. Trial registration number CRD42023375788

P-419 Relevance of intravenous immunoglobulins in patients with unexplained recurrent pregnancy loss that occurred at the same gestational weeks every time

Abstract Study question Are intravenous immunoglobulins (IVIG) effective for the selected patients who experienced unexplained recurrent pregnancy loss (RPL) that occurred at the same gestational weeks every time? Summary answer IVIG before and after the gestational week-limit (GWL), where miscarriage occurred at the same gestational weeks every time, may improve pregnancy outcomes in RPL patients. What is known already There is no established treatment for patients with unexplained RPL. Some investigators have indicated that IVIG may exhibit therapeutic efficacy in women with unexplained RPL. Since it has been reported that live birth rate significantly increased in women with four or more RPL of unexplained etiology, who received a high dose IVIG at 4-5 weeks of gestation in 2022, ESHRE Guideline Group on RPL (2022) has changed the recommendation to the following: the use of repeated and high doses of IVIG very early in pregnancy may improve live birth rate in women with four or more unexplained RPL. Study design, size, duration We performed a retrospective study between September 2013 to March 2023 in two fertility centers. We included 164 patients in the study who experienced 2 or more miscarriages between 5 and 21 weeks of gestation that occurred at the same gestational weeks every time, who had all negative results for our routine RPL work up and still unsuccessful result after treating these conditions, and whose products of conceptus (POC) revealed at least one normal karyotype. Participants/materials, setting, methods IVIG (Venoglobulin IH 5%, Japan Blood Products Organization, 0.4g/kg) injection was performed twice before and after 1 week of GWL. We divided 164 patients into IVIG group and non-IVIG group by their own choice. The primary outcome was live birth rate, and the secondary outcome was modified live birth rate excluding pregnancies with abnormal fetal karyotype, maternal and neonatal complications. All participants provided written informed consent, and Institutional Review Board approval was obtained. Main results and the role of chance IVIG group (n = 116) and non-IVIG group (n = 48) showed no significant differences in the background of patients on BMI (20.3±3.7 and 21.1±2.8), age (37.4±4.2 and 36.7±3.2) and Childbirth history (20.7% and 23.0%), respectively (average±SD), except for the history of past miscarriages. Average numbers of previous miscarriages on IVIG group and non-IVIG group were 3.2±1.3 and 2.5±0.8 (p < 0.001), respectively. After multivariate analysis for BMI, age, Childbirth history and previous miscarriages, live birth rate of IVIG group (70.7%, 82/116) was significantly higher than that of non-IVIG group (60.4%, 29/48; Odds ratio 3.40, 95% CI: 1.49-7.74, p = 0.003). Similarly, modified live birth rate of IVIG group (73.9%, 82/111) was significantly higher than that of non-IVIG group (63.0%, 29/46; Odds ratio 3.40, 95% CI: 1.49-7.74, p = 0.003). Treatment outcomes when IVIG was used for each number of previous miscarriages, the modified birth rate was 88.3% for two times miscarriages, 77.0% for three times, and 57.1% for four or more miscarriages. Maternal complications were observed in 2 cases in IVIG group (chest tightness, obstetric critical bleeding). There were no significant differences in the birth weight, gestational weeks, preterm birth, or fetal growth restriction of newborns between two groups. Limitations, reasons for caution Since retrospective nature and we did not perform POC tests for all patients whose pregnancies had ended in miscarriage, we could not assert the effectiveness of IVIG. We need to conduct randomized controlled trial using placebo group to demonstrate the IVIG efficacy before and after the GWL using euploid blastocysts. Wider implications of the findings IVIG before and after the GWL adjusted for each patient may improve pregnancy outcomes in RPL patients. Although IVIG is expensive, the current method requires only two IVIG injections, that may be acceptable for much more patients who want to avoid miscarriages and who didn’t use IVIG for economic reasons. Trial registration number NA

Effect of intravenous immunoglobulin on mortality in hospitalized patients with COVID-19: A systematic review and meta-analysis of randomized controlled trials.

We performed a meta-analysis of randomized controlled trials (RCTs) to summarize the overall effect of intravenous immunoglobulin (IVIG) on mortality outcomes among hospitalized coronavirus disease 2019 (COVID-19) patients. We systematically searched electronic databases up to June 1, 2023. Pooled odds ratio (OR) of mortality with a 95% confidence interval (CI) was generated using a random-effects model. The risk of bias was appraised using the Cochrane risk-of-bias Version 2 tool for randomized trials. Nine RCTs were included: three RCTs had an overall low risk of bias, four RCTs had some concerns in the overall risk of bias, and two RCTs trials had an overall high risk of bias. The use of IVIG indicated a significant reduction in the odds of mortality (pooled OR = 0.69; 95% CI 0.50-0.96) relative to nonuse of IVIG. Subgroup analysis in patients with a severe course of COVID-19 revealed no significant reduction in the odds of mortality (pooled OR = 0.58; 95% CI 0.29-1.16). We suggest exercising caution when interpreting effectiveness of IVIG in reducing mortality among hospitalized patients with COVID-19. Our findings emphasize for larger trials with rigorous study designs to better understand the impact of IVIG, particularly in those with severe COVID-19.

Effect of intravenous immunoglobulin on mortality in hospitalized patients with COVID-19: A systematic review and meta-analysis of randomized controlled trials.

We performed a meta-analysis of randomized controlled trials (RCTs) to summarize the overall effect of intravenous immunoglobulin (IVIG) on mortality outcomes among hospitalized coronavirus disease 2019 (COVID-19) patients. We systematically searched electronic databases up to June 1, 2023. Pooled odds ratio (OR) of mortality with a 95% confidence interval (CI) was generated using a random-effects model. The risk of bias was appraised using the Cochrane risk-of-bias Version 2 tool for randomized trials. Nine RCTs were included: three RCTs had an overall low risk of bias, four RCTs had some concerns in the overall risk of bias, and two RCTs trials had an overall high risk of bias. The use of IVIG indicated a significant reduction in the odds of mortality (pooled OR = 0.69; 95% CI 0.50-0.96) relative to nonuse of IVIG. Subgroup analysis in patients with a severe course of COVID-19 revealed no significant reduction in the odds of mortality (pooled OR = 0.58; 95% CI 0.29-1.16). We suggest exercising caution when interpreting effectiveness of IVIG in reducing mortality among hospitalized patients with COVID-19. Our findings emphasize for larger trials with rigorous study designs to better understand the impact of IVIG, particularly in those with severe COVID-19.

Beneficial effects of IVIG treatment on experimental-induced osteoporosis.

Estrogen (E2) plays a significant role in postmenopausal osteoporosis, and its deficiency is related to chronic low-grade inflammation. Intravenous immunoglobulin (IVIG) is composed of immunoglobulins derived from the plasma of healthy donors. Numerous anti-inflammatory pathways are responsible for IVIG's anti-inflammatory action The aim of this study is to investigate the effects of IVIG on experimental-induced osteoporosis. Forty adult female Wistar rats were included in the study. Thirty rats underwent bilateral dorsal ovariectomy. Rats were grouped as Group 1 (n = 10, ovariectomy and saline); Group 2 (n = 10, ovariectomy and E2); Group 3 (n = 10, ovariectomy and IVIG), and Control group (n = 10, no oophorectomy). Histopathological examination of bone tissue, and biochemical analysis for beta-catenin, plasma Tumor Necrosis Factor-α, IL-6, receptor activator of nuclear-κB ligand (RANKL), and osteoprotegerin (OPG) levels were made. The IVIG group had increased trabecular number, area, and thickness with increased bone mineral density as well as decreased trabecular separation compared with the saline group. IVIG group had lower serum RANKL and higher serum OPG levels when compared with the saline group. The bone marrow beta-catenin level was significantly higher in the control and ovariectomy + IVIG groups. IVIG has beneficial effects on experimentally induced osteoporosis with a possible action on inflammation and RANKL-β-catenin pathway.

Effectiveness of IVIG on Non-Length-Dependent Skin Biopsies in Small Fiber Neuropathy With Plexin D1, Trisulfated Heparin Disaccharide, and Fibroblast Growth Factor Receptor 3 Autoantibodies.

To demonstrate treatment efficacy on composite and non-length-dependent (NLD) punch biopsy specimens from intravenous immunoglobulin (IVIG) in pure small-fiber neuropathy (SFN) with trisulfated heparin disaccharide (TS-HDS), fibroblast growth factor-3 (FGFR-3), or Plexin D1 antibodies. SFN has an increasing prevalence, and over 30% of cases may be immune-mediated. TS-HDS, FGFR-3, and Plexin D1 autoantibodies have been shown to be present in 44%-55% of cryptogenic SFN cases, suggesting an immune mechanism. Reports have shown IVIG to be effective for this condition, but some controversy exists based on length-dependent (LD) post-IVIG treatment data in a recent trial. In a retrospective review, all pure SFN cases tested for the 3 antibodies from January 2021 to May 2022 were tabulated, and patients who underwent IVIG treatment were separated and analyzed for changes in epidermal nerve fiber density (ENFD) on skin biopsy, as well as SFN-specific questionnaire and pain scores. Ninety-one patients with pure SFN had antibody testing. Sixty of these (66%) were seropositive, and 31 (34%) were seronegative. Seventeen seropositive patients (13 female patients, 4 male patients, 6 FGFR-3, 2 TS-HDS, 4 Plexin D1, 2 with all 3 antibodies, 1 with FGFR-3 and Plexin D1, 1 with FGFR-3 and TS-HDS, and 1 with TS-HDS and Plexin D1) underwent IVIG treatment. Of these, 2 patients stopped treatment due to side effects, and the remaining 15 completed at least 6 months of IVIG. Of these, 12 had a post-IVIG skin biopsy, and of these, 11 (92%) had a 55.1% improved mean composite ENFD (P = 0.01). NLD-ENFD specimens improved by 42.3% (P = 0.02), and LD-ENFD specimens improved by 99.7% (P = 0.01). Composite ENFD in Plexin D1-SFN patients improved by 139% (P = 0.04). In addition, 14 patients had questionnaires pre-IVIG/post-IVIG, and average pain decreased by 2.7 (P = 0.002). IVIG shows disease-modifying effect in immune SFN with novel antibodies, especially Plexin D1-SFN, as well as significantly improved pain. NLD-ENFD should be examined as well as LD-ENFD to see this effect. Further randomized controlled trials looking at NLD-ENFD as well as LD-ENFD improvement, along with pain and SFN-specific questionnaires, are needed to confirm these findings.

Evaluation of the Factors Influencing Mortality in Patients with Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Multicenter Study of 166 Patients.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening acute mucocutaneous disorders usually triggered by drugs. In this study, we aimed to evaluate the factors affecting mortality in patients with SJS-TEN. Our study is a retrospective cohort study, analyzing data collected from a total of 12 tertiary care centers between April 2012 and April 2022. The study included 59 males and 107 females, a total of 166 patients, with an average age of 50.91 ± 21.25years. Disease classification was TEN in 50% of cases, SJS in 33.1%, and SJS-TEN overlap in 16.9%. The average SCORTEN within the first 24h was 2.44 ± 1.42. Supportive care was provided to 99.4% of patients. The most commonly used systemic immunomodulatory treatments were systemic steroids (84.3%), IVIG (intravenous immunoglobulin) (49.3%), and cyclosporine (38.6%). Plasmapheresis was administered to five patients. While 66.3% of patients were discharged, 24.1% resulted in exitus. Our comparative analysis of survivors and deceased patients found no effect of systemic steroids, IVIG, and cyclosporine treatments on mortality. Univariate analysis revealed that the SCORTEN scores on days 1 and 3 as well as the rates of detachment at the onset and during follow-up were significantly higher in deceased patients compared to survivors. The rates of fever, positive blood cultures, and systemic antibiotic use were higher in deceased patients compared to survivors. The presence of comorbidities, diabetes, and malignancy were significantly more common in deceased patients. Multivariate regression analysis indicated that over SCORTEN 2, the mortality risk exponentially rose with each SCORTEN increment, culminating in an 84-fold increase in mortality at SCORTEN 5-6 (odds ratio [95% confidence interval]: 13.902-507.537, p < 0.001) compared to SCORTEN 0-1. Additionally, the utilization of plasmapheresis was associated with a 22-fold increase in mortality (odds ratio [95% confidence interval]: 1.96-247.2, p = 0.012). Our study found that a high SCORTEN score within the first 24h and the use of plasmapheresis were related to increased mortality, while systemic steroids, IVIG, and cyclosporine treatments had no impact on mortality. We believe that data gathered from one of the most comprehensive studies which we conducted on SJS-TEN will enrich the literature, although additional research is warranted.

INTRAVENOUS IMMUNOGLOBULINS LEAD TO FUNCTIONAL VASCULAR AMELIORATION IN LONG-COVID

Objective: The Long-COVID syndrome constitutes a major physical and psychological challenge for many patients after the recovery from COVID-19. We have previously shown positive effects of intravenous immunoglobulins (IVIG) on multiple symptoms. The effect of this therapeutical approach on vascular function and different levels of disease burden remains elusive. Design and method: We performed a prospective study, enrolling 21 patients with diagnosed Long-COVID, who received 3 monthly courses of IVIG (0.5 g/kg Privigen, CSL Behring, Austria) alongside supportive therapy (group 1). The control group (group 2; n=29) was addressed by supportive therapy, only. The study population was homogeneous for age, comorbidities and time since SARS-CoV-2 infection. We assessed vascular endothelial function by flow mediated dilation (FMD). Long-COVID associated fatigue intensity, related disability and quality of life were assessed by Short Form Health Survey-36, Chalder and Bell scale. Neuropsychological assessments utilized the German version of the ’Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Assessment Battery’ (CERAD-Plus). Results: The median FMD at baseline in group 1 was 5.0% (interquartile range [IQR] 4.2-6.1%). We saw a substantial amelioration (+27%) of FMD after IVIG, reaching a median of 6.6% (IQR 4.5-9.4%; p=0.039). Baseline FMD in the comparison group was 5.2% (IQR 3.5-7.6%), supportive treatment resulting in unsignificant increase (FMD 6.1% [IQR 4.6-7.7%; p=0.177). Baseline CERAD-Plus scores were comparable between groups (p=0.280). Only treatment with IVIG resulted in a relevant amelioration of neurocognition (p=0.05; group 2 p=0.430). Furthermore, less Fatigue (Chalder Fatigue scale bimodal and Likert p=0.002, each) and disability was seen after 3 months of IVIG (Bell Score, p=0.008), supportive treatment did not ameliorate this burden (Chalder Fatigue Scale bimodal p=0.086 and Likert p=0.952; Bell Score p=0.121). Health related quality of life (SF-36) increased for both groups (group 1 p=0.003, group 2 p=0.017). Conclusions: Using a broad test battery, addressing neuropsychological function, fatigue, related disability and health related quality of life as well as vascular function, we were able to confirm the potential beneficial effect of IVIG in Long-COVID. IVIG might be a candidate approach in this context, that requires further evaluation in randomized controlled trials.

Effect of intravenous immunoglobulin on the management of Rh- and ABO-mediated hemolytic disease of the newborn

BackgroundRegarding the close association between neonatal hyperbilirubinemia and occurrence of pathological jaundice as a cause of neurotoxicity and kernicterus, the present study aimed to evaluate the use of intravenous immunoglobulin (IVIG) in neonates with hyperbilirubinemia. MethodsA retrospective case-control study of blood group O mothers and their ABO and Rh newborns was conducted. Medical records that included total serum bilirubin levels of 79 patients with hemolytic disease of the newborn (HDN) from between 2017 and 2020 were reviewed. Neonates who were eligible to receive immunoglobulin based on the American Academy of Pediatrics (AAP) guidelines were classified as cases and the rest were included as the Control Group. ResultsThe mean total bilirubin in relation to hemoglobin levels in IVIG-treated neonates was significantly lower than in non-IVIG-treated neonates (13.98 ± 4.23 mg/dL versus 16.61 ± 2.68 mg/dL; p-value = 0.002). Although females had longer hospitalizations in both IVIG-treated (3.81 ± 1.28 versus 3.54 ± 1.30 days; p-value = 0.509) and non-IVIG-treated (3.43 ± 0.811 versus 3.19 ± 0.75 days; p-value = 0.361) groups compared to males, this difference was not significant between the groups. Although four neonates with ABO incompatibility required packed red blood cells, all infants were managed medically and no deaths occurred during the course of treatment. Moreover, no exchange transfusion or adverse effects of IVIG were observed. ConclusionThe results from the present study revealed that IVIG administration is a useful procedure for the management of bilirubin encephalopathy with greater opportunity to reduce exchange transfusion requirements for neonatal hyperbilirubinemia.

Case Series: Efficacy of Polyclonal Intravenous Immunoglobulin for Refractory Clostridioides difficile Infection.

Intravenous immunoglobulin (IVIg) for Clostridioides difficile infection (CDI) no longer features in treatment guidelines. However, IVIg is still used by some clinicians for severe or recurrent CDI (rCDI) cases. The main objective of this study was to investigate the efficacy of IVIg and to identify possible predictors of disease resolution post IVIg administration for patients with CDI. This retrospective observational cohort study of patients ≥2 years old hospitalised with severe, relapsing, or rCDI treated with IVIg therapy was performed in a large UK tertiary hospital between April 2018 and March 2023. Scanned electronic notes from patient admissions and clinical reporting systems were used to collect relevant data. In total, 20/978 patients diagnosed with CDI over the 5-year study were treated with IVIg. Twelve (60%) had hospital-onset CDI. Eleven of the twenty patients (55%) responded to treatment, with a mean of 8.6 (SD 10.7) days to disease resolution. Sixteen (80%) patients were treated for severe CDI and four (20%) for rCDI (n = 3) and relapsing CDI (n = 1). There were no statistically significant differences in possible independent predictors of disease resolution post IVIg administration between groups. There was an average of 6.2 (4.9) days to IVIg administration after diagnosis with no difference between responders and non-responders (p = 0.88) and no further significant difference in additional indicators. Four (36%) of the responders were immunosuppressed compared to just one (11%) of the non-responders (p = 0.15). Six of the responders (two with recurrent and four with severe CDI) improved rapidly within 2 days, and three of these were immunosuppressed. We observed disease resolution post IVIg therapy in over 50% of patients with refractory CDI. Our data also support a potential enhanced effect of IVIg in immunosuppressed individuals. Thus, the role of IVIg for CDI treatment, particularly in the immunosuppressed, warrants future case-control studies coupled to mechanistic investigations to improve care for this ongoing significant healthcare-associated infection.

Intravenous immunoglobulin protects the integrity of the intestinal epithelial barrier and inhibits ferroptosis induced by radiation exposure by activating the mTOR pathway

Radiation exposure often leads to serious health problems in humans. The intestinal epithelium is sensitive to radiation damage, and radiation causes destruction of the intestinal epithelial barrier, which leads to radiation enteritis (RE), the loss of fluids, and the translocation of intestinal bacteria and toxins; radiation can even threaten survival. In this study, we aimed to explore the influence of IVIg on the integrity of the intestinal epithelial barrier after RE. Using a RE mouse model, we investigated the protective effects of intravenous immunoglobulin (IVIg) on the epithelial junctions of RE mice and validated these findings with intestinal organoids cultured in vitro. In addition, transmission electron microscopy (TEM), western blotting (WB) and immunostaining were used to further investigate changes in intestinal epithelial ferroptosis and related signaling pathways. When RE occurs, the intestinal epithelial barrier is severely damaged. IVIg treatment significantly ameliorated this damage to epithelial tight junctions both in vivo and in vitro. Notably, IVIg alleviated RE by inhibiting intestinal epithelial ferroptosis in RE mice. Mechanistically, IVIg promoted activation of the mTOR pathway and inhibited ferroptosis in the intestinal epithelium of mice. Rapamycin, which is a potent inhibitor of the mTOR protein, significantly abolished the protective effect of IVIg against radiation-induced damage to intestinal epithelial tight junctions. Overall, IVIg can prevent RE-induced damage to the intestinal epithelial barrier and inhibit ferroptosis by activating the mTOR pathway; this study provides a new treatment strategy for patients with RE caused by radiotherapy or accidental nuclear exposure.

The mechanism of intravenous immunoglobulin (IVIG) in vascular endothelial injury in kawasaki disease based on neutrophil extracellular traps

This study explores the role of Neutrophil extracellular traps (NETs) in kawasaki disease (KD)-induced vascular inflammatory injury and the protective effect and mechanism of IVIG on vascular endothelial damage. A total of 37 children diagnosed with KD and admitted to Dongguan maternal and Child Health Care Hospital between March 2020 and June 2022 were included in the study. The children were divided into different groups based on their treatment and the presence or absence of coronary artery damage: IVIG treatment group (KDIVIG group), subgroup with coronary artery damage (KDCAL group), and subgroup without coronary artery damage (KDNCAL group), and a Control group consisting of 9 children who underwent surgical treatment. Flow cytometry was used to detect the proportion of neutrophils and the number of NETs in peripheral blood. It was found that the proportion of neutrophils in the peripheral blood of the acute KD group significantly increased with the presence of NETs. RT-PCR and ELISA detection showed that the levels of inflammatory factors TNF-α, IL-6 and CitH3 were abnormally elevated in this acute KD group, and the CAL group exhibited higher proportions of neutrophils and NETs-related markers compared to the NCAL group, while the IVIG group had significantly decreased proportions of neutrophils. PMA culture of neutrophils induced an increase expression of NETs marker protein, the content of NETs cfDNA increased. NETs culture could promote the secretion of TNF-α, whereas IVIG cultured cells inhibited the secretion of TNF-α. Finally, HCAEC cells were cultured with different levels of TNF-α, and the function of HCAEC cells was assessed using CCK8, scratch assay and flow cytometry. The high expression of TNF-α in the NETs group inhibited the proliferation and migration of HUVEC cells and enhanced their apoptosis. In contrast, the IVIG culture group exhibited similar effects to the TNF-α monoclonal antibody, as it inhibited HUVEC cell apoptosis and improved their viability by reducing TNF-α expression. Total protein was extracted from the cells using nano-magnetic beads, and RT-PCR and western blot detection indicated that the increase of TNF-α expression could increase the phosphorylation of NF-κB and and the expression of MMP-9. However, when TNF-α was inhibited by IVIG and TNF-α monoclonal antibody culture, the activity of NF-κB/MMP-9 athway was decreased. Therefore, IVIG may inhibit the production of NETs in KD children, thereby reducing TNF-α/NF-NF-κB/MMP-9 mediated inflammatory response process and protecting the function of vascular endothelial cells.

Intravenous immunoglobulin for patients with unexplained recurrent implantation failure: a 6-year single center retrospective review of clinical outcomes

The effectiveness of intravenous immunoglobulin (IVIg) for patients with unexplained recurrent implantation failure (uRIF) remains debated. We retrospectively analysed outcomes of uRIF patients treated with IVIg compared to a separate control uRIF cohort within our center (01/2014–12/2021). Primary outcomes included live birth, miscarriage, or transfer failure. We documented IVIg side effects and maternal/fetal outcomes. Logistic regression analysis was used to assess for association of IVIg exposure with outcomes and adjust for confounders. The study included 143 patients, with a 2:1 ratio of controls to patients receiving IVIg treatment. Patient characteristics were similar between groups. There was higher live birth rate (LBR) in patients receiving IVIg (32/49; 65.3%) compared to controls (32/94; 34%); p < 0.001). When stratifying patients into moderate and severe uRIF (respectively 3–4 and ≥\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\ge$$\\end{document} 5 previous good quality blastocyst transfer failures), only patients with severe uRIF benefited from IVIg (LBR (20/29 (69%) versus 5/25 (20%) for controls, p = 0.0004). In the logistic regression analysis, IVIg was associated with higher odds of live birth (OR 3.64; 95% CI 1.78–7.67; p = 0.0004). There were no serious adverse events with IVIg. IVIg can be considered in well selected patients with ≥\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\ge$$\\end{document} 5 previous unexplained, high quality blastocyst transfer failures. A randomized controlled trial is needed to confirm these findings.

Restoring immune tolerance in pemphigus vulgaris

Intravenous immunoglobulin (IVIg), a preparation of polyclonal serum IgG pooled from numerous blood donors, has been used for nearly three decades and is proving to be an efficient treatment for many autoimmune blistering diseases, including pemphigus vulgaris (PV). Despite its widespread use and therapeutic success, its mechanisms of action are not completely understood. Some of its anti-inflammatory and immunomodulatory actions have been studied. In this study, the authors present a twenty-year follow-up of 21 patients with clinical and immunopathological confirmed PV, treated with IVIg as monotherapy, according to an established published protocol. IVIg therapy produced long-term sustained, clinical, serological, and immunopathological remission. For 20 y, these patients received no drugs and experienced no disease. This observation suggests that there was the establishment of immune balance or restoration of immune regulation in these PV patients. Twelve (57%) patients experienced no relapse during follow-up. Six (29%) patients experienced a relapse due to acute stress or post-coronavirus infection and/or vaccination. Reinstitution of IVIg resulted in prompt sustained recovery. Three (14.2%) patients, in clinical and serological remission, died due to unrelated causes. No severe adverse effects from IVIg were documented in all 21 patients. The simultaneous or sequential anti-inflammatory and immunomodulatory effects of IVIg may have influenced the long-term clinical remission observed. This study provides a human prototype to examine the pathophysiology of autoimmunity and a model to study immune regulation and mechanisms that can facilitate restoring immune tolerance.

Fc-gamma receptor expression and cytokine responses to intravenous human immunoglobulin in whole blood from non-pregnant and pregnant women and newborns.

Intravenous immunoglobulin (IVIG) can suppress the inflammatory response in adults, but its role in pregnant women and newborns is poorly studied. While the adult immune system is considered mature, it is immature in neonates and suppressed in pregnancy. Since the immune response differs in these 3 groups, the use of IVIG could differentially modulate the immune response. We aimed to explore the effect of IVIG on myeloid blood cells from non-pregnant women, pregnant women and newborns. Whole blood from healthy donors was incubated with lipopolysaccharide (LPS) and/or IVIG. After 0 h, 24 h and 48 h of culture, Fc-gamma receptor (CD16, CD32 and CD64) expression, monocyte and neutrophil bacterial phagocytosis, and cytokine and chemokine concentrations were determined in the supernatant. The baseline expression of monocyte CD16 was higher in newborns than in adult women, but the expression of CD32 and CD64 was similar between groups. Furthermore, LPS and IVIG stimulation, together or separately, did not change Fc-gamma receptor expression in monocytes or neutrophils and did not modify their phagocytosis capacity. On the other hand, IVIG did not downregulate the proinflammatory cytokine response induced by LPS in any group. Interestingly, IVIG induced a strong interleukin 8 (IL-8) response in neonates but not in non-pregnant or pregnant women. Our results show that IVIG did not induce changes in Fc-gamma receptor expression, phagocytic ability, or the cytokine response to LPS in blood cells from neonates, non-pregnant or pregnant women. However, IVIG induced a strong IL-8 response in neonates that could improve immunity.

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.

Effectiveness of Plasmapheresis and IVIG in the Treatment of Guillain-Barre Syndrome: A Cross-Sectional Observational Study

Background: Plasma exchange and intravenous immunoglobulin (IVIG) are the most effective treatments for Guillain-Barre syndrome; both can improve patients' symptoms. However, limited clinical research is available in Bangladesh to compare the effectiveness of both treatment modalities. Aims: This study aimed to compare the effectiveness of plasmapheresis and IVIG in the treatment of Guillain Barre Syndrome. Method: It is a prospective analytical study carried out in the ICU at the Department of Anesthesia, Analgesia, Palliative &amp; Intensive Care Medicine, Dhaka Medical College Hospital, Dhaka, and Transfusion Medicine Department, NINS. Study subjects were patients with GBS, irrespective of gender, race, ethnic group, and age. For this study, they were divided into Group A (treated by IVIG) and Group B (treated by plasmapheresis). The clinical outcome &amp; disability grade were evaluated and compared between groups. Result: In this study plasmapheresis was associated with more improvement compared to IVIg, moreover there was a significant difference in the disability scores between the two groups after 12 weeks of treatment. Group B with plasmapheresis had a significantly lower mean disability score (1.26 ± 0.06) compared to Group A with IVIg (3.05 ± 0.17) with a p-value of 0.011 At presentation and immediate post-therapy, there was no statistically significant difference between the two treatment groups in terms of MRC grade. However, at the later time points (6 and 12 weeks), Group B (plasmapheresis) was associated with a statistically significant improvement in MRC grade compared to Group A (IVIg). Specifically, at six weeks, the mean MRC grade was 3.18 for Group A and 4.04 for Group B (p=0.038), and at 12 weeks, the mean MRC grade was 3.52 for Group A and 4.87 for Group B (p=0.019). The mechanical ventilation rate was higher in IVIg (51.4% vs 14.2%, respectively) group. The difference was statistically significant (p=0.017). The proportion of individuals with complete recovery was significantly higher in Group B (60%) compared to Group A (22.8%) with an odds ratio of 5.06 (95% CI: 1.79-14.31) and a risk ratio of 1.959 (95% CI: 1.24-3.01). The proportion of individuals with residual deficit was significantly lower in plasmapheresis (25.71%) compared to Group A (57.1%) with an odds ratio of 3.85 (95% CI: 1.40-10.59) and a risk ratio of 2.22 (95% CI: 1.18-4.18), and this was statistically significant. There was no statistically significant difference in the proportion of individuals who died between the two groups, with a p-value of 0.530. Conclusions: In point of comparison, plasmapheresis has a potential benefit over intravenous immunoglobulin. Bangladesh Crit Care J September 2023; 11 (2): 95-102

Effect of intravenous immunoglobulin on the outcome of children with septic shock in a PICU: a retrospective cohort study.

In children with septic shock, the use of intravenous immunoglobulin as an adjuvant therapy does not reduce in-hospital mortality. • Guidelines suggest against the routine use of intravenous immuneglobulin in children with septic shock. Some small observational studies have reported conflicting result. • The use of intravenous immunoglobulin as an adjuvant therapy does not reduce in-hospital mortality in children with septic shock.

Intravenous immunoglobulins improve skin fibrosis in experimental models of systemic sclerosis

Systemic sclerosis (SSc) is the most severe systemic autoimmune disease with currently no cure. Intravenous immunoglobulins (IVIg) are an attractive candidate in this disease to counteract inflammation and fibrosis but data are scarce and conflicting. This study, assessed the effects of IVIg in a murine HOCl-induced model of SSc. We showed that IVIg prevented skin inflammation and fibrosis, by mitigating the immune cell infiltration (p = 0.04), proinflammatory cytokines gene overexpression (IL1β, p = 0.04; TNFα, p = 0.04; IL6, p = 0.05), skin and dermal thickening (p = 0.003 at d21 and p = 0.0003 at d42), the expression markers of fibrosis, such as αSMA (p = 0.031 for mRNA and p = 0.05 for protein), collagen (p = 0.05 for mRNA and p = 0.04 for protein, p = 0.05 for the hydroxyproline content) and fibronectin (p = 0.033 for mRNA). Moreover, IVIg prevented HOCl-induced alterations in splenic cell homeostasis. When administered in curative mode, despite their ability to reduce skin and dermal thickness (p < 0.0001 and p = 0.0002), IVIg showed partial or more mixed effects on skin inflammation and established fibrosis. These data favor further clinical trials in SSc patients on the potential efficiency of early and/or repeated IVIg administration.

β-CATENIN stabilizes HIF2 through lncRNA and inhibits intravenous immunoglobulin immunotherapy.

Tumor-initiating cells (TICs) are rare, stem-like, and highly malignant. Although intravenous hepatitis B and C immunoglobulins have been used for HBV and HCV neutralization in patients, their tumor-inhibitory effects have not yet been examined. Hepatitis B immunoglobulin (HBIG) therapy is employed to reduce hepatocellular carcinoma (HCC) recurrence in patients after living donor liver transplantations (LDLT). We hypothesized that patient-derived intravenous immunoglobulin (IVIG) binding to HCC associated TICs will reduce self-renewal and cell viability driven by β-CATENIN-downstream pathways. β-CATENIN activity protected TICs from IVIG effects. The effects of HBIG and HCIG binding to TICs were evaluated for cell viability and self-renewal. Inhibition of β-CATENIN pathway(s) augmented TIC susceptibility to HBIG- and HCIG-immunotherapy. HBV X protein (HBx) upregulates both β-CATENIN and NANOG expression. The co-expression of constitutively active β-CATENIN with NANOG promotes self-renewal ability and tumor-initiating ability of hepatoblasts. HBIG bound to HBV+ cells led to growth inhibition in a TIC subset that expressed hepatitis B surface antigen. The HBx protein transformed cells through β-CATENIN-inducible lncRNAs EGLN3-AS1 and lnc-β-CatM. Co-expression of constitutively active β-CATENIN with NANOG promoted self-renewal ability of TICs through EGLN3 induction. β-CATENIN-induced lncRNAs stabilized HIF2 to maintain self-renewal of TICs. Targeting of EGLN3-AS1 resulted in destabilization of EZH2-dependent β-CATENIN activity and synergized cell-killing of TICs by HBIG or HCIG immunotherapy. Taken together, WNT and stemness pathways induced HIF2 of TICs via cooperating lncRNAs resulting in resistance to cancer immunotherapy. Therefore, therapeutic use of IVIG may suppress tumor recurrence through inhibition of TICs.