Intravenous Immunoglobulin Group Research Articles

Intravenous immunoglobulin‑based adjuvant therapy for severe fever with thrombocytopenia syndrome: A single‑center retrospective cohort study.

Intravenous immunoglobulin (IVIG) is frequently administered to patients with severe fever with thrombocytopenia syndrome (SFTS), particularly those with severe manifestations, although its efficacy remains controversial. The study retrospectively analyzed the effects of IVIG administration on SFTS patients in both mild and severe groups. The primary outcome measure was 28-day mortality. Inverse probability of treatment weighting (IPTW) with propensity score was used to account for baseline confounders. A total of SFTS patients with complete data enrolled from January 1, 2015, to August 1, 2023. Death at 28 days occurred for 68 (17.5%) patients. By unadjusted analysis, no difference was observed for 28-day mortality between the IVIG and non-IVIG groups in both the mild and severe groups. Similar results were found by propensity score matching and by IPTW analysis. Although IVIG is frequently used as adjuvant therapy for severe SFTS patients, no significant association was observed between IVIG treatment and reduced mortality in this patient population.

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.

Prophylactic intravenous immunoglobulin use in allogeneic stem cell transplantation; does intravenous immunoglobulin affect survival, sepsis, and engraftment time?

Abstract: BACKGROUND: Stem cell transplant recipients have an increase in various infections depending on the immunosuppression. The purpose is to explore the effect of the use of proflactıc intravenous immunoglobulin (IVIG) on transplant recıpıents. OBJECTIVE: It was aimed to examine the effect of IVIG on allogeneic stem cell transplantation. MATERIALS AND METHODS: In this study, sepsis status, infection focus causing sepsis, neutrophil and platelet engraftment time of patients the length of stay in the hospital at the time of the stem cell transplant, if the patient died, how many days after the transplant the event developed, and the data of the bone marrow transplant unit were reviewed retrospectively. One hundred and eleven patients who were given IVIG (400 mg/kg/week IVIG intravenous was given to the patients as a weekly prophylactic up to 100 days starting on the 7th day after transplantation) and 190 patients who did not receive IVIG were included in the study. RESULTS: There was no statistically significant difference between the IVIG groups in terms of gender, diagnosis, donor characteristics, and event (P > 0.05). Sepsis was observed significantly less in patients who were given IVIG compared to patients who were not given IVIG (P < 0.001). While it was observed that IVIG did not have a significant effect on platelet engraftment and discharge times (P > 0.05), neutrophil engraftment time was significantly higher in patients given IVIG compared to patients not given IVIG (P < 0.009). It was observed that the use of IVIG in patients with sepsis did not have a positive effect on survival. (with sepsis hazard ratio [HR]: 3.890 P = 0.001, IVIG given HR: 3.244 P = 0.035). CONCLUSION: It was observed that the use of IVIG in allogeneic stem cell transplantation was associated with a decrease in sepsis, but the use of IVIG did not have a positive effect on survival and could prolong neutrophil engraftment.

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

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

Prediction Models for Intravenous Immunoglobulin Non-Responders of Kawasaki Disease Using Machine Learning.

BACKGROUNDAND OBJECTIVE: Intravenous immunoglobulin (IVIG) is a prominent therapeutic agent for Kawasaki disease(KD) that significantly reduces the incidence of coronary artery anomalies. Various methodologies, including machine learning, have been employed to develop IVIG non-responder prediction models; however, their validation and reproducibility remain unverified.This study aimed to develop a predictive scoring system for identifying IVIG nonresponders andrigorously test the accuracy and reliability of this system. METHODS: The study included an exposure group of 228 IVIG non-responders and a control group of 997 IVIG responders. Subsequently, a predictive machine learning model was constructed. The Shizuoka score, including variables such as the "initial treatment date" (cutoff: < 4 days), sodium level (cutoff: < 133 mEq/L), total bilirubin level (cutoff: ≥ 0.5 mg/dL), and neutrophil-to-lymphocyte ratio (cutoff: ≥ 2.6), was established. Patients meeting two or more of these criteria were grouped as high-risk IVIG non-responders. Using the Shizuoka score to stratify IVIG responders, propensity score matching was used to analyze 85 patients each for IVIG and IVIG-added prednisolone treatment in the high-risk group. In the IVIG plus prednisolone group, the IVIG non-responder count significantly decreased (p < 0.001), with an odds ratio of 0.192 (95% confidence interval 0.078-0.441). CONCLUSIONS: Intravenous immunoglobulin non-responders were predicted using machine learning models and validated using propensity score matching. The initiation of initial IVIG-added prednisolone treatment in the high-risk group identified by the Shizuoka score, crafted using machine learning models, appears useful for predicting IVIG non-responders.

Evaluation of the Efficacy and Safety of Intravenous Immunoglobulin (IVIG) in Moderate-to-Severe Hospitalized COVID-19 Patients: A Randomized, Open-Label Parallel-Group Study.

Since February 2020, the world has been overwhelmed by the SARS-CoV-2 outbreak, and several patients suffered interstitial pneumonia and respiratory failure requiring mechanical ventilation, threatening the capability of healthcare systems to handle this amount of critical cases. Intravenous immunoglobulins (IVIG) possess potential immunomodulatory properties beneficial for COVID-19 patients, yet evidence supporting IVIG as adjunctive therapy remains sparse. This study evaluated the outcomes of adjunctive IVIG with the standard of care (SoC) in moderate-to-severe COVID-19 patients. This randomized study included 59 moderate-to-severe COVID-19 patients with known comorbidities. One arm (n = 33) received high-dose IVIG (400 mg/kg/day) within 48 hours for five days alongside SoC, while the other arm (n = 26) received SoC, comprising steroids, enoxaparin, and remdesivir. The primary endpoint was clinical improvement, as measured by the National Early Warning Score 2 (NEWS2) and discharged/death proportions. Secondary outcomes included IVIG safety, hospitalization duration, changes in oxygen saturation, inflammatory markers, IgG titer, CTSS (CT severity score), and radiological findings. There was an improvement in the NEWS2 at the end of treatment in the IVIG arm (5.67 vs. 5.96). A significant absolute effect improvement (Day 1 vs. Day 9) was seen in serum LDH, D-dimer, hs-CRP, IL-6, CTSS, procalcitonin, respiratory rate, and chest radiographic findings. SARS-CoV-2 IgG titer increased significantly in the IVIG arm. There was a statistically significant reduction in mortality in the IVIG group (5 vs. 10). IVIG was a safe and effective adjunctive therapy to SoC treatment in moderate-to-severe COVID-19 patients needing ventilatory support. Furthermore, studies are required to validate our findings. This trial is registered with CTRI/2021/05/033622.

Clinical efficacy of prophylactic intravenous immunoglobulin for elderly DLBCL patients with hypogammaglobulinemia in the COVID-19 pandemic era.

Elderly patients diagnosed with diffuse large B-cell lymphoma (DLBCL) undergoing reduced intensity R-CHOP therapy are at a heightened risk of acquiring infections, notably coronavirus disease 2019 (COVID-19) infection. This study aimed to evaluate the efficacy of intravenous immunoglobulin (IVIG) as prophylaxis against COVID-19 in this vulnerable population. A total of 125 elderly patients with DLBCL undergoing reduced intensity R-CHOP therapy were analyzed in this prospective, multicenter study. Patients with hypogammaglobulinemia were categorized into IVIG and non-IVIG groups, while those with normal immunoglobulin levels constituted the observation group. The study evaluated COVID-19 infection rates, therapy response, and safety outcomes. Among the enrolled patients (median age: 77 years), 89 patients (71.2%) presented with hypogammaglobulinemia at diagnosis, and 56 patients enrolled in the IVIG administration group. IVIG administration remarkably reduced COVID-19 infection rates compared to non-IVIG recipients (8.9% vs. 24.6%; p =0.040). Notably, patients over 80 years old were more susceptible to COVID-19. Patients on IVIG exhibited good tolerance with manageable adverse events. Among patients with hypogammaglobulinemia who received IVIG, 40.5% of patients developed additional immunoglobulin deficiencies during chemotherapy. One or more new hypogammaglobulinemia occurred during chemotherapy in 72% of patients with hypogammaglobulinemia who did not receive IVIG, and in 61.3% of patients who did not have hypogammaglobulinemia at diagnosis. IVIG showed promise in reducing COVID-19 infections among elderly patients with DLBCL receiving reduced intensity R-CHOP therapy. This highlights IVIG's potential as a prophylactic measure, necessitating further investigation to optimize dosing, administration schedules, and potential interactions with vaccination strategies.

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.

High-dose intravenous immunoglobulin versus albumin 4% in paediatric toxic shock syndrome: a randomised controlled feasibility study

PurposeToxic shock syndrome (TSS) is a rare disease responsible for significant morbidity and mortality. Intravenous immunoglobulin (IG) therapy in paediatric TSS could improve shock and organ failure, but more consistent...

Randomized controlled trial of intravenous immunoglobulin for autoimmune postural orthostatic tachycardia syndrome (iSTAND).

This study assesses response to intravenous immunoglobulin (IVIG) in presumed autoimmune postural orthostatic tachycardia syndrome (POTS). POTS may be associated with autoimmune disorders, serum autoantibodies, or recent infection. Uncontrolled case studies suggest that IVIG is beneficial for treating autoimmune POTS. No previous randomized controlled trials have been conducted. This single-site randomized controlled trial compared IVIG with intravenous albumin infusions. Albumin comparator ensured blinding and control for effects of volume expansion. Eligible patients with POTS had COMPASS-31 total weighted score ≥ 40 and met predetermined criteria suggesting autoimmunity. Over 12weeks, participants received eight infusions (0.4gm/kg each). Four infusions were given weekly followed by four infusions every other week. Primary outcome measure was improvement in COMPASS-31 2weeks after final infusion. A total of 50 participants consented; 30 met inclusion criteria and received study drug (16 IVIG and 14 albumin; 29 female). Group baseline characteristics were well matched; 27 participants completed treatment protocol. Change in COMPASS-31 did not differ between groups (median change [IQR]; IVIG: -5.5 [-23.3, 2.5] versus albumin: -10.6 [-14.1, -4.7]; p-value = 0.629). The IVIG group had a higher response rate (46.7% versus 38.5%), but this was not statistically significant. Adverse events were common but usually mild and did not differ between treatment groups. This small randomized controlled trial of IVIG in POTS found no statistical difference in response compared with albumin infusion. Both groups showed improvement possibly related to volume expansion or other effects obscuring group differences. These findings inform development of future immunomodulatory clinical trials in POTS.

Comparison of the oxidative stress status of children with ITP in two therapies using methylprednisolone and methylprednisolone along with IVIG

Background: Idiopathic thrombocytopenic purpura (ITP) is a rare and autoimmune disorder determined by an abnormal reduction in the number of platelets. The current study aims to evaluate the oxidative stress status of children with ITP in two treatment methods using methylprednisolone and methylprednisolone with intravenous immunoglobulin (IVIG).&#x0D; Materials and Methods: This retrospective study was conducted on 60 children with ITP who referred to Baghaei Hospital in Ahvaz in 2021. All the ITP children were equally divided into two groups, 30 receiving methylprednisolone and 30 receiving methylprednisolone and IVIG. The sampling of the patients’ blood was done in two stages before and after the start of treatment. Then, malondialdehyde (MDA), superoxide dismutase (SOD), total antioxidant status (TAS), total oxidative status (TOS), catalase (CAT) and glutathione were measured according to the instructions in the commercial kit. The analyses were performed using SPSS software version 23. P value &lt; 0.05 was significant.&#x0D; Results: The number of platelets after treatment in methylprednisolone and methylprednisolone+ IVIG groups was 133.44 ± 18.93 and 158.76 ± 34.76 (×103/µL), respectively. Itas significantly increased compared to that before the treatment (P = 0.04). The amount of TAC in the group receiving methylprednisolone + IVIG and the methylprednisolone group was 1.64 ± 0.18 and 1.26 ± 0.53 nm, respectively; there was a remarkable difference between the two groups (P = 0.001). Also, SOD, CAT and glutathione in the methylprednisolone + IVIG group were remarkably higher than those in the methylprednisolone group (P &lt; 0.05). Finally, the levels of TOS were lower in the methylprednisolone + IVIG group (19.74 ± 9.93 μmol) than in the methylprednisolone group (26.65 ± 10.64 μmol) (P = 0.01).&#x0D; Conclusion: A combination of IVIG and methylprednisolone was found to have a greater effect on improving antioxidant status and decreasing the oxidative stress indices of ITP children.

Risk factors for coronary artery abnormalities and resistance to immunoglobulin plus ciclosporin A therapy in severe Kawasaki disease: subanalysis of the KAICA trial, randomized trial for cicrosporin A as the first-line treatment.

To investigate risk factors for coronary arterial abnormalities (CAAs) and resistance to treatment in patients with Kawasaki disease (KD) receiving intravenous immunoglobulin (IVIG) plus ciclosporin A (CsA) as the first-line treatment, we performed a subanalysis of baseline data of participants in the KAICA trial, a phase 3, randomized study (JMA-ILA00174). All data of the patients enrolled in the KAICA trial, who had a Gunma score ≥5 at diagnosis and had been randomly assigned to either IVIG (2 g/kg/24 h) plus CsA (5 mg/kg/day for 5 days) (n = 86) or IVIG alone (n = 87), were subjected to this study. CAA was defined by a Z score ≥2.5 observed within 4 weeks after treatment initiation. Baseline data including genotypes of KD susceptibility genes were compared between subgroups of patients for CAA or treatment response for each treatment group. Backword-forward stepwise logistic regression analyses were performed. Pre-Z-max, defined as the maximum among Z scores on four coronary artery branches before treatment, was higher in patients with CAA in both treatment groups and was associated with CAA in IVIG plus CsA treatment group [odds ratio (OR) = 17.0]. High serum total bilirubin level was relevant to treatment resistance only in the IVIG plus CsA group (OR = 2.34). Coronary artery enlargement before treatment is a major determinant of CAA even in KD patients treated with initial IVIG treatment intensified by addition of CsA. Baseline serum total bilirubin level was a risk factor associated with resistance to IVIG plus CsA.

Prednisone Plus Ivig Compared with Prednisone for Immune Thrombocytopenia during Pregnancy

Introduction Immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by an isolated low platelet count and is the most common cause of thrombocytopenia during pregnancy, accounting for 1%-4% of thrombocytopenia in pregnant women. Women with ITP who have severe thrombocytopenia are at an increased risk for life-threatening obstetric complications. However, management of ITP during pregnancy can be challenging because treatment choices are limited. Corticosteroids or intravenous immunoglobulin (IVIg) are recommended as first-line treatments for pregnant women with ITP, but the response to initial treatment is approximately 39% and 38%, respectively, lower than that in nonpregnant patients with ITP. Therefore, in-depth studies investigating new solutions for the first-line treatment of ITP during pregnancy are urgently needed. Our previous retrospective study revealed an advantage of prednisone combined with IVIg compared to prednisone monotherapy for pregnant patients with ITP. Therefore, the aim of this prospective, randomized, open-label study was to further assess the efficacy and safety of prednisone plus IVIg compared to prednisone monotherapy in pregnant women with ITP. The study has been registered at clinicaltrials.gov. NCT05333744 Methods Eligible treatment-naive ITP patients during pregnancy with a platelet count &amp;lt; 30 × 10^9/L, accompanied by or without bleeding symptoms, were randomly assigned 1:1 to receive prednisone 20 mg per day for 4 weeks plus IVIg 400 mg/kg (total dose ≤20 g per day) for 5 days or prednisone 20 mg monotherapy per day for 4 weeks. Prednisone was gradually tapered to the maintenance dose of 5-10 mg per day until 6 weeks after delivery if there was a response to treatment; otherwise, prednisone was gradually tapered to withdrawal. The primary outcome was overall response (OR), defined as a platelet count ≥ 30 × 10^9/L, a doubling of the baseline platelet count and the absence of bleeding. Secondary endpoints included complete response (CR), time to response, platelet counts at delivery, platelet counts of newborns, and adverse events in parturients. CR was defined as platelet count ≥100×10^9/L measured on 2 occasions at least 7 days apart and the absence of bleeding. Results A total of 100 treatment-naive ITP patients during pregnancy were randomly assigned to either the prednisone plus IVIg (n=50) or prednisone monotherapy (n=50) groups. All the baseline characteristics were comparable between the two groups. The median ages of patients in the prednisone plus IVIg group and prednisone monotherapy group were 30.32 years (range, 22-43) and 30 years (range, 28-46), respectively. For patients in the combination and monotherapy groups, the mean estational ages at intervention start were 28.3 weeks and 30.9 weeks, respectively. All patients were followed up for more than 2 months. OR was observed in 23 (46.0%) patients in the combination group and 22 (44%) in the monotherapy group, and no significant difference was observed between the two groups (p=0.91). A significant difference was observed in the time to response between the prednisone plus IVIg group and prednisone monotherapy group (6.14 days vs. 9.84 days, p=0.001). However, the predelivery platelet transfusion of the prednisone plus IVIg group was greater than that of the prednisone monotherapy group. There were no significant differences in the delivery mode between the combined group and monotherapy group. No significant differences were found between the two groups in neonatal outcomes, particularly concerning the neonatal platelet counts. Conclusion Prednisone plus IVIg was an effective and safe treatment for ITP in pregnancy, and this therapy may be a new first-line treatment option for pregnant patients with ITP.

Multicenter, Prospective Study to Investigate the Efficacy and Safety of Intravenous-Immunoglobulin Therapy in Elderly Patients with Diffuse Large B Cell Lymphoma Treated with R-Mini-CHOP

Background The median age at initial diagnosis of DLBCL is estimated to be between the ages of 60 and 70. The number of elderly patients with DLBCL is gradually increasing. But, treatment outcomes of elderly patients were not significantly improved compared to younger patients. Infection is an independent predictor of treatment outcome in patients with DLBCL, and the risk of infection increases with age. The incidence of hypogammaglobulinemia in patients with malignant lymphoma increased from 15% to 39% after rituximab therapy. There was a significant decrease in the occurrence of major infections after intravenous immunoglobulins (IVIG) prophylaxis in hypogammaglobulinemia patients with lymphoproliferative. disorders. In this multicenter prospective study, infection prevention effect and treatment outcomes were identified using IVIG in elderly DLBCL patients with hypogammaglobulinemia who received rituximab combination chemotherapy. Methods In the current study, newly diagnosed DLBCL patients aged 70 years or older who were planning to receive R-mini-CHOP therapy were included. Patients with hypogammaglobulinemia at diagnosis were assigned to the IVIG group. Patients received R-mini-CHOP (rituximab: 375mg/m 2 D1; cyclophosphamide: 400mg/m 2 D1; doxorubicin: 25mg/m 2 D1; vincristine: 1.0mg D1, and prednisolone 40mg/m 2 from D1 to D5), and pegylated G-CSF. After the first cycle of R-mini-CHOP, 400mg/kg of IVIG was administered on D3 and D11. After the second cycle to sixth cycle of chemotherapy, patients received 400mg/kg of IVIG on D11. The primary objective was to evaluate the efficacy of IVIG in reducing severe infections. Grade 3 or 4 infections were defined as severe infections. Results A total of 118 elderly patients were newly diagnosed with DLBCL and were scheduled to receive R-mini-CHOP therapy. Hypogammaglobulinemia was identified in 85 (72.0%) patients. Decreased immunoglobulin D (n=42) and immunoglobulin M (n=39) level were most common, and 18 patients had two or more types of hypogammaglobulinemia at the same time. Fifty-six patients were assigned to the group receiving IVIG. Median age was 77 years (range, 70-90), and 31 (55.4%) were male. In patients who completed R-mini-CHOP and IVIG treatment, complete remission rate was 79.4%. Severe infections of grade 3 or 4 occurred in 3 of 56 (5.4%) patients, and only five (8.9%) patients had COVID-19 infection during the study period. Adverse effects associated with IVIG include fever/chilling, nausea/vomiting which were generally manageable. Only one patient discontinued the study because of chest pain that occurred during IVIG administration. In patients with hypogammaglobulinemia who did not receive IVIG, severe infections occurred in 8 of 29 (27.6%) patients, and COVID-19 infection was developed in 7 of 29 (24.1%). In patients without hypogammaglobulinemia, severe infection occurred in 5 of 33 (15.2%), and COVID-19 infection was developed in 8 of 33 (24.2%) patients. Patients receiving IVIG had a significantly reduced incidence of severe infection compared to patients not receiving IVIG (p=0.028). Furthermore, COVID-19 infection rate during R-mini-CHOP therapy was lower in IVIG receiving patients (p=0.050). Long-term outcomes with relapse rate and survival will be followed up and updated. Conclusion In elderly patients with DLBCL, the combination of R-mini-CHOP and IVIG was safe and effective in preventing infection. In the COVID-19 era, the combination of chemotherapy and IVIG should be considered in elderly DLBCL patients to reduce infection rate and improve treatment outcomes.

Efficacy of intravenous immunoglobulins (IVIg) in improving skin symptoms in patients with dermatomyositis: a post-hoc analysis of the ProDERM study

Dermatomyositis (DM) is a rare autoimmune disease characterized by skin involvement, with or without proximal muscle weakness. Recently, following the ProDERM study, intravenous immunoglobulin (IVIg) was approved for treatment of DM. Until ProDERM evidence from large, placebo-controlled studies supporting its use for dermatological symptoms, was lacking. Here we present efficacy data from ProDERM of IVIg versus placebo for treatment of the cutaneous aspect of DM. ProDERM was a double-blind, randomized, multicenter, Phase 3 study. In the First Period (Weeks 0-16), adults with active DM received 2.0g/kg IVIg (Octagam 10%; Octapharma AG) or placebo every 4 weeks. In the open-label Extension Period (Weeks 16-40), all patients received IVIg for 6 additional cycles. Cutaneous disease was assessed using measures including modified cutaneous DM disease area and severity index activity (CDASI-A) and damage (CDASI-D) scores, and myositis disease activity assessment tool (MDAAT) including visual analogue scale (VAS). This trial is registered with ClinicalTrials.gov, NCT02728752. The study took place from February 2017 to November 2019. 95 patients received IVIg (N=47) or placebo (N=48) in the First Period. Together, 664 IVIg infusion cycles were administered (median dose, 2.0g/kg). At Week 16, mean CDASI-A change from baseline was-9.36 (95% CI:-12.52,-6.19) in the IVIg group versus-1.16 (-3.32, 0.99) in placebo group (p<0.0001). At the end of the Extension Period, mean changes from baseline were-10.44 (95% CI:-13.94,-6.94) and-10.03 (-13.12,-6.94), respectively. Similar changes were seen for CDASI-D and VAS of MDAAT. These observations were seen regardless of baseline disease severity. ProDERM is the first large prospective, randomized trial to demonstrate the efficacy of IVIg to improve the cutaneous manifestations of DM. IVIg treatment significantly improved dermatological symptoms in patients with DM, regardless of disease severity before treatment, suggesting that IVIg is effective for even the most severe cutaneous DM. This study was sponsored by Octapharma Pharmazeutika Produktionsges m.b.H.

Clinical efficacy of immunoglobulin on the treatment of severe fever with thrombocytopenia syndrome: a retrospective cohort study

Optimal treatment strategy for severe fever with thrombocytopenia syndrome (SFTS) remained unknown. We aimed to evaluate the efficacy of intravenous immunoglobulin (IVIG) on SFTS. A retrospective cohort study was conducted based on medical records of the laboratory-confirmed SFTS patients hospitalized during 2010-2020 in the 154th hospital, China. A 1:1 propensity score matching with age, sex, the interval from symptom onset to admission, presence of chronic viral hepatitis, diabetes and disease severity was performed between Non-IVIG group (supportive therapy) and IVIG group (IVIG plus supportive therapy). The matching variables were adjusted to compare the case fatality rates (CFRs), viral load and laboratory parameters between the two groups. Risk ratio (RR) and 95% confidence interval (CI) were reported. Totally 2219 SFTS patients were recruited. CFRs were significantly higher in 1051 patients in IVIG group than 1168 patients in Non-IVIG group (19.0% vs. 4.6%, RR=4.30, 95% CI 3.12-5.93). The difference remained significant after matching (17.2% vs. 5.1%, RR=4.02, 95% CI 2.71-5.97). The CFR of IVIG group was significantly higher in all age groups, two IVIG therapy delay groups and two therapy duration groups compared to that of Non-IVIG group (all P<0.05). IVIG therapy was related to higher viral loads and reduced counts of lymphocytes, T cells, CD4+ T cells and natural killer cells in the blood (all P<0.05). No obvious efficacy of IVIG in saving life or improving outcome of SFTS was observed. Caution is needed for clinical physicians to continue prescribing IVIG for SFTS patients. Natural Science Foundation of China.

Immunomodulatory Therapy for MIS-C.

Studies comparing initial therapy for multisystem inflammatory syndrome in children (MIS-C) provided conflicting results. To compare outcomes in MIS-C patients treated with intravenous immunoglobulin (IVIG), glucocorticoids, or the combination thereof. Medline, Embase, CENTRAL and WOS, from January 2020 to February 2022. Randomized or observational comparative studies including MIS-C patients <21 years. Two reviewers independently selected studies and obtained individual participant data. The main outcome was cardiovascular dysfunction (CD), defined as left ventricular ejection fraction < 55% or vasopressor requirement ≥ day 2 of initial therapy, analyzed with a propensity score-matched analysis. Of 2635 studies identified, 3 nonrandomized cohorts were included. The meta-analysis included 958 children. IVIG plus glucocorticoids group as compared with IVIG alone had improved CD (odds ratio [OR] 0.62 [0.42-0.91]). Glucocorticoids alone group as compared with IVIG alone did not have improved CD (OR 0.57 [0.31-1.05]). Glucocorticoids alone group as compared with IVIG plus glucocorticoids did not have improved CD (OR 0.67 [0.24-1.86]). Secondary analyses found better outcomes associated with IVIG plus glucocorticoids compared with glucocorticoids alone (fever ≥ day 2, need for secondary therapies) and better outcomes associated with glucocorticoids alone compared with IVIG alone (left ventricular ejection fraction < 55% ≥ day 2). Nonrandomized nature of included studies. In a meta-analysis of MIS-C patients, IVIG plus glucocorticoids was associated with improved CD compared with IVIG alone. Glucocorticoids alone was not associated with improved CD compared with IVIG alone or IVIG plus glucocorticoids.

High doses of intravenous immunoglobulin stimulate regulatory T cell and suppress natural killer cell in women with recurrent pregnancy loss

The aim was to evaluate whether natural killer (NK) cells and regulatory T (Treg) cells were involved in mechanisms underlying beneficial effects of a high dose of intravenous immunoglobulin (IVIG) on recurrent pregnancy losses (RPL) of unexplained etiology. In a double-blind, randomized, placebo-controlled trial of IVIG (400 mg/kg, for 5 days in 4–6 weeks of gestation) in women with RPL, blood samples were collected pre-infusion, one week after infusion (1 w), and eight weeks of gestation/when miscarried (8 w). Levels of NK and Treg cells in peripheral blood were compared between women with IVIG (n = 50) and placebo (n = 49), and between women with IVIG who gave live birth (n = 29) and those who had miscarriage with normal chromosome (n = 12). Effector Treg cell percentages in IVIG group at 1 w (mean 1.43 % vs. 1.03 %) and at 8 w (1.91 % vs. 1.18 %) were higher than those in placebo group (p < 0.01). Total Treg cell percentages in IVIG group at 1 w (4.75 % vs. 4.08 %) and at 8 w (5.55 % vs. 4.47 %) were higher than those in placebo group (p < 0.05). In women with live birth, total Treg cell percentages increased at 8 w (5.52 %, p < 0.001) compared with pre-infusion (4.54 %) and 1 w (4.47 %), while NK cell activity decreased at 1 w (20.18 %, p < 0.001) compared with pre-infusion (26.59 %). IVIG increased Treg cell percentages and suppressed NK cell activity very early in pregnancy, and these were associated with subsequent live birth. Stimulation of Treg cells and suppression of NK cell activity very early in pregnancy may be a mechanism of pharmacological effects of high dose IVIG.

Efficacy of intravenous immunoglobulins (IVIG) in COVID-19 patients: a systematic review and meta-analysis.

Though controversial, many clinical trials have been conducted to evaluate the efficacy of intravenous immunoglobulins (IVIG) in COVID-19 cases. Therefore, a systematic review and meta-analysis have been performed to evaluate the efficacy of IVIG in the treatment of COVID-19 patients. A systematic search was performed in electronic databases and preprint servers up to November 20, 2021. Since substantial heterogeneity was expected, a random-effects model was applied to pool effect size from included studies to calculate the standardized mean differences (SMDs) for the continuous variables and relative risks (RRs) for the dichotomous variable with 95% confidence intervals (CIs). Five randomized clinical trials and seven cohort studies were analyzed among the 12 eligible studies with a total of 2,156 patients. The pooled RR of mortality was 0.77 (CI 0.59-1.01, P-value = 0.06), and of mechanical ventilation was 1.50 (CI 0.29-7.83; P-value = 0.63) in the IVIG group compared with the standard care group. The pooled SMD of hospital length of stay was 0.84 (CI -0.43-2.11; P-value = 0.20) and of ICU length of stay was -0.07 (CI -0.92-0.78; P-value = 0.86) in the IVIG group compared with the standard care group. This meta-analysis found that the IVIG therapy was not statistically different from the standard care group. Mortality, ICU admission, mechanical ventilation, length of hospital stay, and length of ICU stay were not significantly improved among IVIG recipients. However, statistical indifference is not equal to clinical indifference.