Use Of Intravenous Immunoglobulin In Patients Research Articles

Intravenous immunoglobulin for treatment of hospitalized COVID-19 patients: an evidence mapping and meta-analysis.

The clinical efficacy and safety of intravenous immunoglobulin (IVIg) treatment for COVID-19 remain controversial. This study aimed to map the current status and gaps of available evidence, and conduct a meta-analysis to further investigate the benefit of IVIg in COVID-19 patients. Electronic databases were searched for systematic reviews/meta-analyses (SR/MAs), primary studies with control groups, reporting on the use of IVIg in patients with COVID-19. A random-effects meta-analysis with subgroup analyses regarding study design and patient disease severity was performed. Our outcomes of interest determined by the evidence mapping, were mortality, length of hospitalization (days), length of intensive care unit (ICU) stay (days), number of patients requiring mechanical ventilation, and adverse events. We included 34 studies (12 SR/MAs, 8 prospective and 14 retrospective studies). A total of 5571 hospitalized patients were involved in 22 primary studies. Random-effects meta-analyses of very low to moderate evidence showed that there was little or no difference between IVIg and standard care or placebo in reducing mortality (relative risk [RR] 0.91; 95% CI 0.78-1.06; risk difference [RD] 3.3% fewer), length of hospital (mean difference [MD] 0.37; 95% CI -2.56, 3.31) and ICU (MD 0.36; 95% CI -0.81, 1.53) stays, mechanical ventilation use (RR 0.92; 95% CI 0.68-1.24; RD 2.8% fewer), and adverse events (RR 0.98; 95% CI 0.84-1.14; RD 0.5% fewer) of patients with COVID-19. Sensitivity analysis using a fixed-effects model indicated that IVIg may reduce mortality (RR 0.76; 95% CI 0.60-0.97), and increase length of hospital stay (MD 0.68; 95% CI 0.09-1.28). Very low to moderate certainty of evidence indicated IVIg may not improve the clinical outcomes of hospitalized patients with COVID-19. Given the discrepancy between the random- and fixed-effects model results, further large-scale and well-designed RCTs are warranted.

Intravenous immunoglobulin use in patients with unexplained recurrent pregnancy loss.

Recurrent pregnancy loss (RPL) affects up to 4% of couples attempting to conceive. RPL is unexplained in over 50% of cases and no effective treatments exist. Due to the immune system's pivotal role during implantation and pregnancy, immune-mediated RPL may be suspected and immunomodulatory treatments like intravenous immunoglobulin (IVIg) have been administered but remain controversial. The goal of our study was to evaluate our center's 6year-outcomes and to develop a framework for IVIg use in RPL. Retrospective, single-center cohort study. All patients having received IVIg for unexplained RPL at the McGill Reproductive Immunology Clinic (MRIC) from January 2014 to December 2020 were included if maternal age was <42years, body mass index (BMI)<35kg/m2 , non-smoker and having had ≥3 consecutive RPL despite previous treatment with aspirin and progesterone. IVIg 0.6-0.8g/kg was given prior to conception and monthly during pregnancy until 16-20weeks' gestation. We compared IVIg treated patient's outcomes to a separate "natural history cohort". This cohort was composed of patients consulting at the McGill recurrent pregnancy loss clinic and the MRIC over a 2-year period (January 2020 to December 2021) with similar inclusion criteria as the treatment cohort but did not receive IVIg or other immunomodulatory treatments. The association of IVIg with outcomes (compared to no IVIg) was evaluated among the groups of patients with primary RPL and secondary RPL. The primary outcome was live birth rate (LBR), secondary outcomes included IVIg safety, obstetrical, and neonatal complications. Among 169 patients with unexplained RPL that were included in the study, 111 had primary RPL (38 exposed to IVIg and 83 controls) and 58 had secondary RPL (nine exposed to IVIG and 49 controls). Among patients with primary RPL (n=111), the LBR was 64.3% (18/28) among patient exposed to IVIg compared to 43.4% (36/83) in controls (p=0.079); regression analysis adjusting for BMI and number of previous miscarriages showed benefit favoring the use of IVIg (OR=3.27, CI 95% (1.15-10.2), p=0.03) when evaluating for live birth. In the subgroup of patients with ≥5 previous RPL and primary RPL (n=31), IVIg was associated with higher LBR compared to control (10/15 (66.7%) vs. 3/16 (18.8%); p=0.0113) but not the in the sub-group of patients with <5 miscarriages and primary RPL (8/13 (61.5%) vs. 33/67 (49.3%); p=0.548). IVIG treatment did not improve LBR in patients with secondary RPL in our study (3/9 (33.3%) vs. 23/49 (47%); p=0.495). There were no serious adverse events in the IVIg treatment group, obstetrical/neonatal complications were similar between groups. IVIg may be an effective treatment for patients with RPL if appropriately used in specific groups of patients. IVIg is a blood product and subject to shortages especially with unrestricted off-label use. We propose considering IVIg in well-selected patients with high order RPL who have failed standard medical therapy. Further mechanistic studies are needed to understand immune-mediated RPL and IVIg's mode of action. This will enable further refinement of treatment criteria and the development of standardized protocol for its use in RPL.

REAL‐WORLD OUTCOMES OF INTRAVENOUS IMMUNOGLOBULIN FOR HYPOGAMMAGLOBULINEMIA AFTER CHIMERIC ANTIGEN RECEPTOR T‐CELL THERAPY IN PATIENTS WITH DIFFUSE LARGE B‐CELL LYMPHOMA

Introduction: Chimeric antigen receptor T-cell (CAR-T) therapy is a treatment for patients with diffuse large B-cell lymphoma (DLBCL) and is associated with toxicities, including hypogammaglobulinemia (HGG). Intravenous immunoglobulin (IVIG) is often used to manage HGG and prevent recurrent infections after CAR-T therapy, but more real-world evidence is needed to support this. Aim: To describe the real-world incidence of HGG and the effectiveness of IVIG after CAR-T therapy in patients with DLBCL. Methods: This observational cohort study used de-identified data from the nationwide (US-based) electronic health record (EHR)-derived Flatiron Health database. Patients were aged ≥18 years, diagnosed with DLBCL, had ≥2 visits in the Flatiron network on/after 1-Jan-11 and had received CAR-T therapy (tisagenlecleucel or axicabtagene ciloleucel) in any treatment line after 1-Jan-18. Baseline characteristics were identified in the 60 days prior to the index date (date of first CAR-T therapy administration). Outcomes, including HGG, were measured from index date until patient death or end of data availability (cut-off: 30-Apr-21). In this ad-hoc analysis, the primary objectives were to evaluate HGG incidence and IVIG use in patients with DLBCL who received CAR-T therapy. Exploratory objectives were to describe overall survival (OS) and progression-free survival (PFS) by IVIG treatment. Proportions and medians were used for patient characteristics. The Kaplan–Meier method was used for clinical outcomes. Results: Overall, 91 patients were included. During follow-up, 14 patients (15.4%) developed HGG, of which six cases were ‘directly attributed’ and one case ‘possibly attributed’ to CAR-T therapy; attribution was not documented for seven patients. Among these 14 patients, eight received treatment for HGG and six had no documented record of treatment. In total, 14/91 patients received IVIG (IVIG cohort). The IVIG cohort was younger (median [range] age 59 [32–67] vs 63 [28–83] years), had more females (50.0% vs 37.7%), had more patients with an Eastern Cooperative Oncology Group score of 2 (14.3% vs 6.5%) and was more frequently treated in a community setting (64.3% vs 49.4%) than the non-IVIG cohort. In the IVIG and non-IVIG cohorts, median (95% confidence interval [CI]) OS was not reached (NR; 5.6–NR) and 18.3 (9.1–NR) months, respectively and median (95% CI) PFS was NR (2.3–NR) and 3.0 (2.7–7.4) months, respectively. Conclusions: In this real-world study, half of the 14 HGG cases in patients with DLBCL were directly/possibly attributed to CAR-T therapy. This may be an underestimate because HGG is primarily assessed using laboratory data but here it was identified using EHRs. Despite a small sample size, the hypothesis-generating analyses of IVIG effectiveness and management outcomes support further evaluation of IVIG for the treatment of HGG in patients with DLBCL after CAR-T therapy. The research was funded by: Takeda Development Center Americas, Inc. Writing support was funded by: Takeda Pharmaceuticals International AG. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Immunotherapy Conflicts of interests pertinent to the abstract D. S. Chun Employment or leadership position: Takeda Development Center Americas, Inc. Stock ownership: Takeda Y. Yin Employment or leadership position: Takeda Development Center Americas, Inc. Stock ownership: Takeda C. Anderson-Smits Employment or leadership position: Takeda Development Center Americas, Inc. Stock ownership: Takeda

Markedly prolonged compound muscle action potential duration in a patient with coronavirus disease 2019 related critical illness myopathy

AbstractA 56‐year‐old man admitted with coronavirus disease 2019 (COVID‐19) became severely ill, required ventilator support and intensive care unit management. After ventilator weaning, he was found to have quadriparesis. Guillain–Barré syndrome (GBS) was suspected and administration of high‐dose intravenous immunoglobulin (IVIg) was considered. However, markedly prolonged compound muscle action potential (CMAP) duration was observed, leading to a diagnosis of critical illness myopathy (CIM). Therefore, IVIg was not given at all, and supportive care was continued. A good functional recovery was obtained. Prolonged CMAP duration is a characteristic finding to CIM. CIM following severe COVID‐19 infection is probably common, although the diagnostic value of prolonged CMAP duration is not widely recognized. This characteristic finding deserves more attention because it contributes to early differentiation between CIM and GBS and the use of IVIg in patients with COVID‐19 may cause thrombotic complications and worsen the prognosis.

International guidelines regarding the role of IVIG in the management of Rh- and ABO-mediated haemolytic disease of the newborn.

Haemolytic disease of the newborn (HDN) can be associated with significant morbidity. Prompt treatment with intensive phototherapy (PT) and exchange transfusions (ETs) can dramatically improve outcomes. ET is invasive and associated with risks. Intravenous immunoglobulin (IVIG) may be an alternative therapy to prevent use of ET. An international panel of experts was convened to develop evidence‐based recommendations regarding the effectiveness and safety of IVIG to reduce the need for ETs, improve neurocognitive outcomes, reduce bilirubin level, reduce the frequency of red blood cell (RBC) transfusions and severity of anaemia, and/or reduce duration of hospitalization for neonates with Rh or ABO‐mediated HDN. We used a systematic approach to search and review the literature and then develop recommendations from published data. These recommendations conclude that IVIG should not be routinely used to treat Rh or ABO antibody‐mediated HDN. In situations where hyperbilirubinaemia is severe (and ET is imminent), or when ET is not readily available, the role of IVIG is unclear. High‐quality studies are urgently needed to assess the optimal use of IVIG in patients with HDN.

Effectiveness of intravenous immunoglobulin for children with severe COVID-19: a rapid review.

BackgroundIntravenous immunoglobulin (IVIG) is usually used as supportive therapy, but the treatment of COVID-19 by IVIG is controversial. This rapid review aims to explore the clinical effectiveness and safety of IVIG in the treatment of children with severe COVID-19.MethodsWe systematically searched the literature on the use of IVIG in patients with COVID-19, severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS), including both adults and children. We assessed the risk of bias and quality of evidence and reported the main findings descriptively.ResultsA total of 1,519 articles were identified by initial literature search, and finally six studies met our inclusion criteria, included one randomized controlled trial (RCT), four case series and one case report involving 198 patients. One case series showed the survival of COVID-19 patients with acute respiratory distress syndrome (ARDS) was not improved by IVIG. One case report showed high-dose IVIG could improve the outcome of COVID-19 adults. Three observational studies showed inconsistent results of the effect of IVIG on SARS patients. One RCT showed that IVIG did not reduce mortality or the incidence of nosocomial infection in adults with severe SARS. The quality of evidence was between low and very low.ConclusionsThe existing evidence is insufficient to support the efficacy or safety of IVIG in the treatment of COVID-19.

P253 ROLE OF HYPOGAMMAGLOBULINEMIA AND INTRAVENOUS IMMUNOGLOBULIN IN OUTCOMES FOR PATIENTS THAT HAVE UNDERGONE LUNG TRANSPLANTATION

The effect of hypogammaglobulinemia on post-transplant outcomes and the role of intravenous immunoglobulin (IVIG) in patients who have undergone lung transplant is unknown. No guidelines have been established for the use of IVIG in patients who have undergone solid organ transplantation.

Evaluation and identification of protocols for safe and efficacious institutional administration of intravenous immune globulin in hypogammaglobulinemia associated with chronic lymphocytic leukemia, non-Hodgkin lymphoma, and multiple myeloma.

250 Background: Hematologic malignancies effect both humoral and cell-mediated immunity. We hypothesize that for patients with Chronic Lymphocytic Leukemia (CLL), Non-Hodgkins Lymphoma (NHL), and Multiple Myeloma (MM) outcomes improve with adherence to National Comprehensive Cancer Network (NCCN) guidelines for intravenous immunoglobulin (IVIG).Our objective is to understand resource allocation and implementation of IVIG in outpatient and inpatient settings. We identified a cohort of patients with hypogammaglobulinemia for assessing incidence of sepsis, outcomes, and resource use. We initiated this project by undertaking a large descriptive study of current IVIG use. Methods: A retrospective Institutional Review Board (IRB) approved data capture was conducted covering 2016-2018. Inclusion criteria involved those on an active chemotherapy plan, age &gt; 18 years and diagnosis of CLL, NHL, or MM. IgA deficiency, anaphylaxis to IVIG, planned chemotherapy, inherited immunodeficiency, and thymic deficiency were excluded. We considered patients to be suitable for IVIG if IgG was &lt; 500 mg/dL for CLL and MM and &lt; 400 mg/dL in NHL. Outcomes, number of admissions, sepsis, ICU care, infectious etiology, and monthly IgG levels were examined. Results: A preliminary i2b2 data capture identified a cohort of 563 patients that yielded 12% with bacteremia, 21% with sepsis, and 23% with pneumonia of which 87% were admitted. 28% received IVIG during the 2-year period. Of the 563, 77% were hospitalized and 21% required ICU care. 54% of ICU patients received inpatient IVIG. All influenza and parainfluenza cases were inpatient. Final data analysis will yield greater detail in comparing inpatient to outpatient IVIG use. Conclusions: Large academic institutions appear to have significant variability in use of IVIG in patients with lymphopenia and hematologic malignancies. With this data, we plan to assess for patient-level outcomes based on adherence to NCCN guidelines as a way to enhance Physician Quality Reporting System (PQRS) standards by prioritizing outpatient use of IVIG.

Intravenous and subcutaneous immunoglobulin replacement: a two-way road. Optimizing healthcare quality in patients with primary immunodeficiencies.

To evaluate the alternate use of subcutaneous immunoglobulin (SCIG) and intravenous immunoglobulin (IVIG) in patients with primary immunodeficiencies (PID) in a third-level Pediatric University Hospital. Retrospective study of all patients receiving SCIG from 2006 to 2012. Data collected included demographics, date SCIG was started, date of switch to IVIG and reasons, administration tolerance, and related adverse events. Effectiveness was defined as the lack of severe infections. Twenty-three patients (15 male, 8 female) with PID were studied. SCIG was initiated at a median age of 14.2 years (8.4 months-25.7 years) and median duration on SCIG treatment was 41 months (4-68). Nine patients (39.1%) temporarily switched from SCIG to IVIG for the following reasons: vacation (8), administration issues (1), and transient need for immunomodulatory therapy (1). A mean of 5.2 IVIG infusions/patient (SD=2.86) was administered while on SCIG. IVIG-related adverse events were documented in 3 patients with 6 infusions. Eight (34.8%) patients definitively discontinued SCIG use for the following reasons: convenience (5), adverse effects (1), coagulopathy (1), and autoimmune thrombocytopenia (1). There were no severe infections requiring hospital admission in any patient during the study period. Alternating SCIG and IVIG use in patients with PID was associated with considerable advantages in terms of convenience for the patients and their caregivers, while maintaining the effectiveness and safety of this therapy. Healthcare units treating these patients should show flexibility with this dual therapy in order to optimize patients' quality of life.

Gammaglobulins in critical care

The use of intravenous immunoglobulin (IVIG) is relatively infrequent in patients admitted to intensive care units (ICUs). However, “off-label” IVIG prescriptions for different conditions are highly prevalent. The aim of this paper is to review the existing evidence for the use of IVIG in patients admitted to ICUs, emphasizing non-infectious diseases and complications: hypogammaglobulinemia of the critically ill,hemophagocytic lymphohistiocytosis (HLH), Guillain-Barré syndrome (GBS), Kawasaki disease (KD), chylothorax, acute myocarditis, toxic shock syndrome (TSS), Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), and sepsis.In conclusion, in critically ill patients, IVIG use is of benefit in KD, GBS, and TSS. It may benefit patients with fulminant acute myocarditis. The benefit is not proven in patients with HLH, chylothorax, and SJS/TEN.

Prophylactic Use of Intravenous Immune Globulin in the Management of Patients Undergoing Hematopoietic Stem Cell Transplantation: A Systematic Review of Literature.

Background: Intravenous immunoglobulin (IVIG) is a scarce resource derived from pooled plasma of whole blood through industrial fractionation. IVIG for the prevention of infections and Graft versus host disease (GVHD) after Hematopoietic Stem cell transplantation (HSCT) is one of only 5 licensed indications; however, its use in HSCT is contentious with multiple conflicting reports. Given this uncertainty, we sought to summarize and quantify the clinical effects of prophylactic IVIG in the context of HSCT.Methods: We conducted a systematic review to summarize evidence from prospective randomized controlled trials (RCTs) addressing prophylactic IVIG use in patients undergoing HSCT. In particular, we included studies which addressed clinical outcomes and excluded studies that addressed only biochemical surrogates. The search strategy included MEDLINE (1966 to 4th week of July 2006), EMBASE (1980 to 4th week of July 2006) and all EBM Reviews (2ndquarter of 2006). A random effects model was used to summarize the outcome data.Results: Twenty two RCTs representing 3346 patients were included in the review; 16 RCTs addressing patients undergoing allogeneic HSCT, 4 RCTs addressing patients undergoing either allogeneic or autologous HSCT and 1 trial in patients undergoing autologous HSCT. Nine RCTs (n=1462) compared conventional IVIG to no treatment, 8 RCTs (n=538) compared CMV specific IVIG to no treatment, 2 RCTs (n=950) compared 2 different doses of conventional IVIG while 3 RCTs (n=212) compared conventional IVIG to CMV specific IVIG/plasma. Eleven RCTs comparing IVIG to no treatment did not demonstrate an overall survival advantage (RR 1.01; 95% 0.92–1.12). IVIG did not attenuate transplant related mortality (RR 1.24; 95% 0.83–1.85), acute GVHD (RR 0.95; 95% 0.80–1.14), chronic GVHD (RR 1.19; 95% 0.85–1.67), interstitial fibrosis (RR 1.00; 95% 0.50–2.00) or relapse (RR 0.76; 95% 0.38–1.52). Although CMV infections were reduced (RR 0.80; 95% 0.66–0.96), this did not result in a reduction in CMV disease (RR 0.90; 95% 0.52–1.56). Of concern, the risk of hepatic sinusoidal obstruction syndrome (HSOS) was increased (RR 3.09; 95% 1.11–8.58). Several a priori defined sensitivity analyses were performed including comparisons of the type of IVIG, dose of IVIG, type of HSCT and the quality of studies.Conclusions: There is no evidence to support the routine use of prophylactic IVIG in improving clinical outcomes in patients undergoing HSCT. Furthermore, no subgroups appear to benefit from IVIG use. The increased risk of HSOS merits further study. Given the lack of benefit of IVIG in patients undergoing HSCT, the labeled indications for IVIG should be reassessed.

Intravenous Immunoglobulin Use in Patients with Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome

Intravenous immunoglobulin (IVIg) has been proposed as a treatment for toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS). A comprehensive search of the literature was conducted to examine the efficacy and safety of IVIg in TEN and SJS patients. Seventeen relevant articles (14 TEN, 3 SJS) were identified. Only three of the TEN studies and one of the SJS studies were prospective; retrospective studies were the most common study design published. Information regarding disease severity, IVIg use, response, and hospitalization were recorded and cumulated. Aggregate level statistics were calculated. The average IVIg doses used were 0.8 +/- 0.4 g/kg/day for a mean duration of 4.0 +/- 1.0 days in TEN patients and 0.8 +/- 0.2 g/kg/day for 3.4 +/- 1.0 days in SJS patients. The clinical experience of IVIg use in TEN and SJS patients was positive in most cases. However, more studies need to be conducted to confirm the benefit of IVIg use in patients with TEN or SJS.

Intravenous Immunoglobulin Therapy in Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is an autoimmune disorder defined by the occurrence of venous and arterial thromboses and pregnancy morbidity, frequently accompanied by a moderate thrombocytopenia, in the presence of antiphospholipid antibodies. There is both laboratory and clinical evidence for the beneficial role of intravenous immunoglobulin (IVIg) in APS. Data on the use of IVIg in patients with APS have focused on its obstetric complications and antiphospholipid antibodies-positive patients undergoing in vitro fertilization, but there are also case reports about treatments of other clinical manifestations (mainly hematological) of the syndrome. Future research should determine when to use anticoagulation, IVIg, or both in the treatment of APS.

Intravenous Immunoglobulin Therapy and Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with diverse manifestations. We suggest that intravenous immunoglobulin (IVIg) therapy may be beneficial and safe for various manifestations in SLE. A structured literature search of articles published on the efficacy of IVIg in the treatment of SLE between 1983 and 2005 was conducted. We searched the terms "IVIg," "intravenous immunoglobulin," "lupus," "SLE," and "systemic lupus erythematosus." The various clinical manifestations of SLE that were reported to be successfully treated by IVIg in case reports include autoimmune hemolytic anemia, acquired factor VIII inhibitors, acquired von Willebrand disease, pure red cell aplasia, thrombocytopenia, pancytopenia, myelofibrosis, pneumonitis, pleural effusion, pericarditis, myocarditis, cardiogenic shock, nephritis, end-stage renal disease, encephalitis, neuropsychiatric lupus, psychosis, peripheral neuropathy, polyradiculoneuropathy, and vasculitis. The most extensive experience is with lupus nephritis. There are only a few case series of IVIg use in patients with SLE with various manifestations, in which the response rate to IVIg therapy ranged from 33 to 100%. We suggest that IVIg devoid of sucrose, at a dose of 2 g/kg over a 5-d period given uniformly and at a slow infusion rate in patients without an increased risk for thromboembolic events or renal failure, is a safe and beneficial adjunct therapy for cases of SLE that are resistant to or refuse conventional treatment. The duration of therapy is yet to be established. Controlled trials are warranted.

Thromboembolic Complications of Intravenous Immunoglobulin Treatment

Intravenous immunoglobulin (IVIg) preparations are increasingly being used in the treatment of neuroautoimmune diseases. Although for most part this treatment is safe, serious side effects such as thromboembolic events have been reported. We report on 7 patients who suffered a thromboembolic event while being treated with IVIg. Four patients suffered a stroke or transient ischemic attack, 1 an inferior wall myocardial infarction, 1 a deep venous thrombosis, and 1 a retinal artery infarct. The age range of the patients was 57–81 and most had underlying risk factors, such as hypertension, hypercholesterolemia, atrial fibrillation, history of vascular disease and stroke, and deep venous thrombosis. Three patients received multiple IVIg infusions before suffering a thromboembolic complication. Therefore, the clinicians should be vigilant about the possibility of thromboembolic complications with each IVIg infusion and be especially judicious with the use of IVIg in patients with underlying risk factors.