Treatment Of Hypogammaglobulinemia Research Articles

Impact of Intravenous Immunoglobulin Replacement Therapy on Hypogammaglobulinemia and Infection in Lung Transplant Recipients

Secondary hypogammaglobulinemia (HGG) from immunosuppression therapy in lung transplant recipients has been associated with increased mortality, morbidity and higher risk of infection. Intravenous immunoglobulin (IVIG) for the treatment of HGG post-lung transplant is not well studied with conflicting evidence regarding efficacy. This single-center, retrospective cohort study analyzed adult lung transplant recipients with HGG receiving ≥1 dose of IVIG 0.3-0.5 g/kg. Resolution of HGG (IgG > 600 mg/dL within 30 days of IVIG) was evaluated for optimal dose and duration of IVIG therapy. Incidence of infection, patient survival, rejection, and chronic lung allograft dysfunction-free survival at 1 year were compared between resolved and persistent HGG. Results demonstrated majority of patients 46/58 (79.3%) achieved HGG resolution. Severe HGG (IgG < 400 mg/dL) was significantly associated with persistent HGG (50.5% vs 15.2%, p = 0.02), with comparable cumulative IVIG dose and duration between both groups (p = 0.96 and p = 0.39, respectively). No other variables correlated with HGG resolution. Overall infection rates were similar between groups (69.6% vs 58.3%, p = 0.50), suggesting HGG resolution did not correlate with incidence of infection. Lastly, use of IVIG for the treatment of HGG appears to be safe with minimal incidence of thrombosis found within each group.

Hypogammaglobulinemia in neonates: illustrative cases and review of the literature.

This article presents a review of causes of hypogammaglobulinemia in neonates utilizing illustrative cases to demonstrate commonly seen conditions. Overall, the causes of low immunoglobulin level can be divided into three main categories: decreased maternal transfer or production (due to physiological nadir, transient hypogammaglobulinemia of infancy, medication effects, or immunodeficiency), increased loss of immunoglobulins (from the gastrointestinal (GI) system, lymphatics, kidneys, skin disease, or blood loss) or destruction/suppression (from medication effects). Treatment of hypogammaglobulinemia is generally tailored to the underlying cause and condition of the patient. This can be through supportive care, prophylactic measures, or with immunoglobulin G (IgG) replacement at the recommendation of an immunologist.

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

Should treatment of hypogammaglobulinemia with immunoglobulin replacement therapy (IgRT) become standard of care in patients with chronic lymphocytic leukemia?

Hypogammaglobulinemia (HGG) is a frequent finding in patients with hematological malignancies, and is commonly described in chronic lymphocytic leukemia (CLL) before or after treatment. We reviewed published literature available online in the last thirty years through Medline search of indexed articles focusing on the main differences and advantages of the products now available on the market, namely intravenous Ig (IVIg) and subcutaneous Ig (SCIg) preparations. IgRT is effective and safe in the prophylaxis of infections in a selected group of patients with CLL and hypogammaglobulinemia and is therefore a valuable tool for clinicians in the everyday management of infectious risk. We encourage the use of SCIg formulations as they appear to have similar efficacy but better cost-effectiveness and tolerability.

Recommendations for screening, monitoring, prevention, and prophylaxis of infections in adult and pediatric patients receiving CAR T-cell therapy: a position paper

Chimeric antigen receptor (CAR) T-cell therapy is one of the most promising emerging treatments for B-cell malignancies. Recently, two CAR T-cell products (axicabtagene ciloleucel and tisagenlecleucel) have been approved for patients with aggressive B-cell lymphoma and acute lymphoblastic leukemia; many other CAR-T constructs are in research for both hematological and non-hematological diseases. Most of the patients receiving CAR-T therapy will develop fever at some point after infusion, mainly due to cytokine release syndrome (CRS). The onset of CRS is often indistinguishable from an infection, which makes management of these patients challenging. In addition to the lymphodepleting chemotherapy and CAR T cells, the treatment of complications with corticosteroids and/or tocilizumab increases the risk of infection in these patients. Data regarding incidence, risk factors and prevention of infections in patients receiving CAR-T cell therapy are scarce. To assist in patient care, a multidisciplinary team from hospitals designated by the Spanish Ministry of Health to perform CAR-T therapy prepared these recommendations. We reviewed the literature on the incidence, risk factors, and management of infections in adult and pediatric patients receiving CAR-T cell treatment. Recommendations cover different areas: monitoring and treatment of hypogammaglobulinemia, prevention, prophylaxis, and management of bacterial, viral, and fungal infections as well as vaccination prior and after CAR-T cell therapy.

Hypogammaglobulinemia Following Heart Transplantation - Prevalence and Clinical Importance

Hypogammaglobulinemia (HGG) can be identified in patients following solid organ transplantation and is thought to be predominantly due to immunosuppression. There is limited data describing the extent, degree and clinical outcomes associated with HGG following heart transplantation. The aim of this study is to investigate the prevalence and clinical significance of HGG in heart transplant recipients. We retrospectively reviewed data of patients who had underwent heart transplantation at our institution between 4/2014 and 12/2018. We excluded patients with multi-organ transplantation. We defined serum IgG <700 mg/dl as mild and <450 mg/dl as severe HGG. We classified patients into normal, mild HGG and severe HGG groups based on the lowest IgG level during follow-up. We compared clinical outcomes between the groups from the date of the lowest IgG level. We enrolled 132 patients who had at least one serum IgG value following heart transplantation during the study period. Mean age was 53±14 years old and 94 (71%) patients were male. During 761 (463, 1266) days of follow-up, patients had a median of 4 (3, 6) IgG measurements. Prevalence of severe HGG was highest (27%) 3-6 months post-heart transplant and then decreased to 5% at 1-2 years (Figure A). Survival freedom of infection was 51%, 35% and 17% at 2 years in the normal, mild HGG and severe HGG groups, respectively (P=0.03, Figure B). Overall survival and rejection-free survival were comparable between the groups. There is a high prevalence of HGG in the early post-heart transplant period that decreases over time. HGG is significantly associated with infectious complications. Further studies are needed to investigate the prophylactic treatment of HGG with IVIG in heart transplant recipients.

IVIG Replacement for Hypogammaglobulinemia in Lung Transplant Patients

After lung transplant, infection is a leading contributor to morbidity and mortality, and hypogammaglobulinemia (HGG) may be an important risk factor for many of these infections. Some reports suggest that HGG not only increases the risk of various infections, but also worsens survival. The incidence of HGG has been shown to increase after lung transplant, and may be as high as 70%. In order to mitigate this risk, intravenous immunoglobulin G (IVIG) replacement for the treatment of HGG has been utilized. However, the safety and efficacy of this practice after lung transplant has not been well described. The aim of this article is to review the current literature evaluating the use of IVIG replacement in HGG after lung transplant. In addition, practical considerations of IVIG including administration, adverse effects, and cost will be discussed.

TCPC術後の蛋白漏出性胃腸症に伴う低IgG血症に対し，pH 4処理酸性人免疫グロブリン（皮下注射）による在宅補充療法を導入した1例

TCPC（total cavo-pulmonary connection）手術後の蛋白漏出性胃腸症（protein-losing enteropathy: PLE）に伴う低IgG血症に対し，pH 4処理酸性人免疫グロブリン（皮下注射）（Subcutaneous Immunoglobulin: SCIG）による在宅補充療法を導入した1例を経験した．症例は左心低形成症候群の21歳男性．5歳時にTCPC手術を施行，術後5年でPLEを発症した．15歳より感染症等によるPLE症状増悪時に静注免疫グロブリン（intravenous immunoglobulin: IVIG）補充を行い，20歳でSCIG在宅補充を導入した．8 g/週で開始したが血清IgGの上昇を認めず，16 g/週に増量した．SCIG使用前と16 g/週補充後を比較し，血清IgG値は370→484 mg/dLと上昇，血清アルブミンは2.7→2.4 g/dLと低下，入院日数は4.7→1.2日/月と減少した．SCIGにより血清IgGが上昇し，感染症による入院回避に効果があった．PLE患者への維持投与量は，重症度に応じた個別の検討が必要と考えられる．

Clinical outcomes of immunoglobulin use in solid organ transplant recipients: protocol for a systematic review and meta-analysis.

BackgroundTransplantation improves survival and the quality of life of patients with end-stage organ failure. Infection, due to surgical issues, host factors such as diabetes, immunosuppression, and hypogammaglobulinemia, is a major post-transplant complication. Clinical outcomes of prophylaxis or treatment of hypogammaglobulinemia in solid organ transplant recipients are not well established and are in need of further study.Methods/designWe will conduct a systematic review of studies investigating clinically relevant outcomes of immunoglobulin use either as prophylaxis or treatment of hypogammaglobulinemia after solid organ transplantation. Both randomized and non-randomized studies (excluding case reports and case series of less than 20 subjects) will be included. Outcomes of interest will include the overall rate of infection, hospital admission, hospital length of stay, intensive care unit admission, 1-year all-cause mortality, incidence of acute organ rejection, allograft survival within 1 year, and adverse events. We will search MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Transplant library, and the International Clinical Trials Registry Platform for randomized and non-randomized studies on adult solid organ transplant patients who received prophylactic immunoglobulin or immunoglobulin treatment. Two reviewers will conduct all screening and data collection independently. We will assess study level of risk of bias using the Cochrane Risk of Bias Assessment Tool for randomized controlled trials and for non-randomized studies. If meta-analysis of outcome data is deemed appropriate, we will use random effects models to combine data for continuous and dichotomous measures.DiscussionThe results of this systematic review may inform guideline development for measuring immunoglobulin level and use of immunoglobulin in solid organ transplant patients and highlight areas for further research.Systematic review registrationPROSPERO CRD42015017620Electronic supplementary materialThe online version of this article (doi:10.1186/s13643-015-0156-6) contains supplementary material, which is available to authorized users.

Первинні дефіцити антитілоутворення: сучасні підходи до діагностики і лікування

Primary antibody deficiencies — the largest group of congenital immunodeficiencies. This clinically and genetically heterogeneous group of congenital immune defects includes mild, often asymptomatic IgA deficiency and IgG subclasses and severe agammaglobulinemia with inhibition of production of all immunoglobulines. The most common clinical manifestation — severe or recurrent synopulmonary infections. It is possible the development of autoimmune diseases, enteropathy. Replacement therapy with immunoglobulin — the main method of treatment of hypogammaglobulinemia. Key worlds: primary antibody deficiency, diagnostic, treatment.

(367) - Hypogammaglobulinemia After Lung Transplantation Increases Risk of Recurrent Pneumonia

Immunosuppressive therapies have led to vast improvements in survival in lung transplant (LT) recipients but these therapies can lead to hypogammaglobulinemia (HGG). To assess the impact of HGG on transplant outcomes, we reviewed one year findings from a prospective observational study examining the relationship of HGG to incidence of pneumonia, antibiotic use, presence of rejection, and steroid use. This is a single center study of LT recipients at the University of Pittsburgh Medical Center. IgG levels were measured pre-transplant, at time of transplant and at 3, 6, and 12 months post-transplant and related to incidence of pneumonia, antibiotic use, presence of rejection, and steroid use. Analysis was performed using non-parametric tests. 133 LT recipients were evaluated. Post-transplant subjects receiving Basiliximab had lower IgG levels at 3 and 6 months than those induced with Alemtuzamab, but those differences were absent at one year after transplant (p=0.2). In subjects who had one or more incidence of pneumonia, there was a negative correlation between IgG level and the number of pneumonias (Spearman’s rho= -0.31, p=0.05). In addition, one-year mortality was associated with lower IgG levels at 3 months post-transplant (p=0.04). There was no relationship between IgG levels and the number of courses of antibiotics, CMV status, steroid use, or presence of rejection. Our results suggest that LT recipients with HGG are at risk for developing recurrent pneumonias and increased mortality at 1 year. Additional analyses to better characterize these patients and to evaluate the efficacy of IgG replacement therapy for prevention of pneumonia and improvement in survival will be needed to further define the clinical importance and treatment of HGG in lung transplant recipients.

Treatment of hypogammaglobulinemia in adults: A scoring system to guide decisions on immunoglobulin replacement

The treatment for primary B-cell defects with global antibody deficiency is replacement of immunoglobulin.1,2 However, what has not been explored is how to make the decision regarding immunoglobulin replacement for subjects with more modest humoral defects. Suitable immunoglobulin preparations are expensive and, once prescribed, usually result in lifelong therapy. Practical guidelines for initiating immunoglobulin therapy would be of value. Here we describe the development and use of a scoring system based on laboratory and clinical data in a cohort of patients referred for varying degrees of hypogammaglobulinemia.

Current usage of intravenous immune globulin and the rationale behind it: the Massachusetts General Hospital data and a review of the literature

Intravenous immune globulin (IVIG) has been approved by the Food and Drug Administration (FDA) for use in 6 conditions: immune thrombocytopenic purpura (ITP), primary immunodeficiency, secondary immunodeficiency, pediatric HIV infection, Kawasaki disease, prevention of graft versus host disease (GVHD) and infection in bone marrow transplant recipients. However, most usage is for off-label indications, and for some of these comprehensive guidelines have been published. We retrospectively reviewed all approved IVIG transfusions at Massachusetts General Hospital in 2004 to identify the current usage pattern and completed a literature review. IVIG was most commonly used in the treatment of chronic neuropathy, which included chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy. For such patients, the annual cost of IVIG can exceed 50,000 dollars per patient. Other common indications were the treatment of hypogammaglobulinemia, ITP, renal transplant rejection, myasthenia gravis, Guillain-Barre syndrome, necrotizing fasciitis, autoimmune hemolytic anemia, and Kawasaki disease. IVIG was administered in a variety of other indications each representing <3% of the total treated patients. Only a few indications account for most of the usage for IVIG. Reports concerning IVIG continue to grow at a tremendous pace but few high-quality randomized controlled trials have been reported. Randomized trials are especially needed for conditions such as CIDP, which consume large quantities of product.

Gastrointestinal infections in immunocompromised hosts

Gastrointestinal infections in the immunocompromised host continue to have significant morbidity and mortality throughout the world. They all have similar exposures to viruses, bacteria and parasites and respond to these infections in a similar way. This review will summarize the latest reports on the epidemiology, diagnosis and treatment of known and emerging infections over the last 12 months.Highly active antiretroviral therapy has reduced esophageal opportunistic infections in HIV patients compared to patients who are not taking this therapy. Esophageal candidiasis responds to escalating doses of micafungin as effectively as fluconazole. HIV-infected patients with untreated Mycobacterium avium-complex diarrhea are associated with a wasting syndrome that disrupts the somatostatin axis. Polymerase chain reaction testing has improved diagnosis of microsporidial infections. Cytomegalovirus polymerase chain reaction of tissue may improve the diagnosis of cytomegalovirus disease of the gastrointestinal tract in organ-transplant recipients. The treatment of hypogammaglobulinemia in transplant recipients with recurrent cytomegalovirus gastrointestinal disease may resolve their symptoms. Community viruses are an emerging threat to transplant recipients and may affect drug levels. Lastly, anti-tumor necrosis factor alpha therapy in the treatment of inflammatory conditions may cause Listeria monocytogenes to disseminate.Immunocompromised hosts remain at risk for severe gastrointestinal and even disseminated infections. Management includes an early rapid diagnosis with rapid restoration of the immune system and appropriate anti-infective therapy. With the immunocompromised population rapidly increasing, prevention of these infections remains the greatest challenge.

Therapeutic Uses of Intravenous Immunoglobulin (IVIG) in Children

Introduction HISTORY Immunologists have been aware of the existence of protective humoral substances in the serum of patients after an infectious episode for a long time. Serum harvested from large animals after their immunization with specific pathogens was injected into humans for the prophylaxis and treatment of serious infections. The concept of immunoglobulin (also called gamma globulin) therapy originated from these early experiments. Subsequently, Paul Ehrlich produced antitoxin to diphtheria in 1897. To avoid complications such as serum sickness with the use of animal serums, attempts were made to concentrate the antibody-containing fractions of human serum. In 1936, placental immunoglobulin samples were used for prophylaxis of measles. In 1952, Bruton recognized that an 8-year-old child who had serious recurrent infections despite conventional therapy was incapable of making significant quantities of immunoglobulin. This was the first time primary immunodeficiency was diagnosed and treated successfully with intramuscular immunoglobulin. Since then, and until 1981, intramuscular gamma globulin or, alternatively, fresh frozen plasma has been the mainstay of treatment of hypogammaglobulinemia and other primary immune deficiencies. In 1981, intravenous immunoglobulin (IVIG) became available commercially in the United States. The advantages of IVIG over intramuscular gamma globulin are: 1) administration is relatively painless; 2) higher doses can be given, resulting in rapid achievement of therapeutic levels, because volume is not a limitation: 3) its absorption is good: 4) it does not undergo local degradation during infusion; and 5) it does not aggregate and activate complement.

Therapeutic Uses of Intravenous Immunoglobulin (IVIG) in Children

Introduction HISTORY Immunologists have been aware of the existence of protective humoral substances in the serum of patients after an infectious episode for a long time. Serum harvested from large animals after their immunization with specific pathogens was injected into humans for the prophylaxis and treatment of serious infections. The concept of immunoglobulin (also called gamma globulin) therapy originated from these early experiments. Subsequently, Paul Ehrlich produced antitoxin to diphtheria in 1897. To avoid complications such as serum sickness with the use of animal serums, attempts were made to concentrate the antibody-containing fractions of human serum. In 1936, placental immunoglobulin samples were used for prophylaxis of measles. In 1952, Bruton recognized that an 8-year-old child who had serious recurrent infections despite conventional therapy was incapable of making significant quantities of immunoglobulin. This was the first time primary immunodeficiency was diagnosed and treated successfully with intramuscular immunoglobulin. Since then, and until 1981, intramuscular gamma globulin or, alternatively, fresh frozen plasma has been the mainstay of treatment of hypogammaglobulinemia and other primary immune deficiencies. In 1981, intravenous immunoglobulin (IVIG) became available commercially in the United States. The advantages of IVIG over intramuscular gamma globulin are: 1) administration is relatively painless; 2) higher doses can be given, resulting in rapid achievement of therapeutic levels, because volume is not a limitation: 3) its absorption is good: 4) it does not undergo local degradation during infusion; and 5) it does not aggregate and activate complement.

Use of Intravenous Immune Globulin Therapy: An Overview

The intravenous immune globulin (IGIV) preparations are reviewed with respect to method of preparation, pharmacokinetics, clinical uses (with emphasis on the labeled indications), and adverse reactions; a brief review of the immune system also is provided. IGIV preparations are approved for the treatment of hypogammaglobulinemia, recurrent bacterial infections due to B-cell chronic lymphocytic leukemia, and idiopathic thrombocytopenic purpura (ITP). The mechanism of action in the first two indications is passive replacement of antibodies, but in ITP the mechanism is not clearly established. The clinical literature on the use of IGIV for these indications is summarized. In patients with ITP, platelet counts return to safe levels and the number of infections is reduced in patients with primary humoral immunodeficiency treated with IGIV. The use of IGIV in pregnant women and premature infants is controversial. Adverse reactions are primarily related to infusion rate, activation of complement, and anaphylactic reactions to a component of the product. There is minimal to no risk of viral transmission with IGIV therapy. IGIV also has been administered safely on an outpatient or homecare basis. This has led to a feeling of greater control by patients over their chronic illness. Other uses of IGIV are under investigation. As our understanding of the immune system and the pharmacology of immune globulin increases, the uses of IGIV will expand.