Treatment Of Primary Immunodeficiencies Research Articles

Insights into Patient Experiences with Facilitated Subcutaneous Immunoglobulin Therapy in Primary Immune Deficiency: A Prospective Observational Cohort

BackgroundImmunoglobulin G replacement therapy (IgRT), intravenous (IV) and subcutaneous (SC) routes, is pivotal in treatment of primary immunodeficiencies (PID). In recent years, facilitated subcutaneous immunoglobulin (fSCIG), a combination of rHuPH20 and 10% IgG has emerged as a delivery method to combine advantages of both IV and SC.MethodIn an observational prospective cohort, we investigated patient experience with fSCIG in PID patients from 5 PID centers for up to 12 months. We assessed the efficacy and safety of this treatment with patient/caregiver- and physician-reported indicators. Additionally, we analyzed patient treatment satisfaction (TSQM-9) and quality of life (QoL).ResultsWe enrolled 29 patients (22 pediatric and 7 adults; 14 females and 15 males; (median: 15, min–max: 2–40.9 years) who initiated fSCIG as IgRT-naive (n = 1), switched from conventional rapid-push 10% SCIG (n = 6) or IVIG (n = 22). Among the participants, 19 (65%) exhibited antibody deficiencies, 8 (27%) combined immunodeficiencies, and 2 (7%) immune dysregulations. Remarkably, targeted trough immunoglobulin G levels were achieved under all previous IgRTs as well as fSCIG. No severe systemic adverse drug reactions were documented, despite prevalent local (%86.45) and mild systemic (%26.45) adverse reactions were noted with fSCIG. Due to mild systemic symptoms, 2 patients switched from fSCIG to 10% SCIG. The patient satisfaction survey revealed a notable increase at 2-4th (p = 0.102); 5-8th (p = 0.006) and 9-12th (p < 0.001) months compared to the baseline. No significant trends were observed in QoL surveys.ConclusionfSCIG demonstrates admissable tolerability and efficacy in managing PIDs in addition to notable increase of patients’ drug satisfaction with IgRT. The identified benefits support the continuation of this therapy despite the local reactions.

Primary immunodeficiency as a cause of immune-mediated kidney diseases.

Primary immunodeficiency (PID) is no longer defined by infections alone, and autoimmunity is an accompanying manifestation of PID. Recurrent infections may trigger autoimmunity through molecular mimicry, bystander activation, or superantigens. The diagnosis of PID is still challenging, but genetic analysis reveals the underlying link between PID and autoimmunity. Mutations in relevant genes affecting central and peripheral immune tolerance, regulatory T-cell function, expansion of autoreactive lymphocytes, antigen clearance, hyperactivation of type I interferon, and NF-κB pathways have all been implicated in triggering autoimmunity in PID. Autoimmunity in PID leads to chronic inflammation, tissue damage, and organ failure and increases the mortality of patients with PID. The kidneys are inextricably linked with the immune system, and kidney diseases can be mediated by both infection and autoimmunity/inflammation in PID patients. The manifestations of kidney involvement in PID patients are very heterogeneous and include lupus nephritis, C3 glomerulopathy, kidney thrombotic microangiopathy, vasculitis, and interstitial nephritis.Patients with PID-caused kidney diseases have defined immune function defects and may benefit from pathway-based biologics, stem cell transplantation, or gene therapy. Early diagnosis and appropriate treatment of PID are crucial for reducing the mortality rate and improving organ function and quality of life.

Immune Globulin Subcutaneous 16.5% in Treatment of Primary Immunodeficiency: A Two-Year, Multi-Center Analysis

Immune Globulin Subcutaneous 16.5% in Treatment of Primary Immunodeficiency: A Two-Year, Multi-Center Analysis

Primary immunodeficiency in the 9-year child

Primary immunodeficiency conditions are a heterogeneous group of disorders caused by defects in various parts of the immune system, manifested in the form of recurrent infectious and autoimmune diseases of varying severity. The authors describe own clinical observation to determine the principles of diagnosis and treatment of primary immunodeficiency in children in modern conditions. The average age of diagnosis of an immunodeficiency condition has been established to be best over 30 days, but often this time increases to several years. The data of the enrolment of primary immunodeficiency states of the Republic of Dagestan on the diagnosis and permanent replacement therapy of immunodeficiency states is also presented.

Perspectives of women in science: data sharing in primary immunodeficiency

Jessica Willett Pachul is a Clinical Nurse Specialist in the Division of Immunology &amp; Allergy at the Hospital for Sick Children in Toronto, Canada. In this commentary, she discusses the implications that the collection and sharing of health data can have in the diagnosis and treatment of primary immunodeficiency (PID), as well as in research and development in the field.

Treatment With Intravenous Immune Globulin 10% In A Real-World Outpatient Setting

Intravenous immune globulin 10% liquid (IVIG 10%) is used in the treatment of primary immunodeficiency (PI). Originally approved in 2012 and then voluntarily withdrawn in 2016, IVIG 10% (BIVIGAM®) underwent manufacturing process improvements by a new manufacturer and was reintroduced to the US market in 2019. The purpose of this real-world study is to assess the tolerability of IVIG 10% infused in an outpatient setting.

CTLA4 VARIANT OF UNCERTAIN SIGNIFICANCE IN A PATIENT WITH A HISTORY OF CYTOPENIAS

<h3>Introduction</h3> CTLA-4 haploinsufficiency is caused by heterozygous mutations in CTLA4, a negative regulator of immune responses. Hypogammaglobulinemia, infections, and autoimmune cytopenias can be seen. Here, we describe a patient with history of ITP who presented with neutropenic fever, lymphopenia, and hypogammaglobulinemia in the setting of COVID-19 with a VUS in <i>CTLA4</i>. <h3>Case Description</h3> The patient is a 24-year-old female diagnosed with ITP at 10-years-old, initially treated with IVIG/steroids, then on mycophenolate for 6-years. 5-years later, she had a relapse of ITP in the setting of viral illness, requiring steroids/IVIG/rituximab. She developed neutropenic fever, unresponsive to GCSF, but responsive to cyclosporine and was noted to have a LGL clone. At 24-years-old, she was admitted with neutropenic fever (ANC 0); adenovirus, parainfluenza-virus, and SARS-CoV-2 were positive. Immunology was consulted due to hypogammaglobulinemia (IgG 140, IgA 7, IgM <5 mg/dL). Prior genetic testing identified a missense VUS in <i>CTLA4</i> c.370A>C (P.Thr124Pro), shown to affect CTLA4 function and observed in individuals with clinical features of CTLA-4 haploinsufficiency. Lymphopenia, absent lymphocyte antigen responses, and impaired vaccine immunity were noted. ANC improved with GCSF. The patient was discharged with immunology follow-up for consideration of abatacept. <h3>Discussion</h3> This case highlights the importance of considering VUS in the diagnosis and treatment of primary immunodeficiency. Our patient had a history of recurrent ITP, neutropenia, and LGL clone, all likely manifestations of CTLA-4 haploinsufficiency. Subsequent recognition of hypogammaglobulinemia and lymphopenia in the setting of neutropenia supported the diagnosis. Abatacept replaces the missing CTLA4-protein and should be considered in patients with CTLA-4 haploinsufficiency presenting with cytopenias.

Growth in diagnosis and treatment of primary immunodeficiency within the global Jeffrey Modell Centers Network

BackgroundPrimary immunodeficiencies (PI), which include more than 450 single-gene inborn errors of immunity and may affect up to 1% of the population, are genetic disorders that impair the immune system. If not properly identified and treated, individuals with PI are subject to serious, prolonged, and sometimes life-threatening infections or autoimmunity. Despite advancements, awareness of PI remains a critical issue for physicians and the public alike, as this leads to the enhanced and expedited management of these conditions. To address this critical issue, the Jeffrey Modell Foundation (JMF) formed a global network of specialized centers. The goal of this endeavor was to raise awareness of PI to better identify, diagnose, and treat patients, reducing associated mortality and morbidity and improving quality of life (QOL). For more than two decades, the Jeffrey Modell Centers Network (JMCN) has served as the foundation upon which these goals have been pursued. The JMCN currently includes 909 Expert Physicians at 400 institutions, in 316 cities, and 86 countries spanning six continents.MethodsA survey was developed by JMF for members of the JMCN, following the most recent Classification of PI from the IUIS Expert Committee, to periodically describe the patient population, including treatment modalities and demographics. Physician-reported data from 2021 was compared to that from 2018 and 2013. Physicians in the JMCN also reported on select outcomes of their PI patients one year prior to and one year following diagnosis.ResultsA total of 300 JMF Physician Surveys from 681 physicians were included in this analysis. This is a 75% physician response rate. From 2013 to 2021, there was a 96.3% increase in patients followed in the US and an 86.1% increase globally. During the same period, patients identified with a specific PI defect increased by 46.6% in the US and 47.9% globally. Patients receiving IgG and HSCT increased by 110% and 201% respectfully since 2013. Early diagnosis led to reported decreased morbidity and mortality and reduced calculated healthcare costs.ConclusionsThis global analysis of physician-reported data on patients with PI demonstrates an increase in both diagnosed and treated patients. This substantial increase from within the JMCN is a testament to its impact. In addition to building an extensive global patient database, the expanding JMCN serves as a unique and critical resource, providing the infrastructure for earliest diagnosis, optimized treatments, and implementation of standard-of-care and best practices. The JMCN provides a critical platform that facilitates the education of physicians and patients, awareness initiatives, and research advances, through collaboration and connectivity, ultimately resulting in improved outcomes and QOL for patients with PI. The JMCN has steadily and substantially grown for more than two decades and continues to substantively impact the field of Immunology globally.

Future of Therapy for Inborn Errors of Immunity.

Over the past 20 years, the rapid evolution in the diagnosis and treatment of primary immunodeficiencies (PI) and the recognition of immune dysregulation as a feature in some have prompted the use of “inborn errors of immunity” (IEI) as a more encompassing term used to describe these disorders [1, 2] . This article aims to review the future of therapy of PI/IEI (referred to IEI throughout this paper). Historically, immune deficiencies have been characterized as monogenic disorders resulting in immune deficiencies affecting T cells, B cells, combination of T and B cells, or innate immune disorders. More recently, immunologists are also recognizing a variety of phenotypes associated with one genotype or similar phenotypes across genotypes and a role for incomplete penetrance or variable expressivity of some genes causing inborn errors of immunity [3]. The IUIS classification of immune deficiencies (IEIs) has evolved over time to include 10 categories, with disorders of immune dysregulation accounting for a new subset, some treatable with small molecule inhibitors or biologics. [1] Until recently, management options were limited to prompt treatment of infections, gammaglobulin replacement, and possibly bone marrow transplant depending on the defect. Available therapies have expanded to include small molecule inhibitors, biologics, gene therapy, and the use of adoptive transfer of virus-specific T cells to fight viral infections in immunocompromised patients. Several significant contributions to the field of clinical immunology have fueled the rapid advancement of therapies over the past two decades. Among these are educational efforts to recruit young immunologists to the field resulting in the growth of a world-wide community of clinicians and investigators interested in rare diseases, efforts to increase awareness of IEI globally contributing to international collaborations, along with advancements in diagnostic genetic testing, newborn screening, molecular biology techniques, gene correction, use of immune modulators, and ex vivo expansion of engineered T cells for therapeutic use. The development and widespread use of newborn screening have helped to identify severe combined immune deficiency (SCID) earlier resulting in better outcomes [4]. Continual improvements and accessibility of genetic sequencing have helped to identify new IEI diseases at an accelerated pace [5]. Advances in gene therapy and bone marrow transplant have made treatments possible in otherwise fatal diseases. Furthermore, the increased awareness of IEI across the world has driven networks of immunologists working together to improve the diagnosis and treatment of these rare diseases. These improvements in the diagnosis and treatment of IEI noted over the past 20 years bring hope for a better future for the IEI community. This paper will review future directions in a few of the newer therapies emerging for IEI. For easy reference, most of the diseases discussed in this paper are briefly described in a summary table, in the order mentioned within the paper (Appendix).

A Systematic Review and Meta-Regression Analysis on the Impact of Increasing IgG Trough Level on Infection Rates in Primary Immunodeficiency Patients on Intravenous IgG Therapy

To determine if increasing IgG trough levels was associated with decreased rates of infection in patients with primary immunodeficiency (PID) who were treated with intravenous immunoglobulin (IVIG).This systematic review included data from 1218 patients with PID who were treated with IVIG from 28 studies between 2001 and 2018. Both children and adults were included in the analysis.This was a systematic review of studies in PubMed and Cochrane and meta-regression analysis in which researchers evaluated immunoglobulin G (IgG) trough levels and their impact on clinical outcomes.The mean IgG trough levels in this analysis ranged from 660 mg/dL to 1280 mg/dL. The mean IVIG dose ranged from 387 mg/kg to 560 mg/kg dosed every 3-4 weeks (the majority were on every 4 week dosing). The most common PIDs reported in this study were common variable immunodeficiency and X-linked agammaglobulinemia (XLA). By using random-effects linear regression slope, IgG trough levels increased by 73 mg/dL for every IVIG dose increase of 100 mg/kg per 4 weeks. Increasing trough level up to a maximum trough of 1280 mg/dL significantly decreased hospitalization (P = .02) but did not significantly decrease infection rates (P = .21) or missed school days or workdays (P = .08). A break point IgG trough level of 960 mg/dL was identified to significantly decrease infection rates (P = .018), and, for >960 mg/dL, there was no significant decrease in infection rates.In patients with PID who were treated with IVIG, increasing IgG trough levels up to 960 mg/dL was associated with improved clinical outcomes and a decreased rate of infection.Goal IgG trough levels have not been clearly established for patients with PID treated with IVIG therapy. In this study, the authors found that increasing IgG trough levels up to a trough of 960 mg/dL decreases the rate of infection. Increasing trough levels >960 mg/dL is significantly associated with decreased hospitalization rates but not with decreased infections or missed school days or workdays. Given that there is a wide range of IVIG dosing used in the treatment of PID, this study is helpful and offers trough targets on the basis of desired effect (eg, reducing infection rates versus reducing hospitalization rates). One limitation of this study is the inability to differentiate between various disease states, such as XLA, which may necessitate a higher IgG trough. Additionally, all studies were cohort studies, which increases the heterogeneity of the population studied.

In Utero Gene Therapy for Primary Immunodeficiencies.

Primary immunodeficiencies (PIDs) have become a prime target for gene therapy given the morbidity, mortality, and the single gene etiology. Given that outcomes are better the earlier gene therapy is implemented, it is possible that fetal gene therapy may be an important future direction for the treatment of PIDs. In this chapter, the current treatments available for several PIDs will be reviewed, as well as the history and current status of gene therapy for PIDs. The possibility of in utero gene therapy as a possibility will then be discussed.

ПРАКТИЧЕСКИЕ АСПЕКТЫ ПРИМЕНЕНИЯ ИММУНОГЛОБУЛИНОВ ДЛЯ ВНУТРИВЕННОГО ВВЕДЕНИЯ ПРИ РАЗЛИЧНОЙ ПАТОЛОГИИ

Human intravenous immunoglobulin (IVIG) – a blood product prepared from the serum of many healthy donors, is the mainstay of therapy for treatment of primary immunodeficiencies, is increasingly used in various fields of medicine. The article reflects practical aspects of use of this group of drugs in a multidisciplinary pediatric hospital not only taking the therapy of defects of the immune system as an example, but also oncohematological, neurological, dermatological diseases, including orphan diseases. The modern data on the mechanisms of action of immunoglobulins, schemes of use for various pathologies are presented. The issues of safety of application, interchangeability of immunoglobulins from different manufacturers are considered.

Real-World Evaluation of Immune Globulin Subcutaneous 16.5% in the Treatment of Primary Immunodeficiency

Immune Globulin Subcutaneous (Human), 16.5% solution (IGSC 16.5%) is a subcutaneous immunoglobulin (IG) indicated for primary immunodeficiencies (PID) in adults. Approved in 5/2019, data is mostly limited to clinical trials. We report efficacy, safety, and tolerability of IGSC 16.5% (Cutaquig®) in a real-world setting.

Executive Summary of the Consensus Document on the Diagnosis and Management of Patients with Primary Immunodeficiencies

Primary immunodeficiencies (PIDs) are rare, undiagnosed and potentially fatal diseases.Clinical manifestations of PID can be fatal or leave sequelae that worsen the quality of life of patients. Traditionally, the treatment of PIDs has been largely supportive, with the exception of bone marrow transplantation and, more recently, gene therapy. The discovering of new affected pathways, the development of new molecules and biologics, and the increasing understanding of the molecular basis of these disorders have created opportunities in PIDs therapy. This document aims to review current knowledge and to provide recommendations about the diagnosis and clinical management of adults and children with PIDs based on the available scientific evidence taking in to account current practice and future challenges. A systematic review was conducted, and evidence levels based on the available literature are given for each recommendation where available.

Fat-soluble vitamins and immunodeficiency: mechanisms of influence and opportunities for use

The role of vitamins in the formation of the immune response, both innate and acquired immunity, is well known. At the same time, deficit of fat-soluble vitamins A, E, D leads to impaired response of the immune system to the infectious invasion and to disorders of immune system functioning. The aim of this article is to analyze the literature data on the impact of fat-soluble vitamins on the function of the human immune system and the possibilities of their use in patients with immunodeficiency. Results. Сurrently, there are enough evidences of the successful use of fat-soluble vitamins in secondary immunodeficiencies. Data on the usage of vitamins A, E, D in the treatment of primary immunodeficiencies are few. However, even reducing of antibiotics and other medicines administration in children with primary immunodeficiency indicates the feasibility of their using. The results of scientific studies on the successful use of vitamins D and A in the treatment of allergic diseases, vitamin D in the prevention and improvement of the treatment of autoimmune and oncological diseases indicate the possibility of their use as adjuvant immunomodulatory therapy in children with primary immunodeficiency. Promising may be the use of vitamins A and E, as powerful antioxidants in patients with primary immunodeficiencies with defects in DNA repair processes. Conclusion. The analysis of the literature data has shown that despite many questions need to be resolved, fat-soluble vitamins A, D, and E, and their analogues can be used in clinical settings to enhance the therapeutic effect in children with immune deficiency.

Primary immunodeficiency in Africa - a review.

Efforts have been made worldwide to improve awareness and treatment of primary immunodeficiency (PID). This has also gained momentum on the African continent albeit at a slower pace.Objective. This review reports on the current status of PID on the African continent regarding its prevalence, distribution, genetic mutations and challenges in diagnosis and treatment of affected patients.Method. We evaluated all studies published from the African continent in the field of PID dealing with prevalence, epidemiology, case reports and genetic findings.Results. The prevalence of PID on the African continent has been estimated to be as high as 902 631 individuals. PID still is mostly underdiagnosed in Africa and although progress has been made in parts of the continent many challenges still remain regarding awareness, diagnosis, registration and care of these patients.Conclusion. Given the unique genetic mutations reported in PID patients on the African continent and the feasibility of hematopoietic stem cell transplantation and gene therapy, increased awareness should be encouraged and new therapeutic options considered.

The German National Registry of Primary Immunodeficiencies (2012-2017).

Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs.Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel.Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy.Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.

CME Exam: Mechanism-Based Precision Therapy for the Treatment of Primary Immunodeficiency and Primary Immunodysregulatory Diseases

CME Exam: Mechanism-Based Precision Therapy for the Treatment of Primary Immunodeficiency and Primary Immunodysregulatory Diseases

Primary immunodeficiencies and haemato-oncology

Primary immunodeficiencies (PID) are rare, congenital disorders, often associated with genetic defects in the immune system. According to our current knowlegde, about 350 genes are involved in distinct immunodeficiency disorders. In PIDs at least one, and often more, immune component is impaired, missing, or has an inappropriate function. The prevalence of PID has been increasing. Due to advances in the treatment of PID, especially immunoglobulin replacement therapy and stem cell transplantation, the life expectancy of patients is longer. As patients with PID live longer, malignancies are diagnosed more commonly. Patients with PID are at an increased risk of malignancy compared with the normal population. Malignancy is the second most common cause of death in these patients after infections. The aim of this article is to review the malignancies and their clinical relevance in patients with PID. Orv Hetil. 2018; 159(49); 2073-2078.

Hematopoietic stem cell gene therapy for the cure of blood diseases: primary immunodeficiencies

This report provides an overview of gene therapy use of stem cell for the treatment of primary immunodeficiencies (PIDs). Human stem cells are non-specialized cells, able to differentiate, starting from the embryo and for the whole duration of the life of each individual, into different cell types, through two types of cell division: symmetrical creating two stem cells and asymmetric differentiating to any cell lineage. These cells represented the ideal target for gene correction to guarantee production of engineered multi-lineage progeny. Their use in gene therapy led to the development of an effective treatment for PIDs, such as ADA deficiency, SCID-X1, WAS, CGD, and providing potential long-term clinical benefit for affected patients.