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Journal of Investigational Allergology... 2020Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by hypogammaglobulinemia and increased susceptibility to recurrent bacterial... (Review)
Review
Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by hypogammaglobulinemia and increased susceptibility to recurrent bacterial infections. It is the most frequent symptomatic antibody deficiency, with a wide variety of infectious and noninfectious complications. Numerous studies have demonstrated that immunological and genetic defects are involved in the pathogenesis of CVID. However, in most cases, the genetic background of the disease remains unidentified. This review aims to discuss various aspects of CVID, including epidemiology, pathogenesis, symptoms, diagnosis, classification, and management.
Topics: Agammaglobulinemia; Animals; Common Variable Immunodeficiency; Gene-Environment Interaction; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulins, Intravenous; Phenotype
PubMed: 30741636
DOI: 10.18176/jiaci.0388 -
Clinical Reviews in Allergy & Immunology Aug 2022Interruptions or alterations in the B cell development pathway can lead to primary B cell immunodeficiency with resultant absence or diminished immunoglobulin... (Review)
Review
Interruptions or alterations in the B cell development pathway can lead to primary B cell immunodeficiency with resultant absence or diminished immunoglobulin production. While the most common cause of congenital agammaglobulinemia is X-linked agammaglobulinemia (XLA), accounting for approximately 85% of cases, other genetic forms of agammaglobulinemia have been identified. Early recognition and diagnosis of these conditions are pivotal for improved outcomes and prevention of sequelae and complications. The diagnosis of XLA is often delayed, and can be missed if patient has a mild phenotype. The lack of correlation between phenotype and genotype in this condition makes management and predicting outcomes quite difficult. In contrast, while less common, autosomal recessive forms of agammaglobulinemia present at younger ages and with typically more severe clinical features resulting in an earlier diagnosis. Some diagnostic innovations, such as KREC level measurements and serum BCMA measurements, may aid in facilitating an earlier identification of agammaglobulinemia leading to prompt treatment. Earlier diagnosis may improve the overall health of patients with XLA.
Topics: Agammaglobulinaemia Tyrosine Kinase; Agammaglobulinemia; Genetic Diseases, X-Linked; Humans; Mutation; Protein-Tyrosine Kinases
PubMed: 34241796
DOI: 10.1007/s12016-021-08870-5 -
Orphanet Journal of Rare Diseases Apr 2018Adenosine deaminase (ADA) deficiency leads to an accumulation of toxic purine degradation by-products, most potently affecting lymphocytes, leading to adenosine... (Review)
Review
Adenosine deaminase (ADA) deficiency leads to an accumulation of toxic purine degradation by-products, most potently affecting lymphocytes, leading to adenosine deaminase-deficient severe combined immunodeficiency. Whilst most notable affects are on lymphocytes, other manifestations include skeletal abnormalities, neurodevelopmental affects and pulmonary manifestations associated with pulmonary-alveolar proteinosis. Affected patients present in early infancy, usually with persistent infection, or with pulmonary insufficiency. Three treatment options are currently available. Initial treatment with enzyme replacement therapy may alleviate acute symptoms and enable partial immunological reconstitution, but treatment is life-long, immune reconstitution is incomplete, and the reconstituted immune system may nullify the effects of the enzyme replacement. Hematopoietic stem cell transplant has long been established as the treatment of choice, particularly where a matched sibling or well matched unrelated donor is available. More recently, the use of gene addition techniques to correct the genetic defect in autologous haematopoietic stem cells treatment has demonstrated immunological and clinical efficacy. This article reviews the biology, clinical presentation, diagnosis and treatment of ADA-deficiency.
Topics: Adenosine Deaminase; Agammaglobulinemia; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Pulmonary Alveolar Proteinosis; Severe Combined Immunodeficiency
PubMed: 29690908
DOI: 10.1186/s13023-018-0807-5 -
The Journal of Allergy and Clinical... May 2022Secondary hypogammaglobulinemia (SHG) is characterized by reduced immunoglobulin levels due to acquired causes of decreased antibody production or increased antibody...
Practical guidance for the diagnosis and management of secondary hypogammaglobulinemia: A Work Group Report of the AAAAI Primary Immunodeficiency and Altered Immune Response Committees.
Secondary hypogammaglobulinemia (SHG) is characterized by reduced immunoglobulin levels due to acquired causes of decreased antibody production or increased antibody loss. Clarification regarding whether the hypogammaglobulinemia is secondary or primary is important because this has implications for evaluation and management. Prior receipt of immunosuppressive medications and/or presence of conditions associated with SHG development, including protein loss syndromes, are histories that raise suspicion for SHG. In patients with these histories, a thorough investigation of potential etiologies of SHG reviewed in this report is needed to devise an effective treatment plan focused on removal of iatrogenic causes (eg, discontinuation of an offending drug) or treatment of the underlying condition (eg, management of nephrotic syndrome). When iatrogenic causes cannot be removed or underlying conditions cannot be reversed, therapeutic options are not clearly delineated but include heightened monitoring for clinical infections, supportive antimicrobials, and in some cases, immunoglobulin replacement therapy. This report serves to summarize the existing literature regarding immunosuppressive medications and populations (autoimmune, neurologic, hematologic/oncologic, pulmonary, posttransplant, protein-losing) associated with SHG and highlights key areas for future investigation.
Topics: Agammaglobulinemia; Common Variable Immunodeficiency; Humans; Iatrogenic Disease; Immunity; Immunoglobulins; Immunologic Deficiency Syndromes
PubMed: 35176351
DOI: 10.1016/j.jaci.2022.01.025 -
The Journal of Allergy and Clinical... 2016The International Collaboration in Asthma, Allergy and Immunology initiated an international coalition among the American Academy of Allergy, Asthma & Immunology; the...
The International Collaboration in Asthma, Allergy and Immunology initiated an international coalition among the American Academy of Allergy, Asthma & Immunology; the European Academy of Allergy and Clinical Immunology; the World Allergy Organization; and the American College of Allergy, Asthma & Immunology on common variable immunodeficiency. An author group was formed and then divided into individual committees. Within the committee, teams of authors were subgrouped to generate content for specific sections of the document. Content was derived from literature searches, relevant published guidelines, and clinical experience. After a draft of the document was assembled, it was collectively reviewed and revised by the authors. Where evidence was lacking or conflicting, the information presented represents the consensus expert opinion of the group. The full document was then independently reviewed by 5 international experts in the field, none of whom was among the authors of the original. The comments of these reviewers were incorporated before submission for publication.
Topics: Agammaglobulinemia; Age Factors; Algorithms; B-Lymphocytes; Common Variable Immunodeficiency; Diagnosis, Differential; Expert Testimony; Humans; Immunophenotyping; International Cooperation
PubMed: 26563668
DOI: 10.1016/j.jaip.2015.07.025 -
The New England Journal of Medicine May 2021Severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a rare and life-threatening primary immunodeficiency.
BACKGROUND
Severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a rare and life-threatening primary immunodeficiency.
METHODS
We treated 50 patients with ADA-SCID (30 in the United States and 20 in the United Kingdom) with an investigational gene therapy composed of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with a self-inactivating lentiviral vector encoding human . Data from the two U.S. studies (in which fresh and cryopreserved formulations were used) at 24 months of follow-up were analyzed alongside data from the U.K. study (in which a fresh formulation was used) at 36 months of follow-up.
RESULTS
Overall survival was 100% in all studies up to 24 and 36 months. Event-free survival (in the absence of reinitiation of enzyme-replacement therapy or rescue allogeneic hematopoietic stem-cell transplantation) was 97% (U.S. studies) and 100% (U.K. study) at 12 months; 97% and 95%, respectively, at 24 months; and 95% (U.K. study) at 36 months. Engraftment of genetically modified HSPCs persisted in 29 of 30 patients in the U.S. studies and in 19 of 20 patients in the U.K. study. Patients had sustained metabolic detoxification and normalization of ADA activity levels. Immune reconstitution was robust, with 90% of the patients in the U.S. studies and 100% of those in the U.K. study discontinuing immunoglobulin-replacement therapy by 24 months and 36 months, respectively. No evidence of monoclonal expansion, leukoproliferative complications, or emergence of replication-competent lentivirus was noted, and no events of autoimmunity or graft-versus-host disease occurred. Most adverse events were of low grade.
CONCLUSIONS
Treatment of ADA-SCID with ex vivo lentiviral HSPC gene therapy resulted in high overall and event-free survival with sustained expression, metabolic correction, and functional immune reconstitution. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01852071, NCT02999984, and NCT01380990.).
Topics: Adenosine Deaminase; Adolescent; Agammaglobulinemia; Child; Child, Preschool; Genetic Therapy; Genetic Vectors; Hematopoietic Stem Cell Transplantation; Humans; Infant; Lentivirus; Lymphocyte Count; Progression-Free Survival; Prospective Studies; Severe Combined Immunodeficiency; Transplantation, Autologous
PubMed: 33974366
DOI: 10.1056/NEJMoa2027675 -
International Journal of Experimental... Aug 2023Rare diseases collectively exact a high toll on society due to their sheer number and overall prevalence. Their heterogeneity, diversity, and nature pose daunting... (Review)
Review
Rare diseases collectively exact a high toll on society due to their sheer number and overall prevalence. Their heterogeneity, diversity, and nature pose daunting clinical challenges for both management and treatment. In this review, we discuss recent advances in clinical applications of gene therapy for rare diseases, focusing on a variety of viral and non-viral strategies. The use of adeno-associated virus (AAV) vectors is discussed in the context of Luxturna, licenced for the treatment of RPE65 deficiency in the retinal epithelium. Imlygic, a herpes virus vector licenced for the treatment of refractory metastatic melanoma, will be an example of oncolytic vectors developed against rare cancers. Yescarta and Kymriah will showcase the use of retrovirus and lentivirus vectors in the autologous ex vivo production of chimeric antigen receptor T cells (CAR-T), licenced for the treatment of refractory leukaemias and lymphomas. Similar retroviral and lentiviral technology can be applied to autologous haematopoietic stem cells, exemplified by Strimvelis and Zynteglo, licenced treatments for adenosine deaminase-severe combined immunodeficiency (ADA-SCID) and β-thalassaemia respectively. Antisense oligonucleotide technologies will be highlighted through Onpattro and Tegsedi, RNA interference drugs licenced for familial transthyretin (TTR) amyloidosis, and Spinraza, a splice-switching treatment for spinal muscular atrophy (SMA). An initial comparison of the effectiveness of AAV and oligonucleotide therapies in SMA is possible with Zolgensma, an AAV serotype 9 vector, and Spinraza. Through these examples of marketed gene therapies and gene cell therapies, we will discuss the expanding applications of such novel technologies to previously intractable rare diseases.
Topics: Humans; Rare Diseases; Severe Combined Immunodeficiency; Genetic Therapy; Agammaglobulinemia
PubMed: 37177842
DOI: 10.1111/iep.12478 -
Clinical Journal of the American... Apr 2023Rituximab is an established therapy in children with idiopathic nephrotic syndrome to sustain short- to medium-term disease remission and avoid steroid toxicities.... (Review)
Review
Rituximab is an established therapy in children with idiopathic nephrotic syndrome to sustain short- to medium-term disease remission and avoid steroid toxicities. Recent trials focus on its use as a first-line agent among those with milder disease severity. Rituximab is used in multidrug refractory nephrotic syndrome and post-transplant disease recurrence, although the evidence is much less substantial. Available data suggest that the treatment response to rituximab depends on various patient factors, dosing regimen, and the concomitant use of maintenance immunosuppression. After repeated treatments, patients are found to have an improving response overall with a longer relapse-free period. The drug effect, however, is not permanent, and 80% of patients eventually relapse and many will require an additional course of rituximab. This underpins the importance of understanding the long-term safety profile on repeated treatments. Although rituximab appears to be generally safe, there are concerns about long-term hypogammaglobulinemia, especially in young children. Reliable immunophenotyping and biomarkers are yet to be discovered to predict treatment success, risk of both rare and severe side effects, e.g. , persistent hypogammaglobulinemia, and guiding of redosing strategy. In this review, we highlight recent advances in the use of rituximab for childhood nephrotic syndrome and how the therapeutic landscape is evolving.
Topics: Child; Humans; Child, Preschool; Rituximab; Nephrotic Syndrome; Agammaglobulinemia; Glucocorticoids; Treatment Outcome
PubMed: 36456193
DOI: 10.2215/CJN.08570722 -
The Journal of Allergy and Clinical... Feb 2022Chimeric antigen receptor (CAR) T-cell therapy is a dynamic therapy of engineered T cells targeting neoplastic cells, which offers impressive long-term remissions for... (Review)
Review
Chimeric antigen receptor (CAR) T-cell therapy is a dynamic therapy of engineered T cells targeting neoplastic cells, which offers impressive long-term remissions for aggressive relapsed/refractory hematologic malignancies. However, side effects including severe infections can be life-threatening. Multiple factors, including cytokine release syndrome, B-cell aplasia, and hypogammaglobulinemia, contribute to infection risk. B-cell aplasia is an expected on-target, off-tumor effect of CD19-targeted CAR T cells and leads to hypogammaglobulinemia. We review hypogammaglobulinemia observed in the 5 currently Food and Drug Administration-approved CAR T-cell therapies and other CAR T-cell products evaluated in clinical trials, and discuss hypogammaglobulinemia onset, duration, and immune recovery. We review associations between hypogammaglobulinemia and infections, with a discussion informed by other known B-cell-depleting contexts. Differences in hypogammaglobulinemia between children and adults are identified. We integrate management strategies for evaluation and immunoglobulin replacement from clinical studies, expert recommendations, and organizational guidelines. Notably, our review also highlights newer CAR T-cell products targeting different B-cell antigens, including B-cell maturation antigen, signaling lymphocytic activation molecule, and κ light chains. Finally, we identify key areas for future study to mitigate and treat hypogammaglobulinemia resulting from this transformative therapy.
Topics: Agammaglobulinemia; Cell- and Tissue-Based Therapy; Humans; Immunotherapy, Adoptive; Neoplasm Recurrence, Local; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen
PubMed: 34757064
DOI: 10.1016/j.jaip.2021.10.037 -
Frontiers in Immunology 2019Antibody deficiency or hypogammaglobulinemia can have primary or secondary etiologies. Primary antibody deficiency (PAD) is the result of intrinsic genetic defects,... (Review)
Review
Antibody deficiency or hypogammaglobulinemia can have primary or secondary etiologies. Primary antibody deficiency (PAD) is the result of intrinsic genetic defects, whereas secondary antibody deficiency may arise as a consequence of underlying conditions or medication use. On a global level, malnutrition, HIV, and malaria are major causes of secondary immunodeficiency. In this review we consider secondary antibody deficiency, for which common causes include hematological malignancies, such as chronic lymphocytic leukemia or multiple myeloma, and their treatment, protein-losing states, and side effects of a number of immunosuppressive agents and procedures involved in solid organ transplantation. Secondary antibody deficiency is not only much more common than PAD, but is also being increasingly recognized with the wider and more prolonged use of a growing list of agents targeting B cells. SAD may thus present to a broad range of specialties and is associated with an increased risk of infection. Early diagnosis and intervention is key to avoiding morbidity and mortality. Optimizing treatment requires careful clinical and laboratory assessment and may involve close monitoring of risk parameters, vaccination, antibiotic strategies, and in some patients, immunoglobulin replacement therapy (IgRT). This review discusses the rapidly evolving list of underlying causes of secondary antibody deficiency, specifically focusing on therapies targeting B cells, alongside recent advances in screening, biomarkers of risk for the development of secondary antibody deficiency, diagnosis, monitoring, and management.
Topics: Agammaglobulinemia; Disease Management; Disease Susceptibility; Evidence-Based Medicine; Humans; Practice Guidelines as Topic
PubMed: 30800120
DOI: 10.3389/fimmu.2019.00033