Practical guidance for the diagnosis and management of secondary hypogammaglobulinemia: A Work Group Report of the AAAAI Primary Immunodeficiency and Altered Immune Response Committees.

Authors: Iris M Otani, Heather K Lehman, Artemio M Jongco...

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

Review

Authors: Ashley L Devonshire, Melanie Makhija

Primary immunodeficiency diseases are inherited defects of the innate or adaptive arms of the immune system that lead to an increase in the incidence, frequency, or severity of infections and/or immune dysregulation. There may be defects in the adaptive arm of the immune system, including combined immunodeficiencies and antibody deficiency syndromes, or abnormalities in innate immunity, such as defects of phagocytes, the complement pathway, or toll-like receptor mediated signaling. Recurrent sinopulmonary infections with encapsulated bacteria such as Haemophilus influenzae type B or Streptococcus pneumoniae may be characteristic of an antibody deficiency syndrome. Frequent viral, fungal, or protozoal infections may suggest T lymphocyte impairment. Multiple Staphylococcus skin infections and fungal infections may imply neutrophil dysfunction or the Hyper-IgE syndrome, and recurrent Neisseria infection is a characteristic manifestation of late complement component (C5-9, or the membrane attack complex) defects. Recurrent viral or pyogenic bacterial infections, often without the presence of a significant inflammatory response, suggest a defect in toll-like receptor signaling. Mycobacterial infections are characteristic of defects in the interleukin (IL) 12/interferon γ pathway. Screening of newborns for T-cell lymphopenia by using polymerase chain reaction to amplify T-cell receptor excision circles, which are formed when a T cell rearranges the variable region of its receptor, serves as a surrogate for newly synthesized naive T cells. Because of very low numbers of T-cell receptor excision circles, severe combined immunodeficiency, 22q11.2 syndrome, and other causes of T-cell lymphopenia have been identified in newborns.

Topics: Adaptive Immunity; Humans; Immunity, Innate; Immunologic Deficiency Syndromes; Infant, Newborn; Infections; Lymphopenia; Primary Immunodeficiency Diseases; Severe Combined Immunodeficiency; T-Lymphocytes

PubMed: 31690396
DOI: 10.2500/aap.2019.40.4273

Review

Authors: Hirokazu Kanegane, Akihiro Hoshino, Tsubasa Okano...

Primary immunodeficiencies (PIDs) are a heterogeneous group of inherited diseases of the immune system. The definite diagnosis of PID is ascertained by genetic analysis; however, this takes time and is costly. Flow cytometry provides a rapid and highly sensitive tool for diagnosis of PIDs. Flow cytometry can evaluate specific cell populations and subpopulations, cell surface, intracellular and intranuclear proteins, biologic effects associated with specific immune defects, and certain functional immune characteristics, each being useful for the diagnosis and evaluation of PIDs. Flow cytometry effectively identifies major forms of PIDs, including severe combined immunodeficiency, X-linked agammaglobulinemia, hyper IgM syndromes, Wiskott-Aldrich syndrome, X-linked lymphoproliferative syndrome, familial hemophagocytic lymphohistiocytosis, autoimmune lymphoproliferative syndrome, IPEX syndrome, CTLA 4 haploinsufficiency and LRBA deficiency, IRAK4 and MyD88 deficiencies, Mendelian susceptibility to mycobacterial disease, chronic mucocuneous candidiasis, and chronic granulomatous disease. While genetic analysis is the definitive approach to establish specific diagnoses of PIDs, flow cytometry provides a tool to effectively evaluate patients with PIDs at relatively low cost.

Topics: Flow Cytometry; Humans; Immunologic Deficiency Syndromes

PubMed: 28684198
DOI: 10.1016/j.alit.2017.06.003

Review

Authors: Mark Ballow, Silvia Sánchez-Ramón, Jolan E Walter...

Primary immunodeficiencies (PIDs), a heterogenous group of inborn errors of immunity, are predetermined at birth but may evolve with age, leading to a variable clinical and laboratory presentation. In contrast, secondary immunodeficiencies (SIDs) are acquired declines of immune cell counts and or/function. The most common type of SID is a decreased antibody level occurring as a consequence of extrinsic influences, such as an underlying condition or a side effect of some medications used to treat hematological malignancies and autoimmune disorders. Paradoxically, immune deficiencies initially attributed to secondary causes may partly be due to an underlying PID. Therefore, in the era of immune-modulating biologicals, distinguishing between primary and secondary antibody deficiencies is of great importance. It can be difficult to unravel the relationship between PID, SID and hematological malignancy or autoimmunity in the clinical setting. This review explores SID and PID crossovers and discusses challenges to diagnosis and treatment strategies. The case of an immunodeficient patient with follicular lymphoma treated with rituximab illustrates how SID in the setting of hematological cancer can mask an underlying PID, and highlights the importance of screening such patients. The risk of hematological cancer is increased in PID: for example, lymphomas in PID may be driven by infections such as Epstein-Barr virus, and germline mutations associated with PID are enriched among patients with diffuse large B-cell lymphoma. Clues suggesting an increased risk of hematological malignancy in patients with common variable immune deficiency (CVID) are provided, as well as pointers for distinguishing PID versus SID in lymphoma patients. Two cases of patients with autoimmune disorders illustrate how an apparent rituximab-induced antibody deficiency can be connected to an underlying PID. We highlight that PID is increasingly recognized among patients with autoimmune cytopenias, and provide guidance on how to identify PID and distinguish it from SID in such patients. Overall, healthcare professionals encountering patients with malignancy and/or autoimmunity who have post-treatment complications of antibody deficiencies or other immune abnormalities need to be aware of the possibility of PID or SID and how to differentiate them.

Topics: Humans; Infant, Newborn; Autoimmune Diseases; Epstein-Barr Virus Infections; Hematologic Neoplasms; Herpesvirus 4, Human; Immunologic Deficiency Syndromes; Primary Immunodeficiency Diseases; Rituximab

PubMed: 35924244
DOI: 10.3389/fimmu.2022.928062

Review

Authors: Carolina Sanchez Aranda, Rafaela Rola Guimarães, Mariana de Gouveia-Pereira Pimentel...

OBJECTIVES

Inborn Errors of Immunity (IEI), also known as primary immunodeficiencies, correspond to a heterogeneous group of congenital diseases that primarily affect immune response components. The main clinical manifestations comprise increased susceptibility to infections, autoimmunity, inflammation, allergies and malignancies. The aim of this article is to review the literature on combined immunodeficiencies (CIDs) focusing on the diagnosis and treatment and the particularities of the clinical management of these patients.

SOURCE OF DATA

Critical integrative review, aimed to present articles related to primary immunodeficiencies combined with a searchin the PubMed and SciELO databases, with evaluation of publications from the last twenty years that were essential for the construction of knowledge on this group of diseases.

SUMMARY OF DATA

We highlight the main characteristics of CIDs, dividing them according to their pathophysiological mechanisms, such as defects in the development of T cells, TCR signaling, co-stimulatory pathways, cytokine signaling, adhesion, migration and organization of the cytoskeleton, apoptosis pathways, DNA replication and repair and metabolic pathways. In CIDs, clinical manifestations vary widely, from sinopulmonary bacterial infections and diarrhea to opportunistic infections, caused by mycobacteria and fungi. Neonatal screening makes it possible to suspect these diseases before clinical manifestations appear.

CONCLUSIONS

The CIDs or IEI constitute a complex group of genetic diseases with T-cell involvement. Neonatal screening for these diseases has improved the prognosis of these patients, especially in severe ones, known as SCIDs.

Topics: Humans; Immunologic Deficiency Syndromes; Infant, Newborn; Neonatal Screening; Severe Combined Immunodeficiency; T-Lymphocytes

PubMed: 33340461
DOI: 10.1016/j.jped.2020.10.014

Review

Authors:

Increased understanding of the nature and variety of immunodeficiency states in man is rapidly accumulating both from studies of human patients and from experimental work on the immune response in animals. Progress is evident in the development of diagnostic tests for deficiencies in both humoral and cellular mechanisms of immunity, and in the introduction of new forms of therapy-for example, the grafting of lymphoid cells. Studies of immunodeficiency provide the most direct evidence concerning the nature of the immune response in man, and hence are of wide general interest. In this paper, current knowledge and concepts are summarized, a logical classification is presented, and recommendations are made for the investigation and treatment of these disorders.

Topics: Antigen-Antibody Reactions; Bone Marrow Cells; Humans; Immune Sera; Immunity, Active; Immunity, Cellular; Immunodiffusion; Immunoelectrophoresis; Immunoglobulin A; Immunoglobulin D; Immunoglobulin E; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Immunologic Deficiency Syndromes; Lymph Nodes; Lymphocyte Activation; Lymphocytes; Radioimmunoassay; Rectum

PubMed: 5004396
DOI: No ID Found

Review

Authors: Alexandra Y Kreins, Fatima Dhalla, Aisling M Flinn...

Congenital athymia is a life-limiting disorder due to rare inborn errors of immunity causing impaired thymus organogenesis or abnormal thymic stromal cell development and function. Athymic infants have a T-lymphocyte-negative, B-lymphocyte-positive, natural killer cell-positive immunophenotype with profound T-lymphocyte deficiency and are susceptible to severe infections and autoimmunity. Patients variably display syndromic features. Expanding access to newborn screening for severe combined immunodeficiency and T lymphocytopenia and broad genetic testing, including next-generation sequencing technologies, increasingly facilitate their timely identification. The recommended first-line treatment is allogeneic thymus transplantation, which is a specialized procedure available in Europe and the United States. Outcomes for athymic patients are best with early diagnosis and thymus transplantation before the development of infectious and inflammatory complications. These guidelines on behalf of the European Society for Immunodeficiencies provide a comprehensive review for clinicians who manage patients with inborn thymic stromal cell defects; they offer clinical practice recommendations focused on the diagnosis, investigation, risk stratification, and management of congenital athymia with the aim of improving patient outcomes.

Topics: Humans; Europe; Immunologic Deficiency Syndromes; Thymus Gland; Infant, Newborn; Disease Management

PubMed: 39303894
DOI: 10.1016/j.jaci.2024.07.031

Review

Authors: Carrie L Lucas, Anita Chandra, Sergey Nejentsev...

Primary immunodeficiencies are inherited disorders of the immune system, often caused by the mutation of genes required for lymphocyte development and activation. Recently, several studies have identified gain-of-function mutations in the phosphoinositide 3-kinase (PI3K) genes PIK3CD (which encodes p110δ) and PIK3R1 (which encodes p85α) that cause a combined immunodeficiency syndrome, referred to as activated PI3Kδ syndrome (APDS; also known as p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency (PASLI)). Paradoxically, both loss-of-function and gain-of-function mutations that affect these genes lead to immunosuppression, albeit via different mechanisms. Here, we review the roles of PI3Kδ in adaptive immunity, describe the clinical manifestations and mechanisms of disease in APDS and highlight new insights into PI3Kδ gleaned from these patients, as well as implications of these findings for clinical therapy.

Topics: Animals; Cell Differentiation; Cellular Senescence; Enzyme Activation; Gene Expression Regulation; Humans; Immune System; Immunity; Immunologic Deficiency Syndromes; Lymphocyte Activation; Lymphocytes; Molecular Targeted Therapy; Mutation; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Subunits; Signal Transduction

PubMed: 27616589
DOI: 10.1038/nri.2016.93

Review

Authors: M Ballow, L Notarangelo, B Grimbacher...

Primary immunodeficiencies (PIDs) are uncommon, chronic and severe disorders of the immune system in which patients cannot mount a sufficiently protective immune response, leading to an increased susceptibility to infections. The treatment of choice for PID patients with predominant antibody deficiency is intravenous immunoglobulin (Ig) replacement therapy. Despite major advances over the last 20 years in the molecular characterization of PIDs, many patients remain undiagnosed or are diagnosed too late, with severe consequences. Various strategies to ensure timely diagnosis of PIDs are in place, and novel approaches are being developed. In recent years, several patient registries have been established. Such registries shed light on the pathology and natural history of these varied disorders. Analyses of the registry data may also reveal which patients are likely to respond well to higher Ig infusion rates and may help to determine the optimal dosing of Ig products. Faster infusion rates may lead to improved convenience for patients and thus increase patient compliance, and may reduce nursing time and the need for hospital resources. Data from two recent studies suggest that Gamunex and Privigen are well tolerated at high infusion rates. Nevertheless, careful selection of patients for high infusion rates, based on co-morbid conditions and tolerance of the current infusion rate, is advisable. Based on the available data, intravenous Ig offers broad protection against encapsulated organisms. As vaccine trends change, careful monitoring of specific antibody levels in the general population, such as those against pneumococcal and meningococcal bacteria, should be implemented.

Topics: Antibodies, Bacterial; Bacterial Infections; Databases, Factual; Humans; Immunoglobulins, Intravenous; Immunologic Deficiency Syndromes; International Cooperation; Opportunistic Infections; Registries

PubMed: 19883420
DOI: 10.1111/j.1365-2249.2009.04023.x

Review

Authors: Hanna IJspeert, Emily S J Edwards, Robyn E O'Hehir...

Ever since the first description of an inherited immunodeficiency in 1952 in a boy with gammaglobulin deficiency, new insights have progressed rapidly in disorders that are now referred to as inborn errors of immunity. In a field where fundamental molecular biology, genetics, immune signaling, and clinical care are tightly intertwined, 2022-24 saw a multitude of advances. Here we report a selection of research updates with a main focus on (1) diagnosis and screening, (2) new genetic defects, (3) susceptibility to severe coronavirus disease 2019 infection and impact of vaccination, and (4) treatment. Importantly, new pathogenic insights more rapidly affect treatment outcomes, either through an earlier and more precise diagnosis or through implementation of novel, personalized treatment. The field is growing rapidly, so awareness, communication, and collaboration are key to improving treatment outcomes.

Topics: Humans; COVID-19; SARS-CoV-2; Vaccination; Male; Immunologic Deficiency Syndromes

PubMed: 39724969
DOI: 10.1016/j.jaci.2024.12.1075