Manish Butte

Allergy Asthma Clin Immunol. 2022 Aug 7;18(1):70. doi: 10.1186/s13223-022-00709-8.

ABSTRACT

BACKGROUND: Real-world data on transitioning to Immune Globulin Subcutaneous (Human) 20% solution (Ig20Gly) are limited. This study aimed to assess infusion parameters and experience of patients with primary (PID) or secondary immunodeficiencies (SID) transitioning to Ig20Gly in clinical practice in Canada.

METHODS: Patients with PID or SID who received subcutaneous immunoglobulin (SCIG) for ≥ 3 months before transitioning to Ig20Gly were eligible for this multicenter (n = 6), phase 4, non-interventional, prospective, single-arm study. Ig20Gly infusion parameters, dosing, and adverse events were collected from patient medical records at Ig20Gly initiation and 3, 6, and 12 months post-initiation. Patient satisfaction and quality of life were assessed 12 months post-initiation using validated questionnaires.

RESULTS: The study included 125 patients (PID, n = 60; SID, n = 64; PID + SID, n = 1). Median volume per infusion was 30.0 ml at initiation, and 40.0 ml at 6 and 12 months post-initiation. Most patients administered Ig20Gly weekly and used two infusion sites (primarily abdomen). At each time point, median infusion duration was ≤ 1 h. At 12 months, 61% of infusions were administered via a pump and 39% manually. Headache and infusion-site reactions were the most reported adverse events of interest. Patients expressed overall satisfaction with Ig20Gly at 12 months post-initiation, with all respondents indicating they would like to continue Ig20Gly.

CONCLUSIONS: This study provides a detailed description of Ig20Gly infusion parameters, tolerability, and quality of life in clinical practice among patients with PID or SID switching to Ig20Gly from another SCIG and confirms the feasibility of infusing Ig20Gly via pump or manual administration. Trial registration NCT03716700, Registered 31 August 2018, https://clinicaltrials.gov/ct2/show/NCT03716700.

PMID:35934726 | DOI:10.1186/s13223-022-00709-8

Clin Microbiol Infect. 2022 Aug 4:S1198-743X(22)00389-5. doi: 10.1016/j.cmi.2022.07.021. Online ahead of print.

ABSTRACT

BACKGROUND: Inborn errors of intrinsic and innate immunity constitute the focus of a growing research field that investigates the molecular mechanisms underlying susceptibility to infections previously not considered part of the spectrum of inborn errors of immunity. These so-called non-conventional inborn errors of immunity often occur as infections caused by a narrow spectrum of microorganisms in otherwise healthy subjects.

OBJECTIVES: This review aims to provide a framework for identifying and evaluating patients with viral, bacterial, mycobacterial, and fungal infection needing further assessment for inborn errors of intrinsic and innate immunity.

SOURCES: A literature search was performed using PubMed, from inception until May 1, 2022. The search included the following keywords: inborn errors of immunity; inborn errors of innate immunity; primary immune deficiency; primary immunodeficiency; infections; infectious susceptibility; virus; pyogenic bacteria; mycobacteria; fungi. All article types were considered.

CONTENT: We review the definition of what can be considered an inborn error of immunity and how the definition changed over the last ∼25 years. We further provide criteria to rule out secondary immunodeficiencies, identify patients needing further clinical and laboratory immunological assessment, and suspect and diagnose an inborn error of intrinsic and innate immunity. These steps are proposed as part of an algorithm.

IMPLICATIONS: Patients with unexplained life-threatening infections, including otherwise healthy subjects, should be systematically screened for known inborn errors of immunity. The early diagnosis can prevent recurrence of life-threatening infections in the patients, and reduce the total burden of infectious diseases.

PMID:35934195 | DOI:10.1016/j.cmi.2022.07.021

J Immunol Methods. 2022 Aug 4:113327. doi: 10.1016/j.jim.2022.113327. Online ahead of print.

ABSTRACT

B cells are one of the fundamental components of the adaptive immune system and are best known for their ability to produce antibodies. Among the various types of inborn errors of immunity, antibody deficiencies represent the largest group in terms of the number of affected individuals. Not all antibody deficiencies are due to B cell intrinsic defects but investigating B cell number and function are a critical part of the diagnostic process. B cells studies in clinical practice almost always rely on flow cytometry as the main tool of investigation. The advantage of flow cytometry is that it allows absolute and relative counting of B cells, and their phenotypic and functional evaluation at a single-cell level, while allowing the analysis of a large number of cells. Although versatile and broad in its utility, clinical flow cytometry has both theoretical and practical limitations. These include lack of consensus about definitions and classifications, and the use of non-standardized methods. Patients in all age groups, from newborns to the elderly, may require testing, yet B cells show significant changes in both numbers and subset distribution over the lifespan, requiring distinct reference ranges for narrowly defined age brackets for accurate interpretation. Sampling for testing is usually restricted to peripheral blood samples, and the number of markers routinely used are limited. This paper will provide a brief overview of flow cytometry and B cell biology, describe the human peripheral B cell subsets most commonly identified in clinical flow cytometry and discuss their clinical relevance in different settings.

PMID:35934071 | DOI:10.1016/j.jim.2022.113327

Cureus. 2022 Aug 1;14(8):e27571. doi: 10.7759/cureus.27571. eCollection 2022 Aug.

ABSTRACT

Primary immunodeficiency syndromes encompass a wide variety of inborn and acquired cellular and signaling defects. They are predominantly diagnosed during childhood but can present later into young adulthood depending on the severity, impact, and access to healthcare. Early clues to diagnosis include atypical and severe or recurrent presentations to common pathogens, vaccine failure, and immune lab abnormalities. Despite seemingly obvious characteristics, diagnosis is frequently delayed by months to years at a cost of greatly increased morbidity. Here we present a case of a challenging hyper IgM syndrome diagnosed after seven months and multiple hospitalizations for unique multisystem pathologies.

PMID:35928175 | PMC:PMC9345625 | DOI:10.7759/cureus.27571

Clin Exp Immunol. 2022 Aug 4:uxac070. doi: 10.1093/cei/uxac070. Online ahead of print.

ABSTRACT

Currently there is no guideline to support the use of immunoglobulin replacement therapy (IgRT) in primary and secondary immunodeficiency disorders in UK. The UK Primary Immunodeficiency Network (UK-PIN) and the British Society of Immunology (BSI) joined forces to address this need. Given the paucity of evidence a modified Delphi approach was employed covering statements for the initiation, monitoring, discontinuation of IgRT as well as home therapy programme. A group of 6 consultant immunologists and 3 nurse specialists created the statements, reviewed responses and feedback and agreed on final recommendations. This guideline includes 22 statements for initiation, 22 statements for monitoring, 11 statement for home therapy and 19 statements for discontinuation of IgRT. Further areas of research are proposed to improve future delivery of care.

PMID:35924867 | DOI:10.1093/cei/uxac070

Front Immunol. 2022 Jul 18;13:928062. doi: 10.3389/fimmu.2022.928062. eCollection 2022.

ABSTRACT

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.

PMID:35924244 | PMC:PMC9340211 | DOI:10.3389/fimmu.2022.928062

South Med J. 2022 Aug;115(8):593-596. doi: 10.14423/SMJ.0000000000001424.

ABSTRACT

OBJECTIVES: Common variable immunodeficiency (CVID) is one of the most common primary immunodeficiencies encountered by physicians, yet it is still poorly described and vastly underdiagnosed and underreported. It is characterized by low levels of immunoglobulins IgG, IgM, and IgA, recurrent infections, and an increased incidence of autoimmune conditions and malignancies. Diverse clinical presentation, poor understanding of its true prevalence, and the daunting, rarely ordered, diagnostic testing make this disease incredibly difficult to diagnose in a primary care setting. Our objectives in this study were to establish a simple marker that can be used in a primary care setting to raise suspicion of CVID and prompt further diagnostic testing and to demonstrate that the true prevalence of CVID is much higher than previously reported.

METHODS: Data on 441 patients who underwent Ig electrophoresis testing during a 4-year period were analyzed retrospectively for the presence of hypogammaglobulinemia and number of clinic visits for infectious processes.

RESULTS: The average number of clinic visits before testing in patients with no identified antibody deficiency was 1.89 and in patients with any deficiency 2.22. The odds ratio for each additional visit was 1.089, which was not statistically significant (P = 0.103). When the data were recoded to be capped at 6 clinic visits, the odds ratio for each visit up to 6 was 1.119, which was marginally significant (P = 0.058).

CONCLUSIONS: Patients with Ig deficiencies tend to have a higher number of office visits related to infectious processes. This difference, however, was not statistically significant in our study, likely because of the small number of participants. Our study also demonstrated that the prevalence of CVID is likely much higher than currently reported, and it highlights the difficulties related to the convoluted diagnostic process of this disease.

PMID:35922044 | DOI:10.14423/SMJ.0000000000001424

Curr Rheumatol Rep. 2022 Aug 3. doi: 10.1007/s11926-022-01083-5. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: To provide a comprehensive review of drugs and neoplastic, infectious, autoinflammatory, and immunodeficiency diseases causing medium- to large-vessel vasculitis in adults with emphasis on information essential for the initial diagnostic process.

RECENT FINDINGS: Entities with medium- to large-vessel vasculitis as clinical manifestations have been described recently (e.g., adenosine deaminase-2 deficiency, VEXAS-Syndrome), and vasculitis in established autoinflammatory or immunodeficiency diseases is increasingly being identified. In the diagnostic process of medium- to large-vessel vasculitis in adults, a large variety of rare diseases should be included in the differential diagnosis, especially if diagnosis is made without histologic confirmation and in younger patients. Although these disorders should be considered, they will undoubtedly remain rare in daily practice.

PMID:35920952 | DOI:10.1007/s11926-022-01083-5

JCI Insight. 2022 Aug 2:e161450. doi: 10.1172/jci.insight.161450. Online ahead of print.

ABSTRACT

Pneumocystis is the most common fungal pulmonary infection in children under 5. In children with primary immunodeficiency, Pneumocystis often presents at 3-6 months that coincides with the nadir of maternal IgG and where IgM is the dominant immunoglobulin isotype. Since B cells are the dominant antigen-presenting cells for Pneumocystis, we hypothesized the presence of fungal specific IgMs in human and mice and that these IgM specificities would predict T cell antigens. We detected fungal specific IgMs in human and mouse serum and utilized immunoprecipitation to determine if any antigens were similar across donors. We then assessed T cell responses to these antigens. We found anti-Pneumocystis IgM in wild-type mice as well as Aicda-/- mice and in human cord blood. Immunoprecipitation of Pneumocystis murina with human cord blood identified shared antigens among these donors. Using class II MHC binding prediction, we designed peptides with these antigens and identified robust peptide specific lung T cell responses after P. murina infection. After mice were immunized with two of the antigens, adoptive transfer of vaccine elicited CD4+ T cells showed effector activity suggesting that these antigens contain protective Pneumocystis epitopes. These data support the notion that germline encoded IgM B-cell receptors are critical in antigen presentation and T cell priming in early Pneumocystis infection.

PMID:35917185 | DOI:10.1172/jci.insight.161450

Pediatr Hematol Oncol. 2022 Aug 1:1-16. doi: 10.1080/08880018.2022.2085830. Online ahead of print.

ABSTRACT

Inborn errors of immunity (IEI) are a group of disorders caused by genetically determined defects in the immune system, leading to infections, autoimmunity, autoinflammation and an increased risk of malignancy. In some cases, a malignancy might be the first sign of an underlying IEI. As therapeutic strategies might be different in these patients, recognition of the underlying IEI by the pediatric hemato-oncologist is important. This article, written by a group of experts in pediatric immunology, hemato-oncology, pathology and genetics, aims to provide guidelines for pediatric hemato-oncologists on how to recognize a possible underlying IEI and what diagnostic tests can be performed, and gives some consideration to treatment possibilities.

PMID:35913104 | DOI:10.1080/08880018.2022.2085830