Background/Objectives: Gastrointestinal diseases are a major cause of morbidity in common variable immunodeficiency disorder (CVID), clinically often mimicking other conditions including celiac disease and inflammatory bowel disease (IBD). Hence, diagnosis of CVID remains challenging. This study aims to raise awareness and highlight histopathological clues for CVID in intestinal biopsies, emphasizing diagnostic pitfalls for the pathologist/gastroenterologist. Methods: We reviewed 63 (18 duodenal, 23 ileal, 22 colonic) biopsies and case histories from seven CVID patients, obtained over a 31-year period, with attention to active inflammation, intraepithelial lymphocytes, plasma cells, lymphoid hyperplasia, crypt/villous architecture, subepithelial collagen, apoptosis, granulomas, and infections. Clinical information of 41 pathology requests was reviewed. Results: Gastrointestinal symptoms were variable. Histological features included IBD-like (3/7), celiac disease-like (2/7), graft-versus-host disease (GVHD)-like (2/7), lymphocytic sprue/colitis-like (3/7), collagenous colitis-like (2/7), and acute colitis-like (4/7) patterns, often overlapping (2/7) and/or changing over time (3/7). Lymphoid hyperplasia was seen in 3/7 patients; 1/7 had giardiasis; and 5/7 had few plasma cells, usually only in part of the gut (3/5). Clinical information of 12/41 (29%) pathology requests mentioned known/suspected CVID, despite being known in 33/41 (80%). Conclusions: Clinical/histological features of CVID in the gut are diverse, often mimicking IBD, microscopic colitis, celiac disease and/or GVHD, hence the importance of adequate clinical information. Some histological features are atypical of these established entities and may indicate CVID, as may overlapping/changing histological patterns and/or few plasma cells in part of the gut. Awareness of the heterogenous clinical presentation and histopathological indicators of CVID may improve diagnosis.

Common variable immunodeficiency (CVID) is a heterogeneous primary immunodeficiency (PID) characterized by an impaired immunoglobulin production, in association with an increased susceptibility to infections and a diversity of clinical manifestations. This narrative review summarizes immunophenotypic abnormalities in CVID patients and their relevance for diagnosis and disease classification. A comprehensive search across four databases - PubMED, Web of Science, EMBASE and Google Scholar - yielded 170 relevant studies published between 1988 and April 31, 2023. Over the past decades, the role of immunophenotyping in CVID diagnosis has become evident by identifying "hallmark" immunophenotypic aberrancies in patient subsets, with some now integrated in the consensus diagnostic criteria. Furthermore, the role of immunophenotyping in subclassifying CVID in relation to clinical presentation and prognosis has been extensively studied. Certain immunophenotypic patterns consistently correlate with clinical manifestations and/or subsets of CVID, particularly those associated with noninfectious complications (i.e. low switched memory B cells, shifts in follicular helper T cell subsets, low naïve CD4⁺ T cells, low regulatory T cells, and expansion of CD21low B cells, often associated with autoimmunity and/or splenomegaly). Also, efforts to associate subset levels of innate immune cells, such as Natural Killer (NK) cells, invariant (i)NKT cells, innate lymphoid cells (ILCs), and dendritic cells (DCs) to CVID complications are evident albeit in a lesser degree. However, inconsistencies regarding the role of flow cytometry in classification and prognosis persist, reflecting the disease complexity, but probably also cohort variations and methodological differences between published studies. This underscores the need for collaborative efforts to integrate emerging concepts, such as standardized flow cytometry and computational tools, for a more precise CVID classification approach. Additionally, recent studies suggest a potential value of (epi)genetic-based molecular assays to this effort.

Distinct in vitro B-cell stimulation strategies, defined by stimulation condition and incubation duration, have been described in diverse studies. Often, these approaches are considered interchangeable due to comparable flow-cytometric outputs concerning fluorescence intensities and B-cell subset distributions. However, whether these phenotypic similarities also reflect comparable underlying transcriptional states have not been systematically evaluated yet. In this study, we provide an unbiased comparison of B-cell activation strategies on healthy individuals, resulting in a single-cell transcriptomic atlas (4 donors; ∼2,029 cells per sample; 81,160 cells in total with 56.3% annotated as B cells). Two T-cell independent stimulators targeting toll-like receptors (ODN2006 and IFN-γ/R-848), were assessed next to two T-cell dependent stimulators (anti-CD40 and anti-CD3/CD28 antibodies), all incubated for eight and 30 hours. Observed overlap for differential abundance, differential gene expression and cell-cell interactions could directly be linked to T-cell (in)dependent working mechanism. Strategy-specific results uncovered time-point specific transcriptional changes, revealed the largest set of differentially expressed genes for IFN-γ/R-848 and ODN2006, and showed that IFN-γ/R-848 and anti-CD3/CD28 induced the majority of the cell-cell interactions. Ultimately, our reference atlas emphasizes the importance and facilitates the rational selection of optimal B-cell stimulation strategies, particularly for studies aiming to interrogate B-cell dysregulation in immune-mediated diseases. GRAPHICAL

We report Ureaplasma parvum septic arthritis in lipopolysaccharide-responsive and beige-like anchor protein deficiency during rituximab-based chemotherapy for relapsed Hodgkin lymphoma. This case highlights culture-negative infection mimicking autoimmune arthritis and supports early 16S ribosomal RNA PCR in immunocompromised patients with a primary immune regulatory disorder.