Research

Front Med (Lausanne). 2026 Jan 7;12:1724196. doi: 10.3389/fmed.2025.1724196. eCollection 2025.

ABSTRACT

BACKGROUND: Intravenous immunoglobulin (IVIg) is widely used to treat primary immunodeficiency, chronic inflammatory demyelinating polyneuropathy, immune thrombocytopenia, and other disorders. Although effective in maintaining IgG trough levels and reducing infections, its safety profile requires further characterization.

METHODS: A large-scale pharmacovigilance study was conducted using the U.S. FDA Adverse Event Reporting System (FAERS) from Q1 2004 to Q4 2024. Four disproportionality methods-reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS)-were applied to detect adverse event signals. Weibull modeling was used to assess temporal risk patterns.

RESULTS: A total of 76,138 IVIg-associated reports were identified. Common events included infusion-site reactions (swelling, erythema, pain), infections (upper respiratory tract infection, bronchitis, pneumonia, influenza, urinary tract infection), and systemic reactions (pyrexia, chills, hypersensitivity, headache, asthenia, nausea, vomiting). Several novel potential safety signals emerged, including blood pressure-related events (hypertension and hypotension), weight changes (loss and gain), and falls.

CONCLUSION: Real-world FAERS data confirm the established tolerability of IVIg while highlighting rare but clinically important safety signals, particularly hemolytic anemia and aseptic meningitis. These findings warrant further clinical investigation to optimize monitoring and promote safer therapeutic use.

PMID:41574383 | PMC:PMC12819674 | DOI:10.3389/fmed.2025.1724196

Rev Prat. 2025 Oct;75(8):885-890.

ABSTRACT

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS. Hemophagocytic lymphohistiocytosis (HLH) is an uncontrolled, life-threatening inflammation caused by immune dysregulation and excessive activation of macrophages and T lymphocytes. HLH is characterized by persistent fever, hepatosplenomegaly, hyperferritinemia, cytopenia, coagulopathy, and hemophagocytosis. A distinction is made between the primary (genetic/familial) form (HLHp), which is caused by mutations in genes involved in the T and NK cells cytotoxicity pathway, and the secondary (acquired) form (HLHs), which usually occurs in the setting of an immunodeficiency associated with a neoplastic, infectious or autoimmune pathology. Early diagnosis and prompt treatment of the triggering factor, combined with HLH control thanks to corticosteroid therapy and sometimes immunosuppressants (etoposide, biotherapies), are the basis of management.

PMID:41575097

Kidney Int Rep. 2025 Dec 16;11(3):103729. doi: 10.1016/j.ekir.2025.103729. eCollection 2026 Mar.

ABSTRACT

IgA vasculitis (IgAV) is an autoimmune disease that affects the small vessels of the skin, joints, gastrointestinal (GI) tract, and kidneys. In the long term, IgAV associated with nephritis (IgAV-N) can progress to kidney failure. Evidence-based clinical studies of IgAV-N are few, leading to huge variations in treatment approaches and suboptimal outcomes. The wealth of emerging efficacious treatments for IgA nephrology brings new opportunities to this disease. The aim of this report is to describe the proceedings of a multiprofessional collaborative workshop convened to identify the barriers to developing high quality evidence for patients with IgAV-N. A multiprofessional group consisting of 53 attendees from 13 countries met. The meeting was represented by a variety of professional backgrounds, including lay attendees, with different levels of expertise (32% professors and 19% midcareer doctors). Using predefined aims, key themes were extracted, and an action plan developed. Consensus was obtained that there is sufficient similarity between adults and children in terms of the organs involved, pathophysiology, histological features, and likely response to treatment. Important differences included the greater spontaneous improvement in children and worse kidney outcomes in some populations. It was agreed that patients at greatest risk of kidney failure should be the primary focus of initial clinical trials. Important considerations included the following: diagnostic classification for adult onset IgAV, observational data, evidence of scientific similarity to IgA nephropathy (IgAN), an age-inclusive approach to trial design, systemic disease secondary end points, and the inclusion of patient-reported outcomes. This manuscript communicates an expert-informed pathway to high-quality evidence for IgAV-N.

PMID:41568275 | PMC:PMC12816797 | DOI:10.1016/j.ekir.2025.103729

J Genet. 2025;104:29.

ABSTRACT

Schimke immunoosseous dysplasia (SIOD) is an uncommon inherited genetic disorder resulting from pathogenic variants in the SMARCAL1 gene. This complex condition exhibits a wide range of clinical features, including skeletal abnormalities, steroid-resistant nephrotic syndrome, and immune system deficiencies. In this study, we report a case series of three patients diagnosed with SIOD, each harbouring copy number variants in the SMARCAL1 gene. The cases expand the current understanding of the genetic diversity underlying SIOD and highlight the significance of copy number variations as a pathogenic mechanism. Our findings contribute to broadening the genotypic spectrum associated with SIOD and underscore the importance of comprehensive genetic analysis for accurate diagnosis and management of this rare disorder.

PMID:41568729

Medicine (Baltimore). 2026 Jan 16;105(3):e47283. doi: 10.1097/MD.0000000000047283.

ABSTRACT

RATIONALE: Type II hereditary angioedema (HAE) is a rare and underrecognized condition. Early diagnosis and family screening are essential to prevent life-threatening attacks.

PATIENT CONCERNS: A 36-year-old woman presented with recurrent facial swelling and dysphagia unresponsive to standard treatments.

DIAGNOSES: Laboratory analysis revealed decreased C4 and low functional C1 inhibitor (C1-INH) activity with normal antigenic levels, confirming type II HAE. Whole-exome sequencing identified a heterozygous SERPING1 mutation, c.1397G > A (p.Arg466His), classified as pathogenic (ClinVar Accession: VCV000003946.13). Three daughters carried the same variant.

INTERVENTIONS: The patient received subcutaneous icatibant for acute management and prophylactic lanadelumab. Her daughters were counseled and provided with emergency medication.

OUTCOMES: Over 7 months of follow-up, the patient remained attack-free without adverse effects. Her daughters were asymptomatic or mildly affected.

LESSONS: This case emphasizes the need to consider HAE in unexplained recurrent angioedema and demonstrates the clinical utility of genetic testing and family screening. Lanadelumab was effective and well-tolerated for prophylaxis, consistent with current guideline recommendations.

PMID:41560114 | DOI:10.1097/MD.0000000000047283

J Allergy Clin Immunol Glob. 2025 Dec 6;5(2):100624. doi: 10.1016/j.jacig.2025.100624. eCollection 2026 Mar.

ABSTRACT

BACKGROUND: Primary immune diseases (PI) encompass over 550 disorders that are associated with substantial risk of mortality and morbidity. Emerging evidence demonstrates significant survival disparities in PI among racial minoritized populations. However, published national data on treatment patterns are lacking.

OBJECTIVE: We investigated variations in the use of immunoglobulin replacement therapy (IgGRT) across different geographic regions (Midwest, West, Northeast, South, and other/unknown) and racial groups (Black, Asian, White, and other/unknown) in the United States.

METHODS: This study analyzed a subset of the Optum deidentified electronic health record dataset, focusing on 3 cohorts of PI patients: common variable immunodeficiency, hypogammaglobulinemia, and combined immunodeficiency (CID). The study compared the treatment status of IgGRT across regional and racial subgroups within each cohort.

RESULTS: Regional differences in IgGRT status were observed among common variable immunodeficiency patients, with treatment rate highest in the West (53.8%) and Midwest (49.9%) and lowest in the South (41.1%) (P < .005). Among patients with hypogammaglobulinemia, a higher proportion of patients in the West (55.8%) received IgGRT than in the South (40.3%) (P < .005). Among patients with CID, those residing in the Midwest (44.4%) had a significantly higher rate of IgGRT utilization compared to the South (32.5%) (P < .005). A greater proportion of White patients with CID (41.3%) received IgGRT compared to African American patients with CID (25.8%) (P < .008).

CONCLUSION: Our results show differences in IgGRT utilization rates across regional and racial categories within each disease cohort, suggesting potential disparities.

PMID:41550088 | PMC:PMC12811437 | DOI:10.1016/j.jacig.2025.100624

Front Immunol. 2026 Jan 2;16:1701384. doi: 10.3389/fimmu.2025.1701384. eCollection 2025.

ABSTRACT

Inborn errors of immunity (IEI), also known as primary immunodeficiencies, are a heterogeneous group of rare disorders characterized by increased susceptibility to infections, immune dysregulation, and malignancy. Early detection remains a major challenge due to the complexity of clinical presentations, limited awareness among non-specialists, and delayed diagnostic pathways. This review explores current strategies to enhance early detection of IEI, highlighting both technological innovations and clinical insights. Tools such as newborn screening, the Jeffrey Modell Foundation (JMF) warning signs, software like SPIRIT, and the PIDCAP project-a structured model designed for primary care implementation using ICD-coded clinical data- have shown promise in identifying at-risk patients. Artificial intelligence (AI) offers additional potential by detecting diagnostic patterns in electronic health records, although challenges related to data quality, heterogeneity, and system interoperability persist. Importantly, hematologic manifestations such as autoimmune cytopenias, lymphoproliferative disorders, and myelodysplastic syndromes often precede or accompany IEI and should prompt immunological evaluation. These conditions, frequently encountered in hematology, may serve as early clinical clues and justify genetic and immunophenotypic assessment. A multidisciplinary approach combining primary care, immunology, hematology, and AI technologies is essential to advance the early detection of IEI. Projects like PIDCAP, and their potential extension to secondary immunodeficiencies, exemplify scalable, patient-centered strategies that may significantly improve diagnostic timeliness and clinical outcomes.

PMID:41550923 | PMC:PMC12808396 | DOI:10.3389/fimmu.2025.1701384

IDCases. 2025 Dec 17;43:e02462. doi: 10.1016/j.idcr.2025.e02462. eCollection 2026.

ABSTRACT

INTRODUCTION: Lophomonas infection is a rare respiratory illness caused by parasites, mostly reported in immunocompromised patients. X-linked agammaglobulinemia (XLA), or Bruton’s disease, is a primary immunodeficiency caused by a defective Bruton’s tyrosine kinase (BTK) gene. This defect results in a deficiency or absence of functional BTK protein, leading to significantly reduced or absent B lymphocytes and serum immunoglobulin levels.

CASE PRESENTATION: A 21-year-old male patient was admitted to our service exhibiting a six-week history of fever, dyspnea, and productive cough. The patient’s condition deteriorated despite prior outpatient management. Following abnormal laboratory values and computed tomography, bronchoscopy was performed. Microscopic evaluation of the bronchoalveolar lavage fluid revealed the presence of viable, oval-shaped, flagellated Lophomonas protozoa.

CONCLUSION: In evaluating immunocompromised patients with sustained respiratory symptoms, clinicians should consider opportunistic infections, such as pulmonary lophomoniasis, in their differential diagnosis. Delayed intervention in this patient population may lead to irreversible adverse sequelae.

PMID:41551350 | PMC:PMC12811521 | DOI:10.1016/j.idcr.2025.e02462

Egypt J Immunol. 2026 Jan;33(1):31-39. doi: 10.55133/eji.330104.

ABSTRACT

Common variable immunodeficiency (CVID) is one of the primary immunodeficiency disorders. The phenotype of peripheral blood memory B cells is a useful tool in the classification of patients into clinically and functionally relevant groups. This study aimed to assess the level of naïve and switched memory B cells level and their correlation with the clinical phenotypes and complications in patients with CVID. This case control study included 30 adult patients with CVID and 30 normal controls, matched for age and sex. Complete blood count, cluster of differentiation 3 (CD3)+, CD4+, CD8+ T cells and CD19+27-IgD+ for naïve B cells and CD19+27+IgD- switched memory B cells levels were assessed. The mean age of the onset of symptoms was 16.9±15.1 years, the mean age of diagnosis was 27.30±14.39 years, with a diagnostic delay of 10.43±10.29 years, and the body mass index was significantly lower in CVID group. Infections including (upper respiratory tract infection, chronic diarrhea, pneumonia and bronchiectasis) were the most frequent phenotypes. CD4+, CD4+/CD8+ T cells, CD19+ and CD19+27+IgD- switch memory B cell, IgG, IgA, and IgM were significantly lower in CVID group than in the control group (p < 0.001 and p < 0.015, respectively). CD8+ T cells and CD19+27-IgD+ naïve B cells were significantly higher in the CVID group (p < 0.001). CD19+27-IgD+ naïve B cells level was significantly lower in cases with bronchiectasis with low baseline serum IgG in lymphadenopathy group (p=0.049), and higher level of CD3+ T cells in cases with splenomegaly. There was no significant difference in laboratory results in CVID patients presented with autoimmune diseases, Granulomas nor enteropathy. In conclusion, high level of CD19+27-IgD+ naïve and low level of CD19+27+IgD- switch memory B cells are characteristic features of CVID. Moreover, the reduced CD19+27-IgD+ naïve B cells level can be a predictor of the development of bronchiectasis in CVID patients.

PMID:41546855 | DOI:10.55133/eji.330104

Mol Ther Nucleic Acids. 2025 Dec 18;37(1):102808. doi: 10.1016/j.omtn.2025.102808. eCollection 2026 Mar 12.

ABSTRACT

Nonsense mutations are among the genetic causes of LRBA (lipopolysaccharide-responsive beige-like anchor) deficiency, a rare autosomal-recessive immunodeficiency disorder. These mutations introduce premature stop codons, leading to the loss of LRBA protein expression. Following the recent market withdrawal of ataluren, the only approved translational readthrough-inducing drug (TRID), there is an urgent need for alternative therapeutic options. In this study, we investigated the efficacy of three 1,2,4-oxadiazole-based TRIDs-NV848, NV914, and NV930-using primary fibroblasts from a patient homozygous for the R1683X nonsense mutation. All compounds restored full-length LRBA protein with correct cytoplasmic localization, as confirmed by western blot and immunofluorescence, outperforming ataluren in readthrough efficiency. NV848 exhibited the strongest activity and uniquely increased LRBA mRNA levels, suggesting transcript stabilization. In contrast, NV930 and NV914 induced readthrough without stabilizing mRNA. Global proteomic profiling revealed minimal off-target effects for NV848, limited protein modulation by NV914, and widespread variations of 828 proteins by NV930, affecting pathways related to vesicular transport and mRNA splicing. However, network analysis revealed poor connectivity among differentially expressed proteins, with LRBA unrelated to any regulated cluster. These findings highlight the reported molecules as promising candidates for precision therapy in LRBA deficiency and shed light on the broader cellular impact of TRIDs.

PMID:41541268 | PMC:PMC12803801 | DOI:10.1016/j.omtn.2025.102808