Manish Butte

Int J Mol Sci. 2025 Oct 12;26(20):9932. doi: 10.3390/ijms26209932.

ABSTRACT

Hyper-IgE syndrome (HIES) is a rare genetic immunodeficiency characterized by elevated serum IgE levels and associated immune dysregulation, manifesting in recurrent infections, eczema, and skeletal abnormalities. Emerging evidence suggests a link between HIES and audiovestibular dysfunction, potentially mediated by IgE-driven inflammation in the inner ear, which is not immunologically privileged. However, the nature of this association remains poorly understood. This systematic review synthesizes current evidence on the characteristics, pathophysiology, diagnostic approaches, and management of audiovestibular dysfunction in HIES patients. Literature searches across PubMed, Embase, ClinicalKey, Web of Science, and ScienceDirect (up to 6 August 2025) were conducted in accordance with PRISMA guidelines. Key findings indicate that HIES-related audiovestibular issues, including sensorineural hearing loss and vestibular impairment, may arise from IgE-mediated endolymphatic sac inflammation, leading to hydrops and hair cell damage. Diagnostic tools such as audiometry, electrocochleography, and allergen challenge tests show promise, with elevated IgE correlating with abnormal otoacoustic emissions and prolonged auditory brainstem response latencies. Treatment focuses on immunomodulation (e.g., corticosteroids, dupilumab) to mitigate IgE effects, though evidence is limited to case reports. A proposed schematic diagram illustrates pathophysiology, emphasizing IgE’s role in inner ear toxicity. Timely recognition and intervention may prevent progression to permanent hearing loss or vestibular disability, improving quality of life. Future research should explore genetic-immunologic mechanisms and prospective trials for targeted therapies. Trial registration: PROSPERO CRD420251120600.

PMID:41155226 | DOI:10.3390/ijms26209932

Allergy Asthma Proc. 2025 Sep 1;46(6):498-505. doi: 10.2500/aap.2025.46.250077.

ABSTRACT

Background: Common variable immunodeficiency (CVID) and selective immunoglobulin G (IgG) deficiency (sIgGD) are primary antibody deficiencies with divergent clinical trajectories. CVID is characterized by recurrent infections and systemic noninfectious complications, whereas sIgGD typically follows a milder course. Despite sharing clinical features such as recurrent infections, comparative data on complications and mortality remain limited, which hinders risk-stratified management. Objective: This study compared the prevalence, clinical impact, and mortality associated with noninfectious complications in CVID and sIgGD, and identified predictors of adverse outcomes to support risk-stratified management and examined clinical differences within the CVID group based on baseline serum IgM levels. Methods: A single-center retrospective cohort study (2018-2024) included 111 patients with CVID and 19 patients with sIgGD. Diagnostic criteria for CVID included hypogammaglobulinemia (IgG level < 400 mg/dL with low IgA/IgM), impaired vaccine responses, and exclusion of secondary causes. The sIgGD required isolated IgG deficiency with normal IgA/IgM and intact vaccine responses. Noninfectious complications, including organ-specific and systemic manifestations as well as bronchiectasis were evaluated. In patients with CVID, a predefined subgroup analysis was performed based on baseline serum IgM levels (normal versus <40 mg/dL). Multivariate logistic regression identified mortality predictors. Results: The patients with CVID exhibited significantly higher rates of recurrent sinopulmonary infections (70.3% versus 42.1%), bronchiectasis (46.8% versus 21.1%), and noninfectious complications (57.7% versus 31.6%), including autoimmune disorders such as hematologic manifestations (33.3% versus 10.5%). In the CVID group, the patients with low IgM levels exhibited a significantly higher prevalence of gastrointestinal involvement (24.0% versus 5.6%; p = 0.035). Bronchiectasis (odds ratio [OR] 5.22) and noninfectious complications (OR 7.95) independently predicted mortality in CVID. Male sex showed borderline risk. In contrast, no mortality was observed in the sIgGD cohort over the study period. Conclusion: CVID is associated with substantial noninfectious morbidity and mortality, which necessitates early identification and long-term monitoring. In contrast, sIgGD exhibits a milder clinical phenotype, although preventive care remains important. These findings support distinct management strategies and highlight the utility of clinical markers for risk stratification.

PMID:41152686 | DOI:10.2500/aap.2025.46.250077

Hematol Rep. 2025 Sep 22;17(5):49. doi: 10.3390/hematolrep17050049.

ABSTRACT

Background and Clinical Significance: Common Variable Immunodeficiency (CVID) is a prevalent manifestation of primary immunodeficiency disorder. The current mainstay of treatment is immunoglobulin replacement therapy; however, in patients with severe complications or refractory disease, hematopoietic stem cell transplant (HSCT) is indicated. Despite this, there has been little research regarding HSCT as a treatment for CVID, with few case reports demonstrating clinical benefit. Case presentation: We present a unique case of common variable immunodeficiency Type XII (CVID12) with rare NFKB mutation and its management. A 20-year-old female with autoimmune alopecia, eczema, and a congenital atrophic right kidney presented to the emergency department with a three-month history of intermittent fever, malaise, lymphadenopathy, mouth sores, diarrhea, and odynophagia, accompanied by a 5 lb. unintentional weight loss and night sweats. Previously, she received multiple steroid prescriptions for these symptoms, providing only temporary relief with each course. Lab findings revealed severe neutropenia and imaging demonstrated hepatosplenomegaly and lymphadenopathy. Flow cytometry revealed a slightly atypical CD8-positive T-cell population and bone marrow biopsy revealed variable cellular marrow with trilineage hematopoiesis. Genetic testing confirmed the diagnosis of Autosomal Dominant Common Variable Immunodeficiency Type XII with an NFKB1 mutation. Pre-transplant treatments included monthly IVIG, weekly rituximab, and daily filgrastim, all of which failed to improve her autoimmune neutropenia and hypogammaglobulinemia and failed to reduce her symptomatic burden. Given the patient’s young age and refractory autoimmune neutropenia, it was decided to manage them definitively with hematopoietic stem cell transplantation (HSCT). She ultimately underwent allogenic stem cell transplantation (haploidentical, donor was the mother) with 3.96 × 10⁸/kg TNC without immediate post-transplant complications. Conclusions: This article demonstrates a rare case of NFKB1-positive CVID that was successfully treated with HSCT and highlights the importance of considering transplant therapy in younger patients with clinically significant, refractory autoimmune cytopenia.

PMID:41148944 | DOI:10.3390/hematolrep17050049

Cells. 2025 Oct 10;14(20):1577. doi: 10.3390/cells14201577.

ABSTRACT

Background: Immunodeficiencies are a heterogeneous group of disorders classified etiologically as primary (congenital) or secondary (acquired). Primary immunodeficiencies (PIDs), such as common variable immunodeficiency (CVID), result from genetic mutations that impair the development and function of lymphocytes. Secondary immunodeficiencies (SIDs) arise as a consequence of chronic diseases, lymphoid malignancies, or immunosuppressive therapies. Aim of the study: The purpose of this study was to assess the serum expression profile of selected microRNAs (miRNAs) in patients with CVID and in those with chronic lymphocytic leukemia (CLL) and coexisting SID, compared to healthy individuals. Methods: Digital PCR (dPCR) was applied to quantify the serum expression levels of selected miRNAs in patients with CVID, patients with CLL and SID, and in healthy controls. Results: dPCR revealed significantly reduced levels of miR-16, miR-30c, miR-181a, miR-29a, miR-150, and miR-326 in the CVID group, potentially reflecting impaired regulatory mechanisms of the immune system. In contrast, elevated levels of miR-21, miR-125b, and miR-155 were observed in the CLL group with SID, suggesting their role in tumorigenesis and secondary immunosuppression. Correlations between miRNA levels and the expression of immune checkpoints (PD-1, CTLA-4, CD200) indicated the involvement of a complex regulatory network encompassing both humoral and cellular immune mechanisms. Conclusions: The results provide preliminary evidence that selected miRNAs could reflect disease-specific immune dysregulation patterns and may hold potential as diagnostic and prognostic biomarkers in both PIDs and SIDs.

PMID:41148792 | DOI:10.3390/cells14201577

JFMS Open Rep. 2025 Oct 21;11(2):20551169251378958. doi: 10.1177/20551169251378958. eCollection 2025 Jul-Dec.

ABSTRACT

CASE SUMMARY: Lymphoma is a prevalent malignancy in cats, commonly involving lymphatic or gastrointestinal tissues; however, primary muscular lymphoma is an exceedingly rare condition in veterinary medicine. This report describes a 7-year-old spayed female domestic shorthair cat that was presented for a 3-day history of progressive change in iris colour in the right eye. After rapid deterioration, the affected eye was enucleated and the cat was diagnosed with large T-cell lymphoma based on ocular histopathology and immunohistochemistry. The initial clinical signs were ocular; however, subsequent diagnostic evaluation revealed muscular involvement. Lymphoma was suspected to have originated in the quadriceps femoris muscle and subsequently metastasised to the eye.

RELEVANCE AND NOVEL INFORMATION: This case underscores the diagnostic complexity of lymphoma and highlights the importance of considering systemic disease in cases of unexplained uveitis. It was not possible to determine whether the muscle or the eye was the primary site; clinical signs were first ocular, but this does not confirm the eye as the origin. The association between primary muscular lymphoma and ocular presentation has not been previously reported. Early detection of lymphoma can improve clinical management, but diagnostic challenges often arise because of atypical presentations and the absence of detectable masses.

PMID:41146873 | PMC:PMC12553844 | DOI:10.1177/20551169251378958

Iran J Allergy Asthma Immunol. 2025 Sep 16;24(5):593-606. doi: 10.18502/ijaai.v24i5.19743.

ABSTRACT

It can sometimes be very difficult to control the manifestations of autoimmunity and lymphoproliferation in patients with primary immunodeficiency diseases, and there is no adequate response to first-line treatments. Rituximab (RTX), as a second-line treatment, is efficacious and well-tolerated for the management of these clinical manifestations. This retrospective study was conducted to analyze the clinical, immunological, and genetic findings together with the response rate to RTX therapy in subjects with inborn errors of immunity (IEI) and autoimmune or autoinflammatory manifestations. In this study, 23 individuals with IEI and autoimmune or lymphoproliferation manifestations who received RTX between April 2008 and 2021 were evaluated. Fifteen out of the 23 patients were female. The median age of cases was 12 years. The moderate and severe adverse reactions, including fever, diarrhea, and anaphylaxis shock, were manifested during RTX infusion in 5 patients. In total, 86.9% of patients responded to rituximab (complete response: n=14, partial response: n=6) while three failed to respond. The median response time to RTX treatment was 50 days. All patients were given monthly intravenous immunoglobulin (IVIG) therapy. Pneumonia and candidiasis occurred in one patient a week after receiving the second injection of RTX. Eight patients expired during follow-up. In conclusion, the response rate of RTX could be improved through administering monthly IVIG for hypogammaglobulinemia treatment following RTX infusion. Early use of rituximab leads to a better response rate in comparison with late use of rituximab in multitreated refractory patients. The efficient cumulative dose of rituximab remains undefined.

PMID:41143608 | DOI:10.18502/ijaai.v24i5.19743

Front Immunol. 2025 Oct 10;16:1666600. doi: 10.3389/fimmu.2025.1666600. eCollection 2025.

ABSTRACT

BACKGROUND: Allergic diseases resulting from aberrant immune function are frequently observed in patients with inborn errors of immunity (IEI). However, the underlying monogenic disorders may not be initially diagnosed, which leads to delays in appropriate diagnosis and treatment. Although recent studies have highlighted the link between IEI and allergic conditions, earlier case series might not have been fully exploited.

OBJECTIVE: To compile a comprehensive database of IEI cases in the literature, analyze the prevalence and characteristics of allergic diseases, and assess the latter’s association with other forms of immune dysregulation.

METHOD: A systematic scoping review of the literature.

RESULTS: A total of 738 articles (reporting on 3050 individual patients) were included. 226 (7.4%) of the patients were described as suffering from an allergy. Monogenetic diseases associated with a marked prevalence of allergy were found in various IEI subgroups. Food allergy was most frequently reported (n=172, 76.1%), followed by allergic rhinitis (n=56, 24.8%). The presence of allergy in patients with IEI was generally associated with the absence of other forms of immune dysregulation, although there were notable exceptions. The overall prevalence of atopic conditions (food allergy, allergic rhinitis, asthma, and eczema) in the dataset was 26.9% (n=821).

CONCLUSION: This systematic scoping review emphasized the relevance of allergic diseases as a manifestation of immune dysregulation in IEI. Our findings might raise awareness of allergy in IEI among clinicians and researchers and constitute a valuable resource for better diagnosis and management of these conditions.

PMID:41142799 | PMC:PMC12549635 | DOI:10.3389/fimmu.2025.1666600

Clin Exp Rheumatol. 2025 Oct;43(10):1753-1762. doi: 10.55563/clinexprheumatol/i9hsfr. Epub 2025 Oct 23.

ABSTRACT

OBJECTIVES: Schnitzler syndrome (SchS) is a rare autoinflammatory disease characterised by a primary pathogenic involvement of interleukin (IL)-1. Therefore, IL-1 blockers are currently considered the optimal therapeutic option for SchS patients. However, while IL-1 blockers are first-line for SchS, long-term real-world evidence is limited by the rarity of the disease. We assessed the long-term effectiveness and safety of the IL-1 inhibitors anakinra and canakinumab used in SchS, also looking for variables capable of affecting global effectiveness and drug retention over time.

METHODS: Data analysed in this study were drawn from the international AutoInflammatory Disease Alliance (AIDA) Registry dedicated to SchS.

RESULTS: 28 SchS patients corresponding to 37 treatment lines were included in the study. Complete and partial responses occurred in 73.1% and 29.9% of anakinra-treated patients, and 66.8% and 33.3% with canakinumab. The overall anakinra and canakinumab drug retention rates at 12-, 36-, and 60-month follow-up were 85.6%, 81.7% and 64.7%, respectively; the probability of discontinuing IL-1 inhibitors at 12-, 36- and 60 months due to loss of effectiveness was 9.6%, 13.7% and 24.5%, respectively. The maximum IgG M-protein levels were found to be significantly higher in patients achieving partial response compared to those benefiting from complete response (p=0.032). Lymphadenopathy independently predicted anti-IL-1 discontinuation due to loss of effectiveness (HR 7.78, 95% CI: 1.27-47.9; p=0.027).

CONCLUSIONS: The present study confirms the high effectiveness of IL-1 inhibitors in controlling SchS, including the complete and partial response rates and the long-term survival. Elevated IgG M-protein levels and the presence of lymphadenopathy should be considered as potential indicators for identifying patients more likely to exhibit a partial response and a possible loss of treatment efficacy.

PMID:41133355 | DOI:10.55563/clinexprheumatol/i9hsfr

Orphanet J Rare Dis. 2025 Oct 23;20(1):535. doi: 10.1186/s13023-025-04039-x.

ABSTRACT

BACKGROUND: Deficiency in ELF4, X-linked (DEX) is a recently recognized monogenic autoinflammatory disorder and a novel type of congenital immunodeficiency. Due to the limited number of reported cases, understanding of DEX remains incomplete. In clinical settings, children with this condition are often misdiagnosed as having diseases such as Behçet’s disease or inflammatory bowel disease, due to overlapping clinical features.

METHODS: Genomic DNA was isolated from peripheral blood samples for genetic analysis, and genomic DNA was extracted from the peripheral blood samples of the proband’s mother for x chromosome inactivation (XCI) analysis.

RESULTS: A retrospective analysis was conducted on the clinical and genetic characteristics of a 3-year-old male patient with DEX in China. This study offers a detailed exploration of the child’s specific clinical symptoms and treatment approach, in addition to a comprehensive review of the primary clinical manifestations and genotypic traits of individuals with DEX.

CONCLUSION: This study aims to increase clinicians’ understanding of DEX. In cases where young male patients present with recurrent fever, oral or mucosal ulcers, or repeated infections, DEX should be strongly considered. Early implementation of gastrointestinal endoscopy and genetic testing is recommended to enable a more precise and timely diagnosis, laying a solid foundation for informed treatment decisions.

PMID:41131646 | DOI:10.1186/s13023-025-04039-x

Pediatrics. 2025 Oct 24:e2024069311. doi: 10.1542/peds.2024-069311. Online ahead of print.

ABSTRACT

ITCH (Itchy E3 Ubiquitin Protein Ligase) deficiency is an exceptionally rare autosomal recessive genetic disorder caused by alterations in the ITCH gene, leading to immunodeficiency and systemic autoimmunity. A 12-year-old Chilean girl presented with chronic malnutrition, short stature, dysmorphic features, global developmental delay, and intellectual disability. She had chronic lung damage, exocrine pancreatic insufficiency, immune-mediated diabetes mellitus, congenital hypothyroidism, and hypoparathyroidism. At 10 years, she experienced severe pneumonia, followed by recurrent respiratory infections. Physical examination findings included alopecic foci on the scalp, skin pigmentation disorder, bilateral crackles on lung auscultation, and a distended abdomen. Laboratory analysis showed hyperglycemia and dyslipidemia. The complete blood cell count revealed normal leukocytes (8870 cells/μL), mild lymphopenia (1130 cells/μL), and mild neutrophilia (6760 cells/μL). Lymphocyte subpopulations demonstrated abnormalities: decreased CD8+ T cells (284 cells/μL) and natural killer cells (38 cells/μL), decreased total memory B cells CD19+/CD27+ (7 cells/μL) with a predominance of naive B cells, and decreased regulatory T cells CD4+/CD127-/CD25+ (20 cells/μL). A chest computed tomographic scan revealed bilateral bronchiectasis secondary to recurrent pneumonia and mediastinal and hilar adenopathies. Genetic testing revealed a likely pathogenic homozygous variant in the ITCH gene c.1569 + 1G>T (splice donor). Despite its rarity, health care clinicians should consider this condition in patients displaying signs of immunodeficiency and systemic autoimmunity due to its potentially life-threatening nature. We report a case of ITCH deficiency associated with the c.1569 + 1G>T variant of the ITCH gene, resulting in growth failure, dysmorphic features, global developmental delay, intellectual disability, chronic lung damage, exocrine pancreatic insufficiency, immune-mediated diabetes mellitus, congenital hypothyroidism, iron deficiency anemia, and hypoparathyroidism.

PMID:41130596 | DOI:10.1542/peds.2024-069311