Manish Butte

Respiration. 2025 Mar 10:1-15. doi: 10.1159/000543792. Online ahead of print.

ABSTRACT

INTRODUCTION: Asthma is a heterogeneous chronic inflammatory disease involving different underling pathogenetic mechanisms. We aimed to investigate the characteristics of patients with the diagnosis of asthma and primary antibody immunodeficiency (PAD) and the impact of immunoglobulin therapy (IVIg) Methods: Thirty-three patients with severe asthma and PAD (either IgG subclasses deficiency or unclassified hypogammaglobulinemia) were retrospectively recruited. Severe asthma was diagnosed according to GINA recommendations and PAD was diagnosed according to ESID diagnostic criteria; normal immunoglobulins serum levels were defined according to the local laboratory values (IgG 700-1600 mg/dl; IgA 70-400 mg/dl; IgM 40-230 mg/dl; IgG1 382-929 mg/dl; IgG2 242-700 mg/dl; IgG3 22-176 mg/dl; IgG4 4-88 mg/dl). Clinical and laboratory features were analyzed before and after immunoglobulin therapy (IVIg).

RESULTS: We observed a high proportion of patients with low T2 markers (36.4%), including low blood eosinophils (BE), compared to patients with elevated T2 markers (BE: 80 (range 30-140) vs 200 (range 50-760) cells/microL, p<0.001). After IVIg, we observed significant reduction of respiratory infections (4 (range 0-20) vs 1 (range 0-5), p<0.001) and exacerbations (6 (range 1-20) vs 1 (range 0-7); p<0.001); moreover, in patients with low T2 markers, BE significantly rose (80 (range 30-140) vs 115 (range 70-520) cells/microL, p<0.05).

CONCLUSION: IVIg therapy reduces infections and infection-related exacerbations in patients with the diagnosis of asthma and PAD, and could modulate asthma phenotype.

PMID:40064152 | DOI:10.1159/000543792

J Allergy Clin Immunol. 2025 Mar 7:S0091-6749(25)00263-5. doi: 10.1016/j.jaci.2025.02.032. Online ahead of print.

ABSTRACT

INTRODUCTION: Common variable immunodeficiency (CVID) is characterized by recurrent sinopulmonary infections. However, in the pediatric population, recurrent sinopulmonary infections early in life are common, which can render key clinical features of CVID less distinctive. Accordingly, the diagnosis of CVID is often delayed due to the heterogeneous nature of the presentation and the broad age of onset. A 10-year lag in diagnosis has been found for CVID, and a critical need is improved time-to-diagnosis.

OBJECTIVE: To utilize machine-learning techniques to identify a clinical signature of CVID in a pediatric population.

METHODS: Our selected cohort included 112 individuals with CVID and 627 controls. Controls were restricted from having other medical conditions associated with infection. A machine learning dataset was constructed by summing patient-level counts of clinical metrics. Three supervised machine learning classifiers were trained, tuned, and performance-tested. We validated our findings using a distinct control cohort with high medical complexity and tested a logistic regression approach.

RESULTS: Key features associated with CVID were chest X-ray count, antibiotic prescriptions, and number of common infections. Our Extreme Gradient Boosting model best predicted eventual CVID diagnosis with an F1 score of 0.77, with 21 of 29 CVID diagnoses classified correctly (false negative: 8), and 179 of 183 non-CVID patients correctly classified (false positive: 4), up to 10 years prior to the eventual clinical diagnosis. Key features with a robust association with pediatric CVID were the frequency of common infections and antibiotic prescriptions.

CONCLUSION: In spite of a high frequency of infections in the comparator population, the clinical signature of pediatric CVID was sufficiently distinctive to enable early identification.

PMID:40058414 | DOI:10.1016/j.jaci.2025.02.032

Pol Arch Intern Med. 2025 Mar 10:16973. doi: 10.20452/pamw.16973. Online ahead of print.

ABSTRACT

INTRODUCTION: The immune system protects against pathogens, and its dysfunction leads to primary and secondary immunodeficiencies, increasing infection susceptibility. Epstein-Barr virus (EBV) reactivation is linked to immune homeostasis disorders, particularly in common variable immunodeficiency (CVID) and chronic lymphocytic leukemia (CLL). Toll-like receptor (TLR) pathways play a crucial role in innate immunity, and their deregulation may contribute to immune dysfunction.

OBJECTIVES: This study aimed to assess the impact of EBV reactivation on immune homeostasis, focusing on TLR2, TLR4, TLR7, and TLR9 expression in T and B lymphocyte subpopulations and their soluble forms in CVID and CLL patients.

PATIENTS AND METHODS: The study included 60 CVID patients, 60 CLL patients, and 30 healthy controls. EBV antigens, viral DNA levels, T and B lymphocyte immunophenotypes, and serum soluble TLR (sTLR) concentrations were analyzed using flow cytometry and ELISA.

RESULTS: EBV reactivation was detected in 55% of CVID and 60% of CLL patients. These patients showed significant TLR expression disturbances and increased sTLR levels. Notably, TLR7 and TLR9 expression was elevated on CD4+ and CD8+ T cells and CD19+ B cells, correlating with EBV load and immune dysfunction severity.

CONCLUSIONS: EBV reactivation plays a key role in TLR pathway deregulation in CVID and CLL, potentially worsening disease progression and infection risk. TLR expression and sTLR levels could serve as biomarkers for EBV reactivation, aiding therapeutic strategies to stabilize immune responses.

PMID:40062898 | DOI:10.20452/pamw.16973

Cureus. 2025 Feb 6;17(2):e78654. doi: 10.7759/cureus.78654. eCollection 2025 Feb.

ABSTRACT

Mendelian susceptibility to mycobacterial disease (MSMD) is a group of inherited inborn errors of immunity due to approximately 21 genetic defects. Interferon-gamma receptor type 1 (IFNGR1) deficiency was the first disease described in this group. IFNGR1 can cause a loss of cellular responsiveness to interferon-γ (IFN-γ). Mycobacterial infections occur due to gene mutations that encode the IFNGR1 chain, leading to a loss of cellular responsiveness to type II IFN-γ, which plays a significant role in controlling intracellular bacteria. MSMD is characterized by increased susceptibility to environmental mycobacteria and low virulent mycobacteria like Bacillus Calmette-Guerin (BCG) vaccine strains. Careful and timely interventions for diagnosis and management are required if a patient develops clinical manifestations after BCG vaccination. Diagnosis can be made by gene study, and bone marrow transplantation remains the mainstay of treatment.

PMID:40062101 | PMC:PMC11890677 | DOI:10.7759/cureus.78654

Paediatr Child Health. 2024 Jun 13;30(1):40-47. doi: 10.1093/pch/pxae026. eCollection 2025 Feb.

ABSTRACT

OBJECTIVES: Inborn errors of immunity (IEI) are a heterogeneous group of genetic diseases that impact normal immune development and function. Individual IEI are rare, but collectively, can represent an important health burden. Little is known about the types of IEI seen in Canadian First Nations (FN) and Inuit populations. We sought to understand the spectrum of serious IEI in FN and Nunavut Inuit children, as a starting point for improving the awareness of these conditions in the community and for health care workers.

METHODS: A questionnaire was distributed to participating Canadian pediatric tertiary-care centers. Providers were asked to report cases of confirmed or suspected severe immunodeficiencies seen in FN and Nunavut Inuit children.

RESULTS: From 2004 to 2022, IEI were reported in 63 FN and 21 Inuit children by 4 pediatric hospitals across 3 Canadian provinces. The majority of cases were immunodeficiencies affecting cellular and humoral immunity (62% of cases in FN and 57% in Inuit children). IKBKB deficiency, adenosine-deaminase severe combined immune deficiency (SCID), and chronic granulomatous disease were the most common IEI. A wide variety of other IEI was reported, many of which would not be detected by current newborn screening for SCID and for which live-attenuated vaccines would have been contraindicated.

CONCLUSIONS: IEI occur in FN and Inuit children and may be underrecognized. Better understanding the prevalence of these conditions in specific communities could help inform public health policies including newborn screening and immunization programs and ultimately improve the health of FN and Inuit children in Canada.

PMID:40061245 | PMC:PMC11885879 | DOI:10.1093/pch/pxae026

Clin Rev Allergy Immunol. 2025 Mar 7;68(1):24. doi: 10.1007/s12016-025-09027-4.

ABSTRACT

Hereditary angioedema (HAE) has been recognized for almost 150 years. The newest form of HAE, where C1 inhibitor levels are normal (HAE-nC1INH), was first described in 2000. Over the last two decades, new types of apparent non-mast cell-mediated angioedema with normal quantity and activity of C1INH have been described, in some cases with proven genetic pathogenic variants that co-segregate with angioedema expression within families. Like HAE due to C1INH deficiency, HAE-nC1INH patients are at risk of serious morbidity and mortality. Therefore, proactive management and treatment of HAE-nC1INH patients after an expert physician diagnosis is critically important. The underlying pathophysiology responsible for the angioedema has also been clarified in some of the HAE-nC1INH types. While several clinical guidelines and practice parameters including HAE-nC1INH have been published, we have made substantial progress in our understanding encompassing diagnostic criteria, pathophysiology, and treatment outcomes. HAE International (HAEi) and the US HAE Association (HAEA) convened a symposium of global HAE-nC1INH experts to synthesize our current knowledge in the area. Given the paucity of high-level evidence in HAE-nC1INH, all recommendations are based on expert opinion. This review and expert opinion on the best practice approach to diagnosing and treating HAE-nC1INH will support physicians to better manage patients with HAE-nC1INH.

PMID:40053270 | DOI:10.1007/s12016-025-09027-4

Dermatologie (Heidelb). 2025 Mar 7. doi: 10.1007/s00105-025-05484-2. Online ahead of print.

ABSTRACT

BACKGROUND: Hereditary ichthyoses are rare, etiologically and clinically heterogeneous epidermal keratinization disorders that are characterized by excessive dryness with scaling of the skin and in some cases increased palmoplantar keratinization. Additional inflammation is common and there are forms associated with blistering. In terms of differential diagnosis, ichthyoses with associated erythroderma in particular must be distinguished from primary atopic diseases with immunodeficiency.

AIM: The aim is to provide basic knowledge of the classification and nomenclature of ichthyoses and of current guideline-based and approved therapies. Readers should also be made aware of the difficulties of treating this rare skin disease in children and adolescents with only a few approved therapies. New and innovative treatment options are described and thereafter the reader should be able to confidently identify potential patients for approved and novel therapies.

MATERIALS AND METHODS: The current guidelines as well as the current literature and expert consensus on systemic therapies for ichthyosis with a focus on pediatric patients are discussed.

RESULTS: Precise phenotyping, endotyping and the inclusion of the patient’s expectations with regard to therapy currently allow comprehensive treatment to alleviate symptoms with good interdisciplinary cooperation. In the absence of causal therapy options, hereditary ichthyosis usually requires lifelong symptomatic individualized therapy. The basis of therapy is local therapy. Acitretin is currently the only approved systemic therapy. Pathophysiologically driven and therefore personalized and targeted therapies, in the form of topical replacement proteins or lipids, small molecules with a variety of target structures and biologics to address inflammation, are the focus of new therapeutic options. Causal therapeutic approaches, such as gene therapies, are currently under development.

PMID:40053102 | DOI:10.1007/s00105-025-05484-2

Mutat Res Genet Toxicol Environ Mutagen. 2025 Feb-Mar;902:503852. doi: 10.1016/j.mrgentox.2025.503852. Epub 2025 Jan 26.

ABSTRACT

Genetic defects in one of the DNA double strand break (DSB) repair proteins lead to distinct human syndromes with severe clinical manifestations, including impaired neurological and immunological development, cancer proneness and sensitivity to ionizing radiation. Since diagnostic and therapeutic procedures frequently use DNA damaging agents, identification of radiosensitive individuals is imperative to optimize patient management. However, patients with a (severe) combined immunodeficiency (S)CID are often ineligible for lymphocyte-based radiosensitivity testing. Therefore, this study investigated the suitability of two fibroblast-based assays as alternative methods. DSB repair was evaluated following X-ray irradiation by an optimized cytokinesis-block micronucleus (MN) assay and the γH2AX focus test in fibroblasts from patients with a confirmed or suspected diagnosis of radiosensitive (S)CID. Using both assays, patients with a defect in Artemis were identified as radiosensitive while those with a RAG1/2 deficiency were not considered as radiosensitive. Although MN scoring was not feasible in irradiated fibroblasts deficient in XLF, LIG4 or NBS1, radiosensitivity could be readily demonstrated through impaired DNA DSB repair kinetics with the γH2AX focus assay in fibroblasts deficient in XLF or LIG4, but not in those deficient in NBS1. While both ATM defective fibroblasts clearly showed increased radiation-induced MN yields, one of the two fibroblast cell lines could not be identified as radiosensitive based on residual γH2AX focus levels. This study suggests that combining the fibroblast MN assay and γH2AX focus test can effectively exclude in vitro radiosensitivity in patients with a suspicion of radiosensitive (S)CID, particularly when lymphocyte-based radiosensitivity testing is not feasible.

PMID:40044379 | DOI:10.1016/j.mrgentox.2025.503852

Front Immunol. 2025 Feb 18;16:1516068. doi: 10.3389/fimmu.2025.1516068. eCollection 2025.

ABSTRACT

Hyper IgE syndromes (HIES) form a rare group of primary immunodeficiency disorders (PIDs) distinguished by persistent skin abscesses, dermatitis, allergies, and infections, in addition to their characteristic high serum IgE levels. Autosomal dominant (AD) and autosomal recessive (AR) genetic defects have been reported in HIES. From a clinical perspective, AD-HIES cases generally exhibit several non-immunologic features, including connective tissue, dental and skeletal abnormalities, whilst AR-HIES conditions have a higher incidence of neurologic complications and cutaneous viral infections. Genetic defects associated with HIES lead to impaired immune signaling, affecting pathways crucial for immune cell development, function, and immune response to pathogens/allergens. As a result, HIES patients are predisposed to recurrent bacterial and/or fungal infections, as well as atopic allergic responses. In many cases, the exact biological mechanisms responsible for the variations observed in the clinical phenotypes between the two inherited forms of HIES are still unclear. In this review, we describe the genetic basis of HIES with a distinction between the AR-HIES and AD-HIES forms, to better comprehend the different underlying molecular mechanisms, a distinction which is imperative for the accurate diagnosis, management, and development of targeted therapies for HIES patients.

PMID:40040707 | PMC:PMC11876172 | DOI:10.3389/fimmu.2025.1516068

Br J Haematol. 2025 Mar 3. doi: 10.1111/bjh.20042. Online ahead of print.

ABSTRACT

Germline homozygous loss-of-function mutations in TET2 result in significant childhood immunodeficiency that resembles autoimmune lymphoproliferative syndrome and predisposes one to lymphoma. The implications of heterozygous variants are less well understood. We describe four patients with heterozygous germline loss-of-function TET2 mutations who presented with B-cell lymphoma on a background of chronic lymphadenopathy and autoimmune features. This expands the association of germline TET2 mutations with lymphoma and an autoimmune lymphoproliferative syndrome-like phenotype to the heterozygous state. Assessment for TET2 mutations and germline origin should be considered in the appropriate context, as recognition of these variants may have implications on patient care.

PMID:40031954 | DOI:10.1111/bjh.20042