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Sci Rep. 2025 Jun 2;15(1):19282. doi: 10.1038/s41598-025-95356-5.

ABSTRACT

This systematic review and meta-analysis aimed to compare the survival outcomes and cytogenetic profile of primary acute lymphoblastic leukemia (p-ALL) and secondary ALL (s-ALL), including antecedent-malignancy ALL (am-ALL) and therapy-related ALL (tr-ALL). The search was performed in PubMed/MEDLINE, Scopus, Web of Science, Embase, and ProQuest databases from January 1, 1990, to July 31, 2023, using the keywords “acute lymphoblastic leukemia” and “second cancer” to identify cohort studies that compared p-ALL and s-ALL in terms of survival outcomes and cytogenetic profile. The risk of bias in the included studies was assessed using the Joanna Briggs Institute (JBI) for Cohort Studies. A total of 7 studies involving 13,542 participants were analyzed. The results revealed an HR of 2.35 (95%CI:1.38-4.01) for overall survival (OS) and 2.06 (95%CI:1.05-4.06) for relapse-free survival (RFS). Subgroup analysis of tr-ALL patients showed a significantly higher HR of 3.40 (95%CI:2.32-4.99) for OS in this subgroup. Furthermore, the meta-analysis indicated an OR of 3.45 and 5.90 for mixed lineage rearrangement (MLL) and hypodiploidy, respectively. The study highlights the need for a better understanding of the survival rates and cytogenetic profile of secondary ALL, particularly tr-ALL, and the importance of personalized treatment strategies for this subtype.

PMID:40456857 | DOI:10.1038/s41598-025-95356-5

Nat Commun. 2025 Jun 2;16(1):5109. doi: 10.1038/s41467-025-60304-4.

ABSTRACT

Ataxia-telangiectasia is a rare genetic disorder characterized by neurological defects, immunodeficiency, cancer predisposition, radiosensitivity, decreased blood vessel integrity, and diabetes. ATM, the protein mutated in Ataxia-telangiectasia, responds to DNA damage and oxidative stress, but its functional relationship to the progressive clinical manifestation of this disorder is not understood. CD98HC chaperones cystine/glutamate and cationic/neutral amino acid antiporters to the cell membrane, and CD98HC phosphorylation by ATM accelerates membrane localization to acutely increase amino acid transport. Loss of ATM impacts tissues reliant on heterodimeric amino acid transporters relevant to Ataxia-telangiectasia phenotypes, such as endothelial cells (telangiectasia) and pancreatic α-cells (fatty liver and diabetes), with toxic glutamate accumulation. Bypassing the antiporters restores intracellular metabolic balance in ATM-deficient cells and mouse models. These findings provide insight into the long-known benefits of N-acetyl cysteine in Ataxia-telangiectasia cells beyond oxidative stress through removing glutamate excess by producing glutathione.

PMID:40456742 | DOI:10.1038/s41467-025-60304-4

Dig Dis Sci. 2025 Jun 2. doi: 10.1007/s10620-025-09106-8. Online ahead of print.

ABSTRACT

BACKGROUND: Common variable immunodeficiency (CVID) is an umbrella term for numerous primary immunodeficiency syndromes characterized by B-cell, and sometimes T-cell, impairment. While CVID is commonly associated with recurrent sinopulmonary infections, gastrointestinal (GI) disease-often presenting atypically due to immune dysregulation-can significantly the increase morbidity and mortality of those affected.

OBJECTIVES: This review summarizes the diagnostic criteria, epidemiology, and GI manifestations of CVID to increase awareness among general practitioners and gastroenterologists. This review may help facilitate prompt diagnosis and treatment of affected patients.

METHODS: We conducted a narrative review of the literature focusing on the GI manifestations of CVID. This review investigates the GI infections, gastric and bowel diseases, liver involvement, and malignancies associated with this immunodeficiency.

RESULTS: There is no universal definition for CVID, but rather several commonly used diagnostic criteria. Patients with CVID are susceptible to GI infections including those caused by Giardia, norovirus, Salmonella, Campylobacter, and cytomegalovirus. Gastric diseases such as atrophic gastritis and pernicious anemia may present atypically. Bowel involvement may include nodular lymphoid hyperplasia, small intestinal bacterial overgrowth, CVID enteropathy, celiac-like disease, and inflammatory bowel-like colitis. Liver involvement can include autoimmune hepatitis, nodular regenerative hyperplasia, and viral hepatitis. In addition, patients with CVID may have a higher incidence of malignancies such as lymphoma and gastric cancer compared to the general population.

CONCLUSION: CVID is associated with a broad spectrum of infectious and noninfectious GI manifestations that can increase the morbidity and mortality of affected patients. Increased awareness of these complications may facilitate earlier diagnosis and effective management.

PMID:40455348 | DOI:10.1007/s10620-025-09106-8

Cureus. 2025 May 1;17(5):e83304. doi: 10.7759/cureus.83304. eCollection 2025 May.

ABSTRACT

Ataxia-telangiectasia (A-T) is a rare neurological disorder that leads to early death due to immunodeficiency, leukemia, and lymphoma. Given the underlying immune dysfunction and predisposition to hematologic cancers, bone marrow transplantation (BMT) or hematopoietic stem cell transplantation (HSCT) has emerged as a potential therapeutic strategy in pediatric patients with A-T. Therefore, longer follow-ups are needed to assess associated risks, side effects, procedures, and eligibility criteria. This systematic review aims to fill this gap by consolidating evidence from different parts of the world on the use of HSCT in pediatric patients diagnosed with A-T. The study used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to search five databases (PubMed, Web of Science, ScienceDirect, Google Scholar, and MEDLINE) for relevant published papers. The review covered studies on both classical and variant forms of A-T. The studies included are those with primary outcomes related to engraftment success, immunological reconstitution, survival rates, transplant-associated toxicity, infection prevalence, cancer management, and neurological progression. Only papers published in English between 2010 and 2024 were eligible for inclusion. Two experienced researchers independently assessed the retrieved papers for inclusion. A structured data collection sheet was used to retrieve relevant information from the selected articles. The risk of bias of the items included prospective and retrospective, cross-sectional, and cohort studies was assessed using the Newcastle Ottawa Quality Assessment Scale. Eight studies were included, comprising various designs including prospective, retrospective, and population-based cohorts. Among these, three studies reported actual use of HSCT or BMT in pediatric patients with A-T, showing immune reconstitution and reduced infections, but limited impact on neurological decline. Reduced-intensity conditioning (RIC) was associated with better survival and fewer complications compared to myeloablative regimens. The remaining studies discussed HSCT theoretically or focused on supportive care, immunological profiles, cancer risk, or nutritional challenges. Overall, outcomes varied, with limited evidence supporting routine use of HSCT in A-T due to associated risks and uncertain long-term benefits. In conclusion, HSCT shows potential in improving immune function and reducing infections in A-T patients. However, it has minimal effect on halting neurological progression. Given the risks and limited long-term data, HSCT is not currently recommended as a standard treatment for A-T.

PMID:40452674 | PMC:PMC12126933 | DOI:10.7759/cureus.83304

Ann Allergy Asthma Immunol. 2025 May 29:S1081-1206(25)00266-2. doi: 10.1016/j.anai.2025.05.024. Online ahead of print.

ABSTRACT

BACKGROUND: Food allergies and inborn errors of immunity (IEIs) were once viewed as distinct disorders-hypersensitivity versus infection susceptibility. However, IEIs are now recognized to include immune dysregulation, with autoimmunity, autoinflammation, lymphoproliferation, and severe atopy. Understanding the overlap between food allergies and IEIs is critical, as allergic inflammation often complicates immune deficiencies.

OBJECTIVE: To examine the shared immunologic mechanisms linking food allergies and IEIs, with a focus on immune dysregulation, barrier defects, microbial dysbiosis, and impaired regulatory T cell (Treg) function.

METHODS: A comprehensive literature review was conducted using PubMed applying search terms including food allergy, primary immunodeficiency, inborn errors of immunity (IEIs), Treg cells, immune dysregulation, autoimmunity, autoinflammation, epithelial barrier dysfunction, and microbiome. Particular focus was placed on identifying studies describing monogenic IEIs characterized by severe allergic phenotypes and elevated IgE levels. Articles were selected based on relevance to the themes of the review, quality of study design, and their contribution to advancing understanding in the field. Priority was given to original research articles, systematic reviews, meta-analyses, and key historical studies.

RESULTS: Allergic symptoms, including food allergy and atopic dermatitis, frequently present early in IEIs and may precede infection susceptibility. Common features include Treg dysfunction, cytokine signaling defects, epithelial barrier compromise, and microbiome alterations. Recognition of these pathways has enhanced diagnosis and led to targeted therapies such as biologics and gene therapy.

CONCLUSION: Regulatory T cells are central to maintaining immune tolerance across allergic, autoimmune, and immunodeficient states. Advances in understanding dysregulated immunity and barrier defects are driving personalized treatment strategies for patients with both food allergy and IEIs.

PMID:40449791 | DOI:10.1016/j.anai.2025.05.024

Front Immunol. 2025 May 15;16:1589052. doi: 10.3389/fimmu.2025.1589052. eCollection 2025.

ABSTRACT

BACKGROUND: Common variable immune deficiency (CVID) is the most prevalent inborn error of immunity (IEI), marked by diverse clinical-immunological phenotypes and significant immune-dysregulation, including granulomatous lymphocytic interstitial lung disease (GLILD). GLILD is a severe manifestation of CVID, contributing to reduced life expectancy and a challenging diagnosis due to its insidious and non-specific clinical course. Current management strategies for GLILD rely on expert opinion due to a lack of randomized controlled trials (RCTs).

OBJECTIVES: This study aims to provide a comprehensive immunophenotypical characterization of CVID patients with and without GLILD, investigate predictive biomarkers for GLILD development, and explore therapeutic strategies, particularly during concomitant SARS-CoV-2 and chronic cytomegalovirus (CMV) infections.

SOURCES: Primary data were collected from a cohort of 25 patients with CVID who underwent high-resolution computed tomography (HRCT), immunophenotyping, and serum immunoglobulin analysis at diagnosis and after immunoglobulin replacement therapy. Existing literature on CVID and GLILD biomarkers, immunological profiles, and therapeutic interventions informed comparative analyses.

CONTENT: Patients with GLILD exhibited distinct immunophenotypical features, including reduced regulatory T-cells, CD8+ naïve, central memory T-cells, and B-cell subsets (memory and switched memory), alongside increased CD21low B-cells and naïve B-cells, indicative of chronic inflammation-driven immune activation. IgA and IgG4 concentrations were significantly lower in patients with GLILD at diagnosis. Immunosuppressive therapy, predominantly mycophenolate mofetil (MMF), demonstrated favorable clinical and functional outcomes, though radiological progression persisted in some cases. CMV infection in patients with GLILD on immunosuppressants resulted in favorable outcomes, underscoring the importance of personalized treatment strategies.

IMPLICATIONS: This study highlights novel immunological markers and clinical-radiological patterns as potential predictors for GLILD, advocating for their integration into diagnostic and monitoring frameworks to reduce reliance on invasive histopathology. Future research should focus on validating biomarkers and conducting RCTs to establish evidence-based guidelines for GLILD management.

PMID:40443662 | PMC:PMC12119541 | DOI:10.3389/fimmu.2025.1589052

J Manag Care Spec Pharm. 2025 Jun;31(6):578-589. doi: 10.18553/jmcp.2025.31.6.578.

ABSTRACT

BACKGROUND: Hereditary angioedema (HAE) is a rare disease characterized by unpredictable recurrent, debilitating, and potentially fatal attacks of subcutaneous and submucosal tissue swelling.

OBJECTIVE: To evaluate all-cause, angioedema-related, and HAE attack-related medical visits and hospitalizations before and after initiation of berotralstat long-term prophylaxis (LTP) for patients with HAE in the United States.

METHODS: This retrospective pre-post analysis used Komodo’s Healthcare Map claims data to identify patients who initiated berotralstat (December 2020 to December 2022). The first entry for berotralstat dispensing was defined as the index date. Inclusion criteria comprised patients aged at least 12 years at index with at least 6 months of continuous insurance eligibility pre-index and evidence consistent with HAE pre-index (International Classification of Diseases, Tenth Revision, Clinical Modification diagnosis codes D84.1, D68.2, or T78.3x; medication use [on-demand or LTP]; or presence of diagnostic HAE laboratory tests). Rates of all-cause, angioedema-related, and HAE attack-related medical visits per person-year were compared post-index vs pre-index using rate ratios with 95% CIs and P values from generalized estimating equation Poisson regression models with robust SEs. Study limitations included the inability to distinguish HAE types and the uncertainty of whether a dispensed medication was consumed or taken as prescribed.

RESULTS: The study population included 260 patients treated with berotralstat (mean age = 39.7 years; 74.2% female). After berotralstat initiation, there were significant decreases in the rates of all-cause health care resource utilization (HRU): all-cause inpatient (IP) visits decreased by 34% (P = 0.037) and all-cause outpatient/emergency department (OP/ED) visits decreased by 14% (P = 0.005). There were also significant decreases in rates of angioedema-related HRU (IP visits: 52%, P = 0.001; OP/ED visits: 44%, P < 0.001) as well as HAE attack-related HRU (IP visits: 60%, P < 0.001; OP/ED visits: 50%, P < 0.001). Use of on-demand medications decreased significantly after berotralstat initiation (32%, P = 0.002). Results were similar among subgroups of patients defined by HAE treatment history, including patients who were LTP-experienced (n = 126) and LTP-naive but on-demand treatment-experienced (n = 67).

CONCLUSIONS: Prophylactic treatment of HAE with berotralstat was associated with significant reductions in all-cause HRU, including decreases to angioedema-related and HAE attack-related medical visits, hospitalizations, and administration of on-demand treatment.

PMID:40443005 | DOI:10.18553/jmcp.2025.31.6.578

World J Gastrointest Endosc. 2025 May 16;17(5):101618. doi: 10.4253/wjge.v17.i5.101618.

ABSTRACT

BACKGROUND: Common variable immunodeficiency (CVID) is a primary antibody immunodeficiency disorder characterized by diminished IgG levels. Despite ongoing research, the precise pathogenesis of CVID remains unclear. Genetic factors account for only 10%-20% of cases, with an estimated incidence of 1 in 10000 to 1 in 100000, affecting individuals across all age groups.

CASE SUMMARY: We report the case of a 32-year-old man with CVID who presented with a chief complaint of “recurrent diarrhea and significant weight loss over the past 2 years”. Laboratory tests on admission showed fat droplets in stool, while other parameters were within normal ranges. Gastroscopy revealed a smooth gastric mucosa without bile retention or signs of Helicobacter pylori infection; however, the mucosa of the descending segment of the duodenum appeared rough. Further evaluation of the small intestine using computed tomography indicated no abnormalities. Finally, the whole-small bowel double-balloon enteroscopy (DBE) was performed, which revealed various phenotypic changes in the small intestinal mucosa. The patient was diagnosed with CVID, which improved after immunoglobulin therapy, with favorable follow-up outcomes.

CONCLUSION: Non-infectious enteropathy in CVID is rare. Therefore, DBE is essential for diagnosing small intestinal involvement in such cases.

PMID:40438712 | PMC:PMC12110145 | DOI:10.4253/wjge.v17.i5.101618

Front Immunol. 2025 May 14;16:1576235. doi: 10.3389/fimmu.2025.1576235. eCollection 2025.

ABSTRACT

Hereditary angioedema (HAE) types 1/2 are rare genetic disorders leading to C1 inhibitor (C1INH) deficiency/dysfunction. Guidelines recommend long-term prophylaxis (LTP) to prevent HAE attacks. Subcutaneous (SC) C1INH replacement therapy is approved for LTP in patients with HAE (age indication varies between countries). There is little real-world data on the outcomes of patients who switch to C1INH SC in Europe, particularly those who switch from C1INH IV. This retrospective patient chart analysis captured real-world evidence of the effectiveness of C1INH SC LTP in patients with HAE in Germany (n=69) and Spain (n=37). The primary endpoint was change in annualized attack rate (AAR) in patients who used C1INH IV LTP during a 6-month baseline period and switched to C1INH SC LTP for ≥6 months. Switching to C1INH SC LTP from C1INH IV LTP was associated with a 73.2% reduction in AAR (n=48; P<0.001) compared to baseline. Emergency Room (ER) visits and rescue medication use were also significantly reduced after switching to C1INH SC LTP from C1INH IV LTP. A similar reduction in AAR (68.9%), ER visits (49.8%), and rescue medication use (61.9%) was observed in the overall population (n=105), regardless of treatment at baseline. Similar changes from baseline were seen in patients from Germany and Spain.

PMID:40438099 | PMC:PMC12116583 | DOI:10.3389/fimmu.2025.1576235

Front Immunol. 2025 May 14;16:1536128. doi: 10.3389/fimmu.2025.1536128. eCollection 2025.

ABSTRACT

BACKGROUND: In this study we included patients with hereditary angioedema (HAE) caused by decreased levels of C1 inhibitor (HAE-C1INH). An increased risk of autoimmune disorders, particularly systemic lupus erythematosus (SLE), has been reported in HAE-C1INH. This suggests that complement consumption affects adaptive immunity.

OBJECTIVE: To investigate lymphocyte subpopulations in relation to disease activity and complement activation in HAE-C1INH patients and matched controls.

METHODS: Flow cytometry of peripheral blood lymphocyte populations, measurements of complement and complement fragments, and collection of clinical data.

RESULTS: NK cell counts were lower in HAE-C1INH patients, and their frequencies were related to disease activity. The T helper (Th) cell balance was skewed towards more Th2 cells and less Th1 cells in HAE-C1INH patients compared to controls. There were also lower frequencies of class-switched B cells and plasmablasts in patients. Levels of C4 and the complement activation fragment C3d were related to disease activity.

CONCLUSIONS: Blood lymphocyte populations are altered in HAE-C1INH, a finding which may be of pathophysiological importance considering the increased risks of both autoimmunity and allergy associated with HAE-C1INH.

PMID:40438097 | PMC:PMC12116338 | DOI:10.3389/fimmu.2025.1536128