Research

Front Oncol. 2025 Oct 13;15:1668762. doi: 10.3389/fonc.2025.1668762. eCollection 2025.

ABSTRACT

OBJECTIVES: Primary hemophagocytic lymphohistiocytosis (p-HLH), a genetic disorder characterized by hyperinflammation, is associated with high mortality in pediatric hematology. This study investigates laboratory and imaging risk factors for mortality in p-HLH and its subtypes.

METHODS: A retrospective analysis (2012-2024) was conducted on 264 pediatric patients with HLH, categorized into p-HLH and secondary HLH (s-HLH). Five laboratory markers and nine imaging findings were compared between groups and across p-HLH subtypes: familial HLH (F-HLH), immunodeficiency-related HLH (I-HLH), and EBV-driven HLH. Mortality risk factors were analyzed.

RESULTS: The cohort included 264 pediatric patients (median age: 4 years, IQR: 2-7 years, 141 males), with 99 having p-HLH (28 F-HLH, 34 I-HLH, 37 EBV-driven HLH), and 165 having s-HLH (EBV-associated). No significant differences in laboratory parameters were observed between p-HLH and s-HLH. Imaging revealed that p-HLH was associated with less severe ascites, more pronounced hepatomegaly, and greater central nervous system (CNS) involvement than s-HLH. Subgroup analysis showed that F-HLH had more severe CNS involvement, while I-HLH had higher rates of pulmonary complications. Independent mortality risk factors for HLH overall included severe thrombocytopenia (HR = 2.93, 95%CI:1.62-5.30, p < 0.01), CNS involvement (HR = 1.80, 95%CI:1.14-2.84, p = 0.01), and liver/spleen damage (HR = 2.78, 95%CI:1.85-4.18, p < 0.01). For p-HLH, specifically, severe liver/spleen damage (HR = 2.68, 95%CI:1.38-5.21, p < 0.01) and pleural effusion (HR = 3.98, 95%CI:1.20-13.2, p=0.02) were critical factors.

CONCLUSION: No significant differences in mortality risk were found between p-HLH and s-HLH or among p-HLH subtypes. For p-HLH, severe liver/spleen damage and pleural effusion emerged as key mortality predictors.

PMID:41158863 | PMC:PMC12554580 | DOI:10.3389/fonc.2025.1668762

Rev Esp Quimioter. 2025 Oct 24;38 Suppl 1:38-42. doi: 10.37201/req/s01.06.2025. Epub 2025 Oct 24.

ABSTRACT

Primary immunodeficiencies, now referred to as inborn errors of immunity (IEI), are increasingly recognized in adults, not only in the pediatric population. In adults, they may present with recurrent, severe, or unusual infections, but also with autoimmunity, malignancy, allergies, or inflammation, posing a diagnostic challenge. This review is based on clinical experience and the 2022 International Union of Immunological Societies classification. It includes four clinical cases and proposes a practical approach for the evaluation of adults. In the presence of suspected IEI, a stepwise laboratory approach is proposed to facilitate early detection and improve prognosis. Initial screening with basic immunological tests-including complete blood count, immunoglobulin and complement levels, and lymphocyte immunophenotyping-is emphasized. Confirmation of each IEI requires more specific testing, often involving molecular techniques.

PMID:41159229 | DOI:10.37201/req/s01.06.2025

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

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

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

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

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

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