Research

Top Companion Anim Med. 2025 Sep 25:101023. doi: 10.1016/j.tcam.2025.101023. Online ahead of print.

ABSTRACT

Feline herpesvirus (FHV) and feline calicivirus (FCV) are the primary causative agents of respiratory disease in cats. Although fatal respiratory disease is frequently observed in routine pathological diagnostics, the role of viral involvement is rarely investigated. This study aimed to assess the involvement of FHV and FCV in necropsied cats with fatal respiratory disease using immunohistochemistry, and to characterize the affected tissues, along pathological and epidemiological findings of the positive cats. Sixty cats were assessed. Immunolabeling for FHV was observed in 12 cats, for FCV in seven cats, and for both viruses in three cats. These FHV and FCV-positive cats (n=22) were included in the study. Co-infection with feline immunodeficiency virus (FIV) and feline leukaemia virus (FeLV) was observed in 14 cats (six FeLV-positive, four FIV-positive, and four FeLV and FIV-positive). Gross lesions were mainly restricted to the respiratory and upper digestive tracts. Histological analysis revealed that the affected tissues included the nasal and oral cavities, esophagus, larynx, trachea, and lungs. All FCV-positive cats and most FHV-positive cats presented erosive, ulcerative, and fibrinonecrotic lesions in the upper respiratory/digestive tracts, concomitant with pneumonia (18/22). The remaining 4/22 cats, all infected with FHV, had lesions restricted to the upper respiratory tract. FHV-positive cats showed a bronchointerstitial pneumonia, whereas FCV-positive cats exhibited a fibrinosuppurative pneumonia. This study highlights pneumonia as an important cause of death in cats with FCV and FHV infection, particularly in those co-infected with retroviruses. It also emphasizes the importance of collecting samples from the respiratory and upper digestive tracts during necropsy and using immunohistochemistry to confirm the involvement of viral infectious agents-even in adult and aging cats. The findings of this study may contribute to further investigations into feline respiratory diseases.

PMID:41015115 | DOI:10.1016/j.tcam.2025.101023

Medicina (Kaunas). 2025 Aug 29;61(9):1549. doi: 10.3390/medicina61091549.

ABSTRACT

Background and Objectives: Inborn errors of immunity are increasingly diagnosed in developing countries. Immunoglobulin replacement therapy (IGRT) remains the cornerstone of treatment in these patients, and its monitoring has gained importance for optimizing outcomes. We conducted a retrospective study to evaluate the relationship between IgG trough levels and infections in adults with inborn errors of immunity receiving IGRT. Materials and Methods: Adults diagnosed with primary immunodeficiency and receiving IGRT for at least six months were included. Serum IgG trough levels were measured, and infections during follow-up were systematically recorded. Results: A total of 31 adult patients (CVID: 29, XLA: 2) were analyzed. The mean follow-up was 13 months, with a mean serum IgG trough level of 815.8 ± 205.9 mg/dL, achieved with an average IGRT dose of 498.8 ± 93.0 mg/kg/month. Dose adjustments were made in 35.5% of patients, mostly due to weight changes and clinical indications. Overall, 74.2% of patients had at least one infection requiring antibiotics. Patients with mean IgG trough levels below 850 mg/dL had significantly higher rates of antibiotic-requiring infections (p = 0.032, Mann-Whitney U; mean difference = 0.109, 95% CI: 0.037-0.182; p = 0.005 via t-test). Multivariate regression confirmed that lower IgG trough levels were independently associated with higher antibiotic-requiring infection rates (B = -0.024, 95% CI: -0.045 to -0.002, p = 0.033), while IGRT dose and comorbidities were not significant. Conclusions: IGRT plays a key role in reducing antibiotic-requiring infections in patients with primary immunodeficiency. Regular monitoring and individualized dose adjustments may help optimize outcomes. Further prospective studies are needed to confirm these findings.

PMID:41010940 | DOI:10.3390/medicina61091549

Medicina (Kaunas). 2025 Sep 11;61(9):1644. doi: 10.3390/medicina61091644.

ABSTRACT

Background and Objectives: Severe combined immunodeficiency (SCID) represents a group of rare and potentially fatal monogenic disorders arising from pathogenic variants in a broad spectrum of genes. Diagnostic delays beyond the first few months of life have been associated with poor overall survival and hematopoietic stem cell transplantation (HSCT) outcomes. Therefore, the aim of our study was to apply an NGS assay enabling the rapid and reliable diagnosis of SCID. Materials and Methods: We developed a targeted NGS panel of 30 genes implicated in the pathogenesis of most SCID cases and we applied it to three Greek infants with suspected SCID. Results: Each patient displayed a distinct immunophenotype-T^–B^–NK^–, T^–B^–NK⁺ and T^–B⁺NK^–, respectively-and was found to harbor pathogenic or likely pathogenic variants in the analyzed SCID-related genes. In particular, patient 1 carried two heterozygous ADA variants (c.58G>A, p.Gly20Arg and c.956_960del, p.Glu319Glyfs); patient 2 harbored two discrete pathogenic variants in the DCLRE1C gene (a large deletion of exons 1-3 and the nonsense mutation c.241C>T, p.Arg81*), causing Artemis deficiency; and patient 3 carried a hemizygous IL2RG missense variant (c.437T>C, p.Leu146Pro), associated with X-linked SCID. All variants were confirmed by Sanger sequencing. Conclusions: Our method successfully identified the underlying genetic defects in all patients, thereby establishing a molecular diagnosis of SCID. These findings highlight the potential of targeted NGS assays for achieving rapid and accurate molecular diagnosis of SCID, which is crucial for the timely treatment of life-threatening conditions in affected children.

PMID:41011036 | DOI:10.3390/medicina61091644

BMC Infect Dis. 2025 Sep 26;25(1):1168. doi: 10.1186/s12879-025-11385-5.

ABSTRACT

BACKGROUND: Herpes simplex virus(HSV) encephalitis is typically an acute, monophasic illness but can rarely present as a chronic granulomatous encephalitis, especially among immunocompromised individuals. The diagnosis of chronic HSV encephalitis is challenging due to its prolonged latency period, atypical imaging findings, and potential false-negative cerebrospinal fluid (CSF) polymerase chain reaction (PCR) results. This report describes a rare case of chronic granulomatous HSV encephalitis in a child with an underlying immunodeficiency disorder- DiGeorge syndrome (DGS).

CASE PRESENTATION: A developmentally normal 10-month-old girl initially presented with fever and seizures, was diagnosed with acute encephalitis, and received intravenous acyclovir. Following the illness, she exhibited neurodevelopmental delay and gliotic changes in brain imaging. At 12 years of age, she was admitted with refractory seizures and a respiratory infection. MRI revealed new cortical lesions and CSF analysis showed mild pleocytosis with elevated proteins. Despite symptomatic management, her condition worsened, with progressive neurological decline and radiological evidence of tumefactive or granulomatous lesions. A brain biopsy was performed, revealing HSV-1 positivity on PCR and immunohistochemistry, confirming chronic HSE. Given the atypical course, genetic testing was conducted, showing a 22q11.2 microdeletion consistent with DGS. The patient was treated with intravenous acyclovir and corticosteroids, followed by long-term oral acyclovir prophylaxis. Over two years of follow-up, she showed significant clinical and radiological improvement, with seizure resolution and partial recovery of developmental milestones.

CONCLUSION: This case highlights the potential for HSV to cause chronic granulomatous encephalitis, particularly among children with underlying immunodeficiency. It underscores the diagnostic challenge posed by prolonged latency and false-negative CSF PCR results and the importance of brain biopsy for definitive diagnosis. Additionally, this report suggests a potential link between DGS-related immunodeficiency and chronic HSV infection, emphasizing the need for genetic evaluation in atypical encephalitis cases. Long-term acyclovir therapy may be beneficial in such patients, although the optimal duration remains uncertain.

PMID:41013330 | DOI:10.1186/s12879-025-11385-5

J Allergy Clin Immunol Pract. 2025 Sep 23:S2213-2198(25)00915-8. doi: 10.1016/j.jaip.2025.09.021. Online ahead of print.

ABSTRACT

BACKGROUND: Liver disease is associated with increased mortality in patients with common variable immunodeficiency (CVID), yet we lack population-level data on its impact on CVID-associated hospitalizations in the United States.

OBJECTIVE: To conduct a nationwide analysis evaluating the prevalence, spectrum, clinical correlates, and outcomes of hepatic manifestations among admitted adults with CVID.

METHODS: We performed a retrospective cross-sectional analysis using the National Readmission Database, part of the Healthcare Cost and Utilization Project (HCUP) by the Agency for Healthcare Research and Quality. International Classification of Diseases (ICD)-10 codes were used to assess hepatic complications, comorbidities, risk factors, and outcomes in CVID-associated admissions with liver involvement.

RESULTS: Of 181,288 CVID-related index hospitalizations, 10% (18,823) had a co-diagnosed hepatic complication, specifically hepatic steatosis (38%), cirrhosis (24%), nonalcoholic fatty liver disease (17%), portal hypertension (PH) (15%), and nodular regenerative hyperplasia (NRH) (14%). CVID-associated admissions with hepatic disease had longer median lengths of stay (7 vs. 5 days, P<0.0001), higher in-hospital mortality (11% vs. 4%, P<0.0001), and higher median hospital charges ($68,114 vs. $44,757, P<0.0001). They also had a higher prevalence of hypertension, chronic kidney disease, diabetes, obesity, and autoimmune cytopenia (P<0.0001 for all). Alcohol use, hepatitis C, and hepatitis B were strong predictors of hepatic manifestations in CVID admissions (P<0.0001). CVID patients with NRH (HR: 1.3; 95% CI: 1.2-1.5, P<0.0001) and PH (HR: 1.4; 95% CI: 1.2-1.5, P<0.0001) had lower survival.

CONCLUSIONS: CVID-associated admissions with liver disease, particularly those with NRH and PH, were longer, more costly, and associated with increased mortality. Further studies are needed to improve early detection and long-term outcomes.

PMID:40998257 | DOI:10.1016/j.jaip.2025.09.021

Bol Med Hosp Infant Mex. 2025;82(5):273-281. doi: 10.24875/BMHIM.25000036.

ABSTRACT

Bronchiectasis is characterized by the permanent dilation of bronchi, clinically presenting with chronic cough, sputum production, dyspnea, and recurrent exacerbations. Bronchiectasis can occur due to genetic disorders, congenital malformations, endobronchial obstruction of infectious and inflammatory origin, and chronic aspiration, among other causes. Bronchial dilation leads to impaired mucociliary clearance, trapping particles and microorganisms in the airways. Macrophages and epithelial cells release proinflammatory cytokines that promote neutrophil chemotaxis. Neutrophils release enzymes causing epithelial cell damage, reducing ciliary motility, promoting glandular hyperplasia, and increasing mucus secretion. Persistent infection perpetuates local inflammation in bronchiectasis patients. Diagnosis requires high clinical suspicion and early detection improves clinical outcomes. High-resolution computed tomography is the gold standard for confirmation. A comprehensive medical history, initial assessments with complete blood count, total serum immunoglobulins, iontophoresis, and spirometry help assess the underlying etiology and disease severity. The primary goal is preserving lung function and halting disease progression. This involves adopting healthy lifestyles, expanded vaccination schedules, respiratory therapy, and early antibiotic use for exacerbations and colonization by specific microorganisms.

PMID:40997339 | DOI:10.24875/BMHIM.25000036

Am J Rhinol Allergy. 2025 Sep 25:19458924251382514. doi: 10.1177/19458924251382514. Online ahead of print.

ABSTRACT

BackgroundAcute invasive fungal rhinosinusitis (AIFRS) is an aggressive and often fatal disease process that principally impacts immunocompromised patients. Maxillary dental trauma and infections have been associated with the development of maxillary sinus fungal balls, but the role of dental procedures/trauma in the pathogenesis of AIFRS remains poorly defined.ObjectiveThis study seeks to review a single-institutional experience with AIFRS and examine the association between dental events and AIFRS severity and outcomes.MethodsRetrospective review of 95 consecutive patients with biopsy-proven AIFRS treated at a tertiary institution between 2010 and 2024. Demographic information, comorbidities, disease course and outcomes were evaluated. The primary objective was to evaluate the impact of antecedent dental events on AIFRS morbidity and mortality. Secondary objectives included evaluating variability in demographic factors, comorbidities, and extent of disease.ResultsEleven patients with an antecedent dental event within 2 weeks of AIFRS diagnosis were identified for a rate of 11.6%. Dental AIFRS patients were more likely to be African American (P = .003) and more likely to have diabetes mellitus as their underlying immunodeficiency (P = .03) than non-dental AIFRS patients. Patients with dental-related AIFRS were more likely to present with invasion of the orbit (OR 6.0, 95% CI 1.2-29.5) and nasal floor (OR 4.2, 95% CI 1.1-17.1) than non-dental AIFRS patients. There was no difference in mortality between dental and non-dental AIFRS (36.4% vs 52.4%, P = .31).ConclusionMore investigation is necessary to further evaluate the association between dental events and the development of AIFRS. In our cohort, 11.6% of patients experienced AIFRS within 2 weeks of a dental event and these patients tended to present with higher rates of orbital involvement without a resultant increase in mortality.

PMID:40997227 | DOI:10.1177/19458924251382514

J Clin Immunol. 2025 Sep 25;45(1):128. doi: 10.1007/s10875-025-01910-1.

ABSTRACT

PURPOSE: Inborn Errors of Immunity (IEI) often lead to recurrent infections, immune dysregulation, and an increased risk of malignancies. Due to the heterogeneity in IEI presentations, personalized monitoring is essential for early detection of non-infectious complications. This study aims to document the characteristics and prevalence of malignancies in IEI patients.

METHODS: A retrospective review of 355 patients diagnosed with IEI at the Adult Allergy and Immunology Clinic of Ege University was conducted. Data on demographics, clinical presentations, laboratory results, and immunological and genetic profiles of patients with malignancies were analyzed. RESULTS: A total of 40 patients with neoplasia (F/M: 18/22; median age: 51.58 years, range: 18-91) were evaluated. The median ages at IEI symptom onset, diagnosis, and neoplasm diagnosis were 16.5, 45, and 39.5 years, respectively. Malignancy was diagnosed in 60% of patients before IEI, with referrals for low immunoglobulin levels and/or severe infections, and for a genetic profile suggestive of immunodeficiency. The prevalence of malignancy in the overall cohort was 10.42% (37/355), while it was significantly higher in the common variable immunodeficiency (CVID) subgroup, reaching 20.44% (28/137). Lymphoma was the most common malignancy at 45.9%, primarily non-Hodgkin lymphoma (NHL) at 40.5%, with diffuse large B-cell lymphoma (DLBCL) as a key subtype; carcinomas were the second most common at 35.1%. Hematologic malignancies were significantly more frequent among patients with CVID (90.5%), whereas non-hematologic malignancies predominated in the non-CVID group (77.8%) (p = 0.024). Lymphoproliferation was more common in hematologic malignancies (85.7%) compared to non-hematologic malignancies (25.0%) (p < 0.001). Genetic variants were identified in 61% of cases, with 37% classified as pathogenic or likely pathogenic, including variants in TNFRSF13B/TACI, CCDC40, PLCG2, ATM, CARD11, CHEK2, CNV, COPB1, HPS5, LYST, MAPK8IP1, NBS1, NF1, NFKBIA, PI4KA, POLE, SPI1, and TAP2.

CONCLUSIONS: Findings confirm that NHL, particularly DLBCL, is the most prevalent malignancy in this cohort. Given the link between malignancies and underlying IEI, immunologic evaluation is recommended, particularly for NHL patients. The observed predominance of hematologic malignancies among CVID patients and the association with lymphoproliferation further emphasize the need for heightened malignancy surveillance and early immunologic workup in this subgroup. Further research on biomarkers for malignancy prediction in IEI is warranted.

PMID:40993321 | DOI:10.1007/s10875-025-01910-1

BMC Immunol. 2025 Sep 24;26(1):66. doi: 10.1186/s12865-025-00752-1.

ABSTRACT

BACKGROUND: Autoimmune cytopenias (AICs) are among the most frequent non-infectious complications in inborn errors of immunity (IEIs) and may represent early or even initial manifestations. The genetic underpinnings of AICs in IEIs remain heterogeneous and incompletely defined.

OBJECTIVE: This study aimed to determine the prevalence and distribution of AICs and to investigate their associations with underlying monogenic mutations and selected immunophenotypic parameters in adult patients with IEI.

METHODS: A total of 121 adult IEI patients from a single tertiary immunology center were evaluated retrospectively. Clinical, immunophenotypic, and genetic data were obtained from electronic medical records. Comparisons were made between patients with and without autoimmune manifestations and AICs. Monogenic mutations were identified using targeted next-generation sequencing (NGS).

RESULTS: Autoimmune manifestations were present in 48 of 121 patients (39.6%), and autoimmune cytopenias (AICs) were identified in 33 patients (27.5%). Autoimmune hemolytic anemia (AIHA) was the most frequently observed subtype, followed by combined cytopenias and immune thrombocytopenia (ITP). The most common genetic alteration detected was a mutation in TNFRSF13B (TACI), with additional variants identified in DOCK8, RAG1, LRBA, PRF1, PSTPIP1, CECR1, PRKDC, and MRTFA. Logistic regression revealed a strong independent association between TACI mutations and ITP (OR: 46.5, p = 0.002), while no significant relationship was found with autoimmune cytopenias overall. No statistically significant differences were found in class-switched memory B cells (CD27⁺IgD⁻) percentages, CD4⁺/CD8⁺ T-cell ratios, or baseline IgG concentrations between patients with and without autoimmune manifestations or AICs.

CONCLUSION: AICs represent a significant clinical burden in adult IEIs and may occur in association with a wide range of genetic variants. Class-switched memory B cells (CD27⁺IgD⁻) percentages, CD4⁺/CD8⁺ T-cell ratio, and baseline IgG were not significantly associated with autoimmunity in this cohort. These findings underscore the need for broader immunophenotypic and genetic screening to improve the early recognition and management of autoimmune complications in IEIs.

PMID:40993545 | DOI:10.1186/s12865-025-00752-1

Cureus. 2025 Aug 18;17(8):e90448. doi: 10.7759/cureus.90448. eCollection 2025 Aug.

ABSTRACT

Activated PI3 kinase delta syndrome (APDS) is a rare, inherited primary immunodeficiency characterized by gain-of-function mutations in the PIK3CD or PIK3R1 genes, resulting in hyperactivation of the PI3Kδ pathway and consequent immune dysregulation. This review provides an in-depth exploration of the genetic and molecular mechanisms underlying APDS, highlighting the complex interplay between immunodeficiency and autoimmunity. Clinical manifestations include recurrent infections, lymphoproliferation, autoimmune cytopenias, and inflammatory complications, which often begin in early childhood. Diagnostic strategies have evolved with the advent of genetic sequencing and immunologic biomarkers, enabling the more accurate identification and classification of APDS subtypes than previously possible. Therapeutic advances, particularly the development of PI3Kδ inhibitors such as leniolisib and duvelisib, have significantly improved patient outcomes by targeting the underlying molecular defects. Additional management approaches include immunoglobulin replacement, immunomodulators, and hematopoietic stem cell transplantation in severe cases. Despite these advances, challenges such as delayed diagnosis, treatment-related complications, and variability in clinical presentation persist. Continued research on targeted therapies, long-term outcomes, and gene-editing technologies is essential to optimize care and enhance the quality of life for individuals with APDS.

PMID:40978950 | PMC:PMC12446750 | DOI:10.7759/cureus.90448