Common variable immunodeficiency (CVID) constitutes a heterogenic group of primary immunodeficiency disorders with a wide-ranging clinical spectrum. CVID-associated non-infectious morbidity constitutes a major challenge requiring a full understanding of its pathophysiology and its clinical importance and global variability, especially considering the broad clinical, genetic, and regional heterogeneity of CVID disorders. This work aimed to develop a nationwide, multicenter, retrospective study over a 3-year period describing epidemiological, clinical, laboratory, therapeutic, and prognostic features of 250 CVID patients in Spain. The mean diagnostic delay was around 10 years and most patients initially presented with infectious complications followed by non-infectious immune disorders. However, infectious diseases were not the main cause of morbimortality. Non-infectious lung disease was extraordinarily frequent in our registry affecting approximately 60% of the patients. More than one-third of the patients in our cohort showed lymphadenopathies and splenomegaly in their follow-up, and more than 33% presented immune cytopenias, especially Evans’ syndrome. Gastrointestinal disease was observed in more than 40% of the patients. Among biopsied organs in our cohort, benign lymphoproliferation was the principal histopathological alteration. Reaching 15.26%, the global prevalence of cancer in our registry was one of the highest reported to date, with non-Hodgkin B lymphoma being the most frequent. These data emphasize the importance of basic and translational research delving into the pathophysiological pathways involved in immune dysregulation and diffuse lymphocytic infiltration. This would reveal new tailored strategies to reduce immune complications, and the associated healthcare burden, and ensure a better quality of life for CVID patients.

Background and aim: Subcutaneous immunoglobulin (SCIg) has emerged as an alternative to intravenous administration for patients with primary (PID) and secondary immunodeficiencies (SID), offering benefits such as fewer systemic adverse reactions and greater patient autonomy. However, comprehensive real-world data on SCIg use, including clinical and patient-centered outcomes, remain scarce. This study, conducted by expert immunodeficiency nursing teams, assesses the clinical characteristics, reported adverse effects, and quality-of-life outcomes associated with SCIg therapy with different formulations in patients with PID and SID across Spain.Methods: A multicenter, cross-sectional study was conducted across 8 immunodeficiency nursing units in Spain, involving 223 adult patients treated with SCIg from 2004 to 2024. Data on demographics, comorbidities, SCIg treatment characteristics, reported adverse events, and quality-of-life metrics (EuroQol-5D-3L, Gijón Scale) were collected and analyzed.Results: The cohort (61.4% female, mean age: 47.1 years) included 65% PID patients, with common variable immunodeficiency being the most frequent diagnosis (39.8%). SCIg demonstrated good tolerability overall, with no significant differences in global adverse event rates between facilitated 10% (fSCIg) and 20% formulations. However, 10% fSCIg was associated with higher reported frequencies of mild local rash (58.7% vs. 36.9%, p=0.002) and fever (10.6% vs. 1.7%, p=0.01). Quality-of-life scores indicated minimal limitations in mobility and self-care, with a mean subjective health rating of 72.7/100. Patients using 20% SCIg required fewer educational sessions for self-administration compared to the 10% group.Conclusion: The different SCIg formulations in this large, multicenter cohort was effective and generally well-tolerated, supporting its use for maintaining adequate IgG levels and promoting patient independence in PID and SID. The study’s findings advocate for tailored approaches that optimize patient satisfaction and address individual needs, emphasizing the critical role of dedicated immunodeficiency nursing teams in ensuring safe, effective, and patient-centered SCIg administration.

Background and aims: Immunoglobulin replacement therapy (IgRT), administered intravenously (IVIg) or subcutaneously (SCIg), is the cornerstone treatment for patients with Common Variable Immunodeficiency (CVID). Although both modalities demonstrate similar efficacy, SCIg is associated with fewer systemic adverse events and increased patient autonomy. Despite these advantages, its utilization remains limited in certain regions, particularly in the Mediterranean region. This study aimed to evaluate real-world patterns of IgRT use in Spanish CVID patients and provide a comprehensive analysis of the factors associated with IVIg and SCIg administration in routine clinical practice.Methods: A cross-sectional, multicenter study was conducted using data from the GTEM-SEMI-CVID Registry, encompassing 212 adult CVID patients receiving IgRT across Spain. Patients were grouped based on the administration route: IVIg and SCIg. Demographic, clinical, and immunological data, including IgRT modality, dosage, administration setting, and comorbidities, were collected. Comparative statistical analyses were performed to identify differences between both treatment groups.Results: Of the 212 patients, 58.5% received IVIg and 41.5% received SCIg. SCIg recipients were younger (47.5 vs. 54.8 years, p = 0.003) and predominantly treated at home (80.6% vs. 1.6%, p < 0.001), compared to those receiving IVIg. SCIg use was significantly higher in tertiary hospitals compared to secondary ones (44.4% vs. 17.4%, p = 0.0136). Infection rates, autoimmune comorbidities, weekly doses (7.2 g for IVIg vs. 7.7 g for SCIg, p = 0.142), and IgG trough levels were comparable across groups.Conclusion: This study provides real-world evidence on IgRT patterns in Spanish patients with CVID, revealing a marked increase in SCIg use over the past decade, although IVIg remains predominant, especially in secondary hospitals. Age significantly influenced the choice of modality, with IVIg preferred for older patients and SCIg for younger ones, while disease severity did not impact this decision. These findings underscore the need to optimize access to SCIg, particularly in secondary centers, to enhance patient autonomy and improve therapeutic outcomes.

Background and objectives: Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by decreased immunoglobulins and recurrent infections, with non-infectious complications such as granulomatous–lymphocytic interstitial lung disease (GLILD) affecting up to 30% of patients. Methods: Using high-throughput 16S rRNA gene sequencing, salivary, sputum, and fecal microbiome from CVID patients with GLILD, comparing them to CVID patients without GLILD—with immune dysregulation (dCVID) and only infections (iCVID)—and healthy controls was analyzed. Results: A total of 41 CVID patients, 7 with GLILD, and 15 healthy donors were included. Global fecal biodiversity was significantly lower in GLILD patients compared to CVID subgroups and controls. GLILD patients harbored different specific bacterial communities in all niches, with some keystone species common to dCVID. Conchiformibius, Micrococcales, and Capnocytophaga are more frequent in the sputum of GLILD patients. Saliva in GLILD shows higher frequencies of Conchiformibius and Haemophilusparainfluenzae. Fecal samples from GLILD patients have higher levels of Gemella morbilorum, Lacticaseibacillus, and Cellulosimicrobium. A non-assigned Conchiformibius spp. is consistently associated with GLILD across different niches and could be a potential pathobiont or relevant microbiological marker for GLILD. Cluster network and correlation analyses show profound dysbiosis in the sputum, saliva, and feces of GLILD patients. Conclusions: These findings highlight significant microbiome alterations in CVID patients with GLILD, particularly in the respiratory tract, suggesting a possible link to both local and systemic immune dysregulation.

Background/Objectives: Subcutaneous immunoglobulin (SCIg) is a well-established alternative to intravenous immunoglobulin (IVIg) in patients with primary (PID) and secondary immunodeficiency (SID), with demonstrated benefits in safety and quality of life. However, its implementation remains limited in parts of Southern Europe, partly due to frequent local adverse reactions (LARs), which, despite being mild, can affect adherence and clinician confidence. This study aimed to identify clinical, anatomical, psychosocial, and geographical factors associated with LARs and to develop an exploratory model for individualized risk estimation. Methods: We conducted a retrospective, multicenter observational study in eight Spanish hospitals using data from the GEIE Registry. Patients aged ≥14 years with PID or SID receiving SCIg for ≥1 month were included. Demographic, clinical, anatomical, and psychosocial variables were collected. A multivariable logistic regression model was built to identify independent predictors of LARs and internally validated using bootstrap resampling (500 iterations). A nomogram was constructed for personalized risk prediction. Results: Among 223 included patients, 73.1% reported LARs, primarily swelling, pruritus, and rash. Independent predictors included smaller abdominal perimeter (OR 0.955, p < 0.001), history of skin disease (OR 2.75, p = 0.044), greater distance to hospital (OR 1.01, p = 0.050), and absence of anxiety (OR 0.089, p = 0.001). Model discrimination was good (AUC 0.801), with minimal optimism after internal validation (validated AUC 0.788). Conclusions: LARs are common among patients receiving SCIg and could be influenced by anatomical, dermatological, psychological, and geographical factors. This exploratory multicenter study underscores the clinical relevance of these factors and may guide more personalized and safer use of SCIg.