RARE DISEASE
Primary immunodeficiency
Primary immunodeficiency
Primary immunodeficiency
Drug discovery
1
drug
With orphan designation
Overview
Primary immunodeficiency (PI) encompasses over 450 genetic disorders impairing immune function, increasing susceptibility to infections, autoimmunity, and malignancy [1][6][18]. Diagnosis is often delayed due to variable presentations, leading to complications like organ damage and lymphoproliferative disorders [1][14]. Management involves infection prevention, immune modulation, and targeted therapies [3][6][8].
Burden
Recurrent infections drive chronic lung damage, hearing loss, and hospitalizations, with 63% of patients requiring inpatient care [6][7][11].
22-30% develop autoimmune or lymphoproliferative complications [1][6].
Delayed diagnosis (9-15 years) amplifies morbidity and healthcare costs, with 70% of cases undiagnosed [14][19].
Therapies
Immunoglobulin replacement (IV/SC) for antibody deficiencies, used in 42.9% of patients with B-cell defects [6][8][16].
Antimicrobial prophylaxis (antibiotics, antifungals) tailored to immune defect profiles [3][16].
Curative approaches: Hematopoietic stem cell transplantation for severe cases (e.g., SCID) and emerging gene therapies targeting specific mutations [3][8][16].
Categories: rare genetic diseases, rare immunological diseases
Research Papers
2,145 drug discovery papers about Primary immunodeficiency, with 5 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2,145 drug discovery papers about Primary immunodeficiency, with 5 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-09-10 | X-linked hyper-IgM syndrome presenting as severe Pneumocystis pneumonia in a 6-month-old infant: a case report.
X-linked hyper-immunoglobulin M (XHIGM) syndrome is a rare primary immunodeficiency caused by mutations in the CD40 ligand gene (CD40LG), characterized by defective T-cell-dependent B-cell class-switch recombination. Patients typically present with recurrent infections in early childhood, but diagnosis is often delayed due to heterogeneous clinical manifestations and the fact that serum IgM levels may remain within the normal range in a significant proportion of patients. Here we report a case of XHIGM in an infant whose diagnostic journey began with recurrent lymphadenitis and culminated in life-threatening Pneumocystis jirovecii pneumonia (PJP). A 6-month-old male infant was admitted with severe respiratory distress and hypoxemia. He had recurrent axillary lymphadenitis at 1 and 2 months of age and significant failure to thrive. Chest CT showed bilateral consolidative and interstitial opacities. Immunological evaluation revealed markedly decreased IgA, normal IgM and IgG, and profound T-cell lymphopenia. Sputum metagenomic sequencing identified Pneumocystis jirovecii. Whole-genome sequencing identified a hemizygous likely pathogenic CD40LG mutation (NM_000074.3:c.520C>T, p.Q174*); his mother was a carrier. He was treated with mechanical ventilation, trimethoprim-sulfamethoxazole (TMP-SMX), micafungin, corticosteroids, and intravenous immunoglobulin (IVIG), and was discharged after 36 days. In infants with recurrent or opportunistic infections, persistently low IgA and declining T-cell counts-even when initial screening appears normal-should raise suspicion for underlying immunodeficiency and prompt genetic evaluation. Early aggressive management and evaluation for hematopoietic stem cell transplantation are essential to improve outcomes.Serial immunological evaluation is essential in infants with recurrent or opportunistic infections, as persistently low IgA and declining T-cell counts-even when initial screening appears normal-should prompt genetic evaluation for underlying immunodeficiency. Early aggressive management and evaluation for hematopoietic stem cell transplantation are essential to improve outcomes.
2026-08-29 | Clinical spectrum and survival outcomes of malignancies in pediatric patients with inborn errors of immunity.
Inborn errors of immunity (IEI) predispose patients to malignancy, particularly lymphoma, but data on diagnostic sequence and outcomes are limited. We retrospectively analyzed IEI-associated malignancies diagnosed at a single center between January 2004 and December 2025. Among 1,668 patients with IEI, 67 (4.0%) developed malignancy. Median ages at IEI and malignancy diagnosis were 8 and 10 years, respectively. Malignancy-first presentation occurred in 45 patients (67%), especially adolescents, and was associated with advanced-stage disease (p = 0.007). Lymphoid malignancies accounted for 90% of cases; non-Hodgkin lymphoma and Hodgkin lymphoma comprised 54% and 36%, respectively, and 84.7% presented with stage III-IV disease. Median event-free and overall survival were 66 and 155 months, respectively. In a clinically selected multivariable Cox model, NHL, solid/plasma cell tumors, older age at malignancy diagnosis, and DNA repair defect status were associated with worse OS. Twelve patients underwent allogeneic HSCT; one died early, and no post-transplant relapses occurred. Early immunologic evaluation and timely, individualized consideration of HSCT may support optimized management in children and adolescents, in whom cancer may be the first manifestation of IEI.
2026-08-26 | Pulmonary alveolar proteinosis and Pneumocystis jirovecii infection in an infant with hyper-IgM syndrome caused by a novel CD40LG variant: a case report.
Pulmonary alveolar proteinosis (PAP) is a rare interstitial lung disease. While autoimmunity is the leading cause of PAP in adults, the majority of pediatric cases occur secondary to immunodeficiency and opportunistic infections. Secondary PAP associated with CD40 ligand (CD40L) deficiency is extremely rare, and the underlying pathophysiology remains poorly understood. We report the case of a 4-month-old boy admitted due to failure to thrive and severe hypoxemic respiratory failure. Chest computed tomography demonstrated diffuse ground-glass opacities with interlobular septal thickening. Bronchoalveolar lavage yielded clear fluid containing Periodic acid-Schiff-positive material consistent with PAP, and polymerase chain reaction was positive for Pneumocystis jirovecii. An immunologic evaluation showed hypogammaglobulinemia (IgG and IgA), a normal IgM level for his age, an absence of class-switched memory B cells, and significantly reduced CD40L expression on activated T lymphocytes. Targeted genetic testing identified a previously unreported hemizygous CD40LG missense variant [c.137T>C, p.(Leu46Pro)]. Integration of the patient's immunophenotype, an in silico variant evaluation, and segregation data permitted classification of this variant as likely pathogenic, confirming X-linked hyper-IgM syndrome. The patient improved with ventilatory support, high-dose trimethoprim-sulfamethoxazole, and immunoglobulin replacement therapy. Early-onset PAP associated with P. jirovecii infection may reveal CD40L deficiency and should prompt evaluation for primary immunodeficiency. An integrated clinico-immunologic assessment coupled with genetic testing is essential to provide a molecular diagnosis, guide management, and prognostication, and to support timely consideration of curative hematopoietic stem cell transplantation.
2026-06-23 | Unmanipulated Haploidentical Stem Cell Transplantation Outcome in a Pediatric Patient With CD27 Deficiency and EBV-Induced Diffuse Large B-Cell Lymphoma With Primary CNS Involvement.
CD27 deficiency is a rare primary immunodeficiency associated with severe Epstein-Barr virus (EBV)-related complications, including lymphoma. We report a pediatric patient with CD27 deficiency who developed EBV-associated diffuse large B-cell lymphoma with primary CNS involvement and early relapse. The patient underwent unmanipulated haploidentical stem cell transplantation using post-transplant cyclophosphamide. Engraftment was successful, graft-versus-host disease was controlled, and full donor chimerism was achieved. After 40 months, the patient remains free of GVHD, PID, and lymphoma relapse, demonstrating successful lymphoma control and correction of the underlying immunodeficiency, thereby highlighting the feasibility of haploidentical HSCT in these patients.
2026-05-08 | Clinical, immunological, treatment characteristics, and outcomes in 22 patients with major histocompatibility complex class II deficiency.
Major histocompatibility complex (MHC) class II deficiency is a rare, life-threatening primary immunodeficiency that presents in early infancy with a SCID phenotype. However, emerging data indicate substantial clinical and immunological heterogeneity, including atypical presentations and neurological involvement. We retrospectively evaluated the clinical, immunological, genetic, and treatment-related characteristics and outcomes of 22 patients from 19 unrelated families diagnosed with MHC class II deficiency at a single referral center (2000-2019). Ten patients underwent HSCT at our center; transplant-related outcomes were evaluated, and long-term follow-up data were available for the six surviving patients through 2025. The median age at symptom onset and diagnosis was 9 and 12 months, respectively. Pneumonia, chronic diarrhea, and failure to thrive were the most common presenting features; neurological manifestations and developmental delay were observed in a subset of patients. Two patients showed residual HLA-DR expression and survived with a milder clinical course. CD4+ T cell lymphopenia and humoral dysfunction were consistent, while total lymphocyte counts were variable. RTE levels were mildly to moderately reduced in all tested patients, suggesting impaired thymic output. Severe viral infections were frequent and could be rapidly fatal. Fourteen patients required PICU admission, associated with high mortality. Genetic analysis (n:15) identified homozygous pathogenic variants in RFXANK (n=5), RFXAP (n=4), RFX5 (n=3), and CIITA (n=3). Ten patients underwent HSCT, with superior survival compared to non-transplanted patients (60% vs. 18%). Among transplanted patients, survival appeared higher following RTC than MAC (75% vs. 50%). Post-transplant mortality was observed in association with severe pre-transplant disease, delayed diagnosis, graft failure, and infectious complications. At ≥10 years post-HSCT, all survivors were IVIG-independent; CD4+ T cell recovery was higher after MAC than RTC, while T-cell chimerism remained mixed in both groups. MHC class II deficiency is a SCID-like pediatric immunological emergency that is fatal without HSCT in most patients. Early diagnosis is critical, as initial infections may be rapidly progressive. HSCT provides durable engraftment and sustained clinical stability in long-term survivors. Incorporating HLA-DR expression analysis into first-line immunological screening, even in the absence of profound lymphopenia, may facilitate earlier diagnosis, prompt HSCT referral, and improve survival.
proteins
2026-09-28 | Multi-Indication Budget Impact Analysis of Subcutaneous IgPro20 Pre-filled Syringes for the Treatment of Primary Immunodeficiency Syndromes, Secondary Immunodeficiencies, and Chronic Inflammatory Demyelinating Polyneuropathy in Italy.
Primary immunodeficiency (PID) and secondary immunodeficiency (SID) are chronic conditions associated with impaired immune function and increased susceptibility to infections. Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare autoimmune neurological disorder characterized by progressive motor and sensory deficits due to immune-mediated demyelination of peripheral nerves. Patients with these diseases often require long-term immunoglobulin (IG) therapy, which can be costly and burdensome, particularly when administered intravenously in hospital settings. IgPro20 pre‑filled syringes (PFS) offer a simplified, subcutaneous IG alternative that may reduce treatment burden and improve cost‑efficiency. The aim of this study was to estimate the budget impact of introducing IgPro20 PFS into the Italian healthcare system for patients with PID, SID, and CIDP. A population-based budget impact model was developed in Microsoft Excel® from the perspective of the Italian National Health Service (Servizio Sanitario Nazionale). The model used a 3-year time horizon and incorporated drug acquisition, administration, and adverse event costs. Model comparators included intravenous and subcutaneous IG and IgPro20 vials. Population estimates and market shares were informed by Italian affiliates. The introduction of IgPro20 PFS resulted in total cost savings of €31,524,488 for 4794 patients over 3 years. Savings were distributed across PID (€8,840,041), SID (€5,413,035), and CIDP (€17,271,412). Sensitivity analyses identified IgPro20 PFS and vial pricing as key drivers. IgPro20 PFS are a cost-saving, patient-centric treatment option for PID, SID, and CIDP. These findings support their adoption in Italy's healthcare system and may inform policy and payer decisions at regional and national levels.
2026-09-24 | Cardiac tamponade caused by effusive-constrictive pericarditis in a patient with common variable immunodeficiency: a case report.
Common variable immunodeficiency (CVID) is an immunodeficiency syndrome that is marked by impaired antibody formation and chronic infections. However, it is also associated with immune dysregulation and non-infectious inflammatory disorders. Cardiac involvement is not common, but effusive-constrictive pericarditis (ECP) complicated by cardiac tamponade is rarely seen in CVID patients. A 17-year-old male patient with CVID (diagnosis made in 2022) under regular replacement therapy with monthly intravenous immunoglobulin (IVIG) was admitted due to progressive dyspnea, dry cough, weakness, fatigue, and severe hypoxemia lasting for several days. Previous medical history included frequent lower respiratory tract infections, inflammatory bowel disease, celiac disease, malnutrition, and psoas abscess. Admission examination revealed arterial blood pressure 90/60 mmHg, oxygen saturation 75% in room air, increased jugular venous pressure, dullness in auscultation, pulsus paradoxus, bilateral rales and peripheral edema. Echo showed a 12-15 mm thick pericardial effusion, mobile fibrin-rich mass in pericardium, dilatation of inferior vena cava (23 mm with < 50% collapse), respiratory variation of mitral and tricuspid inflow with septal bounce. Left ventricle ejection fraction was 40%. Pericardiocentesis was done in an emergency manner and 320 ml of turbid serosanguineous effusion with fibrinous clots was drained. Microbiologic investigations of the sample including bacteriological cultures, acid-fast bacilli, mycobacteria, and MTB/RIF showed negative results. There were no malignant cells in cytological and cell-block analysis. After pericardiocentesis, central venous pressure remained elevated and Doppler investigation showed signs of constrictive physiology such as more than 25% variation in mitral inflow, expiratory reverse flow in hepatic veins, plethoric IVC, and septal bounce, which helped to confirm ECP. Ventricular function and constrictive physiology gradually improved after supportive therapy and IVIG and nutrition treatment without pericardiectomy. ECP with tamponade is a rare life-threatening complication in CVID patients. In the case of unexplained cardiopulmonary failure in an immunocompromised patient, tamponade cannot be considered only due to the infection. Urgent echocardiography, drainage, and investigation of various infectious, tuberculous, malignant and inflammatory causes is crucial.
2026-07-15 | Bronchiectasis With Inborn Errors of Immunity: Zooming in on Predominantly Antibody Deficiencies.
Bronchiectasis is a chronic inflammatory lung disease characterized by permanent airway dilation, mucus production, recurrent infections, and progressive structural injury. Inborn errors of immunity (IEIs), particularly predominantly antibody deficiencies (PADs), are important and potentially under-recognized causes of non-cystic fibrosis bronchiectasis (NCFB). Antibody deficiency increases susceptibility to bacterial infection, but the observation that bronchiectasis develops in only a subset of patients with PADs, and may develop despite immunoglobulin replacement therapy (IGRT), indicates that serum antibody measurements alone do not fully define the airway risk. Bronchiectasis in IEI likely reflects the interaction of impaired systemic humoral immunity impacting mucosal immune defenses, altered IgG transport or catabolism, B-cell dysregulation, T-cell and innate immune dysfunction, autoimmunity, environmental exposures, comorbid lung disease, and chronic airway infection. In this review, we summarize reported frequencies of NCFB among selected IEIs with antibody deficiency, discuss the limitations of IgG subclass and serum-based antibody testing as predictors of airway disease, and review evidence supporting higher individualized IGRT dosing in patients with antibody deficiency and bronchiectasis to achieve therapeutic IgG levels. We also propose a practical clinical framework for evaluating immune defects in bronchiectasis and for longitudinal pulmonary screening in patients with IEIs at increased risk of bronchiectasis.
2026-07-11 | Evaluation of sleep, fatigue, and quality of life in patients with primary immunodeficiency.
Primary immunodeficiency (PID) is a heterogeneous group of genetic disorders characterized by recurrent infections and immune dysregulation. Despite advances in therapy, many patients experience impaired quality of life (QoL), fatigue, and sleep disturbances. This study aimed to evaluate sleep quality, fatigue, and health-related QoL in adults with PID and to explore the associations between comorbidities and treatment modalities. This retrospective, observational, single-center study was conducted at the University of Health Sciences, Gülhane Training and Research Hospital between May and August 2024. Forty-nine adult patients with PID, diagnosed according to international criteria, completed validated questionnaires: the Pittsburgh Sleep Quality Index (PSQI), Fatigue Severity Scale (FSS), and SF-36 QoL scale. Clinical and demographic data were retrieved from the medical records. Statistical analyses included t-tests, Mann-Whitney U, chi-square, and Pearson's correlation, with significance set at P < 0.05. Of 49 patients (55.1% males, mean follow-up 9.9 years), 36.7% had poor sleep quality, 42.9% reported severe fatigue, 49% showed impaired SF-36 physical scores, and 87.8% had preserved mental scores. Poor sleep quality was correlated positively with fatigue (r = 0.623, P < 0.001) and negatively correlated with physical QoL (r = -0.491, P < 0.001). Patients with autoimmune and inflammatory bowel disease had significantly worse PSQI and FSS scores, whereas bronchiectasis was associated with reduced SF-36 physical scores. No differences were observed between the IVIG and SCIG groups in fatigue or mental scores; however, SCIG recipients had significantly higher physical scores (P = 0.018). Patients with PID experience substantial impairment in physical QoL, with fatigue and poor sleep quality frequently coexisting. Comorbidities, such as autoimmunity, bronchiectasis, and inflammatory bowel disease, exacerbate these impairments. SCIG therapy confers better physical outcomes than IVIG therapy. Comprehensive care strategies that address psychosocial and physical health are essential for the management of PID.
2026-07-06 | Adult-Onset LRBA Deficiency Presenting with Rheumatoid Arthritis-Like Manifestations: A Case Report.
Lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency is a primary inborn error of immunity characterized by immune dysregulation and frequently associated with autoimmune connective tissue manifestations. We describe an adult woman diagnosed with rheumatoid arthritis who was subsequently found to have LRBA deficiency based on genetic testing and investigated inflammatory proteins potentially involved in the pathogenesis of LRBA deficiency. A 44-year-old woman with rheumatoid arthritis presented with persistent diarrhea and abdominal distention lasting over eight months. Abdominal imaging revealed intestinal pseudo-obstruction. Her medical history included megaloblastic anemia, type 1 diabetes, and chronic thyroiditis since childhood. Her brother had died of unexplained diarrhea during childhood. Given her multiple autoimmune manifestations and family history, a primary immune deficiency (PID) was suspected. Genetic analysis identified a heterozygous LRBA splice-site variant (c.1162-1G > A) and a possible heterozygous deletion involving exons 18-41, suggesting compound heterozygous LRBA variants. Thus, the diagnosis of LRBA deficiency-associated autoimmunity. Following the diagnosis, she was treated with abatacept, a CTLA4-immunoglobulin fusion protein, resulting in improvement of gastrointestinal symptoms. Proximity extension assay (Olink® Target) revealed marked decreases in serum interleukin-17 A (from 3.36 to 2.22 normalized protein expression), tumor necrosis factor (3.26 to 0.69), and chemokine (C-C motif) ligand 20 (3.14 to 0.84) after treatment. LRBA deficiency is characterized by an imbalance of CD4⁺ T cells with increased Th1 and Th17 populations and reduced regulatory T cells. This case highlights that patients with PID, including LRBA deficiency, can present with autoimmune manifestations, and abatacept may represent an effective targeted treatment option for LRBA-deficiency.
small molecules
2026-09-17 | Associations Between Short-Term Changes in Disease Activity and Long-Term Clinical Outcomes in Activated Phosphoinositide 3-Kinase Delta Syndrome.
Clinical trials in activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS), an ultra-rare disease, have evaluated treatment response to the PI3Kδ inhibitor leniolisib using disease activity endpoints, including those measuring immunodeficiency and immune dysregulation. However, the relationship between disease activity endpoints and long-term clinical outcomes has not been quantified. Data from a randomised controlled trial and its open-label extension (OLE) investigating leniolisib were used to evaluate associations between short-term disease activity endpoints and longer-term clinical outcomes. Both single time point and repeated measures analyses were conducted using linear regression modelling and random effects multilevel regression modelling, respectively. In total, 39 patients were included (≤6 years of follow-up). Improvements in multiple immunodeficiency and dysregulation disease activity endpoints were significantly associated with increases in the patient global assessment (PtGA) and the 36-item short form survey (SF-36) physical component score and mental component score (PCS/MCS). Increasing proportion of naïve B cells was associated with reduction in infection rates (2.3% fewer infections per 1% increase in naïve B cells). In this clinical trial setting, short-term improvements in immunodeficiency and dysregulation following treatment with leniolisib were associated with longer-term improvements in clinical outcomes, including infection rates and quality of life, for patients with APDS.
2026-09-13 | Case Report: Activated phosphoinositide 3-kinase δ syndrome mimicking Hyper-IgM syndrome: early hepatosplenomegaly as a key diagnostic clue.
APDS is a combined immunodeficiency disorder, characterized by impaired antibody production and lymphoproliferation, with a high risk of malignancy and autoimmunity. The disease may be caused by autosomal dominant gain-of-function variants in the PIK3CD or loss-of-function variants in the PIK3R1 gene. We report an 11-year-old girl with a history of recurrent respiratory infections, lymphoproliferation, and hepatosplenomegaly from early childhood. She was diagnosed with Hyper-IgM syndrome (HIGM) because of decreased IgA and IgG but increased IgM, and was treated with immunoglobulin replacement therapy, but there was no improvement in respiratory symptoms, and hepatosplenomegaly remained marked. Immunologic testing showed that, in addition to a reduced peripheral B-cell count, there was also a reduced CD4+ T-cell count and an inverted CD4/CD8 ratio, suggesting a diagnosis other than classical HIGM. The patient was diagnosed with APDS, confirmed by whole-exome sequencing, identifying the PIK3CD c.3061G>A p.(Glu1021Lys) variant. The patient maintained on immunoglobulin replacement therapy and corticosteroid therapy, with subsequent addition of sirolimus, and showed a rapid response with improvement in chronic productive cough, enlarged lymph nodes, and hepatosplenomegaly after 2 months. After 6 months of treatment, lymphodenopathy had resolved, and the liver and spleen returned to normal size. Early hepatosplenomegaly and lymphadenopathy are important warning signs of APDS in children with a Hyper IgM-like phenotype. This is particularly relevant in patients with CD4+ T-cell lymphopenia, an inverted CD4/CD8 ratio, and marked B-cell lymphopenia. Sirolimus improved lymphoproliferative manifestations and partially controlled chronic respiratory and gastrointestinal disease but did not eliminate the need for immunoglobulin replacement therapy.
2026-08-27 | APDS treatment in Germany: decision criteria, costs and contribution of leniolisib to outcomes.
Activated PI3 Kinase Delta Syndrome (APDS) is a rare inborn error of immunity. To better classify the contribution of a potential new therapeutic precision agent, leniolisib, medically relevant decision criteria were assessed upon which an outcomes model was built. Two online surveys and two roundtable discussions with 6 medical and scientific experts were conducted to obtain and discuss clinical and cost components. Based on the discussion results, key decision outcomes were modelled in an outcomes model. Key decision therapeutic criteria of physicians were reliably found in two rounds of Maximum Difference Scaling, with efficacy being most important, followed by safety, disease severity, and quality of life impact. Relevant clinical outcomes in APDS, that were considered well quantifiable, were frequency of infections, lymphoproliferation, bronchiectasis, lymphoma, and mortality. For these outcomes, relevant improvements versus current standard of care were estimated for the new therapeutic precision agent leniolisib. Expert assessments in the online surveys, which were carried out by the 6 participants independently, showed low variance across participants. Ratings resulted in a projected reduction of mortality by use of leniolisib of ~16% at an age of 40 years (95% CI: [9%; 22%]). This age is currently reached only by 65% of APDS patients. Other changes were expected for costs, immunoglobulin replacement, treatment of lymphoma and other malignancies, bronchiectasis, and advanced lung disease, as well as allogeneic hematopoietic cell transplantation (alloHCT). Decision criteria of physicians for treating APDS are well in line with other therapeutic areas, with efficacy considered to be most relevant. Based on currently available data on leniolisib therapy, mortality and several patient-relevant morbidity endpoints are expected to improve in future clinical practice in Germany. Leniolisib may significantly modify the course of disease in APDS patients.
2026-08-20 | Living with Primary Immunodeficiencies: CVID—Enteropathy from the Perspective of a Gastroenterologist
Common variable immunodeficiency (CVID), the most prevalent symptomatic primary antibody deficiency (∼1:25,000), in its symptomatic spectrum reaches way beyond intractable, chronic, and recurrent infections. Noninfectious enteropathy (CVID-E)—affecting 15–30% of patients—has emerged as a pivotal manifestation of the natural disease trajectory, with approximately 11-fold increased mortality risk. CVID-E is pathologically determined by villous atrophy, absent mucosal plasma cells, and abundant CD8+ T cell infiltration—yielding the phenotype that often mimics celiac disease. There are three pathogenic determinants that have been elucidated so far. First, almost absent mucosal IgA is permeating and facilitating gut pathogen expansion. With this process, gut membrane lipid metabolism is shifted toward inflammatory cascades, which may render an inflammatory bowel disease (IBD)-like phenotype. Second, a mixed and specific type I/III and type II interferon release drives CD8+ T cell cytotoxicity and macrophage recruitment, producing a graft-versus-host-like mucosal damage pattern yielding apparent villous injury. Third, chronic norovirus infection further augments this interferon-driven pathway, leading to high-grade epithelial damage even in early-onset disease. USIDNET registry analysis (n = 1,415) confirmed that CVID-E patients exhibit significantly lower performance status, higher rates of concomitant autoimmunity (30.7%), granulomatous disease, and even malignancy. Treatment is largely empirical with limited evidence-based data. Immunoglobulin replacement does not mitigate symptoms of enteropathy, and although corticosteroids restore architecture, they impose prohibitive infectious risk. Although TNF-α blockers and thiopurines achieved complete remission in select patient cohorts, overall therapeutic response was unsatisfying. Molecular medical tactics—employing JAK inhibitors targeting the interferon-specific pathways, namely abatacept for CTLA-4-related dysregulation—represent the most promising tool. CVID-E is a complicated disorder because it stands at the very intersection of immunodeficiency, immune dysregulation, and mucosal pathology where these determinants encompass collapsed humoral defense, gut dysbiosis, and unbalanced interferon-driven epithelial necrosis converge. Multicenter randomized controlled trials and precision therapeutics are urgently needed to supersede the current empirical interventions with a fully evidence-based approach.
2026-07-15 | A scientometric analysis of research related to the 'oral-placental axis' hypothesis: current status, hotspots, and future directions.
Oral diseases and placental disorders are closely associated with adverse pregnancy outcomes, and accumulating evidence supports their crosstalk that constitutes the "oral-placental axis". This study integrated scientometric and bioinformatic approaches to systematically analyze global research trends, collaboration networks, research hotspots, and core molecular-microbial mechanisms of the oral-placental axis covering the period from 2016 to 2025. A total of 196 eligible publications were retrieved from the Web of Science Core Collection, Scopus, and PubMed. Bibliometric visualization was performed using VOSviewer, CiteSpace, and R-bibliometrix, and bioinformatic analysis was conducted to identify shared genes, signaling pathways, and microbial links between oral and placental diseases. The results revealed an annual publication growth rate of 5.03%, with the United States, China, and Australia as major contributing countries, the University of Queensland as the leading institution, and Gomez-Arango Luisa F. and Nitert Marloes Dekker as the most influential authors. Core keywords included preterm birth, periodontal diseases, gestational diabetes mellitus, and oral microbiome, reflecting a research shift from phenotypic association to mechanistic exploration such as microbial vertical transmission and inflammatory signaling. Mechanistic analyses identified shared hub genes (e.g., KRT19, ADAMDEC1, AQP9, SPAG4, PLAT) and key pathways, predominantly primary immunodeficiency and complement and coagulation cascades. Pathogenic bacteria including Fusobacterium nucleatum and Porphyromonas gingivalis mediated adverse pregnancy outcomes via hematogenous spread and placental barrier disruption. This study established a bidirectional regulatory model of the oral-placental axis involving shared risks, microbial transmission, and systemic inflammation, providing a theoretical basis for preconception oral intervention and precise prevention during pregnancy, and supporting the integration of oral care into routine perinatal management.
antibodies
2026-09-25 | Levels of IgG subclasses 1-4 in BT595, a 10% IVIG: A sub-analysis of a clinical trial.
The 10% intravenous immunoglobulin (IVIG) BT595 was evaluated in an open-label, prospective, multicenter clinical trial (Trial 991; NCT02810444) to characterize IgG subclass pharmacokinetics as replacement therapy in patients with primary immunodeficiency (PID). Patients received BT595 at either a 3-week (Q3W) or 4-week (Q4W) dosing interval for approximately 12 months. Secondary endpoints included steady state trough concentrations and pharmacokinetic parameters of IgG subclasses 1-4 and total IgG. IgG subclass trough concentrations were assessed at baseline and at steady state prior to the 7th infusion (Q3W) or 5th infusion (Q4W). Pharmacokinetic parameters at steady state were determined in patients aged ≥6 years using serum samples collected predose and up to 28 days post infusion. At steady state, trough concentrations of total IgG and all IgG subclasses were comparable between BT595 and patients' previous IVIG therapy, indicating preservation of systemic IgG exposure following treatment switch. IgG subclass trough concentrations were stable across dosing regimens and age categories, with a proportional distribution closely matching physiological IgG composition. IgG1 and IgG2 accounted for the majority of total IgG, whereas IgG3 and IgG4 contributed smaller fractions, consistent with endogenous IgG and published IVIG data. Pharmacokinetic profiles of all IgG subclasses were consistent with those reported for licensed IVIG products. Maximum concentrations occurred rapidly after infusion, and systemic exposure was robust under both dosing regimens. Mean concentrations and Cmax values were higher with Q3W dosing, while exposure over the dosing interval (AUCtau) was lower compared with Q4W dosing due to the shorter interval. Estimated half-life values were within or above ranges reported for other IVIG products, with numerically prolonged persistence of IgG2 and IgG4 under Q4W dosing. Overall, BT595 provides sustained IgG subclass exposure at steady state, supporting its suitability as IVIG replacement therapy in PID under both Q3W and Q4W regimens.
2026-09-24 | Appraisal of primary immunodeficiencies in Latin America and the Caribbean using the IPOPI PID Life Index – where are we now?
Objective Analyse the implementation of the 6 Principles of Care (PoC) for primary immunodeficiencies (PIDs) in Latin America and the Caribbean countries. Methodology Data was extracted from the IPOPI PID Life Index, an interactive tool measuring how it is to live with a PID in the 13 countries in Latin America and the Caribbean (Argentina, Bolivia, Brazil, Chile, Ecuador, El Salvador, Honduras, Mexico, Paraguay, Peru, Puerto Rico, Uruguay and Venezuela). Results Care for PIDs in the region varies greatly. Low diagnostic rates and limited diagnostic test options are a reality for the region. Almost all countries provide certain therapies for the treatment of PIDs, mostly anti-infectious therapies, immunoglobulin replacement therapies and vaccines. Biological therapies and curative treatments are less frequent in the countries covered. Universal health coverage for people living with PIDs remains heterogeneous and incomplete. Specialised centres and registries are also heterogeneously implemented. National organisations representing patients with PIDs exist in almost all countries, mainly focussing on general and medical awareness raising, and patient support through social activities. Discussion and conclusion PID care in Latin America and the Caribbean is steadily becoming a reality for many people living with PID. There have been significant improvements in terms of diagnosis, treatment and care in the region over the past decades. Still, there are significant inequalities across the different countries for the 6 PoCs for PID analysed. Joint efforts of medical specialists and patient organizations must continue to ensure an optimal environment for people living with PIDs in the region.
2026-08-28 | Beyond B cells: T and Innate Immune Mechanisms of Autoimmunity in Common Variable Immunodeficiency.
Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency, affecting approximately 1 in 25 000-50 000 individuals. Although classically characterized by hypogammaglobulinemia and recurrent bacterial infections, over 50% of patients develop non-infectious complications that constitute the major determinants of morbidity and mortality. The coexistence of immunodeficiency and immune dysregulation challenges the traditional B-cell-centric model of CVID pathogenesis. In this narrative review, we synthesize current evidence demonstrating that autoimmune manifestations in CVID arise from complex, multilayered immune dysfunction extending far beyond the B-cell compartment. Key abnormalities include Th1-skewed CD4⁺ T-cell responses with persistent IFN-γ production, numerical and functional defects in regulatory T cells, disruption of follicular T-cell subset balance favoring autoreactive germinal center responses, and progressive CD8⁺ T-cell exhaustion. At the innate immune level, NK-cell lymphopenia, constitutive monocyte activation, dendritic cell deficiency, neutrophil dysregulation, and proinflammatory innate lymphoid cell activity collectively contribute to the breakdown of self-tolerance. These immune perturbations are further amplified by systemic cytokine dysregulation. Pathogenic variants identified in patients with CVID-like disorders may further underlie autoimmune pathology and immune dysregulation, particularly those affecting T-cell co-stimulation, immune checkpoint signaling, NF-κB, and PI3K pathways. Collectively, CVID-associated autoimmunity represents a paradigm of systems-level immune dysregulation, underscoring the need for comprehensive immune phenotyping, genotype-informed stratification, and precision immunomodulatory strategies targeting the full spectrum of immune abnormalities involved.
2026-08-21 | Expert consensus recommendations for the prevention and management of immunoglobulin therapy-related adverse reactions in primary and secondary immunodeficiencies: a national Delphi study from the Immunodeficiency Group of the Spanish Society of Immunology.
Human immunoglobulin (IG) therapy, administered intravenously (IVIG) or subcutaneously (SCIG), is a cornerstone treatment for primary and secondary immunodeficiencies (PID and SID) and is increasingly used in autoimmune and inflammatory diseases. Although generally safe, adverse drug reactions (ADR) may affect treatment adherence, patient safety, and quality of care. Practical recommendations for the prevention and management of IG-associated ADR remain limited. To develop expert-based recommendations for the prevention, monitoring, classification, and management of ADR associated with IVIG and SCIG therapy in patients with PID and SID. A modified Delphi consensus was conducted by the Immunodeficiency Group of the Spanish Society of Immunology (GISEI). An expert coordinating committee developed 44 preliminary statements based on scientific evidence and clinical experience. Statements covered eight domains, including administration practices, ADR classification, premedication, acute management, complementary studies, anti-IgA antibodies, and SCIG-related issues. A national panel of specialists evaluated each statement using a 6-point Likert scale. Consensus was defined as ≥75% agreement. Forty-two recommendations achieved consensus and were included in the final document. High agreement was reached regarding individualized risk assessment, infusion rate adjustment, patient monitoring, and early ADR management. Most IVIG-related ADR were considered mild, occurring during or shortly after infusion, and generally not requiring treatment discontinuation. Premedication was recommended only for selected high-risk patients. SCIG was recognized as a safe and effective alternative associated with fewer systemic reactions and predominantly mild local ADR. The panel also highlighted the limited utility of serial anti-IgA antibody testing and emphasized patient education and periodic retraining for home-based SCIG administration. This Delphi-based consensus provides practical and clinically applicable recommendations for the prevention and management of ADR associated with IVIG and SCIG therapy. These recommendations may contribute to standardizing clinical practice, improving patient safety, optimizing treatment tolerability, and reducing variability in IG administration across healthcare settings. Further prospective studies are needed to better define risk factors and preventive strategies for severe ADR associated with IG therapy.
2026-08-20 | SGPI 2026 2nd International Symposium on Inborn Errors of Immunity of the Serbian Group for Primary Immunodeficiencies - PDF
A collection of abstracts from the SGPI 2026 2nd International Symposium on Inborn Errors of Immunity of the Serbian Group for Primary Immunodeficiencies, April 24–25, 2026, Belgrade and Novi Sad, Serbia. All abstracts were reviewed and approved by the SGPI scientific committee, which held full responsibility for the abstract selections.
other
2026-07-28 | Evolution of Inborn Errors of Immunity in China: Discoveries and Treatment Paradigms.
Inborn errors of immunity (IEI) are monogenic disorders of the immune system that lead to immunodeficiency, autoimmunity, autoinflammation, allergy, and/or cancer. This review provides a comparative review of the epidemiology, clinical manifestations, and management of IEI in China. While individual forms of IEI are generally rare disorders globally, collectively they represent a significant disease burden. China has recently made great strides in the diagnosis and treatment of IEIs with the increasing utility of next-generation sequencing and the availability of hematopoietic stem cell transplantation. Challenges remain in the establishment of national registry databases comparable to the European Society for Immunodeficiencies and The United States Immunodeficiency Network. Also, the absence of a national newborn screening program for severe combined immunodeficiency poses risks regarding live attenuated vaccination in undiagnosed infants. Current access to treatment including subcutaneous immunoglobulin, targeted molecular therapies, and commercialized gene therapy remains limited in China. Nevertheless, the therapeutic landscape is rapidly evolving, marked by an increasing clinical application of precision molecular-targeted treatments and the emergence of AI-empowered gene editing therapies. Ultimately, advancing the field of IEI necessitates global collaboration, integrating the complementary strengths of both regions to establish scientific breakthroughs and clinical innovation.
2026-06-24 | Disseminated BCGosis in immunocompromised infants: a five-case series in the context of a national BCG vaccination policy change.
Disseminated Bacillus Calmette-Guérin (BCG) infection (BCGosis) is a rare but serious complication that primarily affects infants with underlying immunodeficiency disorders. In Saudi Arabia, where consanguinity rates are high and primary immunodeficiency disorders are more prevalent, concerns have been raised regarding the safety of routine neonatal BCG vaccination. In 2019, the national immunization schedule was revised to delay BCG vaccination from birth to six months of age. This retrospective case series was conducted at a tertiary referral center in Jeddah, Saudi Arabia. Pediatric patients diagnosed with disseminated BCGosis between 2016 and 2023 were identified through electronic medical records. Disseminated BCGosis was defined as systemic infection with involvement of two or more noncontiguous organ systems with microbiological or molecular confirmation of Mycobacterium bovis. Clinical, microbiological, and immunological data were collected and analyzed descriptively. Five cases of disseminated BCGosis were identified during the study period, all occurring in immunocompromised infants who had received BCG vaccination at birth. Underlying primary immunodeficiency disorders included defects in the IL-12/interferon-gamma pathway and severe combined immunodeficiency. The median age at presentation was approximately 7 months. Clinical manifestations included persistent BCG-site inflammation, lymphadenopathy, and systemic symptoms. The interval from symptom onset to diagnosis ranged from 4 weeks to 7 months, with longer delays observed in cases presenting initially with localized disease. All cases were confirmed microbiologically. One patient died despite treatment, while the remaining patients responded to prolonged anti-tuberculous therapy and adjunctive immunotherapy. No cases of disseminated BCGosis were identified at our institution in the four years following the implementation of delayed BCG vaccination. This case series describes disseminated BCGosis occurring exclusively in immunocompromised infants vaccinated at birth and not being observed after the implementation of delayed BCG vaccination. Given the observational design and small sample size, these findings should be interpreted with caution. Delaying BCG vaccination may reduce exposure to live vaccination in vulnerable infants without apparent compromise of tuberculosis control. Multicenter studies are needed to validate these observations and inform immunization strategies in high-risk populations.
2026-05-25 | Modeling and correction of SCID-X1 using CRISPR-Cas9 homology-directed repair in human HSPCs.
X-linked severe combined immunodeficiency (SCID-X1) is a severe primary immunodeficiency caused by mutations in the IL2RG gene, a shared subunit of cytokine receptors critical for the development and function of T and natural killer (NK) cells. The standard treatment, allogeneic hematopoietic stem cell transplantation (HSCT), requires a compatible donor and is often associated with significant transplant-related complications. We aimed to develop a more robust and universal gene therapy by ex vivo modification of patient hematopoietic stem and progenitor cells (HSPCs) using the CRISPR-Cas9/rAAV6 gene-editing platform. To evaluate efficiency, we utilized a feeder-free, in vitro platform enabling T and NK cell differentiation from modified HSPCs. We investigated two approaches: the cut-site method (inserting a corrective cassette downstream of the start codon within the IL2RG locus) and a replacement method (replacing the entire IL2RG gene under endogenous regulation). We demonstrated that the cut-site insertion strategy is preferable for SCID-X1 correction, achieving superior homology-directed repair rates, lower toxicity, and significantly improved T and NK cell differentiation, based on phenotypic marker expression. Importantly, corrected patient-derived HSPCs from two SCID-X1 patients, modified using the cut-site approach, successfully demonstrated phenotypic evidence of T cell differentiation. Therefore, our findings firmly establish the feasibility of the cut-site strategy as a universal, high-efficiency, therapeutic solution for SCID-X1.
2026-02-16 | Gene therapy for inborn errors of immunity: past progress, current status and future directions.
Inborn errors of immunity (IEIs), also known as primary immunodeficiencies, are a group of rare inherited disorders that affect the immune system. They result in severe, opportunistic infections, severe autoimmune manifestations and a predisposition to malignancy. The only curative treatment for many years has been allogenic haematopoietic stem cell transplantation (alloHSCT). However, this requires the availability of a suitable donor and has risks of morbidity and mortality. Autologous gene therapy (GT) abrogates the immunological complications of alloHSCT and uses the patient's own cells, removing the need for a donor. Preclinical proof-of-concept and clinical trials in humans have demonstrated that GT is safe and effective and can be used to correct a variety of IEIs. In this review, we outline the progress in developing GT for IEIs over the last four decades. We describe the gene editing technologies available to correct IEIs and their current applications. We also examine advances in GT development, the challenges to its application, and discuss future developments in the field, including emerging in vivo approaches.
2026-02-10 | Research Progress on Chronic Granulomatous Disease in Children.
Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder characterized by defective neutrophil oxidative burst function, leading to impaired host defense against pathogenic microorganisms. This condition significantly increases the risk of invasive infections in affected patients. However, the clinical manifestations of CGD are not limited to infection-related complications; non-infectious complications can also lead to a variety of clinical symptoms. The global occurrence rate of CGD varies, and its inheritance patterns include X-linked and autosomal recessive forms. Research indicates that CGD patients are predominantly children who frequently face life-threatening infections and related complications, with early diagnosis often being challenging. Currently, hematopoietic stem cell transplantation (HSCT) is the only widely applied curative treatment for CGD. Recent advances in gene therapy offer a promising, safer, and more directly suitable alternative. This review primarily focuses on the pathophysiology, molecular genetics, occurrence rate, clinical manifestations, laboratory diagnosis, and cellular therapies of pediatric CGD, aiming to offer ideas for its clinical diagnosis.
cell therapies
2026-09-10 | X-linked hyper-IgM syndrome presenting as severe Pneumocystis pneumonia in a 6-month-old infant: a case report.
X-linked hyper-immunoglobulin M (XHIGM) syndrome is a rare primary immunodeficiency caused by mutations in the CD40 ligand gene (CD40LG), characterized by defective T-cell-dependent B-cell class-switch recombination. Patients typically present with recurrent infections in early childhood, but diagnosis is often delayed due to heterogeneous clinical manifestations and the fact that serum IgM levels may remain within the normal range in a significant proportion of patients. Here we report a case of XHIGM in an infant whose diagnostic journey began with recurrent lymphadenitis and culminated in life-threatening Pneumocystis jirovecii pneumonia (PJP). A 6-month-old male infant was admitted with severe respiratory distress and hypoxemia. He had recurrent axillary lymphadenitis at 1 and 2 months of age and significant failure to thrive. Chest CT showed bilateral consolidative and interstitial opacities. Immunological evaluation revealed markedly decreased IgA, normal IgM and IgG, and profound T-cell lymphopenia. Sputum metagenomic sequencing identified Pneumocystis jirovecii. Whole-genome sequencing identified a hemizygous likely pathogenic CD40LG mutation (NM_000074.3:c.520C>T, p.Q174*); his mother was a carrier. He was treated with mechanical ventilation, trimethoprim-sulfamethoxazole (TMP-SMX), micafungin, corticosteroids, and intravenous immunoglobulin (IVIG), and was discharged after 36 days. In infants with recurrent or opportunistic infections, persistently low IgA and declining T-cell counts-even when initial screening appears normal-should raise suspicion for underlying immunodeficiency and prompt genetic evaluation. Early aggressive management and evaluation for hematopoietic stem cell transplantation are essential to improve outcomes.Serial immunological evaluation is essential in infants with recurrent or opportunistic infections, as persistently low IgA and declining T-cell counts-even when initial screening appears normal-should prompt genetic evaluation for underlying immunodeficiency. Early aggressive management and evaluation for hematopoietic stem cell transplantation are essential to improve outcomes.
2026-08-29 | Clinical spectrum and survival outcomes of malignancies in pediatric patients with inborn errors of immunity.
Inborn errors of immunity (IEI) predispose patients to malignancy, particularly lymphoma, but data on diagnostic sequence and outcomes are limited. We retrospectively analyzed IEI-associated malignancies diagnosed at a single center between January 2004 and December 2025. Among 1,668 patients with IEI, 67 (4.0%) developed malignancy. Median ages at IEI and malignancy diagnosis were 8 and 10 years, respectively. Malignancy-first presentation occurred in 45 patients (67%), especially adolescents, and was associated with advanced-stage disease (p = 0.007). Lymphoid malignancies accounted for 90% of cases; non-Hodgkin lymphoma and Hodgkin lymphoma comprised 54% and 36%, respectively, and 84.7% presented with stage III-IV disease. Median event-free and overall survival were 66 and 155 months, respectively. In a clinically selected multivariable Cox model, NHL, solid/plasma cell tumors, older age at malignancy diagnosis, and DNA repair defect status were associated with worse OS. Twelve patients underwent allogeneic HSCT; one died early, and no post-transplant relapses occurred. Early immunologic evaluation and timely, individualized consideration of HSCT may support optimized management in children and adolescents, in whom cancer may be the first manifestation of IEI.
2026-08-26 | Pulmonary alveolar proteinosis and Pneumocystis jirovecii infection in an infant with hyper-IgM syndrome caused by a novel CD40LG variant: a case report.
Pulmonary alveolar proteinosis (PAP) is a rare interstitial lung disease. While autoimmunity is the leading cause of PAP in adults, the majority of pediatric cases occur secondary to immunodeficiency and opportunistic infections. Secondary PAP associated with CD40 ligand (CD40L) deficiency is extremely rare, and the underlying pathophysiology remains poorly understood. We report the case of a 4-month-old boy admitted due to failure to thrive and severe hypoxemic respiratory failure. Chest computed tomography demonstrated diffuse ground-glass opacities with interlobular septal thickening. Bronchoalveolar lavage yielded clear fluid containing Periodic acid-Schiff-positive material consistent with PAP, and polymerase chain reaction was positive for Pneumocystis jirovecii. An immunologic evaluation showed hypogammaglobulinemia (IgG and IgA), a normal IgM level for his age, an absence of class-switched memory B cells, and significantly reduced CD40L expression on activated T lymphocytes. Targeted genetic testing identified a previously unreported hemizygous CD40LG missense variant [c.137T>C, p.(Leu46Pro)]. Integration of the patient's immunophenotype, an in silico variant evaluation, and segregation data permitted classification of this variant as likely pathogenic, confirming X-linked hyper-IgM syndrome. The patient improved with ventilatory support, high-dose trimethoprim-sulfamethoxazole, and immunoglobulin replacement therapy. Early-onset PAP associated with P. jirovecii infection may reveal CD40L deficiency and should prompt evaluation for primary immunodeficiency. An integrated clinico-immunologic assessment coupled with genetic testing is essential to provide a molecular diagnosis, guide management, and prognostication, and to support timely consideration of curative hematopoietic stem cell transplantation.
2026-06-23 | Unmanipulated Haploidentical Stem Cell Transplantation Outcome in a Pediatric Patient With CD27 Deficiency and EBV-Induced Diffuse Large B-Cell Lymphoma With Primary CNS Involvement.
CD27 deficiency is a rare primary immunodeficiency associated with severe Epstein-Barr virus (EBV)-related complications, including lymphoma. We report a pediatric patient with CD27 deficiency who developed EBV-associated diffuse large B-cell lymphoma with primary CNS involvement and early relapse. The patient underwent unmanipulated haploidentical stem cell transplantation using post-transplant cyclophosphamide. Engraftment was successful, graft-versus-host disease was controlled, and full donor chimerism was achieved. After 40 months, the patient remains free of GVHD, PID, and lymphoma relapse, demonstrating successful lymphoma control and correction of the underlying immunodeficiency, thereby highlighting the feasibility of haploidentical HSCT in these patients.
2026-05-08 | Clinical, immunological, treatment characteristics, and outcomes in 22 patients with major histocompatibility complex class II deficiency.
Major histocompatibility complex (MHC) class II deficiency is a rare, life-threatening primary immunodeficiency that presents in early infancy with a SCID phenotype. However, emerging data indicate substantial clinical and immunological heterogeneity, including atypical presentations and neurological involvement. We retrospectively evaluated the clinical, immunological, genetic, and treatment-related characteristics and outcomes of 22 patients from 19 unrelated families diagnosed with MHC class II deficiency at a single referral center (2000-2019). Ten patients underwent HSCT at our center; transplant-related outcomes were evaluated, and long-term follow-up data were available for the six surviving patients through 2025. The median age at symptom onset and diagnosis was 9 and 12 months, respectively. Pneumonia, chronic diarrhea, and failure to thrive were the most common presenting features; neurological manifestations and developmental delay were observed in a subset of patients. Two patients showed residual HLA-DR expression and survived with a milder clinical course. CD4+ T cell lymphopenia and humoral dysfunction were consistent, while total lymphocyte counts were variable. RTE levels were mildly to moderately reduced in all tested patients, suggesting impaired thymic output. Severe viral infections were frequent and could be rapidly fatal. Fourteen patients required PICU admission, associated with high mortality. Genetic analysis (n:15) identified homozygous pathogenic variants in RFXANK (n=5), RFXAP (n=4), RFX5 (n=3), and CIITA (n=3). Ten patients underwent HSCT, with superior survival compared to non-transplanted patients (60% vs. 18%). Among transplanted patients, survival appeared higher following RTC than MAC (75% vs. 50%). Post-transplant mortality was observed in association with severe pre-transplant disease, delayed diagnosis, graft failure, and infectious complications. At ≥10 years post-HSCT, all survivors were IVIG-independent; CD4+ T cell recovery was higher after MAC than RTC, while T-cell chimerism remained mixed in both groups. MHC class II deficiency is a SCID-like pediatric immunological emergency that is fatal without HSCT in most patients. Early diagnosis is critical, as initial infections may be rapidly progressive. HSCT provides durable engraftment and sustained clinical stability in long-term survivors. Incorporating HLA-DR expression analysis into first-line immunological screening, even in the absence of profound lymphopenia, may facilitate earlier diagnosis, prompt HSCT referral, and improve survival.
proteins
2026-09-28 | Multi-Indication Budget Impact Analysis of Subcutaneous IgPro20 Pre-filled Syringes for the Treatment of Primary Immunodeficiency Syndromes, Secondary Immunodeficiencies, and Chronic Inflammatory Demyelinating Polyneuropathy in Italy.
Primary immunodeficiency (PID) and secondary immunodeficiency (SID) are chronic conditions associated with impaired immune function and increased susceptibility to infections. Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare autoimmune neurological disorder characterized by progressive motor and sensory deficits due to immune-mediated demyelination of peripheral nerves. Patients with these diseases often require long-term immunoglobulin (IG) therapy, which can be costly and burdensome, particularly when administered intravenously in hospital settings. IgPro20 pre‑filled syringes (PFS) offer a simplified, subcutaneous IG alternative that may reduce treatment burden and improve cost‑efficiency. The aim of this study was to estimate the budget impact of introducing IgPro20 PFS into the Italian healthcare system for patients with PID, SID, and CIDP. A population-based budget impact model was developed in Microsoft Excel® from the perspective of the Italian National Health Service (Servizio Sanitario Nazionale). The model used a 3-year time horizon and incorporated drug acquisition, administration, and adverse event costs. Model comparators included intravenous and subcutaneous IG and IgPro20 vials. Population estimates and market shares were informed by Italian affiliates. The introduction of IgPro20 PFS resulted in total cost savings of €31,524,488 for 4794 patients over 3 years. Savings were distributed across PID (€8,840,041), SID (€5,413,035), and CIDP (€17,271,412). Sensitivity analyses identified IgPro20 PFS and vial pricing as key drivers. IgPro20 PFS are a cost-saving, patient-centric treatment option for PID, SID, and CIDP. These findings support their adoption in Italy's healthcare system and may inform policy and payer decisions at regional and national levels.
2026-09-24 | Cardiac tamponade caused by effusive-constrictive pericarditis in a patient with common variable immunodeficiency: a case report.
Common variable immunodeficiency (CVID) is an immunodeficiency syndrome that is marked by impaired antibody formation and chronic infections. However, it is also associated with immune dysregulation and non-infectious inflammatory disorders. Cardiac involvement is not common, but effusive-constrictive pericarditis (ECP) complicated by cardiac tamponade is rarely seen in CVID patients. A 17-year-old male patient with CVID (diagnosis made in 2022) under regular replacement therapy with monthly intravenous immunoglobulin (IVIG) was admitted due to progressive dyspnea, dry cough, weakness, fatigue, and severe hypoxemia lasting for several days. Previous medical history included frequent lower respiratory tract infections, inflammatory bowel disease, celiac disease, malnutrition, and psoas abscess. Admission examination revealed arterial blood pressure 90/60 mmHg, oxygen saturation 75% in room air, increased jugular venous pressure, dullness in auscultation, pulsus paradoxus, bilateral rales and peripheral edema. Echo showed a 12-15 mm thick pericardial effusion, mobile fibrin-rich mass in pericardium, dilatation of inferior vena cava (23 mm with < 50% collapse), respiratory variation of mitral and tricuspid inflow with septal bounce. Left ventricle ejection fraction was 40%. Pericardiocentesis was done in an emergency manner and 320 ml of turbid serosanguineous effusion with fibrinous clots was drained. Microbiologic investigations of the sample including bacteriological cultures, acid-fast bacilli, mycobacteria, and MTB/RIF showed negative results. There were no malignant cells in cytological and cell-block analysis. After pericardiocentesis, central venous pressure remained elevated and Doppler investigation showed signs of constrictive physiology such as more than 25% variation in mitral inflow, expiratory reverse flow in hepatic veins, plethoric IVC, and septal bounce, which helped to confirm ECP. Ventricular function and constrictive physiology gradually improved after supportive therapy and IVIG and nutrition treatment without pericardiectomy. ECP with tamponade is a rare life-threatening complication in CVID patients. In the case of unexplained cardiopulmonary failure in an immunocompromised patient, tamponade cannot be considered only due to the infection. Urgent echocardiography, drainage, and investigation of various infectious, tuberculous, malignant and inflammatory causes is crucial.
2026-07-15 | Bronchiectasis With Inborn Errors of Immunity: Zooming in on Predominantly Antibody Deficiencies.
Bronchiectasis is a chronic inflammatory lung disease characterized by permanent airway dilation, mucus production, recurrent infections, and progressive structural injury. Inborn errors of immunity (IEIs), particularly predominantly antibody deficiencies (PADs), are important and potentially under-recognized causes of non-cystic fibrosis bronchiectasis (NCFB). Antibody deficiency increases susceptibility to bacterial infection, but the observation that bronchiectasis develops in only a subset of patients with PADs, and may develop despite immunoglobulin replacement therapy (IGRT), indicates that serum antibody measurements alone do not fully define the airway risk. Bronchiectasis in IEI likely reflects the interaction of impaired systemic humoral immunity impacting mucosal immune defenses, altered IgG transport or catabolism, B-cell dysregulation, T-cell and innate immune dysfunction, autoimmunity, environmental exposures, comorbid lung disease, and chronic airway infection. In this review, we summarize reported frequencies of NCFB among selected IEIs with antibody deficiency, discuss the limitations of IgG subclass and serum-based antibody testing as predictors of airway disease, and review evidence supporting higher individualized IGRT dosing in patients with antibody deficiency and bronchiectasis to achieve therapeutic IgG levels. We also propose a practical clinical framework for evaluating immune defects in bronchiectasis and for longitudinal pulmonary screening in patients with IEIs at increased risk of bronchiectasis.
2026-07-11 | Evaluation of sleep, fatigue, and quality of life in patients with primary immunodeficiency.
Primary immunodeficiency (PID) is a heterogeneous group of genetic disorders characterized by recurrent infections and immune dysregulation. Despite advances in therapy, many patients experience impaired quality of life (QoL), fatigue, and sleep disturbances. This study aimed to evaluate sleep quality, fatigue, and health-related QoL in adults with PID and to explore the associations between comorbidities and treatment modalities. This retrospective, observational, single-center study was conducted at the University of Health Sciences, Gülhane Training and Research Hospital between May and August 2024. Forty-nine adult patients with PID, diagnosed according to international criteria, completed validated questionnaires: the Pittsburgh Sleep Quality Index (PSQI), Fatigue Severity Scale (FSS), and SF-36 QoL scale. Clinical and demographic data were retrieved from the medical records. Statistical analyses included t-tests, Mann-Whitney U, chi-square, and Pearson's correlation, with significance set at P < 0.05. Of 49 patients (55.1% males, mean follow-up 9.9 years), 36.7% had poor sleep quality, 42.9% reported severe fatigue, 49% showed impaired SF-36 physical scores, and 87.8% had preserved mental scores. Poor sleep quality was correlated positively with fatigue (r = 0.623, P < 0.001) and negatively correlated with physical QoL (r = -0.491, P < 0.001). Patients with autoimmune and inflammatory bowel disease had significantly worse PSQI and FSS scores, whereas bronchiectasis was associated with reduced SF-36 physical scores. No differences were observed between the IVIG and SCIG groups in fatigue or mental scores; however, SCIG recipients had significantly higher physical scores (P = 0.018). Patients with PID experience substantial impairment in physical QoL, with fatigue and poor sleep quality frequently coexisting. Comorbidities, such as autoimmunity, bronchiectasis, and inflammatory bowel disease, exacerbate these impairments. SCIG therapy confers better physical outcomes than IVIG therapy. Comprehensive care strategies that address psychosocial and physical health are essential for the management of PID.
2026-07-06 | Adult-Onset LRBA Deficiency Presenting with Rheumatoid Arthritis-Like Manifestations: A Case Report.
Lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency is a primary inborn error of immunity characterized by immune dysregulation and frequently associated with autoimmune connective tissue manifestations. We describe an adult woman diagnosed with rheumatoid arthritis who was subsequently found to have LRBA deficiency based on genetic testing and investigated inflammatory proteins potentially involved in the pathogenesis of LRBA deficiency. A 44-year-old woman with rheumatoid arthritis presented with persistent diarrhea and abdominal distention lasting over eight months. Abdominal imaging revealed intestinal pseudo-obstruction. Her medical history included megaloblastic anemia, type 1 diabetes, and chronic thyroiditis since childhood. Her brother had died of unexplained diarrhea during childhood. Given her multiple autoimmune manifestations and family history, a primary immune deficiency (PID) was suspected. Genetic analysis identified a heterozygous LRBA splice-site variant (c.1162-1G > A) and a possible heterozygous deletion involving exons 18-41, suggesting compound heterozygous LRBA variants. Thus, the diagnosis of LRBA deficiency-associated autoimmunity. Following the diagnosis, she was treated with abatacept, a CTLA4-immunoglobulin fusion protein, resulting in improvement of gastrointestinal symptoms. Proximity extension assay (Olink® Target) revealed marked decreases in serum interleukin-17 A (from 3.36 to 2.22 normalized protein expression), tumor necrosis factor (3.26 to 0.69), and chemokine (C-C motif) ligand 20 (3.14 to 0.84) after treatment. LRBA deficiency is characterized by an imbalance of CD4⁺ T cells with increased Th1 and Th17 populations and reduced regulatory T cells. This case highlights that patients with PID, including LRBA deficiency, can present with autoimmune manifestations, and abatacept may represent an effective targeted treatment option for LRBA-deficiency.
small molecules
2026-09-17 | Associations Between Short-Term Changes in Disease Activity and Long-Term Clinical Outcomes in Activated Phosphoinositide 3-Kinase Delta Syndrome.
Clinical trials in activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS), an ultra-rare disease, have evaluated treatment response to the PI3Kδ inhibitor leniolisib using disease activity endpoints, including those measuring immunodeficiency and immune dysregulation. However, the relationship between disease activity endpoints and long-term clinical outcomes has not been quantified. Data from a randomised controlled trial and its open-label extension (OLE) investigating leniolisib were used to evaluate associations between short-term disease activity endpoints and longer-term clinical outcomes. Both single time point and repeated measures analyses were conducted using linear regression modelling and random effects multilevel regression modelling, respectively. In total, 39 patients were included (≤6 years of follow-up). Improvements in multiple immunodeficiency and dysregulation disease activity endpoints were significantly associated with increases in the patient global assessment (PtGA) and the 36-item short form survey (SF-36) physical component score and mental component score (PCS/MCS). Increasing proportion of naïve B cells was associated with reduction in infection rates (2.3% fewer infections per 1% increase in naïve B cells). In this clinical trial setting, short-term improvements in immunodeficiency and dysregulation following treatment with leniolisib were associated with longer-term improvements in clinical outcomes, including infection rates and quality of life, for patients with APDS.
2026-09-13 | Case Report: Activated phosphoinositide 3-kinase δ syndrome mimicking Hyper-IgM syndrome: early hepatosplenomegaly as a key diagnostic clue.
APDS is a combined immunodeficiency disorder, characterized by impaired antibody production and lymphoproliferation, with a high risk of malignancy and autoimmunity. The disease may be caused by autosomal dominant gain-of-function variants in the PIK3CD or loss-of-function variants in the PIK3R1 gene. We report an 11-year-old girl with a history of recurrent respiratory infections, lymphoproliferation, and hepatosplenomegaly from early childhood. She was diagnosed with Hyper-IgM syndrome (HIGM) because of decreased IgA and IgG but increased IgM, and was treated with immunoglobulin replacement therapy, but there was no improvement in respiratory symptoms, and hepatosplenomegaly remained marked. Immunologic testing showed that, in addition to a reduced peripheral B-cell count, there was also a reduced CD4+ T-cell count and an inverted CD4/CD8 ratio, suggesting a diagnosis other than classical HIGM. The patient was diagnosed with APDS, confirmed by whole-exome sequencing, identifying the PIK3CD c.3061G>A p.(Glu1021Lys) variant. The patient maintained on immunoglobulin replacement therapy and corticosteroid therapy, with subsequent addition of sirolimus, and showed a rapid response with improvement in chronic productive cough, enlarged lymph nodes, and hepatosplenomegaly after 2 months. After 6 months of treatment, lymphodenopathy had resolved, and the liver and spleen returned to normal size. Early hepatosplenomegaly and lymphadenopathy are important warning signs of APDS in children with a Hyper IgM-like phenotype. This is particularly relevant in patients with CD4+ T-cell lymphopenia, an inverted CD4/CD8 ratio, and marked B-cell lymphopenia. Sirolimus improved lymphoproliferative manifestations and partially controlled chronic respiratory and gastrointestinal disease but did not eliminate the need for immunoglobulin replacement therapy.
2026-08-27 | APDS treatment in Germany: decision criteria, costs and contribution of leniolisib to outcomes.
Activated PI3 Kinase Delta Syndrome (APDS) is a rare inborn error of immunity. To better classify the contribution of a potential new therapeutic precision agent, leniolisib, medically relevant decision criteria were assessed upon which an outcomes model was built. Two online surveys and two roundtable discussions with 6 medical and scientific experts were conducted to obtain and discuss clinical and cost components. Based on the discussion results, key decision outcomes were modelled in an outcomes model. Key decision therapeutic criteria of physicians were reliably found in two rounds of Maximum Difference Scaling, with efficacy being most important, followed by safety, disease severity, and quality of life impact. Relevant clinical outcomes in APDS, that were considered well quantifiable, were frequency of infections, lymphoproliferation, bronchiectasis, lymphoma, and mortality. For these outcomes, relevant improvements versus current standard of care were estimated for the new therapeutic precision agent leniolisib. Expert assessments in the online surveys, which were carried out by the 6 participants independently, showed low variance across participants. Ratings resulted in a projected reduction of mortality by use of leniolisib of ~16% at an age of 40 years (95% CI: [9%; 22%]). This age is currently reached only by 65% of APDS patients. Other changes were expected for costs, immunoglobulin replacement, treatment of lymphoma and other malignancies, bronchiectasis, and advanced lung disease, as well as allogeneic hematopoietic cell transplantation (alloHCT). Decision criteria of physicians for treating APDS are well in line with other therapeutic areas, with efficacy considered to be most relevant. Based on currently available data on leniolisib therapy, mortality and several patient-relevant morbidity endpoints are expected to improve in future clinical practice in Germany. Leniolisib may significantly modify the course of disease in APDS patients.
2026-08-20 | Living with Primary Immunodeficiencies: CVID—Enteropathy from the Perspective of a Gastroenterologist
Common variable immunodeficiency (CVID), the most prevalent symptomatic primary antibody deficiency (∼1:25,000), in its symptomatic spectrum reaches way beyond intractable, chronic, and recurrent infections. Noninfectious enteropathy (CVID-E)—affecting 15–30% of patients—has emerged as a pivotal manifestation of the natural disease trajectory, with approximately 11-fold increased mortality risk. CVID-E is pathologically determined by villous atrophy, absent mucosal plasma cells, and abundant CD8+ T cell infiltration—yielding the phenotype that often mimics celiac disease. There are three pathogenic determinants that have been elucidated so far. First, almost absent mucosal IgA is permeating and facilitating gut pathogen expansion. With this process, gut membrane lipid metabolism is shifted toward inflammatory cascades, which may render an inflammatory bowel disease (IBD)-like phenotype. Second, a mixed and specific type I/III and type II interferon release drives CD8+ T cell cytotoxicity and macrophage recruitment, producing a graft-versus-host-like mucosal damage pattern yielding apparent villous injury. Third, chronic norovirus infection further augments this interferon-driven pathway, leading to high-grade epithelial damage even in early-onset disease. USIDNET registry analysis (n = 1,415) confirmed that CVID-E patients exhibit significantly lower performance status, higher rates of concomitant autoimmunity (30.7%), granulomatous disease, and even malignancy. Treatment is largely empirical with limited evidence-based data. Immunoglobulin replacement does not mitigate symptoms of enteropathy, and although corticosteroids restore architecture, they impose prohibitive infectious risk. Although TNF-α blockers and thiopurines achieved complete remission in select patient cohorts, overall therapeutic response was unsatisfying. Molecular medical tactics—employing JAK inhibitors targeting the interferon-specific pathways, namely abatacept for CTLA-4-related dysregulation—represent the most promising tool. CVID-E is a complicated disorder because it stands at the very intersection of immunodeficiency, immune dysregulation, and mucosal pathology where these determinants encompass collapsed humoral defense, gut dysbiosis, and unbalanced interferon-driven epithelial necrosis converge. Multicenter randomized controlled trials and precision therapeutics are urgently needed to supersede the current empirical interventions with a fully evidence-based approach.
2026-07-15 | A scientometric analysis of research related to the 'oral-placental axis' hypothesis: current status, hotspots, and future directions.
Oral diseases and placental disorders are closely associated with adverse pregnancy outcomes, and accumulating evidence supports their crosstalk that constitutes the "oral-placental axis". This study integrated scientometric and bioinformatic approaches to systematically analyze global research trends, collaboration networks, research hotspots, and core molecular-microbial mechanisms of the oral-placental axis covering the period from 2016 to 2025. A total of 196 eligible publications were retrieved from the Web of Science Core Collection, Scopus, and PubMed. Bibliometric visualization was performed using VOSviewer, CiteSpace, and R-bibliometrix, and bioinformatic analysis was conducted to identify shared genes, signaling pathways, and microbial links between oral and placental diseases. The results revealed an annual publication growth rate of 5.03%, with the United States, China, and Australia as major contributing countries, the University of Queensland as the leading institution, and Gomez-Arango Luisa F. and Nitert Marloes Dekker as the most influential authors. Core keywords included preterm birth, periodontal diseases, gestational diabetes mellitus, and oral microbiome, reflecting a research shift from phenotypic association to mechanistic exploration such as microbial vertical transmission and inflammatory signaling. Mechanistic analyses identified shared hub genes (e.g., KRT19, ADAMDEC1, AQP9, SPAG4, PLAT) and key pathways, predominantly primary immunodeficiency and complement and coagulation cascades. Pathogenic bacteria including Fusobacterium nucleatum and Porphyromonas gingivalis mediated adverse pregnancy outcomes via hematogenous spread and placental barrier disruption. This study established a bidirectional regulatory model of the oral-placental axis involving shared risks, microbial transmission, and systemic inflammation, providing a theoretical basis for preconception oral intervention and precise prevention during pregnancy, and supporting the integration of oral care into routine perinatal management.
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2026-09-25 | Levels of IgG subclasses 1-4 in BT595, a 10% IVIG: A sub-analysis of a clinical trial.
The 10% intravenous immunoglobulin (IVIG) BT595 was evaluated in an open-label, prospective, multicenter clinical trial (Trial 991; NCT02810444) to characterize IgG subclass pharmacokinetics as replacement therapy in patients with primary immunodeficiency (PID). Patients received BT595 at either a 3-week (Q3W) or 4-week (Q4W) dosing interval for approximately 12 months. Secondary endpoints included steady state trough concentrations and pharmacokinetic parameters of IgG subclasses 1-4 and total IgG. IgG subclass trough concentrations were assessed at baseline and at steady state prior to the 7th infusion (Q3W) or 5th infusion (Q4W). Pharmacokinetic parameters at steady state were determined in patients aged ≥6 years using serum samples collected predose and up to 28 days post infusion. At steady state, trough concentrations of total IgG and all IgG subclasses were comparable between BT595 and patients' previous IVIG therapy, indicating preservation of systemic IgG exposure following treatment switch. IgG subclass trough concentrations were stable across dosing regimens and age categories, with a proportional distribution closely matching physiological IgG composition. IgG1 and IgG2 accounted for the majority of total IgG, whereas IgG3 and IgG4 contributed smaller fractions, consistent with endogenous IgG and published IVIG data. Pharmacokinetic profiles of all IgG subclasses were consistent with those reported for licensed IVIG products. Maximum concentrations occurred rapidly after infusion, and systemic exposure was robust under both dosing regimens. Mean concentrations and Cmax values were higher with Q3W dosing, while exposure over the dosing interval (AUCtau) was lower compared with Q4W dosing due to the shorter interval. Estimated half-life values were within or above ranges reported for other IVIG products, with numerically prolonged persistence of IgG2 and IgG4 under Q4W dosing. Overall, BT595 provides sustained IgG subclass exposure at steady state, supporting its suitability as IVIG replacement therapy in PID under both Q3W and Q4W regimens.
2026-09-24 | Appraisal of primary immunodeficiencies in Latin America and the Caribbean using the IPOPI PID Life Index – where are we now?
Objective Analyse the implementation of the 6 Principles of Care (PoC) for primary immunodeficiencies (PIDs) in Latin America and the Caribbean countries. Methodology Data was extracted from the IPOPI PID Life Index, an interactive tool measuring how it is to live with a PID in the 13 countries in Latin America and the Caribbean (Argentina, Bolivia, Brazil, Chile, Ecuador, El Salvador, Honduras, Mexico, Paraguay, Peru, Puerto Rico, Uruguay and Venezuela). Results Care for PIDs in the region varies greatly. Low diagnostic rates and limited diagnostic test options are a reality for the region. Almost all countries provide certain therapies for the treatment of PIDs, mostly anti-infectious therapies, immunoglobulin replacement therapies and vaccines. Biological therapies and curative treatments are less frequent in the countries covered. Universal health coverage for people living with PIDs remains heterogeneous and incomplete. Specialised centres and registries are also heterogeneously implemented. National organisations representing patients with PIDs exist in almost all countries, mainly focussing on general and medical awareness raising, and patient support through social activities. Discussion and conclusion PID care in Latin America and the Caribbean is steadily becoming a reality for many people living with PID. There have been significant improvements in terms of diagnosis, treatment and care in the region over the past decades. Still, there are significant inequalities across the different countries for the 6 PoCs for PID analysed. Joint efforts of medical specialists and patient organizations must continue to ensure an optimal environment for people living with PIDs in the region.
2026-08-28 | Beyond B cells: T and Innate Immune Mechanisms of Autoimmunity in Common Variable Immunodeficiency.
Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency, affecting approximately 1 in 25 000-50 000 individuals. Although classically characterized by hypogammaglobulinemia and recurrent bacterial infections, over 50% of patients develop non-infectious complications that constitute the major determinants of morbidity and mortality. The coexistence of immunodeficiency and immune dysregulation challenges the traditional B-cell-centric model of CVID pathogenesis. In this narrative review, we synthesize current evidence demonstrating that autoimmune manifestations in CVID arise from complex, multilayered immune dysfunction extending far beyond the B-cell compartment. Key abnormalities include Th1-skewed CD4⁺ T-cell responses with persistent IFN-γ production, numerical and functional defects in regulatory T cells, disruption of follicular T-cell subset balance favoring autoreactive germinal center responses, and progressive CD8⁺ T-cell exhaustion. At the innate immune level, NK-cell lymphopenia, constitutive monocyte activation, dendritic cell deficiency, neutrophil dysregulation, and proinflammatory innate lymphoid cell activity collectively contribute to the breakdown of self-tolerance. These immune perturbations are further amplified by systemic cytokine dysregulation. Pathogenic variants identified in patients with CVID-like disorders may further underlie autoimmune pathology and immune dysregulation, particularly those affecting T-cell co-stimulation, immune checkpoint signaling, NF-κB, and PI3K pathways. Collectively, CVID-associated autoimmunity represents a paradigm of systems-level immune dysregulation, underscoring the need for comprehensive immune phenotyping, genotype-informed stratification, and precision immunomodulatory strategies targeting the full spectrum of immune abnormalities involved.
2026-08-21 | Expert consensus recommendations for the prevention and management of immunoglobulin therapy-related adverse reactions in primary and secondary immunodeficiencies: a national Delphi study from the Immunodeficiency Group of the Spanish Society of Immunology.
Human immunoglobulin (IG) therapy, administered intravenously (IVIG) or subcutaneously (SCIG), is a cornerstone treatment for primary and secondary immunodeficiencies (PID and SID) and is increasingly used in autoimmune and inflammatory diseases. Although generally safe, adverse drug reactions (ADR) may affect treatment adherence, patient safety, and quality of care. Practical recommendations for the prevention and management of IG-associated ADR remain limited. To develop expert-based recommendations for the prevention, monitoring, classification, and management of ADR associated with IVIG and SCIG therapy in patients with PID and SID. A modified Delphi consensus was conducted by the Immunodeficiency Group of the Spanish Society of Immunology (GISEI). An expert coordinating committee developed 44 preliminary statements based on scientific evidence and clinical experience. Statements covered eight domains, including administration practices, ADR classification, premedication, acute management, complementary studies, anti-IgA antibodies, and SCIG-related issues. A national panel of specialists evaluated each statement using a 6-point Likert scale. Consensus was defined as ≥75% agreement. Forty-two recommendations achieved consensus and were included in the final document. High agreement was reached regarding individualized risk assessment, infusion rate adjustment, patient monitoring, and early ADR management. Most IVIG-related ADR were considered mild, occurring during or shortly after infusion, and generally not requiring treatment discontinuation. Premedication was recommended only for selected high-risk patients. SCIG was recognized as a safe and effective alternative associated with fewer systemic reactions and predominantly mild local ADR. The panel also highlighted the limited utility of serial anti-IgA antibody testing and emphasized patient education and periodic retraining for home-based SCIG administration. This Delphi-based consensus provides practical and clinically applicable recommendations for the prevention and management of ADR associated with IVIG and SCIG therapy. These recommendations may contribute to standardizing clinical practice, improving patient safety, optimizing treatment tolerability, and reducing variability in IG administration across healthcare settings. Further prospective studies are needed to better define risk factors and preventive strategies for severe ADR associated with IG therapy.
2026-08-20 | SGPI 2026 2nd International Symposium on Inborn Errors of Immunity of the Serbian Group for Primary Immunodeficiencies - PDF
A collection of abstracts from the SGPI 2026 2nd International Symposium on Inborn Errors of Immunity of the Serbian Group for Primary Immunodeficiencies, April 24–25, 2026, Belgrade and Novi Sad, Serbia. All abstracts were reviewed and approved by the SGPI scientific committee, which held full responsibility for the abstract selections.
other
2026-07-28 | Evolution of Inborn Errors of Immunity in China: Discoveries and Treatment Paradigms.
Inborn errors of immunity (IEI) are monogenic disorders of the immune system that lead to immunodeficiency, autoimmunity, autoinflammation, allergy, and/or cancer. This review provides a comparative review of the epidemiology, clinical manifestations, and management of IEI in China. While individual forms of IEI are generally rare disorders globally, collectively they represent a significant disease burden. China has recently made great strides in the diagnosis and treatment of IEIs with the increasing utility of next-generation sequencing and the availability of hematopoietic stem cell transplantation. Challenges remain in the establishment of national registry databases comparable to the European Society for Immunodeficiencies and The United States Immunodeficiency Network. Also, the absence of a national newborn screening program for severe combined immunodeficiency poses risks regarding live attenuated vaccination in undiagnosed infants. Current access to treatment including subcutaneous immunoglobulin, targeted molecular therapies, and commercialized gene therapy remains limited in China. Nevertheless, the therapeutic landscape is rapidly evolving, marked by an increasing clinical application of precision molecular-targeted treatments and the emergence of AI-empowered gene editing therapies. Ultimately, advancing the field of IEI necessitates global collaboration, integrating the complementary strengths of both regions to establish scientific breakthroughs and clinical innovation.
2026-06-24 | Disseminated BCGosis in immunocompromised infants: a five-case series in the context of a national BCG vaccination policy change.
Disseminated Bacillus Calmette-Guérin (BCG) infection (BCGosis) is a rare but serious complication that primarily affects infants with underlying immunodeficiency disorders. In Saudi Arabia, where consanguinity rates are high and primary immunodeficiency disorders are more prevalent, concerns have been raised regarding the safety of routine neonatal BCG vaccination. In 2019, the national immunization schedule was revised to delay BCG vaccination from birth to six months of age. This retrospective case series was conducted at a tertiary referral center in Jeddah, Saudi Arabia. Pediatric patients diagnosed with disseminated BCGosis between 2016 and 2023 were identified through electronic medical records. Disseminated BCGosis was defined as systemic infection with involvement of two or more noncontiguous organ systems with microbiological or molecular confirmation of Mycobacterium bovis. Clinical, microbiological, and immunological data were collected and analyzed descriptively. Five cases of disseminated BCGosis were identified during the study period, all occurring in immunocompromised infants who had received BCG vaccination at birth. Underlying primary immunodeficiency disorders included defects in the IL-12/interferon-gamma pathway and severe combined immunodeficiency. The median age at presentation was approximately 7 months. Clinical manifestations included persistent BCG-site inflammation, lymphadenopathy, and systemic symptoms. The interval from symptom onset to diagnosis ranged from 4 weeks to 7 months, with longer delays observed in cases presenting initially with localized disease. All cases were confirmed microbiologically. One patient died despite treatment, while the remaining patients responded to prolonged anti-tuberculous therapy and adjunctive immunotherapy. No cases of disseminated BCGosis were identified at our institution in the four years following the implementation of delayed BCG vaccination. This case series describes disseminated BCGosis occurring exclusively in immunocompromised infants vaccinated at birth and not being observed after the implementation of delayed BCG vaccination. Given the observational design and small sample size, these findings should be interpreted with caution. Delaying BCG vaccination may reduce exposure to live vaccination in vulnerable infants without apparent compromise of tuberculosis control. Multicenter studies are needed to validate these observations and inform immunization strategies in high-risk populations.
2026-05-25 | Modeling and correction of SCID-X1 using CRISPR-Cas9 homology-directed repair in human HSPCs.
X-linked severe combined immunodeficiency (SCID-X1) is a severe primary immunodeficiency caused by mutations in the IL2RG gene, a shared subunit of cytokine receptors critical for the development and function of T and natural killer (NK) cells. The standard treatment, allogeneic hematopoietic stem cell transplantation (HSCT), requires a compatible donor and is often associated with significant transplant-related complications. We aimed to develop a more robust and universal gene therapy by ex vivo modification of patient hematopoietic stem and progenitor cells (HSPCs) using the CRISPR-Cas9/rAAV6 gene-editing platform. To evaluate efficiency, we utilized a feeder-free, in vitro platform enabling T and NK cell differentiation from modified HSPCs. We investigated two approaches: the cut-site method (inserting a corrective cassette downstream of the start codon within the IL2RG locus) and a replacement method (replacing the entire IL2RG gene under endogenous regulation). We demonstrated that the cut-site insertion strategy is preferable for SCID-X1 correction, achieving superior homology-directed repair rates, lower toxicity, and significantly improved T and NK cell differentiation, based on phenotypic marker expression. Importantly, corrected patient-derived HSPCs from two SCID-X1 patients, modified using the cut-site approach, successfully demonstrated phenotypic evidence of T cell differentiation. Therefore, our findings firmly establish the feasibility of the cut-site strategy as a universal, high-efficiency, therapeutic solution for SCID-X1.
2026-02-16 | Gene therapy for inborn errors of immunity: past progress, current status and future directions.
Inborn errors of immunity (IEIs), also known as primary immunodeficiencies, are a group of rare inherited disorders that affect the immune system. They result in severe, opportunistic infections, severe autoimmune manifestations and a predisposition to malignancy. The only curative treatment for many years has been allogenic haematopoietic stem cell transplantation (alloHSCT). However, this requires the availability of a suitable donor and has risks of morbidity and mortality. Autologous gene therapy (GT) abrogates the immunological complications of alloHSCT and uses the patient's own cells, removing the need for a donor. Preclinical proof-of-concept and clinical trials in humans have demonstrated that GT is safe and effective and can be used to correct a variety of IEIs. In this review, we outline the progress in developing GT for IEIs over the last four decades. We describe the gene editing technologies available to correct IEIs and their current applications. We also examine advances in GT development, the challenges to its application, and discuss future developments in the field, including emerging in vivo approaches.
2026-02-10 | Research Progress on Chronic Granulomatous Disease in Children.
Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder characterized by defective neutrophil oxidative burst function, leading to impaired host defense against pathogenic microorganisms. This condition significantly increases the risk of invasive infections in affected patients. However, the clinical manifestations of CGD are not limited to infection-related complications; non-infectious complications can also lead to a variety of clinical symptoms. The global occurrence rate of CGD varies, and its inheritance patterns include X-linked and autosomal recessive forms. Research indicates that CGD patients are predominantly children who frequently face life-threatening infections and related complications, with early diagnosis often being challenging. Currently, hematopoietic stem cell transplantation (HSCT) is the only widely applied curative treatment for CGD. Recent advances in gene therapy offer a promising, safer, and more directly suitable alternative. This review primarily focuses on the pathophysiology, molecular genetics, occurrence rate, clinical manifestations, laboratory diagnosis, and cellular therapies of pediatric CGD, aiming to offer ideas for its clinical diagnosis.
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Drug Discovery Landscape
1 orphan drug designation for Primary immunodeficiency.
1 orphan drug designation for Primary immunodeficiency.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Immune Globulin Subcutaneous (Human) | proteins | FDA | CSL Behring |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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