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Purpose A subset of patients with common variable immunodeficiency (CVID) develops granulomatous and lymphocytic interstitial lung disease (GLILD), a restrictive lung disease associated with early mortality. The optimal therapy for GLILD is unknown. This study was undertaken to see if rituximab and azathioprine (combination chemotherapy) would improve pulmonary function and/or radiographic abnormalities in patients with CVID and GLILD. Methods A retrospective chart review of patients with CVID and GLILD who were treated with combination chemotherapy was performed. Complete pulmonary function tests (PFTs) and high-resolution computed tomography (HRCT) scans of the chest were done prior to therapy and >6 months later. HRCT scans of the chest were blinded, randomized, and scored independently (in pairs) by two radiologists. The differences between pre- and post-treatment HRCT scores and PFT parameters were analyzed. Results Seven patients with CVID and GLILD met inclusion criteria. Post-treatment increases were noted in both FEV1 ( p  = 0.034) and FVC ( p  = 0.043). HRCT scans of the chest demonstrated improvement in total score ( p  = 0.018), pulmonary consolidations ( p  = 0.041), ground-glass opacities ( p  = 0.020) nodular opacities ( p  = 0.024), and both the presence and extent of bronchial wall thickening ( p  = 0.014, 0.026 respectively). No significant chemotherapy-related complications occurred. Conclusions Combination chemotherapy improved pulmonary function and decreased radiographic abnormalities in patients with CVID and GLILD.

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

Granulomatous disease affects up to 20% of patients with Common Variable Immunodeficiency (CVID). Granulomas are comprised of highly activated immune cells, and emerge in response to antigenic triggers. In CVID granulomas however, the underlying pathophysiology is unclear and the specific trigger remains unknown. Granuloma formation in CVID is often compared to sarcoidosis, although clinical context and prognosis differ, suggesting a different pathogenesis. The aim of this study was to investigate if the cellular organization and proteomics of granulomas in CVID is different from other granulomatous diseases. Therefore, tissue slides from formaldehyde fixed paraffin embedded biopsies obtained from patients with CVID, sarcoidosis, tuberculosis and foreign-material induced pseudo-sarcoidosis were stained with hematoxylin and eosin and assessed for histopathological characteristics. Targeted spatial protein analysis was performed, and immune fluorescent multiplex assays were used to analyze the cellular organization. Histological analysis revealed that CVID granulomas were smaller, less circumscribed, with fewer multinucleated giant cells and minimal fibrosis compared to the other granulomatous diseases. Spatial protein analysis showed that granulomas in all diseases expressed CD68, CD11c, CD44, CD127, and PD-L1. However in CVID, reduced expression of the fibrosis-related protein fibronectin, but enrichment of CD163, CD3 and FAPα inside CVID granulomas was observed. Immunofluorescence analysis conformed a different cellular organization in CVID granulomas with increased influx of neutrophils, macrophages, T and B lymphocytes. In conclusion, granulomas in CVID display a different histological and cellular organization with increased influx of myeloid and lymphoid cells, compared to sarcoidosis, tuberculosis and pseudo-sarcoidosis, indicating a distinct pathogenesis underlying granuloma formation.

Subcutaneous human IgG (SCIG) therapy in primary immunodeficiency (PID) offers sustained IgG levels throughout the dosing cycle and fewer adverse events (AEs) compared to intravenous immunoglobulin (IVIG). A phase I study showed good local tolerability of IgPro20, a new 20% liquid SCIG stabilized with L-proline. A prospective, open-label, multicenter, single-arm, phase III study evaluated the efficacy and safety of IgPro20 in patients with PID over 15 months. Forty-nine patients (5-72 years) previously treated with IVIG received weekly subcutaneous infusions of IgPro20. The mean serum IgG level was 12.5 g/L. No serious bacterial infections were reported. There were 96 nonserious infections (rate 2.76/patient per year). The rate of days missed from work/school was 2.06/patient per year, and the rate of hospitalization was 0.2/patient per year. Ninety-nine percent of AEs were mild or moderate. No serious, IgPro20-related AEs were reported. IgPro20 effectively protected patients with PID against infections and maintained serum IgG levels without causing unexpected AEs.

PurposeTo evaluate mortality risk factors in pediatric-onset common variable immunodeficiency disorders (CVID), we evaluated the largest single-institution cohort of pediatric-onset CVID patients. Previous publications on CVID have provided valuable descriptive data, but lack risk stratification to guide physicians in management of these patients.MethodsRetrospective chart review of 198 subjects with CVID at a single institution, of whom 91 had disease onset at a pediatric age. Clinical and laboratory data were collected at diagnosis and in follow-up. Odds ratios and Fisher tests were utilized to examine trends. This study was approved by an institutional review board.ResultsClinical features and laboratory results for subjects diagnosed with CVID at a pediatric age are similar to those who had adult-onset CVID. However, majority of the deceased subjects (13/18) were at a pediatric age at CVID symptom onset. These subjects had a lower age at mortality, multiple comorbidities, and often depression. The most common cause of death was infection. Lung disease (OR 5, p < 0.05) and infection with severe/opportunistic organisms (OR 9, p < 0.05) are directly related to increased mortality. Delay in diagnosis of CVID is also correlated with mortality. Intermediary markers correlating with mortality include anemia, GERD, and depression.ConclusionsThere are many similarities between patients with pediatric- and adult-onset CVID; however, the mortality of pediatric CVID in our cohort is striking. This is the first study to identify specific factors correlated with mortality in pediatric-onset CVID to guide pediatricians and subspecialists in managing these immunodeficient patients.

A multi-center, prospective, open-label study was conducted in primary immunodeficiency disease patients to determine the tolerability and pharmacokinetics of a 10% liquid IgG preparation administered subcutaneously. Forty-nine subjects (3–77 years old) were enrolled. Pharmacokinetic equivalence of subcutaneous treatment was achieved at a median dose of 137% of the intravenous dose, with a mean trough IgG level of 1,202 mg/dL at the end of the assessment period. The overall infection rate during subcutaneous treatment was 4.1 per subject-year. Three acute serious bacterial infections were reported, resulting in a rate of 0.067 per subject-year. A low overall rate of temporally associated adverse events (8%), and a very low rate of infusion site adverse events (2.8%), was seen at volumes up to 30 mL/site and rates ≤30 mL/h/site. Thus, subcutaneous replacement therapy with a 10% IgG preparation proved effective, safe and well-tolerated in our study population of subjects with primary immunodeficiency disease.

The disease course of COVID-19 in patients with immunodeficiencies is unclear, as well as the optimal therapeutic strategy. We report a case of a 37-year old male with common variable immunodeficiency disorder and a severe SARS-CoV-2 infection. After administration of convalescent plasma, the patient’s condition improved rapidly. Despite clinical recovery, viral RNA remained detectable up to 60 days after onset of symptoms. We propose that convalescent plasma might be considered as a treatment option in patients with CVID and severe COVID-19. In addition, in patients with immunodeficiencies, a different clinical course is possible, with prolonged viral shedding.

Non-infectious complications in common variable immunodeficiency (CVID) have emerged as a major clinical challenge. Detailed clinical spectrum, organ-specific pathologies and associated sequelae from 623 CVID patients followed in New York since 1974 were analyzed, and recent insights to pathogenesis were reviewed. Non-infectious manifestations were present in 68.1% of patients, and they do not tend to be present in isolation. They include autoimmunity (33.2%), chronic lung disease (30.3%), lymphoid hyperplasia/splenomegaly (20.9%), liver disease (12.7%), granulomas (9.3%), gastrointestinal disease (7.3%), lymphoma (6.7%), and other malignancies (6.4%). In the lungs, interstitial disease and bronchiectasis were the most common findings, with lymphoma at this site being a rare ( = 6), but serious, manifestation. Bronchiectasis was not a prerequisite for the development of interstitial disease. In the liver, granulomas and nodular regenerative hyperplasia were the most common. Gastrointestinal disease may affect any segment of the intestinal tract, with lymphoid infiltrations and villous blunting being the leading histologic findings. With progression of organ-specific diseases, a wide spectrum of associated sequelae was observed. Lymphoma was more common in females ( = 0.036)-all B cell types except in one subject. Solid organ transplantations (liver, = 5; lung, = 4; combined lung and heart, = 2) and hematopoietic stem cell transplantations (for B cell lymphoma, = 1) have rarely been performed in this cohort, with mixed outcomes. Recent identification of monogenic defects, in ~10-30% of various CVID cohorts, has highlighted the molecular pathways that can affect both antibody production and broader immune regulation. In addition, cellular defects in both innate and adaptive immune systems are increasingly recognized in this syndrome.

Purpose Enteropathy is a non-infectious complication in Common Variable Immune Deficiency (CVID) associated with increased morbidity and mortality. We characterized this group of CVID enteropathy (CVID-E) patients and investigated the effectiveness of immunosuppressive treatments on its clinical course. Method We identified patients with CVID-E in two academic teaching hospitals and obtained informed consents. Using electronic patient health care records, we retrospectively collected clinical information in the national Primary immunodeficiency disorder database until 01-2023. Results We included 39 patients with CVID-E. Bronchiectasis (69.2%) and lymphoproliferation (46.1%) were the most frequent co-occurring symptoms. The most common endoscopy findings concerned inflammation (72.2%) and erythema (69.4%); The most prevalent histopathologic findings were IBD-like inflammation (55.6%), indiscriminate chronic inflammation (47.2%) and indiscriminate active inflammation (38.9%). We assessed 88 events of treatment response in the 25 treated patients. Overall treatment response was poor, however there were 31 events of remission observed, ranging from partial to sustained remission. Of these 26 were the result of tumor necrosis factor inhibitors (TNFi) or thiopurines, either as monotherapy or in combination with other immunosuppressive treatment. 10 patients achieved complete remission. Conclusion In this study, we describe a cohort of CVID-E patients including related comorbidity, clinical course and response to therapy. CVID-E patients frequently develop other, sometimes severe comorbidities. Our study confirms the alleged heterogeneity regarding endoscopic and histopathological findings, and in one third of patients even multiple distinct abnormalities co-occurred in the same biopsy. We found azathioprine and/or TNFi to be the most effective current treatment.

IntroductionAutosomal recessively inherited lipopolysaccharide-responsive beige-like anchor (LRBA) protein deficiency was shown to be responsible for different types of inborn errors of immunity, such as common variable immunodeficiency (CVID) and autoimmune lymphoproliferative syndrome (ALPS). The aim of this study was to compare patients with LRBA-related ALPS and LRBA-related CVID, to describe their clinical and laboratory phenotypes, and to prepare an algorithm for their diagnosis and management.MethodsFifteen LRBA-deficient patients were identified among 31 CVID and 14 possible ALPS patients with Western blotting (WB), primary immunodeficiency disease (PIDD) gene, next-generation panel screening (NGS), and whole exome sequencing (WES).ResultsThe median age on admission and age of diagnosis were 7 years (0.3–16.5) and 11 years (5–44), respectively. Splenomegaly was seen in 93.3% (14/15) of the patients on admission. Splenectomy was performed to 1/5. Recurrent upper respiratory tract infections (93.3% (14/15)), autoimmune cytopenia (80% (12/15)), chronic diarrhea (53.3% (8/15)), lower respiratory tract infections (53.3% (8/15)), lymphoma (26.6% (4/15)), Evans syndrome (26.6% (4/15)), and autoimmune thyroiditis (20% (3/15)) were common clinical findings and diseases. Lymphopenia (5/15), intermittant neutropenia (4/15), eosinophilia (4/15), and progressive hypogammaglobulinemia are recorded in given number of patients. Double negative T cells (TCRαβ+CD4−CD8−) were increased in 80% (8/10) of the patients. B cell percentage/numbers were low in 60% (9/15) of the patients on admission. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Thelper (Th) cells, markedly increased effector memory/effector memory RA+ (TEMRA) Th were documented. Large PD1+ population, increased memory, and enlarged follicular helper T cell population in the CD4+ T cell compartment was seen in one of the patients. Most of the deleterious missense mutations were located in the DUF1088 and BEACH domains. Interestingly, one of the two siblings with the same homozygous LRBA defect did not have any clinical symptom. Hematopoietic stem cell transplantation (HSCT) was performed to 7/15 (46.6%) of the patients. Transplanted patients are alive and well after a median of 2 years (1–3). In total, one patient died from sepsis during adulthood before HSCT.ConclusionPatients with LRBA deficiency may initially be diagnosed as CVID or ALPS in the clinical practice. Progressive decrease in B cells as well as IgG in ALPS-like patients and addition of IBD symptoms in the follow-up should raise the suspicion for LRBA deficiency. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Th cells, and markedly increased effector memory/effector memory RA+ Th cells (TEMRA Th) cells are important for the diagnosis of the patients in addition to clinical features. Analysis of protein by either WB or flow cytometry is required when the clinicians come across especially with missense LRBA variants of uncertain significance. High rate of malignancy shows the regulatory T cell’s important role of immune surveillance. HSCT is curative and succesful in patients with HLA-matched family donor.