RARE DISEASE
Common variable immunodeficiency
Common variable immunodeficiency
Common variable immunodeficiency
Synonyms: CVID, Idiopathic immunoglobulin deficiency, Primary antibody deficiency, Primary hypogammaglobulinemia
Synonyms: CVID, Idiopathic immunoglobulin deficiency, Primary antibody deficiency, Primary hypogammaglobulinemia
Synonyms: CVID, Idiopathic immunoglobulin deficiency, Primary antibody deficiency, Primary hypogammaglobulinemia
Drug discovery
5
drugs
With orphan designations
Overview
Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by impaired B-cell differentiation, leading to hypogammaglobulinemia and recurrent bacterial infections. Clinical features include sinopulmonary infections, autoimmune disorders, granulomatous disease, and increased risk of lymphoid malignancies. Diagnosis involves low IgG/IgA levels and poor vaccine response, with management centered on immunoglobulin replacement therapy and infection prophylaxis [1][4][5].
Burden
Morbidity: Chronic lung disease (e.g., bronchiectasis) in 30–50%, autoimmune cytopenias in ~25%, and GI disorders in ~10% [1][4][6].
Mortality: Reduced life expectancy (median 42–44 years) linked to lymphoma, respiratory failure, or sepsis [6][9].
Quality of Life: Frequent hospitalizations, treatment costs, and complications like anxiety/depression [9][15].
Therapies
Categories: rare genetic diseases, rare immunological diseases, rare neoplastic diseases
Research Papers
1,170 drug discovery papers about Common variable immunodeficiency, with 6 first-in-class and 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,170 drug discovery papers about Common variable immunodeficiency, with 6 first-in-class and 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-15 | Elevated IL-10 is Linked With the Expansion of T-bethighCD21low B Cells in Patients With Common Variable Immunodeficiency.
Common variable immunodeficiency (CVID) is frequently complicated by autoimmune and inflammatory manifestations associated with profound immune dysregulation (CVIDc), including expansion of T-bethighCD21low B cells (CD21low B cells). Elevated serum IL-10 levels have repeatedly been reported in CVIDc, yet their relationship to CD21low B-cell differentiation remains unclear. In this study, we determined a significant correlation between increased serum IL-10 levels and frequency of circulating CD21low B cells, particularly marked in CVIDc patients. Transcriptomic and protein analyses identified multiple cellular sources of IL-10 in CVID, including monocytes, T cells, and a subset of CD21low B cells in peripheral blood and inflamed tissues. CD21low B cells expressed elevated levels of IL-10 receptor subunits and displayed intact IL-10-induced STAT3 signaling, indicating preserved responsiveness to IL-10. Functionally, IL-10 alone neither induced CD21low B-cell differentiation nor inhibited IFN-γ-driven polarization. However, in vitro differentiation assays showed that IL-10 can substitute for IL-21 during CD40L/T cell-dependent differentiation of CD21low-like B cells and promote their survival in vitro. These findings suggest that IL-10 may support the expansion and persistence of CD21low B cells at inflammatory sites. Collectively, our data identify IL-10 as a component of the inflammatory environment associated with CD21low B-cell expansion and suggest that IL-10 can functionally replace IL-21 during their differentiation and promote their survival in CVID-associated immune dysregulation.
2026-08-10 | Dissecting the molecular heterogeneity of common variable immunodeficiency using an integrative multi-omics approach
Common variable immunodeficiency (CVID), the most common clinically significant inborn error of immunity (IEI), is characterized by hypogammaglobulinemia and impaired antibody responses to infections and vaccination. Although monogenic defects have been identified in a subset of patients, the molecular basis of CVID remains unresolved in most cases, reflecting substantial clinical and biological heterogeneity and contributions from polygenic, epigenetic, and environmental factors. In this narrative review, we summarize recent advances in genomics, epigenomics, transcriptomics, proteomics, microbiomics, metabolomics, and multi-omic integration based on published literature identified through searches of major biomedical databases. These approaches have uncovered dysregulated immune signaling pathways, impaired B-cell differentiation programs, inflammatory molecular endotypes, altered immune tolerance mechanisms, and host–microbiome–metabolite interactions contributing to disease heterogeneity. Emerging multi-omic studies further demonstrate mechanistic links among microbial translocation, metabolic re-programming, inflammatory signaling, and immune dysfunction in CVID. Integrative multi-omic approaches enable improved disease stratification, refined molecular classification of CVID phenotypes, enhanced diagnostic resolution, and identification of biomarkers and therapeutic targets, particularly in genetically unresolved patients. Emerging evidence also supports precision medicine strategies by linking molecular endotypes with pathway-directed therapeutic interventions. Continued advances in integrated multi-omic approaches are expected to improve molecular diagnosis and facilitate more personalized management of CVID.
2026-07-01 | Common Variable Immunodeficiency Associated With Connective Tissue Diseases: A Report of Two Cases
Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency in adults and is increasingly recognized as a disorder of immune dysregulation. Autoimmune diseases, including connective tissue diseases, may precede the diagnosis of CVID and contribute significantly to morbidity, particularly through pulmonary involvement. We report two adult women patients with connective tissue diseases (rheumatoid arthritis and primary Sjögren’s syndrome) complicated by recurrent respiratory infections, interstitial lung disease, and severe hypogammaglobulinemia. In both cases, the diagnosis of CVID was established after a prolonged diagnostic delay, and immunoglobulin replacement therapy was indicated. These cases highlight the importance of considering CVID in patients with connective tissue diseases who present with recurrent infections or unexplained pulmonary involvement. Early diagnosis and timely initiation of immunoglobulin replacement therapy are essential for improving outcomes and preventing irreversible complications.
2026-06-12 | Prolonged Infections and Inflammatory Diseases in Common Variable Immune Deficiency as a Cause of AA Amyloidosis.
Background/Objectives: AA amyloidosis is a serious complication of chronic inflammation, which may arise in the setting of inborn errors of immunity (IEIs) due to recurrent or persistent infections. Common variable immunodeficiency (CVID) is the most frequent symptomatic IEI in adults, yet its association with secondary AA amyloidosis remains rarely reported. Case presentation: We describe a 37-year-old male with a history of recurrent pneumonia, chronic sinusitis, and osteomyelitis with sepsis since childhood. At age 33, he developed bilateral pneumonia after COVID-19, followed by repeated lower respiratory tract infections. At age 36, nephrotic syndrome (proteinuria 10.69 g/day, hypoalbuminemia) led to kidney and gastric mucosa biopsies, which confirmed AA amyloidosis. Immunological workup revealed panhypogammaglobulinemia (IgG 0.1 g/L, IgA 0.01 g/L, IgM 0.28 g/L), markedly reduced switched memory B cells, and an inverted CD4+/CD8+ ratio. Chest CT showed bronchiectasis, bronchiolitis, and mediastinal lymphadenopathy. Whole-exome sequencing excluded known monogenic IEIs, autoinflammatory, or hereditary amyloidosis genes; a heterozygous likely pathogenic variant in ODAD2 (associated with primary ciliary dyskinesia) was considered incidental. A diagnosis of CVID with secondary AA amyloidosis was established. Conclusions: This case illustrates that CVID may remain undiagnosed for decades and present with secondary AA amyloidosis as the first major complication. In any patient with nephrotic syndrome and a history of recurrent or unusual infections, an IEI should be actively excluded. Early recognition of CVID and appropriate immunoglobulin replacement therapy can prevent infectious exacerbations and potentially halt amyloid progression.
2026-06-08 | Clinical, genetic, and functional characterization of novel NFKB1 variants in Chinese patients with primary immunodeficiency.
The nuclear factor κB (NF-κB)-related disorders encompassed not only common variable immunodeficiency but also manifestations of autoinflammation, autoimmunity, and malignancies. While most cases have been reported in European populations, reports in the Chinese population are sparse. Clinical data and genetic variants from four Chinese patients with NFKB1 variants, alongside four previously reported cases, were analyzed and compared with an international cohort. Additionally, comprehensive in vitro functional assays-including immunoblotting, transcript analyses, dual-luciferase reporter, and co-immunoprecipitation assays-were conducted to explore the molecular defects of the novel variants. Our cohort included three men and one woman, all presenting with recurrent fever and hypogammaglobulinemia. Three patients experienced recurrent sinopulmonary infections, accompanied by decreased B cells and NK cells, while two patients developed pneumonia, bronchiectasis, and hepatitis. Three novel NFKB1 (NM_003998) variants were identified: c.559C > T (p. Arg187Trp), c.1509del (p. Glu504Argfs*19), and c.1753-11_1760del (p. Thr585Alafs*9). Functional analyses revealed distinct pathomechanisms: the frameshift/splicing variants drive classical haploinsufficiency via nonsense-mediated mRNA decay (NMD), triggering compensatory inflammatory hyperactivation; conversely, the p.Arg187Trp missense variant maintains protein stability and heterodimerization but strictly abolishes DNA-binding capacity. Compared to a previously reported cohort, Chinese patients were predominantly male, had a later median age of onset and diagnosis. Notably, Chinese patients exhibited a higher prevalence of hepatitis (25%) and cirrhosis (12.5%), potentially reflecting the high endemicity of hepatitis B virus in China. They also showed increased rates of viral infections, sepsis, and bronchiectasis, with more pronounced reductions in NK and B cells. In contrast, autoimmune diseases and bronchitis were less frequent than in the foreign cohort. This study represents the first and largest case series of Chinese patients with NF-κB1-related diseases, providing molecular characterization for three novel variants. In this limited case series, the observed delayed onset and frequent hepatic complications in our cohort may reflect regional factors, such as HBV endemicity, or ascertainment bias. Our findings underscore that suspected AOSD accompanied by hypogammaglobulinemia warrants immediate genetic investigation. Early diagnosis is essential to prioritize immunoglobulin replacement and prevent fatal complications from immunosuppressive therapy.
2026-08-15 | Elevated IL-10 is Linked With the Expansion of T-bethighCD21low B Cells in Patients With Common Variable Immunodeficiency.
Common variable immunodeficiency (CVID) is frequently complicated by autoimmune and inflammatory manifestations associated with profound immune dysregulation (CVIDc), including expansion of T-bethighCD21low B cells (CD21low B cells). Elevated serum IL-10 levels have repeatedly been reported in CVIDc, yet their relationship to CD21low B-cell differentiation remains unclear. In this study, we determined a significant correlation between increased serum IL-10 levels and frequency of circulating CD21low B cells, particularly marked in CVIDc patients. Transcriptomic and protein analyses identified multiple cellular sources of IL-10 in CVID, including monocytes, T cells, and a subset of CD21low B cells in peripheral blood and inflamed tissues. CD21low B cells expressed elevated levels of IL-10 receptor subunits and displayed intact IL-10-induced STAT3 signaling, indicating preserved responsiveness to IL-10. Functionally, IL-10 alone neither induced CD21low B-cell differentiation nor inhibited IFN-γ-driven polarization. However, in vitro differentiation assays showed that IL-10 can substitute for IL-21 during CD40L/T cell-dependent differentiation of CD21low-like B cells and promote their survival in vitro. These findings suggest that IL-10 may support the expansion and persistence of CD21low B cells at inflammatory sites. Collectively, our data identify IL-10 as a component of the inflammatory environment associated with CD21low B-cell expansion and suggest that IL-10 can functionally replace IL-21 during their differentiation and promote their survival in CVID-associated immune dysregulation.
2026-08-10 | Dissecting the molecular heterogeneity of common variable immunodeficiency using an integrative multi-omics approach
Common variable immunodeficiency (CVID), the most common clinically significant inborn error of immunity (IEI), is characterized by hypogammaglobulinemia and impaired antibody responses to infections and vaccination. Although monogenic defects have been identified in a subset of patients, the molecular basis of CVID remains unresolved in most cases, reflecting substantial clinical and biological heterogeneity and contributions from polygenic, epigenetic, and environmental factors. In this narrative review, we summarize recent advances in genomics, epigenomics, transcriptomics, proteomics, microbiomics, metabolomics, and multi-omic integration based on published literature identified through searches of major biomedical databases. These approaches have uncovered dysregulated immune signaling pathways, impaired B-cell differentiation programs, inflammatory molecular endotypes, altered immune tolerance mechanisms, and host–microbiome–metabolite interactions contributing to disease heterogeneity. Emerging multi-omic studies further demonstrate mechanistic links among microbial translocation, metabolic re-programming, inflammatory signaling, and immune dysfunction in CVID. Integrative multi-omic approaches enable improved disease stratification, refined molecular classification of CVID phenotypes, enhanced diagnostic resolution, and identification of biomarkers and therapeutic targets, particularly in genetically unresolved patients. Emerging evidence also supports precision medicine strategies by linking molecular endotypes with pathway-directed therapeutic interventions. Continued advances in integrated multi-omic approaches are expected to improve molecular diagnosis and facilitate more personalized management of CVID.
2026-07-01 | Common Variable Immunodeficiency Associated With Connective Tissue Diseases: A Report of Two Cases
Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency in adults and is increasingly recognized as a disorder of immune dysregulation. Autoimmune diseases, including connective tissue diseases, may precede the diagnosis of CVID and contribute significantly to morbidity, particularly through pulmonary involvement. We report two adult women patients with connective tissue diseases (rheumatoid arthritis and primary Sjögren’s syndrome) complicated by recurrent respiratory infections, interstitial lung disease, and severe hypogammaglobulinemia. In both cases, the diagnosis of CVID was established after a prolonged diagnostic delay, and immunoglobulin replacement therapy was indicated. These cases highlight the importance of considering CVID in patients with connective tissue diseases who present with recurrent infections or unexplained pulmonary involvement. Early diagnosis and timely initiation of immunoglobulin replacement therapy are essential for improving outcomes and preventing irreversible complications.
2026-06-12 | Prolonged Infections and Inflammatory Diseases in Common Variable Immune Deficiency as a Cause of AA Amyloidosis.
Background/Objectives: AA amyloidosis is a serious complication of chronic inflammation, which may arise in the setting of inborn errors of immunity (IEIs) due to recurrent or persistent infections. Common variable immunodeficiency (CVID) is the most frequent symptomatic IEI in adults, yet its association with secondary AA amyloidosis remains rarely reported. Case presentation: We describe a 37-year-old male with a history of recurrent pneumonia, chronic sinusitis, and osteomyelitis with sepsis since childhood. At age 33, he developed bilateral pneumonia after COVID-19, followed by repeated lower respiratory tract infections. At age 36, nephrotic syndrome (proteinuria 10.69 g/day, hypoalbuminemia) led to kidney and gastric mucosa biopsies, which confirmed AA amyloidosis. Immunological workup revealed panhypogammaglobulinemia (IgG 0.1 g/L, IgA 0.01 g/L, IgM 0.28 g/L), markedly reduced switched memory B cells, and an inverted CD4+/CD8+ ratio. Chest CT showed bronchiectasis, bronchiolitis, and mediastinal lymphadenopathy. Whole-exome sequencing excluded known monogenic IEIs, autoinflammatory, or hereditary amyloidosis genes; a heterozygous likely pathogenic variant in ODAD2 (associated with primary ciliary dyskinesia) was considered incidental. A diagnosis of CVID with secondary AA amyloidosis was established. Conclusions: This case illustrates that CVID may remain undiagnosed for decades and present with secondary AA amyloidosis as the first major complication. In any patient with nephrotic syndrome and a history of recurrent or unusual infections, an IEI should be actively excluded. Early recognition of CVID and appropriate immunoglobulin replacement therapy can prevent infectious exacerbations and potentially halt amyloid progression.
2026-06-08 | Clinical, genetic, and functional characterization of novel NFKB1 variants in Chinese patients with primary immunodeficiency.
The nuclear factor κB (NF-κB)-related disorders encompassed not only common variable immunodeficiency but also manifestations of autoinflammation, autoimmunity, and malignancies. While most cases have been reported in European populations, reports in the Chinese population are sparse. Clinical data and genetic variants from four Chinese patients with NFKB1 variants, alongside four previously reported cases, were analyzed and compared with an international cohort. Additionally, comprehensive in vitro functional assays-including immunoblotting, transcript analyses, dual-luciferase reporter, and co-immunoprecipitation assays-were conducted to explore the molecular defects of the novel variants. Our cohort included three men and one woman, all presenting with recurrent fever and hypogammaglobulinemia. Three patients experienced recurrent sinopulmonary infections, accompanied by decreased B cells and NK cells, while two patients developed pneumonia, bronchiectasis, and hepatitis. Three novel NFKB1 (NM_003998) variants were identified: c.559C > T (p. Arg187Trp), c.1509del (p. Glu504Argfs*19), and c.1753-11_1760del (p. Thr585Alafs*9). Functional analyses revealed distinct pathomechanisms: the frameshift/splicing variants drive classical haploinsufficiency via nonsense-mediated mRNA decay (NMD), triggering compensatory inflammatory hyperactivation; conversely, the p.Arg187Trp missense variant maintains protein stability and heterodimerization but strictly abolishes DNA-binding capacity. Compared to a previously reported cohort, Chinese patients were predominantly male, had a later median age of onset and diagnosis. Notably, Chinese patients exhibited a higher prevalence of hepatitis (25%) and cirrhosis (12.5%), potentially reflecting the high endemicity of hepatitis B virus in China. They also showed increased rates of viral infections, sepsis, and bronchiectasis, with more pronounced reductions in NK and B cells. In contrast, autoimmune diseases and bronchitis were less frequent than in the foreign cohort. This study represents the first and largest case series of Chinese patients with NF-κB1-related diseases, providing molecular characterization for three novel variants. In this limited case series, the observed delayed onset and frequent hepatic complications in our cohort may reflect regional factors, such as HBV endemicity, or ascertainment bias. Our findings underscore that suspected AOSD accompanied by hypogammaglobulinemia warrants immediate genetic investigation. Early diagnosis is essential to prioritize immunoglobulin replacement and prevent fatal complications from immunosuppressive therapy.
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Drug Discovery Landscape
5 orphan drug designations for Common variable immunodeficiency.
5 orphan drug designations for Common variable immunodeficiency.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Leniolisib | small molecules | FDA | 2025-10-03 | — | Pharming Technologies B.V. (Pharming Technologies B.V. is a subsidiary of Pharming Group N.V.) |
Leniolisib | small molecules | EMA | 2025-08-22 | — | Pharming Technologies B.V. |
IgA extracted from human milk | antibodies | FDA | 2024-10-25 | — | Lactiga US, Inc. |
B Lymphocyte Stimulator | antibodies | FDA | 2001-02-21 | — | Human Genome Sciences, Inc. |
Loxoribine | small molecules | FDA | 1992-02-24 | — | R. W. Johnson Pharmaceutical Research Institute |
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