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
1,165 drug discovery papers related to Common variable immunodeficiency, with 5 first-in-class and 8 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
1,165 drug discovery papers related to Common variable immunodeficiency, with 5 first-in-class and 8 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
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.
2026-07-01 | 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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