Common variable immunodeficiency (CVID) is the most common type of primary immunodeficiencies affecting both children and adults with the peak onset of symptoms during the first and third decades of life. It is characterized by a constellation of hypogammaglobulinemia, failure of specific antibody production, vulnerability to infections, and an array of comorbidities. CVID typically has a combination of decreased levels of IgG, IgA, and/or IgM associated with poor vaccine response, and prone to have bacterial infections. it consists of heterogeneous constituents of rare diseases considering numerous ways in impairment of antibody production, and therefore managing this disease poses a significant challenge for clinicians. Despite CVID has been recognized since the 1950s, its underlying mechanisms remains not completely understood. The clinical heterogeneity suggests the involvement of multiple genetic and immunoregulatory defects with hypogammaglobulinemia as the final outcome.
The majority of patients with common variable immunodeficiency have no history of affected family members. In other words, it is mostly a sporadic disease. Genetics plays some role in a minority of CVID. About 10% to 15% of patients have at least one first-degree relative with CVID, immunoglobulin A deficiency (IgAD), IgG subclass deficiency, or other immunity disorders, including specific antibody deficiency and relative hypogammaglobulinemia. CVID can be both autosomal dominant and autosomal recessive.
Potential susceptibility loci have been recognized in major histocompatibility complex (MHC) genes. Major histocompatibility complex (MHC), particularly HLA A1-B8-DR3 and B14-DR1, has been shown to be associated with CVID. Other studies demonstrated an association between homozygosity for genes encoding HLA class II molecules, especially HLA-DQ and/or genes in the centromeric class III region with CVID.
CVID is also related to gene mutations. Around 25% to 50% of patients presenting with clinical features of CVID have a single gene defect identified. These mutations can be inherited by either autosomal recessive or dominant pattern with variable penetrance up to 30%. Some mutations may affect the B cell maturation and differentiation into memory B cells. A recent study of the whole-exome sequencing study of more than 500 patients with CVID further strengthens the argument of heterogeneous and polygenic nature of CVID.
Several genes mutations that were identified in patients with common variable immunodeficiency include mutations in the genes transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), lipopolysaccharide (LPS), syntax binding protein 2 (STXBP2), cytotoxic T-lymphocyte antigen 4 (CTLA4), nuclear factor (NF)-kappa-B1 (NFKB1), signal transducer and activator of transcription 3 (STAT3), the catalytic subunit of phosphatidylinositol 3-kinase delta (PIK3CD), the gene encoding IKAROS (IKZF1), etc. TACI gene mutations are found in 10% of patients with CVID, but nevertheless, it does not directly cause the disease as these mutations can be found in healthy people. These mutations may lead individuals to be more susceptible to CVID. Mutations in nuclear factor (MF)-kappa-B1 (NF-kB1) subunit p50 has been studied in a Dutch-Australian CVID-affected family and inherited as an autosomal dominant trait. Both above mutations were identified in early-onset (presented before the age of 10) with inflammatory or autoimmune complications patients with CVID.
CVID is the most common type of primary immunodeficiency, 1 in every 25,000 individuals is affected by this disease, men and women are equally affected. Based on the registries and databases of patients with primary immunodeficiencies in the united states, CVID affects more than 20 percent of registered patients. Although it can occur at any age but more typical after puberty. In the United States, the majority of patients are diagnosed between the ages of 20 and 45. A prospective cohort study of 248 referred patients with common variable immunodeficiency in New York, which the patients were followed for 1 to 25 years, did show a median age of onset of symptoms was 23 years for males and 28 years for females with 20 years survival rate after diagnosis was 64% for males and 67% for females. CVID if occurs at before the age of four might difficult to distinguish with transient hypogammaglobulinemia of infancy which is relatively common in young infants.
The pathogenesis of CVID is very complex and involves various alterations at the cellular level. Many studies have investigated the pathogenesis of CVID and our understanding of this disease has increased in recent years. Genetic and molecular defects, immune cell abnormalities, epigenetic, and microbiome dysbiosis may have some roles in the pathogenesis in CVID.
Genetic and Molecular Defects
Genetic defects in CVID can involve mutations at 3 cellular levels (nucleus, cytoplasm, and surface). Tumor Necrosis Factor (TNF) receptor superfamily gene defects have been investigated to be involved in this disease. These TNF receptors are involved in pathways that affect TACI, B-cell activating factor that belongs to tumor necrosis factor family BAFF (BAFF-R) receptor, and apoptosis inducer. TACI and BAFF-R participate in B-cell development and its activation. TACI regulates both B-cell receptor (BCR) and Toll-like receptor (TLR) 7 and 9 molecules hence mutations in TACI could impact B-cell development/maturation and may lead to autoimmunity.
Epigenetic changes influence gene expression without changing the germline DNA gene sequences. In other words, a change in phenotype without a change in genotype. These changes involve DNA methylation, histone modification, noncoding RNAs, transcription factor expression, and chromatin remodeling. These mechanisms can alter B-cell development in both early and late stages and causing hypogammaglobulinemia, decreased number of naïve and memory B cells, and an increase in the CD21 with low B-cell population.
Immune Cell Abnormalities
CVID can involve both innate and adaptive immune systems, especially defects in B-cell and T-cell. Most patients with common variable immunodeficiency have normal B-cell counts, denoting the defect affects the terminal stages of B-cell differentiation. Further studies have shown B-cell subsets disruption might increase terminal B-cell apoptosis, interrupt differentiation of B cells into memory and plasma cells that can lead to impaired antibody production. T-cell abnormalities also reported in patients with common variable immunodeficiency include the total numbers, percentages, and surface markers along with the function of T-cell subpopulations. Innate immune system leukocytes include dendritic cells, natural killer cells, innate lymphoid cells, and macrophages, exhibit significant roles in B and T cells responses, are also affected in CVID.
Bacteria in the gut can produce lipopolysaccharide that may activate our immune system through the recognition of the microbe-associated molecular patterns by the innate immune system. Overgrowth of proinflammatory products the bacteria can lead to further disruption in the immune system. These disruptions may involve decreased plasma IgA levels and increased T-cell activation markers.
A retrospective study of 51 patients with primary hypogammaglobulinemia and liver abnormalities who underwent liver biopsy showed 84% of them had non-fibrosing architectural features consistent with nodular regenerative hyperplasia (NRH). Other histopathologic characteristics in the liver include intrasinusoidal lymphocytic infiltration, abnormalities of portal vessels and epithelioid granulomas that were observed in 90% of the patients. Histopathologic characteristics of the intestinal tissue of patients with common variable immunodeficiency are inflammatory lymphocytic infiltrate, deep follicular lymphoid hyperplasia with reduced plasma cell counts, and villous atrophy in small-bowel disease.
Patients with CVID have broad clinical presentations because CVID can involve multi-organ systems from the nature of lacking immune defenses to fight infections, immune dysregulation causing autoimmunity, malignancy, inflammatory disorders, and also from the complications. Patients typically present with recurrent infections that mostly involve the respiratory and gastrointestinal tracts. Both upper and lower respiratory tract are frequently involved and contribute significantly to overall mortality and morbidity in patients with common variable immunodeficiency. Recurrent sinusitis, otitis, and bronchitis are found in half of the patients. From the European Society for Immunodeficiencies (ESID) database, the commonly reported disorders were pneumonia (32%), autoimmunity (29%), splenomegaly (26%), and bronchiectasis (23%). Recurrent and severe lung infections can lead to bronchiectasis and interstitial lung disease. Microorganisms that commonly cause respiratory infections in patients with CVID are Streptococcus sp., Moraxella catarrhalis, Haemophilus species, Staphylococcus sp., Neisseria meningitides, Mycoplasma sp., Herpes Zoster, and Rhinovirus. Gastrointestinal manifestations can manifest in the form of acute, chronic diarrhea, malabsorption, and weight loss with Giardia lamblia, Campylobacter jejuni, and Salmonella sp. as the main pathogens.
It is fairly common to see patients with CVID develop autoimmune conditions hence autoimmunity should always be considered in patients with CVID. The most common and severe manifestations are hematologic disorders including idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, and autoimmune neutropenia. Symptoms of easy bruising, bleeding in the mucocutaneous surface, anemia manifestations (weakness, pallor, fatigue, etc.) are often obtained in history. In patients with older age, we should also evaluate for lymphoid malignancies and gastric cancers. We should always obtain a family history in suspected patients with CVID. The affected family member with antibody deficiency is part of the diagnostic criteria for CVID.
Physical examination of patients with CVID may vary depending on the spectrum of the disease. Patients may have a normal physical examination, or they may have developed signs of chronic illness such as failure to thrive in children and malnutrition in adults. In patients with chronic respiratory infections, they often have nasal congestion or discharge and/or facial pain with chronic sinusitis, tympanic membranes scarring with chronic otitis, and abnormal lungs sound on auscultation with digital clubbing with chronic pulmonary disease. Other physical examination findings that we might encounter in patients with CVID are splenomegaly, lymphadenopathy, and findings related to underlying autoimmune diseases such as arthritis, skin rashes, etc.
The European Society for Immunodeficiencies (ESID) clinical criteria to diagnose CVID are listed below:
Initial history, including family history and physical examination, will help us determine if there are other risk factors predisposing the patients to be susceptible to infections. High index suspicion for CVID based on the history and physical exam should guide the laboratory investigations and immune function testing. The initial laboratory evaluation should include routine blood tests, such as complete blood counts with differential, serum chemistries, electrolytes, or urinalysis. These tests will aid in finding other secondary causes of immunodeficiency/secondary hypogammaglobulinemia (discussed below), the extend of the disease process and complications. Immunoglobulin levels should be obtained; serum immunoglobulin levels are markedly abnormal in patients with common variable immunodeficiency. Serum IgG should be <2 SD of the normal levels for their age with at least 2 measurements, and IgA and/or IgM levels should be below the lower limit of normal. The test is done during illness, it should be repeated three months after the resolution of the illness. After we establish hypogammaglobulinemia, we should proceed to further testing, such as flow cytometry to enumerate B-cell subsets, specific antibody response to immunization, IgG subclass analysis, Ig production in response to stimuli, and genetic testing.
For primary care physicians, we should refer to clinical immunologists in patients with a high index of suspicion of CVID with low immunoglobulin levels.
Medical treatment for patients with common variable immunodeficiency are illustrated below:
Monitoring disease progression with pulmonary function testing and a lung CT scan every one to two years after therapeutic interventions have been started. Live vaccines should not be given to patients with CVID, especially those with significantly impaired T cell function.
Nowadays, with the use of immune globulin, infection rates of patients with common variable immunodeficiency have been declining; therefore, the major causes of death are more associated with chronic lung disease, and malignancies. A prospective study of 473 patients who were followed for 4 decades, showed the leading causes of death were respiratory failure due to chronic lung disease (36 percent), lymphoid and other malignancies (29 percent), and liver disease (9 percent). During the study, 19.6 percent died, with a median age at death of 44 for males and 42 for females.
CVID is the most common type of primary immunodeficiencies that can affect both adults and children. It presents heterogeneous ways which make it challenging for clinicians to recognize and eventually come up with the precise diagnosis. In fact, patients can present after the disease progresses with signs and symptoms of autoimmunity, chronic lung disease, malignancies, etc., which makes it more difficult to diagnose. Primary health practitioners (family physicians, internists, pediatricians, and nurse practitioners) have significant roles of identifying, delivering early management including appropriate referral to an immunologist, and establishing a long term plan for the patients with common variable immunodeficiency. Nurses can provide patient counsel regarding how to reduce the risks of infections, medication compliance, and vaccine restrictions. Pharmacists can help to monitor adverse reactions, a history of hypersensitivity reactions, and the need for premedications. An interprofessional team approach will optimize the management and outcomes of patients with CVID. [Level 5]
|||Odnoletkova I,Kindle G,Quinti I,Grimbacher B,Knerr V,Gathmann B,Ehl S,Mahlaoui N,Van Wilder P,Bogaerts K,de Vries E, The burden of common variable immunodeficiency disorders: a retrospective analysis of the European Society for Immunodeficiency (ESID) registry data. Orphanet journal of rare diseases. 2018 Nov 12; [PubMed PMID: 30419968]|
|||Orange JS,Glessner JT,Resnick E,Sullivan KE,Lucas M,Ferry B,Kim CE,Hou C,Wang F,Chiavacci R,Kugathasan S,Sleasman JW,Baldassano R,Perez EE,Chapel H,Cunningham-Rundles C,Hakonarson H, Genome-wide association identifies diverse causes of common variable immunodeficiency. The Journal of allergy and clinical immunology. 2011 Jun; [PubMed PMID: 21497890]|
|||Chapel H,Lucas M,Lee M,Bjorkander J,Webster D,Grimbacher B,Fieschi C,Thon V,Abedi MR,Hammarstrom L, Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood. 2008 Jul 15; [PubMed PMID: 18319398]|
|||Bonilla FA,Barlan I,Chapel H,Costa-Carvalho BT,Cunningham-Rundles C,de la Morena MT,Espinosa-Rosales FJ,Hammarström L,Nonoyama S,Quinti I,Routes JM,Tang ML,Warnatz K, International Consensus Document (ICON): Common Variable Immunodeficiency Disorders. The journal of allergy and clinical immunology. In practice. 2016 Jan-Feb; [PubMed PMID: 26563668]|
|||Abbott JK,Gelfand EW, Common Variable Immunodeficiency: Diagnosis, Management, and Treatment. Immunology and allergy clinics of North America. 2015 Nov; [PubMed PMID: 26454311]|
|||Tangye SG,Al-Herz W,Bousfiha A,Chatila T,Cunningham-Rundles C,Etzioni A,Franco JL,Holland SM,Klein C,Morio T,Ochs HD,Oksenhendler E,Picard C,Puck J,Torgerson TR,Casanova JL,Sullivan KE, Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee. Journal of clinical immunology. 2020 Jan; [PubMed PMID: 31953710]|
|||Vorechovský I,Cullen M,Carrington M,Hammarström L,Webster AD, Fine mapping of IGAD1 in IgA deficiency and common variable immunodeficiency: identification and characterization of haplotypes shared by affected members of 101 multiple-case families. Journal of immunology (Baltimore, Md. : 1950). 2000 Apr 15; [PubMed PMID: 10754342]|
|||Fuchs HB,Slater L,Novey H,Ong K,Gupta S, Immunological analysis in familial common variable immunodeficiency. Clinical and experimental immunology. 1984 Apr; [PubMed PMID: 6609034]|
|||Hammarström L,Smith CI, HLA-A, B, C and DR antigens in immunoglobulin A deficiency. Tissue antigens. 1983 Jan; [PubMed PMID: 6601317]|
|||Schaffer FM,Palermos J,Zhu ZB,Barger BO,Cooper MD,Volanakis JE, Individuals with IgA deficiency and common variable immunodeficiency share polymorphisms of major histocompatibility complex class III genes. Proceedings of the National Academy of Sciences of the United States of America. 1989 Oct; [PubMed PMID: 2573059]|
|||De La Concha EG,Fernandez-Arquero M,Martinez A,Vidal F,Vigil P,Conejero L,Garcia-Rodriguez MC,Fontan G, HLA class II homozygosity confers susceptibility to common variable immunodeficiency (CVID). Clinical and experimental immunology. 1999 Jun; [PubMed PMID: 10361244]|
|||Picard C,Al-Herz W,Bousfiha A,Casanova JL,Chatila T,Conley ME,Cunningham-Rundles C,Etzioni A,Holland SM,Klein C,Nonoyama S,Ochs HD,Oksenhendler E,Puck JM,Sullivan KE,Tang ML,Franco JL,Gaspar HB, Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. Journal of clinical immunology. 2015 Nov; [PubMed PMID: 26482257]|
|||Maffucci P,Filion CA,Boisson B,Itan Y,Shang L,Casanova JL,Cunningham-Rundles C, Genetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency. Frontiers in immunology. 2016; [PubMed PMID: 27379089]|
|||Bogaert DJ,Dullaers M,Lambrecht BN,Vermaelen KY,De Baere E,Haerynck F, Genes associated with common variable immunodeficiency: one diagnosis to rule them all? Journal of medical genetics. 2016 Sep; [PubMed PMID: 27250108]|
|||Abolhassani H,Hammarström L,Cunningham-Rundles C, Current genetic landscape in common variable immune deficiency. Blood. 2020 Feb 27; [PubMed PMID: 31942606]|
|||Castigli E,Wilson SA,Garibyan L,Rachid R,Bonilla F,Schneider L,Geha RS, TACI is mutant in common variable immunodeficiency and IgA deficiency. Nature genetics. 2005 Aug; [PubMed PMID: 16007086]|
|||Fliegauf M,Bryant VL,Frede N,Slade C,Woon ST,Lehnert K,Winzer S,Bulashevska A,Scerri T,Leung E,Jordan A,Keller B,de Vries E,Cao H,Yang F,Schäffer AA,Warnatz K,Browett P,Douglass J,Ameratunga RV,van der Meer JW,Grimbacher B, Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency. American journal of human genetics. 2015 Sep 3; [PubMed PMID: 26279205]|
|||Cunningham-Rundles C,Bodian C, Common variable immunodeficiency: clinical and immunological features of 248 patients. Clinical immunology (Orlando, Fla.). 1999 Jul; [PubMed PMID: 10413651]|
|||Sullivan KE,Puck JM,Notarangelo LD,Fuleihan R,Caulder T,Wang C,Boyle M,Cunningham-Rundles C, USIDNET: a strategy to build a community of clinical immunologists. Journal of clinical immunology. 2014 May; [PubMed PMID: 24711005]|
|||Yazdani R,Habibi S,Sharifi L,Azizi G,Abolhassani H,Olbrich P,Aghamohammadi A, Common Variable Immunodeficiency: Epidemiology, Pathogenesis, Clinical Manifestations, Diagnosis, Classification, and Management. Journal of investigational allergology [PubMed PMID: 30741636]|
|||Martinez-Gallo M,Radigan L,Almejún MB,Martínez-Pomar N,Matamoros N,Cunningham-Rundles C, TACI mutations and impaired B-cell function in subjects with CVID and healthy heterozygotes. The Journal of allergy and clinical immunology. 2013 Feb; [PubMed PMID: 23237420]|
|||Rae W, Indications to Epigenetic Dysfunction in the Pathogenesis of Common Variable Immunodeficiency. Archivum immunologiae et therapiae experimentalis. 2017 Apr; [PubMed PMID: 27484309]|
|||Ahn S,Cunningham-Rundles C, Role of B cells in common variable immune deficiency. Expert review of clinical immunology. 2009 Sep; [PubMed PMID: 20477641]|
|||Jørgensen SF,Trøseid M,Kummen M,Anmarkrud JA,Michelsen AE,Osnes LT,Holm K,Høivik ML,Rashidi A,Dahl CP,Vesterhus M,Halvorsen B,Mollnes TE,Berge RK,Moum B,Lundin KE,Fevang B,Ueland T,Karlsen TH,Aukrust P,Hov JR, Altered gut microbiota profile in common variable immunodeficiency associates with levels of lipopolysaccharide and markers of systemic immune activation. Mucosal immunology. 2016 Nov; [PubMed PMID: 26982597]|
|||Malamut G,Ziol M,Suarez F,Beaugrand M,Viallard JF,Lascaux AS,Verkarre V,Bechade D,Poynard T,Hermine O,Cellier C, Nodular regenerative hyperplasia: the main liver disease in patients with primary hypogammaglobulinemia and hepatic abnormalities. Journal of hepatology. 2008 Jan; [PubMed PMID: 17998147]|
|||Gathmann B,Mahlaoui N,Gérard L,Oksenhendler E,Warnatz K,Schulze I,Kindle G,Kuijpers TW,van Beem RT,Guzman D,Workman S,Soler-Palacín P,De Gracia J,Witte T,Schmidt RE,Litzman J,Hlavackova E,Thon V,Borte M,Borte S,Kumararatne D,Feighery C,Longhurst H,Helbert M,Szaflarska A,Sediva A,Belohradsky BH,Jones A,Baumann U,Meyts I,Kutukculer N,Wågström P,Galal NM,Roesler J,Farmaki E,Zinovieva N,Ciznar P,Papadopoulou-Alataki E,Bienemann K,Velbri S,Panahloo Z,Grimbacher B, Clinical picture and treatment of 2212 patients with common variable immunodeficiency. The Journal of allergy and clinical immunology. 2014 Jul; [PubMed PMID: 24582312]|
|||Hampson FA,Chandra A,Screaton NJ,Condliffe A,Kumararatne DS,Exley AR,Babar JL, Respiratory disease in common variable immunodeficiency and other primary immunodeficiency disorders. Clinical radiology. 2012 Jun; [PubMed PMID: 22226567]|
|||Urschel S,Kayikci L,Wintergerst U,Notheis G,Jansson A,Belohradsky BH, Common variable immunodeficiency disorders in children: delayed diagnosis despite typical clinical presentation. The Journal of pediatrics. 2009 Jun; [PubMed PMID: 19230900]|
|||Mellemkjaer L,Hammarstrom L,Andersen V,Yuen J,Heilmann C,Barington T,Bjorkander J,Olsen JH, Cancer risk among patients with IgA deficiency or common variable immunodeficiency and their relatives: a combined Danish and Swedish study. Clinical and experimental immunology. 2002 Dec; [PubMed PMID: 12452841]|
|||Seidel MG,Kindle G,Gathmann B,Quinti I,Buckland M,van Montfrans J,Scheible R,Rusch S,Gasteiger LM,Grimbacher B,Mahlaoui N,Ehl S, The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity. The journal of allergy and clinical immunology. In practice. 2019 Jul - Aug; [PubMed PMID: 30776527]|
|||Busse PJ,Razvi S,Cunningham-Rundles C, Efficacy of intravenous immunoglobulin in the prevention of pneumonia in patients with common variable immunodeficiency. The Journal of allergy and clinical immunology. 2002 Jun; [PubMed PMID: 12063531]|
|||Roifman CM,Levison H,Gelfand EW, High-dose versus low-dose intravenous immunoglobulin in hypogammaglobulinaemia and chronic lung disease. Lancet (London, England). 1987 May 9; [PubMed PMID: 2883406]|
|||Resnick ES,Moshier EL,Godbold JH,Cunningham-Rundles C, Morbidity and mortality in common variable immune deficiency over 4 decades. Blood. 2012 Feb 16; [PubMed PMID: 22180439]|