Common variable immunodeficiency (CVID) is an inborn immune disorder characterized by recurrent infections and low antibody levels, specifically in immunoglobulin (Ig) types IgG, IgM, and IgA. Symptoms generally include high susceptibility to pathogens, chronic lung disease, as well as inflammation and infection of the gastrointestinal tract.
CVID affects males and females equally. The condition can be found in children or teens, but is generally not diagnosed or recognized until adulthood. The average age of diagnosis is between 20 and 50.
However, symptoms vary greatly between people. The term "variable" refers to the heterogeneous clinical manifestations of this disorder, which include recurrent bacterial infections and gastrointestinal disease, as well as increased risk for autoimmune disease and lymphoma.Cunningham-Rundles, C. Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults. In: UpToDate, Notarangelo, LD, Feldweg, AM (Eds), UpToDate, Waltham, MA, 2020. Retrieved April 8, 2020. CVID is a lifelong disease.
Signs and complications
The symptoms of CVID vary between those affected. Its main features are hypogammaglobulinemia and recurrent infections. Hypogammaglobulinemia manifests as a significant decrease in the levels of IgG antibodies, usually alongside IgA antibodies; IgM antibody levels are also decreased in about half of those affected.
Infectious complications People with common variable immunodeficiency have trouble fighting off infections due to the lack of antibodies produced, which normally resist invading microbes. Infections are also the leading cause of morbidity and mortality in CVID patients. Due to impaired antibody development, vaccination is not effective for CVID patients.
The prevalence of bacterial complications (42%) is higher in comparison to viral (25%), parasitic (19%) or fungal (3%). Recurring bacterial infections are generally found in the upper and lower areas of the respiratory tract and in gastrointestinal tract. Many who have a recurring lung infection report developing chronic lung diseases and potentially life-threatening complications later in life.
Common infections include: Pneumonia Ear infections Sinusitis Chronic coughing (lasting from a few weeks to many months) Gastrointestinal infections
The microorganisms that most frequently cause infections in CVID are Haemophilus influenzae, Streptococcus pneumoniae, and Staphylococcus aureus. Pathogens less often isolated from those affected include Neisseria meningitidis, Pseudomonas aeruginosa, respectively Giardia lamblia, Salmonella sp., Campylobacter jejuni for gastrointestinal tract.
Infections mostly affect the respiratory tract (nose, sinuses, bronchi, lungs) and the gastrointestinal tract; they can also occur at other sites, such as the eyes, skin, and ears. These infections respond to antibiotics but can recur upon discontinuation of antibiotics. Bronchiectasis can develop when severe, recurrent pulmonary infections are left untreated.
Gastrovascular infections or inflammation are very common for those with CVID. Signs of a gastrovascular infection include abdominal pain, nausea, bloating, vomiting, diarrhea, and weight loss. Many individuals with CVID have an impaired ability to absorb nutrients, including vitamins, proteins, minerals, fats, and sugar, within the digestive tract.
Autoimmune disorders CVID is frequently associated with a variety of autoimmune diseases. They could present as the first or the only clinical manifestation of the disease. The reported prevalence of autoimmunity ranged from 14% to 54% in CVID patients and is higher for females. The most common autoimmune disorders observed in CVID are autoimmune cytopenia, idiopathic thrombocytopenic purpura (ITP), AIHA and neutropenia. Furthermore, autoimmune endocrinological (insulin-dependent diabetes, autoimmune thyroiditis), gastrointestinal (anemia, autoimmune enteropathy), dermatological (psoriasis, vitiligo) and rheumatological disorders were described in CVID too.
The reason for such a high prevalence of autoimmunity in CVID individuals is not fully understood. CVID patients with autoimmunity show decreased number of immunosuppressive regulatory T cells (Treg) and impaired selection process of self-reactive antibodies, suggesting the possible mechanism.
Malignancy and CVID The patients with CVID have a risk 5 to 12 times higher than the general population. The most frequent malignancies are Non-Hodgkin lymphoma (NHL), gastric carcinoma and leukemia.
Enteropathy There is a wide spectrum of noninfectious gastrointestinal pathology and inflammation in CVID that is a part of the general immune dysregulation affecting patients with CVID.
The most common upper gastrointestinal inflammation is chronic gastritis, which may in rare cases develop to gastric cancer, and duodenal inflammation resembling celiac disease. The inflammation affecting the lower GI tract is heterogenous and often characterized as an unspecific colitis.
Recent studies have suggested a role of gut microbiota in the etiology of CVID, and the reduction of mucosal IgA in CVID enteropathy. The heterogenous group of patients makes it difficult to find common grounds for treatment for the GI inflammation in CVID.
Other complications Due to changes in B cell development, some individuals with CVID have accumulations of lymphocytes in lymphoid tissues. This can cause mild to severely swollen lymph nodes or inflammation of the spleen.
Lymphocytic infiltration to tissues may cause enlargement of lymph nodes (lymphadenopathy), of the spleen (splenomegaly), and of the liver (hepatomegaly), as well as the formation of granulomas. In the lung, this is known as granulomatous–lymphocytic interstitial lung disease.
Anxiety and depression can occur as a result of dealing with the other symptoms.Sanger, David E. "An Investigation of Coping and Psychosocial Functioning in Persons with Common Variable Immunodeficiency (CVID)" , Barts and The London NHS Trust, 2003, accessed August 7, 2011.
CVID patients generally complain of severe fatigue.
Pathogenesis of CVID
Genetic defects The causative factors of CVID are not fully known. Genetic mutations can be identified as the cause of disease in about 10% of people, while familial inheritance accounts for 10–25% of cases. Rather than arising from a single genetic mutation, CVID seems to result from a variety of mutations that all contribute to a failure in antibody production.
Mutations in the genes encoding ICOS, TACI, CD19, CD20, CD21, CD80, and BAFFR have been identified as causative of CVID. Susceptibility to CVID may also be linked to the major histocompatibility complex (MHC) of the genome, particularly to DR-DQ haplotypes. A mutation in the NFKB2 gene has recently been shown to cause CVID-like symptoms in a murine model. The frequency of this NFKB2 mutation in the CVID population is, however, yet to be established. +The examples of molecular defects in CVID MoleculeRole in CVIDSurface moleculesTACIB-cell activation defect and autoimmunityBAFF-RLow peripheral B-cell numbers, decreased antibody responsesCD27Hypogammaglobulinemia, absent memory B cellsCD19 complex (CD19,CD81, CD21)Impaired BCR signalingIL-21R and IL-21Impaired germinal center formation, impaired class-switch process and plasma cell differentiationCTLA-4Impaired function of Treg cellsICOSReduced B cell counts and low levels of antibodiesCytosolic moleculesPKC-deltaDecreased number of memory B cellsPLC-gamma-2Defective BCR signalingPI3KImpaired B and T cell homeostasisZAP70Impaired T cell functionTLR7 and TLR9Defects in B cells activation in response to TLRs ligandsNuclear defectsSTAT1Hypogammaglobulinemia, reduced number of memory and plasma cellsNF-κBImpaired B cell maturation, differentiation and class switching
Epigenetic factors Several recent studies have described a potential role of epigenetics factor (including DNA methylation, chromatin and histone modulation and also non-coding RNAs) in pathogenesis of CVID.
Immune cell abnormalities There are several abnormalities described in CVID patients connected to the count of particular cell (sub)populations.
The majority of CVID patients have normal B cell counts, suggesting the impaired antibody production is mainly a defect in the differentiation process of B cells into memory and plasma cells.
There are also T cell abnormalities in CVID including counts, percentages, surface markers and function differences. +The examples of possible immune cell population changes in CVID PopulationChangeB cellsMemory B (CD19+CD27+)decreasedPlasma cellsdecreasedTransitional B cellsincreasedCD21low B cellsincreasedT cellsNaive CD4+decreasedMemory CD4+increasedNaive CD8+decreasedMemory CD8+increased
Diagnosis According to a European registry study, the mean age at onset of symptoms was 26.3 years old. As per the criteria laid out by ESID (European Society for Immunodeficiencies) and PAGID (Pan-American Group for Immunodeficiency), CVID is diagnosed if: the person presents with a marked decrease in serum IgG levels (<4.5 g/L) and a marked decrease below the lower limit of normal for age in at least one of the isotypes IgM or IgA; the person is four years of age or older; the person lacks an antibody immune response to protein antigens or immunization.
Diagnosis is chiefly by exclusion, i.e., alternative causes of hypogammaglobulinemia, such as X-linked agammaglobulinemia, must be excluded before a diagnosis of CVID can be made.
Diagnosis is difficult because of the diversity of phenotypes seen in people with CVID. For example, serum immunoglobulin levels in people with CVID vary greatly. Generally, people can be grouped as follows: no immunoglobulin production, immunoglobulin (Ig) M production only, or both normal IgM and IgG production. Additionally, B cell numbers are also highly variable. 12% of people have no detectable B cells, 12% have reduced B cells, and 54% are within the normal range. In general, people with CVID display higher frequencies of naive B cells and lower frequencies of class-switched memory B cells. Frequencies of other B cell populations, such as IgD memory B cells, transitional B cells, and CD21 B cells, are also affected and are associated with specific disease features.
Although CVID is often thought of as a serum immunoglobulin- and B cell-mediated disease, T cells can display abnormal behavior. Affected individuals typically present with low frequencies of CD4+, a T-cell marker, and decreased circulation of regulatory T cells and iNKT cells. Notably, approximately 10% of people display CD4+ T cell counts lower than 200 cells/mm3; this particular phenotype of CVID has been named LOCID (Late Onset Combined Immunodeficiency) and has a poorer prognosis than classical CVID.
Types The following types of CVID have been named, and correspond to mutations in different gene segments: Type OMIM Gene CVID1 ICOS CVID2 TACI CVID3 CD19 CVID4 TNFRSF13C CVID5 CD20 CVID6 CD81
Treatment
Treatment options are limited and usually include lifelong immunoglobulin replacement therapy. This therapy is thought to help reduce bacterial infections. This treatment alone is not wholly effective, and many people still experience other symptoms such as lung disease and noninfectious inflammatory symptoms. This treatment replenishes Ig subtypes that the person lacks, is given at frequent intervals for life, and is thought to help reduce bacterial infections and boost immune function. Before therapy begins, plasma donations are tested for known blood-borne pathogens, then pooled and processed to obtain concentrated IgG samples. Infusions can be administered in three different forms: intravenously (IVIg), subcutaneously (SCIg), and intramuscularly (IMIg).