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.^[2] Symptoms generally include high susceptibility to pathogens, chronic lung disease, as well as inflammation and infection of the gastrointestinal tract.^[2]

Quick Facts Specialty, Symptoms ...

Common variable immunodeficiency
Specialty	Immunology
Symptoms	Hypogammaglobulinemia, recurrent opportunistic infections, fatigue
Complications	Autoimmune manifestations; increased risk of malignancies such as gastric carcinomas, non-Hodgkin lymphoma; lymphocytic infiltration of tissues; nodular regenerative hyperplasia; enteropathy
Usual onset	Varies; median age for symptoms is early 20s for males and mid-20s for females
Duration	Lifelong
Types	CVID1, CVID2, CVID3, CVID4, CVID5, CVID6
Causes	Uncertain; at least 30% have an identified heterogeneous gene mutation and/or inheritance of mutations
Diagnostic method	Exclusion of other possible causes of hypogammaglobulinemia
Differential diagnosis	Varies by age group Age <4: leaky SCID, transient hypogammaglobulinemia of infancy, XLP, XLA, hyper-IgM syndromes, myelodysplastic syndromes, Wiskott-Aldrich syndrome, rare combined immune deficiencies, cystic fibrosis, HIV Age 5-55: loss of immunoglobulin due to renal/gut disease; side effects of medications (particularly anticonvulsants and anti-rheumatics) Age >56: thymoma, lymphoid malignancies, side effects of medications (particularly anticonvulsants and anti-rheumatics), loss of immunoglobulin due to renal/gut disease[1]
Treatment	Immunoglobulin replacement therapy, symptom management
Prognosis	Varies by type; recent studies suggest those with only recurrent infections have little or no reduced life expectancy post-diagnosis, while those with disease-related complications have around 50% survival rate 33 years post-diagnosis
Frequency	Less than 1 in 30,000

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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. "Variable" refers to the heterogeneous clinical manifestations of this disorder, which include recurrent bacterial infections, increased risk for autoimmune disease and lymphoma, as well as gastrointestinal disease.^[3] CVID is a lifelong disease.

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.^[4]

According to a European registry study, the mean age at onset of symptoms was 26.3 years old.^[21] As per the criteria laid out by ESID (European Society for Immunodeficiencies) and PAGID (Pan-American Group for Immunodeficiency), CVID is diagnosed if:^[22]

• 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.^[23] 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.^[22] 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.

Treatment options are limited and usually include lifelong immunoglobulin replacement therapy.^[24] 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.^[25] 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),^[26] subcutaneously (SCIg), and intramuscularly (IMIg).

The administration of intravenous immunoglobulins requires the insertion of a cannula or needle in a vein, usually in the arms or hands. Because a highly concentrated product is used, IVIg infusions take place every three to four weeks. Subcutaneous infusions slowly release the Ig serum underneath the skin, again through a needle, and take place every week.^[27] Intramuscular infusions are no longer widely used, as they can be painful and are more likely to cause reactions.

People often experience adverse side effects from immunoglobulin infusions, including:

• swelling at the insertion site (common in SCIG)
• chills
• headache
• nausea (common in IVIG)
• fatigue (common in IVIG)
• muscle aches and pain, or joint pain
• fever (common in IVIG and rare in SCIG)
• hives (rare)
• thrombotic events (rare)
• aseptic meningitis (rare, more common in people with SLE)
• anaphylactic shock (very rare)

In addition to Ig replacement therapy, treatment may also involve immune suppressants to control autoimmune symptoms of the disease and high-dose steroids like corticosteroids.^[22] In some cases, antibiotics are used to fight chronic lung disease resulting from CVID.^[28] The outlook for people varies greatly depending on their level of lung and other organ damage prior to diagnosis and treatment.

CVID has an estimated prevalence of about 1:50,000 in Caucasians.^[29] The disease seems to be less prevalent among Asians and African Americans. Males and females are equally affected; however, among children, boys predominate.^[23] A recent study of people in Europe with primary immunodeficiencies found that 30% had CVID as opposed to a different immunodeficiency.^[13] 10–25% of people inherit the disease, typically through autosomal-dominant inheritance. Given the rarity of the disease, it is not yet possible to generalize about its prevalence among ethnic and racial groups. CVID shortens the lifespan, but no study currently has a median age recorded. One study suggests the median age of death for men and women is 42 and 44 years old, respectively, but most patients involved in the study are still alive.^[24] Those people with accompanying disorders had the worst prognosis (50% survival 33 years after diagnosis), and those with only CVID-caused frequent infections had the longest survival rates, with another study stating a life expectancy almost equaling that of the general UK population.^[1] Additionally, people with CVID with one or more noninfectious complications have an 11 times higher risk of death as compared to people with only infections.

Immunodeficiencies comprise many diseases and are genetic defects affecting the immune system. There are roughly 150 immunodeficiencies spanning over 120 genetic defects.^[22] Charles Janeway Sr. is generally credited with the first description of a case of CVID in 1953.^[30] The case involved a 39-year-old who had recurrent infections, bronchiectasis, and meningitis.^[13] CVID has since emerged as the predominant class of primary antibody deficiencies. It is thought to affect between 1 in 25,000 to 1 in 50,000 people worldwide. Though described in 1953, there was no standard definition for CVID until the 1990s, which caused widespread confusion during diagnosis. During the 1990s, the European Society for Immunodeficiency (ESID) and Pan-American Group for Immunodeficiency (PAGID) developed diagnostic criteria for the disease, including the minimum age of diagnosis and the need to exclude other conditions. Since publication in 1999, some criteria have been changed, such as increasing the minimum age of diagnosis.

Current research is aimed at studying large cohorts of people with CVID in an attempt to better understand the age of onset as well as the mechanism, genetic factors, and progression of the disease.^[23]

Funding for research in the US is provided by the National Institutes of Health. Key research in the UK was previously funded by the Primary Immunodeficiency Association (PiA) until its closure in January 2012,^[31] and funding is raised through the annual Jeans for Genes campaign. Current efforts are aimed at studying the following:^[22]

• Causes of complications. Little is known about why such diverse complications arise during treatment.
• Underlying genetic factors. Though many polymorphisms and mutations have been identified, their respective roles in CVID development are poorly understood and not represented in all people with CVID.
• Finding new ways to study CVID. Given that CVID arises from more than one gene, gene knock-out methods are unlikely to be helpful. It is necessary to seek out disease-related polymorphisms by screening large populations of people with CVID, but this is challenging given the rarity of the disease.