Common variable immunodeficiency

Common variable immunodeficiency (CVID) is an inborn

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.

Signs and complications

The symptoms of CVID vary between those affected. Its main features are

People with common variable immunodeficiency have trouble fighting off infections due to the lack of antibodies produced, which normally resist invading microbes.[5] 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. ^[6]

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

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.^[5]

Autoimmune disorders

CVID is frequently associated with a variety of

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.^[8]

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. ^[9]

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

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.[7]

Other complications

Due to changes in B cell development, some individuals with CVID have accumulations of lymphocytes in lymphoid tissues.^[10] This can cause mild to severely swollen lymph nodes or inflammation of the spleen.

Lymphocytic infiltration to tissues may cause enlargement of lymph nodes (

Anxiety and depression can occur as a result of dealing with the other symptoms.[11]

CVID patients generally complain of severe fatigue.^[12]

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.^[13] 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

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. ^[19][20]

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. ^[19]

Diagnosis

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
  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.

• 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.

Epidemiology

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.

History

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.

Research

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.

References