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Common variable immunodeficiency
Common variable immunodeficiency (CVID) affects the immune system, leading to a reduced ability to produce functional antibodies. This can result in frequent and severe infections, impacting various organs and often requiring long-term medical management.
Overview
Common variable immunodeficiency (CVID) is a significant primary immunodeficiency, meaning it is an inherited condition that impairs the immune system from birth. It is characterised by a reduced ability to produce certain types of antibodies, primarily immunoglobulins G (IgG), A (IgA), and M (IgM), which are crucial for fighting off infections [PMID:32066840]. This deficiency results in individuals with CVID being more vulnerable to recurrent and severe infections, particularly of the respiratory and gastrointestinal tracts. While it can be diagnosed at any age, symptoms often become apparent in childhood or early adulthood.
CVID is considered a diagnosis of exclusion: it is identified when other causes of low antibody levels have been ruled out. The exact prevalence of CVID is estimated to be between 1 in 25,000 and 1 in 50,000 people, making it one of the more common severe primary immunodeficiencies [PMID:24606180]. The condition can vary significantly from person to person, both in symptoms and severity, even within the same family.
Symptoms & clinical features
The primary clinical feature of CVID is a heightened susceptibility to infections. These commonly include recurrent bacterial infections affecting the lungs, such as pneumonia and bronchitis, and often the sinuses and ears. Individuals may also experience chronic diarrhoea and other gastrointestinal issues due to infections or inflammation.
Beyond infections, CVID can be associated with other health problems. Autoimmune conditions, where the immune system mistakenly attacks the body's own tissues, are common; examples include autoimmune haemolytic anaemia or immune thrombocytopenia. Inflammatory conditions, such as granulomatous disease (collections of immune cells forming lumps), can affect various organs. Some individuals may also have an increased risk of certain cancers, particularly lymphomas [PMID:28989506]. Symptoms can appear gradually and worsen over time, making early diagnosis challenging.
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Affected organs
CVID can affect multiple organ systems due to recurrent infections, inflammation, and autoimmune processes. The lungs are frequently impacted, leading to chronic lung disease if infections are not controlled effectively. The gastrointestinal tract often experiences issues such as chronic diarrhoea, malabsorption, and inflammatory bowel disease-like symptoms.
Other organs that may be affected include the spleen, which can become enlarged (splenomegaly), and the lymph nodes. Autoimmune manifestations can target blood cells, leading to anaemia or low platelet counts, and can also affect joints, the thyroid, or other endocrine glands. Granulomas can form in various tissues, such as the lungs, lymph nodes, liver, or skin, causing further complications.
Risks & severity
The severity of CVID is highly variable, ranging from relatively mild forms with infrequent infections to severe, life-threatening complications. The lifetime risk of developing serious infections is significantly increased for individuals with CVID, especially if untreated. The average age of diagnosis can be broad, typically from childhood into adulthood, with many experiencing a delay in diagnosis due to the diverse and sometimes non-specific nature of symptoms.
Complications such as chronic lung damage (bronchiectasis), persistent gastrointestinal inflammation, and the development of autoimmune conditions can significantly impact quality of life and long-term health outcomes. There is also an increased risk of certain cancers, notably lymphoma and gastric carcinoma, requiring regular monitoring. The prognosis often depends on the type and severity of these associated complications and the effectiveness of ongoing management.
Genetic causes
While CVID is often referred to as 'common variable,' its genetic basis is highly complex and heterogeneous. Pathogenic variants in several different genes have been identified that can contribute to CVID, though for many individuals, a specific genetic cause is not yet found. Genes implicated in some cases include NFKB1, PIK3CD, and TNFRSF13B.
These genes play critical roles in the development and function of B cells, which are the immune cells primarily responsible for producing antibodies. For example, TNFRSF13B (also known as TACI) is involved in B cell maturation and antibody production. Pathogenic variants in NFKB1 can disrupt the NF-κB signalling pathway, which is essential for immune cell development and function, affecting both B and T cells. Similarly, PIK3CD is part of a signalling pathway crucial for immune cell activation and survival. When these genes are altered, the normal processes required for effective antibody production are impaired, leading to the immunodeficiency seen in CVID.
Inheritance pattern
CVID can have various inheritance patterns, including autosomal dominant, autosomal recessive, and polygenic depending on the specific genetic cause. In cases with an autosomal dominant pattern, only one altered copy of a specific gene is sufficient to cause the condition. This means an affected individual has a 50% chance of passing the condition to each of their children.
For an autosomal recessive inheritance, an individual must inherit two altered copies of a gene (one from each parent) to develop the condition. Parents who carry one altered copy are typically unaffected but can pass the gene to their children. In some instances, CVID is considered polygenic, meaning multiple genetic factors, along with environmental influences, may contribute to the condition's development. It is also important to note that many cases of CVID appear to occur without a clear genetic cause found to date.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosing CVID typically involves a comprehensive evaluation of a person's medical history, clinical symptoms, and laboratory tests. The diagnostic process focuses on identifying persistently low levels of immunoglobulins (IgG, IgA, IgM) and impaired antibody responses to vaccines, while ruling out other causes of secondary immunodeficiency, such as medication effects or other underlying conditions [PMID:32066840]. This is often guided by a consultant immunologist.
Genetic testing is increasingly important in confirming a diagnosis and identifying specific genetic causes of CVID. In the UK, individuals suspected of having primary immunodeficiencies, including CVID, may be referred to specialist immunology services. Genetic testing can be accessed through the NHS Genomic Medicine Service (GMS) following referral by a clinician, often an immunologist or clinical geneticist. This testing may involve specific R-codes for primary immunodeficiencies, as determined by the clinical genomics laboratory. A genetic counsellor can provide support and information regarding genetic testing options and results.
Management & lifestyle
Management of CVID aims to prevent and treat infections, as well as manage associated complications such as autoimmune and inflammatory conditions. The cornerstone of treatment is typically immunoglobulin replacement therapy, where antibodies are administered intravenously or subcutaneously to supplement the deficient immune system. This therapy helps to reduce the frequency and severity of infections.
Prophylactic antibiotics may also be used in some cases to prevent bacterial infections. Other management strategies include vigilant monitoring for associated complications, such as lung disease, gastrointestinal issues, autoimmune disorders, and potential malignancies. Regular follow-ups with an immunologist and other specialists are crucial. Lifestyle adjustments, such as maintaining good hygiene and avoiding exposure to infections, are also advised. Management plans are individualised and depend on the specific symptoms and severity of the condition, guided by specialist NHS care pathways.
UK care pathway
In the UK, individuals suspected of having Common variable immunodeficiency (CVID) are generally referred by their GP or another hospital specialist to a clinical immunologist. These specialists work within the NHS Genomic Medicine Service (GMS) framework. Following a clinical assessment, if a genetic cause is suspected, appropriate genetic testing can be requested, often using specific R-codes for primary immunodeficiencies. Support from a genetic counsellor is available to explain the implications of genetic testing and results, both for the individual and their family.
Frequently asked questions
What is immunoglobulin replacement therapy?
Immunoglobulin replacement therapy involves providing a regular supply of antibodies (immunoglobulins) that the body is unable to produce sufficiently. These antibodies are usually given through an injection into a vein (intravenously) or under the skin (subcutaneously) to help fight off infections.
Can CVID be cured?
Currently, there is no cure for CVID. However, the condition can be effectively managed with treatments like immunoglobulin replacement therapy, which significantly reduce the risk of severe infections and improve quality of life. Research into new therapies is ongoing.
Is CVID always inherited?
CVID can be inherited in families, often following autosomal dominant or autosomal recessive patterns depending on the specific genetic cause. However, in many cases, a clear genetic cause is not identified, and the condition may appear without a known family history (sporadic cases).
What are the common infections experienced with CVID?
People with CVID are particularly susceptible to recurrent bacterial infections. These commonly affect the respiratory system, leading to pneumonia, bronchitis, and sinus infections, and the gastrointestinal tract, causing chronic diarrhoea and other digestive issues.
How often do I need to see a specialist if I have CVID?
Individuals with CVID typically require regular follow-up appointments with an immunology specialist. The frequency will depend on the severity of the condition, the chosen treatment regimen, and the presence of any associated complications. This ensures ongoing monitoring and adjustment of care as needed.
References
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