Common Variable Immunodeficiency (CVID) is a disorder characterized by low levels of immunoglobulins (antibodies) in the blood serum and increased susceptibility to infections. In most cases, the genetic causes of low immunoglobulin levels in the serum are unknown. This form of immunodeficiency is relatively common, which is why the word “common” is included in its name. The degree and type of immunoglobulin deficiency in the serum, as well as the clinical course, vary among patients, explaining the presence of the word “variable.”
Some patients experience a deficiency of immunoglobulins such as IgG and IgA. Others may have decreased levels of all three major types of immunoglobulins (IgG, IgA, and IgM). Clinical signs and symptoms can range from mild to severe. Frequent and unusual infections may first appear in early childhood, adolescence, or adulthood. In most patients, this condition is diagnosed only between the ages of 20 and 40. However, in approximately 20% of patients, symptoms of the disease or signs of immunodeficiency manifest before the age of 16.
Due to the relatively late onset of symptoms and diagnosis, this disorder also has other names, including acquired agammaglobulinemia, adult agammaglobulinemia, or late-onset hypogammaglobulinemia. The term “acquired immunodeficiency” is now used to define the syndrome caused by the AIDS virus (HIV), and it should not be used to refer to Common Variable Immunodeficiency (CVID) due to the significant differences between these disorders.
Causes
The causes of CVID remain largely unknown, although recent studies have identified the involvement of a small group of genes in some patients. Over the past decades, research on immune system cells in CVID patients has revealed significant lymphocyte abnormalities. Most patients have a normal number of B-lymphocytes, but these cells fail to mature into plasma cells capable of producing different types of immunoglobulins and antibodies. In other patients, the function of T-helper lymphocytes is insufficient for normal antibody production. A third group of patients exhibits an excessive number of cytotoxic T-lymphocytes, though the role of these cells in the disease remains unclear.
Clinical Manifestations
CVID can occur in both men and women. While some patients develop symptoms within the first few years of life, many do not experience them until they are 10–30 years old or even later. The primary manifestation of CVID in most patients is recurrent infections of the ears, sinuses, bronchi, and lungs. In severe cases with frequent lung infections, irreversible bronchial damage with chronic changes—dilation and scarring of these structures—may occur. This condition is called bronchiectasis. These infections are usually caused by bacteria commonly found among humans and often responsible for pneumonia (Haemophilus influenzae, pneumococci, and staphylococci). Treatment of lung infections aims to prevent recurrences and associated chronic lung tissue damage. A regular morning cough with yellow or green phlegm may indicate chronic infection or bronchiectasis.
Patients with CVID may have enlarged lymph nodes in the neck, chest, or abdomen. The exact cause is unknown, but lymph node enlargement may result from infection, immune regulation disorders, or a combination of these factors. Similarly, spleen enlargement and increased lymphoid tissue in the intestinal walls (Peyer’s patches) are often observed.
Despite the decreased antibody production and low serum immunoglobulin levels (hypogammaglobulinemia) in CVID patients, some antibodies produced by their bodies may attack their own tissues (autoantibodies). These antibodies can destroy blood cells (e.g., red blood cells, white blood cells, or platelets). While recurrent bacterial infections are the primary manifestation of CVID, in about 20% of cases, immunodeficiency first presents as a significant decrease in platelet levels or even severe anemia due to the destruction of red blood cells (erythrocytes). Autoantibodies can also cause arthritis or endocrine disorders, such as thyroid disease.
Some CVID patients who do not receive adequate immunoglobulin replacement therapy may develop painful inflammation of one or more joints, a condition known as polyarthritis. In such cases, joint fluid usually does not contain bacteria. To confirm this, a sample of synovial fluid can be taken with a needle and tested for bacterial presence. In some difficult-to-diagnose cases, the cause of joint inflammation may be Mycoplasma bacteria. CVID-related arthritis most commonly affects large joints, such as the knees, ankles, elbows, and wrists. Smaller joints (e.g., finger joints) are rarely involved. Symptoms of joint inflammation usually resolve with adequate immunoglobulin therapy and appropriate antibiotic administration. However, in some patients, arthritis may persist even with sufficient replacement therapy.
Some CVID patients experience gastrointestinal symptoms, such as abdominal pain, bloating, nausea, diarrhea, and weight loss. A thorough examination of the digestive system may reveal malabsorption of fats and certain sugars. A biopsy of the intestinal mucosa can identify characteristic changes that help diagnose and treat this condition. In some patients with gastrointestinal dysfunction, microscopic analysis of biopsy samples and stool tests may reveal Giardia lamblia parasites. Eliminating this parasite with medication can alleviate gastrointestinal symptoms.
Additionally, CVID may increase the risk of developing cancer, particularly cancers of the lymphoid system, skin, and gastrointestinal tract.
In the absence of complications, CVID does not lead to physical abnormalities. Some patients may have an enlarged spleen and lymph nodes. If chronic lung disease develops, patients may experience reduced physical endurance and lung capacity (the maximum amount of air that can be voluntarily inhaled). Gastrointestinal involvement may, in some cases, affect normal growth in children or lead to weight loss in adults.
Diagnosis
CVID is suspected when evaluating children or adults with recurrent infections of the ears, sinuses, bronchi, and lungs. The diagnosis is confirmed by detecting low levels of immunoglobulins, including IgG, IgA, and usually IgM. In fully immunized patients against polio, measles, diphtheria, and tetanus, antibody levels to one or more of these vaccines may be extremely low or absent. To assess immune function, patients may be immunized with other vaccines, such as pneumococcal vaccines. These tests help determine whether immunoglobulin replacement therapy will benefit the patient. Blood samples can also be analyzed to assess T-lymphocyte counts and function. Specialized laboratory techniques allow researchers to determine whether B-lymphocytes produce antibodies in test tubes (tissue cultures) and whether T-lymphocyte functions are normal.
Genetics and Inheritance
Since the genetic nature of CVID remains unclear, the exact inheritance pattern is unknown. In some families, multiple members have deficiencies in one or more immunoglobulin types. For example, one family member may have CVID, while another may have selective IgA deficiency.
Recent studies have identified a connection between CVID and mutations in certain genes. For instance, autosomal recessive inheritance of CVID has been linked to inducible costimulation (ICOS) in one family, while in others, it has been associated with the B-cell protein CD19. In about 10% of CVID cases, mutations in the TACI receptor, which interacts with the factors BAFF or APRIL for normal B-cell growth and regulation, have been found. However, it is unclear whether these mutations directly cause immunodeficiency, as some are also found in individuals with normal immunoglobulin levels.
Treatment
CVID treatment is similar to that for other disorders with low serum immunoglobulin levels. If T-lymphocyte function is not significantly impaired and there is no organ damage, immunoglobulin replacement therapy almost always alleviates symptoms. Immunoglobulins are derived from large volumes of human plasma and primarily consist of IgG, containing all essential antibodies present in healthy individuals.
Patients with chronic sinusitis or lung disease may require long-term broad-spectrum antibiotic therapy. If infection with Mycoplasma or Chlamydia bacteria is suspected, targeted antibiotics may be prescribed. In cases of bronchiectasis, physiotherapy and daily postural drainage procedures help clear mucus from the lungs and bronchi.
Gastrointestinal symptoms or malabsorption should be investigated for Giardia, rotavirus, and other gastrointestinal infections. Most patients with immunodeficiency and arthritis respond well to immunoglobulin replacement therapy.
Prognosis
Immunoglobulin replacement therapy combined with antibiotic treatment has significantly improved the prognosis for CVID patients. The goal is to protect the patient from infections and prevent chronic lung damage. The prognosis depends on the extent of organ damage at diagnosis and the success of infection prevention through immunoglobulin and antibiotic therapy.
Based on materials from IPOPI (International Patient Organisation for Primary Immunodeficiencies).