Common variable immune deficiency (CVID)

Overview

CVID is a relatively frequent form of primary immunodeficiency, found in about 1 in 25,000 persons; this is the reason it is called common. The degree and type of deficiency of serum immunoglobulins, and the clinical course, varies from person to person, hence, the word variable. An additional characteristic is a decreased IgA and/ or IgM level, or a low level of all three major types of immunoglobulins (IgG, IgA, and IgM). In some individuals, there are defects of the T cells, and this may also contribute to increased susceptibility to infections as well as autoimmunity, granulomatous disease, and cancer.

To be sure that CVID is the correct diagnosis, there must be evidence of a lack of specific antibodies (measured antibodies in response to vaccines). Other possible causes of these immunologic abnormalities, such as loss in the gastrointestinal tract or urine, must be excluded. Frequent and/or unusual infections may first occur during early childhood, adolescence, or adult life. As mentioned earlier, some people with CVID also have an increased incidence of autoimmune or inflammatory conditions, granulomas, and an increased susceptibility to cancer when compared to the general population. Sometimes, it is the presence of one of these other conditions that prompts an evaluation for CVID.

Although CVID is a distinct diagnosis, some may confuse it with other antibody deficiencies. The medical terms for absent or low blood immunoglobulins are agammaglobulinemia and hypogammaglobulinemia, respectively. Due to the late onset of symptoms, other names that have been used in the past for CVID include: 

• Acquired agammaglobulinemia/hypogammaglobulinemia.
• Adult-onset agammaglobulinemia/hypogammaglobulinemia.
• Late-onset agammaglobulinemia/hypogammaglobulinemia.
• Dysgammaglobulinemia.

The term “acquired immunodeficiency” refers to a syndrome caused by the human immunodeficiency virus (HIV) and should not be used for individuals with CVID, as these disorders are very different.

Clinical features

Both males and females may have CVID. In many, the diagnosis is not made until the third or fourth decade of life. About 20% of people with CVID, however, have symptoms of the disease or are found to be immunodeficient in childhood. Because the antibody arm of defense (the humoral immune system) is slow to mature, the diagnosis of CVID is generally not made until after the age of 4. The usual presenting features of CVID are recurrent infections involving the ears, sinuses, bronchi (breathing tubes), and lungs (respiratory tract). When the lung infections are severe and occur repeatedly, permanent damage with widening and scarring of the airways, a condition termed bronchiectasis, may develop.

The organisms most commonly found in sinus and lung infections are bacteria that are widespread in the population and that often cause pneumonia (Haemophilus influenzae, Streptococcus pneumoniae) even in people who do not have CVID. The purpose of treatment of lung infections is to prevent their recurrence and to prevent the accompanying chronic and progressive damage to lung tissue. A regular cough in the morning and the production of yellow or green sputum (a mixture of saliva and mucus) may suggest the presence of chronic bronchitis or bronchiectasis.

Individuals with CVID may also develop enlarged lymph nodes in the neck, chest, or abdomen. Enlarged lymph nodes may be caused by infection, an abnormal immune response, or both. Similarly, enlargement of the spleen is relatively common, as is enlargement of Peyer’s patches, which are collections of lymphocytes in the walls of the intestine.

In some cases, other collections of inflammatory cells called granuloma (comprised of white blood cells including monocytes and macrophages) can be found in the lungs, lymph nodes, liver, skin, or other organs. Granuloma may form in response to an infection, but the cause of their collection in tissues in CVID is not really known.

Although people with CVID have depressed antibody responses and low levels of immunoglobulins in their blood, some of the antibodies they produce may attack their own tissues (autoantibodies). These autoantibodies may attack and destroy blood cells, like red cells, white cells, or platelets. Although, most individuals with CVID present first with recurrent bacterial infections, in about 20% of cases, the first manifestation of the immune deficiency is a finding of very low platelets in the blood or less commonly, severe anemia due to destruction of red cells. Autoantibodies may also cause other diseases such as arthritis or endocrine disorders, like thyroid disease.

Gastrointestinal (GI) complaints, such as abdominal pain, bloating, nausea, vomiting, diarrhea, and weight loss, can also be associated with CVID. Approximately 21% of people with CVID may have significant GI problems. Careful evaluation of the digestive organs may reveal a reduced ability to absorb fat and certain sugars or inflammatory bowel disease. If a small biopsy (sample) of the bowel mucosa (tissue) is obtained, characteristic changes may be seen. These changes are helpful in diagnosing the problem and treating it. In some people with digestive problems, the detection and eradication of infections due to bacteria, parasites, or viruses may help eliminate the GI symptoms.

Some people with CVID, particularly those who have not received the ideal immunoglobulin (Ig) replacement therapy, may also develop a painful inflammation of one or more joints. This condition is called polyarthritis. In the majority of these cases, the joint fluid, if tested, does not contain bacteria. To be certain that the arthritis is not caused by a treatable infection, the joint fluid may be removed by needle aspiration and studied for the presence of bacteria. In some instances, a bacterium called Mycoplasma may be the cause and can be difficult to diagnose. The typical arthritis associated with CVID may involve the larger joints such as knees, ankles, elbows, and wrists. The smaller joints, like the finger joints, are more rarely affected. Symptoms of joint inflammation may disappear with adequate Ig replacement therapy and appropriate antibiotics. In some, however, arthritis may occur even when the individual is receiving adequate Ig replacement therapy.

Finally, people with CVID may have an increased risk of cancer, especially cancer of the lymphoid system or possibly the gastrointestinal tract. However in a recent study of cancer incidence of people with PI enrolled in the United States Immunodeficiency Network (USIDNET) patient registry, of the four most common malignancies in men and women (lung, colon, breast, and prostate cancers), there was no significant increase of these cancers in people with PI versus the age-adjusted population. 

Diagnosing CVID

CVID should be suspected in children or adults who have a history of recurrent bacterial infections involving ears, sinuses, bronchi, and lungs. The characteristic laboratory features include low levels of serum immunoglobulins, including IgG, often IgA, and sometimes IgM. Another part of the diagnosis of CVID is to determine if there is a lack of functional antibody. This is done by measuring serum levels of antibodies that are specific to vaccine antigens such as Tetanus/Diphtheria, or pneumococcal polysaccharide. People with CVID have very low or absent antibody levels to most of these vaccines.

Immunization with killed vaccines is used to measure antibody function, and this functional testing is crucial prior to beginning treatment. These tests also help the healthcare providers decide if the individual will benefit from Ig replacement therapy and are often essential in obtaining insurance authorization for this therapy. The number of B and T lymphocytes may also be determined, and their function can be tested in laboratories. Recent studies have also shown that examining the maturity of the B cells in the blood by looking at the surface receptors (B cell memory markers) can help in predicting the relative severity of the immune deficiency.