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Common Variable Immunodeficiency (CVID, CVI)
Wednesday, 16 July 2003
Monday, 09 January 2006
CVID, adult-onset hypogammaglobulinemia,acquired agammaglobulinemia, dysgammaglobulinemia

What

Common variable immunodeficiency (CVID) is an immunological disorder of antibody production. An antibody is a protein that attaches to an invading particle and leads to its destruction. The body makes several classes of antibodies, or immunoglobulins (Ig), including IgG, IgA, IgE, IgD, and IgM. People with CVID have low antibody levels (especially IgG, IgA, and IgM) and thus experience repeated infections. The severity of the disease varies from one person to the next, but with timely treatment people with CVID may have a normal lifespan.

Who

Most people develop symptoms of CVID between 15-35 years of age. However, older people and younger children, including those in their first year of life, may also be affected. The disorder is most frequently diagnosed in teenagers and is equally prevalent in both sexes. The disorder is very rare in those of Asian descent: the incidence in Japan is estimated at 1 in 2 million. In the United States, between 1 in 25,000 people are estimated to have CVID. Though the disease is not directly passed from parents to children, it does seem to cluster in some families. An individual has a higher risk of developing CVID if he or she has a family history of CVID or Selective IgA deficiency, another immune deficiency with milder symptoms. However, the majority of new CVID cases are actually sporadic; that is, there is no family history of any immune system disorders.

Signs and Symptoms

Signs and symptoms vary significantly from one person to the next. The following is a list of signs and symptoms that are associated with CVID, but it is important to remember that not all of these apply to every individual. CVID symptoms can be very similar to those of people that suffer from AIDS or from severe asthma.

  • Recurring respiratory infections, especially pneumonia and bronchitis, that may eventually lead to a chronic morning cough which yields yellow or green sputum (viscous mucous from the lungs or sinuses)
  • Sinus and ear infections
  • Intestinal problems including diarrhea, pain, vomiting, and difficulty absorbing nutrients which leads to weight loss, anemia (low amount of oxygen-transporting material in the blood), and edema (swelling). Intestinal difficulties may be linked to infection with the parasite Giardia lamblia.
  • Enlarged spleen and lymph nodes
  • Granulomas, or small lumps of immune cells, in the lungs, liver, spleen, and/or skin (found in 8-22% of CVID patients). This may be the first indication of an immune system defect.
  • Patients with CVID have an increased risk of developing associated autoimmune diseases. These occur when the immune system mistakenly attacks an innate body component. One target of the immune system is red blood cells, and their destruction can lead to anemia (or low numbers of red blood cells which carry oxygen). Other autoimmune conditions including lupus, rheumatoid arthritis, and thyroid problems have increased incidence in people with CVID.
  • CVID patients are also at increased risk of developing lymphoproliferative disease. Lymphoid disorders include abnormalities of the lymph nodes, with the most serious being malignancies. About 8% of CVID patients develop lymphomas.

Possible Causes

The exact cause of CVID is unknown but appears to be a defect in the way the immune system operates. The immune system is the body’s defensive force against invading substances and infections. Three types of white blood cells that have a prominent role in the immune system are T cells (or T lymphocytes), B cells (or B lymphocytes), and macrophages. Some T cells kill diseased body cells while others, known as “helper T cells,” assist killer T cells and B cells in their efforts to fight infection. B cells mature into cells known as plasma cells that produce antibodies, proteins manufactured by the body to defend against unwanted substances and diseases. Macrophages are cells that “eat” bacteria or other foreign particles and communicate to T cells and B cells that there is an infection and which antibodies to produce. It appears that certain gene mutations related to the immune system are linked to CVID, but many healthy individuals also have these mutated genes and are unaffected. Environmental triggers--such as certain medications--in combination with genetic factors may be necessary to cause CVID. Whatever the underlying causes, the result is decreased antibody production. Some patients have low IgG, IgA, and IgM antibody (immunoglobulin) levels, while others show no deficiency of IgM. Patients will have macrophages, but these cells do not effectively engulf the bacteria or communicate that there is an infection to the B cells and T cells. Most patients have a normal numbers of B cells, but the B cells do not properly mature into antibody-secreting plasma cells. In some people, this may be caused by T cells that do not correctly aid the conversion of B cells to plasma cells. Additionally, killer T cells may block antibody formation. With a diminished antibody response to germs, individuals with CVID are more susceptible to illness, especially bacterial infections. Because the immune system is very complex, there are many different ways that CVID can occur, with dysfunction in many different kinds of cells; therefore, the severity of the disease and how it is transmitted in families can be extremely variable among different patients.

Diagnosis

A comprehensive physical is done and a medical history taken when a patient presents with recurrent infections and the doctor suspects an immune deficiency. Blood is drawn to measure antibody levels. Most people with CVID will have low IgG, IgA, and (possibly) IgM antibody levels despite a normal number of B cells. The degree of antibody insufficiency varies from one person to the next, and there is not necessarily a correlation between the degree of insufficiency and the severity of clinical symptoms. If immunoglobulin levels are low, a vaccine may be given to monitor the body’s ability to produce protective antibodies against the vaccine. Patients with CVID will not be able to mount a sufficient antibody response to the vaccine. Certain tests of T cell function may also be done to help with the diagnosis. Additionally, biopsies (small tissue samples) of a lymph node or the intestine may be carried out. An intestinal biopsy can help delineate the cause of digestive tract problems. A test of lung function may also help evaluate how severely recurrent infections have affected lung performance.

Treatment

People with CVID who have significantly low immunoglobulin levels are treated with antibody therapy and antibiotics. They receive an infusion of intravenous immunoglobulin (IVIG) approximately once a month. The solution is made from the combined plasma (non-cellular part of blood that contains immunoglobulins) of a large number of healthy donors. Additionally, treatment with antibiotics is often needed to fight bacterial infections. These therapies help to prevent significant lung damage from recurrent infections. Patients who develop significant lung damage may need fluid drained from their lungs each day using body positioning techniques (postural drainage).

Prognosis

People diagnosed with CVID will have a life-long condition. The prognosis for CVID is highly variable but depends on the severity of the disease, timing of treatment, and the presence of associated conditions. People who seek and receive therapy early in the course of their disease are less likely to suffer major lung damage from recurrent infection. Antibody replacement decreases the frequency of infections and diminishes many associated symptoms. This treatment allows many patients to have a normal lifespan. Unfortunately, in some patients lung damage can ensue even if they receive regular antibody therapy. The prognosis also depends on whether a patient develops an associated autoimmune disease or malignancy. In order to make one’s prognosis as positive as possible, an individual should strictly adhere to the antibody treatment regimen, seek timely antibiotic treatment for infections, eat a balanced diet, get proper rest, avoid contact with others who have known infections, and closely follow physicians’ recommendations. Statistically, 64% of male patients and 67% of female patients will still be alive 20 years after their diagnosis of CVID, compared with 92-94% in the general population. Much research is ongoing into the various causes of CVID, which is a heterogenous disease, and novel therapies are being developed which may be available in the near future.

Connect with other parents

In the spirit of community and support, Madisons Foundation offers the unique service of connecting parents of children with rare diseases. If you would like to be connected to other parents of children with this disease, please fill out this brief form.

Weblinks

Immune Deficiency Foundation Patient/Family Handbook for Primary Immune Deficiency Diseases, Chapter III
Gives a summary of the aspects of CVID for patients and families. This is a PDF file and requires Adobe Acrobat Reader which can be downloaded for free.

National Primary Immunodeficiency Resource Center
Provides an overview of CVID along with links to other organizations.

Lucile Packard Children s Hospital (Stanford Medical Center)
An easy to read, informative description of the disease.

Primary Immunodeficiency Association
A great website with general information and links to support groups and other sites.

Google Search for Common Variable Immunodeficiency (CVID, CVI)

References and Sources

Chatila TA, Section 11.4—“Primary Immunodeficiencies,” Rudolph’s Pediatrics, 21st ed., online.statref.com/document.aspx?fxid=13&docid=572. Di Renzo M, Pasqui A.L., Auteri A (2004). “Common Variable Immunodeficiency: a Review,” Clin Exp Med 3:211-217. Kokron CM, et al (2004).”Clinical and laboratory aspects of common variable immunodeficiency,” An Acad Bras Cienc 76 (4) 707-726. Bayry J., et al (2005). “Common variable immunodeficiency: the immune system in chaos,” Trends in Mol Med 11 (8) 370-376.