Common variable immunodeficiency

Synonyms

6

Overview

Common variable immune deficiency is a disorder that impairs the immune system. People with CVID are highly susceptible to infection from foreign invaders such as bacteria, or more rarely, viruses. CVID is characterized by low levels of most or all of the immunoglobulin (Ig) classes. This causes affected people to get frequent infections, particularly in the sinuses, lungs, ears and digestive tract. Pneumonia is common in people with CVID. Over time, recurrent infections can lead to chronic lung disease. Affected individuals may also experience infection or inflammation of the gastrointestinaltract, which can cause diarrhea and weight loss. Abnormal accumulation of immune cells causes enlarged lymph nodes (lymphadenopathy) or an enlarged spleen (splenomegaly) in some people with CVID. Immune cells can accumulate in other organs, forming small lumps called granulomas.

Approximately 25 percent of people with CVID have an autoimmune disorder, which occurs when the immune system malfunctions and attacks the body's tissues and organs. The blood cells are most frequently affected by autoimmune attacks in CVID; the most commonly occurring autoimmune disorders are immune thrombocytopenia purpura, which is an abnormal bleeding disorder caused by a decrease in platelets, and autoimmune hemolytic anemia, which results in premature destruction of red blood cells. Other autoimmune disorders such as rheumatoid arthritiscan occur. Individuals with CVID also have a greater than normal risk of developing certain types of cancer, including a cancer of immune system cells called non-Hodgkin lymphoma and less frequently, stomach (gastric) cancer.

People with CVID may start experiencing signs and symptoms of the disorder anytime between childhood and adulthood; most people with CVID are diagnosed in their twenties or thirties. The life expectancy of individuals with CVID varies depending on the severity and frequency of illnesses they experience. Most people with CVID live into adulthood.

There are many different types of CVID that are distinguished by genetic cause. People with the same type of CVID may have varying signs and symptoms.

 

Symptoms

CVID is a clinically heterogeneous disease. Its main features are hypogammaglobulinemia and recurrent infections. Hypogammaglobulinemia manifests as a significant decrease in the levels of IgG antibodies, usually alongside IgA antibodies; IgM antibody levels are also decreased in about 50% of patients. Infections are a direct result of the low antibody levels in the circulation of patients, which do not adequately protect them against pathogens. The microorganisms that most frequently cause infections in CVID are bacteria Haemophilus influenzae, Streptococcus pneumoniae and Staphylococcus aureus. Pathogens less often isolated from patients include Neisseria meningitidis, Pseudomonas aeruginosa and Giardia lamblia. Infections mostly affect the respiratory tract (nose, sinuses, bronchi, lungs) and the ears; they can also occur at other sites, such as the eyes, skin and gastrointestinal tract. These infections respond to antibiotics but can recur upon discontinuation of antibiotics. Bronchiectasis can develop when severe, recurrent pulmonary infections are left untreated.

In addition to infections, CVID patients can develop complications of different kinds. These include:

  • Autoimmune manifestations, e.g. pernicious anemia, autoimmune haemolytic anemia (AHA), idiopathic thrombocytopenic purpura (ITP), psoriasis, vitiligo, rheumatoid arthritis, primaryhypothyroidism, atrophic gastritis. Autoimmunity is the main type of complication in CVID patients, appearing in some form in up to 50% of individuals;
  • Malignancies, particularly Non-Hodgkin's lymphoma and gastric carcinoma;
  • Enteropathy, which manifests with a blunting of intestinal villi and inflammation, and is usually accompanied by symptoms such as abdominal cramps, diarrhea, constipation and, in some cases, malabsorption and weight loss. Symptoms of CVID enteropathy are similar to those of celiac disease, but don't respond to a gluten-free diet. Infectious causes must be excluded before a diagnosis of enteropathy can be made, as CVID patients are more susceptible to intestinal infections, e.g. by Giardia lamblia;
  • Lymphocytic infiltration of tissues, which can cause enlargement of lymph nodes (lymphadenopathy), of the spleen (splenomegaly) and of the liver (hepatomegaly), as well as the formation of granulomas.

 

Anxiety and depression can occur as a result of dealing with the other symptoms. Patients generally complain of severe fatigue.

 

Signs and symptoms: 

  • Decreased antibody level in blood
  • Lymphopenia
  • Otitis media
  • Sinusitis
  • Thrombocytopenia
  • Recurring ear infections
  • Recurring sinus infections
  • Recurring lung infections
  • Pneumonia
  • Recurring bronchial infections
  • Gastrointestinal infections
  • Painful swollen joints
  • Swollen knee
  • Swollen ankle
  • Swollen elbow
  • Swollen wrist
  • Digestive symptoms
  • Enlarged spleen
  • Swollen glands
  • Swollen lymph nodes
  • Autoimmune diseases
  • Sinus infections
  • Ear infections
  • Conjunctivitis
  • Respiratory infections
  • Pneumonia
  • Enlarged spleen
  • Diarrhea
  • Meningitis
  • Recurring bacterial infections
  • Recurring viral infections
  • Enlarged spleen
  • Lymphadenopathy
  • Low number of plasma cells in bone marrow
  • T cell dysfunction
  • Bronchietasis
  • Chronic diarrhea
  • Reduced IgA levels
  • Reduced IgG levels
  • Reduced IgM levels
  • Lack of normal antibody levels
  • Chronic recurring infections

Presence of anti-IgA antibodies

Causes

Common variable immunodeficiency is usually sporadic and thought to result from a combination of genetic and environmental factors. In most cases, the exact cause of CVID is unknown.

Genetic factors associated with CVID include mutations in genes involved in the development and function of immune system cells (B cells) which help protect against infection. B cells make proteins called antibodies (also known as immunoglobulins), which attach to foreign agents and "mark" them to be destroyed. Mutations in genes associated with CVID result in B cells that don't make enough antibodies. This causes difficulty fighting infections, causing the signs and symptoms of CVID.

Mutations in at least 10 genes have been associated with CVID. About 10% of affected people have mutations in the TNFRSF13B gene. However, not all people who inherit a mutation associated with CVID develop the disease. This is why additional genetic and/or environmental factors are probably needed for the disorder to occur.

While CVID usually occurs in people with no family history of the condition, some cases are inherited in an autosomal dominant or autosomal recessive manner.

Diagnosis

The list of diagnostic tests mentioned in various sources as used in the diagnosis of Common Variable Immunodeficiency includes:

  • Immune function blood tests
  • IgG blood test
  • IgA blood test

Prognosis

The long-term outlook (prognosis) and life expectancy for people with common variable immunodeficiency varies. The prognosis largely depends on whether there is severe autoimmune disease; whether there are recurrent infections that cause structural lung damage; and the development of a malignancy (cancer). Other major factors that influence prognosis include the extent of end-organ damage and how successfully infections can be prevented.

Affected people who have only bacterial infections have a better prognosis than those with additional complications and can have nearly normal life expectancy. This is especially the case if they are diagnosed early and begin treatment soon after the onset of symptoms.

Severe complications relating to recurrent infections, autoimmune disease and/or cancer can be fatal. Lymphoma is a common cause of death in people with CVID. Other causes include cor pulmonale from chronic pulmonary infections; liver failure caused by viral or autoimmune hepatitis; malnutrition from digestive disease; and other viral infections.

Treatment

The main treatment for common variable immunodeficiency is Ig replacement therapy, which stops the cycle of recurrent infections. Ig may be taken intravenously (through the vein) or subcutaneously (by injection). Adverse reactions to Ig must be monitored during therapy.

Ig therapy is effective in most people, leading to less frequent infections and arthritic symptoms. However, gastrointestinal (digestive) symptoms have little improvement with IVIG. In some people wwith CVID and severe autoimmune disease, steroids or other immunosuppressive drugs in addition to Ig therapy may be needed.

Resources

  • NIH
  • Mayo Clinics
  • Genetics Home Reference