Common variable immunodeficiency

Common variable immunodeficiency (CVID) is the most commonly diagnosed primary immunodeficiency.^[1] It is characterized by hypogammaglobulinemia and recurrent infections.

Epidemiology

CVID has an estimated prevalence of about 1:50,000 in caucasians.^[2] The disease seems to be less prevalent amongst Asians and African-Americans. Males and females are equally affected.

Clinical features

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 their discontinuation. 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, primary hypothyroidism, 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.^[3]

Diagnosis

As per the criteria laid out by ESID (European Society for Immunodeficiencies) and PAGID (Pan-American Group for Immunodeficiency), CVID is likely if:

• the patient presents with a marked decrease of IgG and a marked decrease in at least one of the isotypes IgM or IgA;
• the onset of the disease was at greater than 2 years of age;
• isohemagglutinins are absent and/or responses to vaccines are poor

Diagnosis is chiefly by exclusion, i.e. alternative causes of hypogammaglobulinemia, such as X-linked agammaglobulinemia, must be excluded before a diagnosis of CVID can be made.

Causes and types

The underlying causes of CVID are largely obscure. Genetic mutations can be identified as the cause of disease in only about 10% of cases, usually in families comprising more than one affected individual. Rather than a single disease, CVID is most likely a group of disorders with different causes but a similar outcome, i.e. a failure in antibody production.

Mutations in the genes encoding ICOS, TACI, CD19 and CD20 have been identified as causative of CVID.^[4][5] Susceptibility to CVID may also be linked to the Major Histocompatibility Region (MHC) of the genome, particularly to DR-DQ haplotypes.^[6] A mutation in the NFKB2 gene has recently been shown to cause CVID-like symptoms in a murine model. The frequency of this NFKB2 mutation in the CVID population is, however, yet to be established.^[7]

Types include:

Immunological features

B cells are usually found in normal numbers in CVID, however they are functionally deficient. This is due to a block of their maturation and differentiation process, which can occur at different stages in different patients. In general, CVID patients display higher frequencies of naive B cells and lower frequencies of class-switched memory B cells. Frequencies of other B cell populations are also affected: plasmablasts are for example significantly decreased. Although CVID is often thought of as a B cell-mediated disease, non-B lymphocytes display abnormal behavior as well. Affected individuals typically present with low frequencies of CD4⁺ and high frequencies of CD8⁺ T cells, while regulatory T cell and iNKT cell frequencies are decreased in circulation; NK cell frequencies can also be lower than in healthy individuals. Notably, approximately 10% of patients display CD4⁺ T cell counts lower than 200 cells/mm³; this particular phenotype of CVID has been named LOCID (Late Onset Combined Immunodeficiency), and has a poorer prognosis than classic CVID.

Treatment

Treatment consists in infusions of protective antibodies, which patients would otherwise lack. Plasma donations are tested for known blood-borne pathogens, then pooled and processed to obtain concentrated IgG preparations. Infusions can be administered in different forms:

• intravenously (IVIg):^[8]
• subcutaneously (SCIg);
• intramuscularly (IMIg).

The administration of intravenous immunoglobulins requires the insertion of a cannula or needle in a vein, usually in the arms or hands; as they use highly concentrated product, IVIg infusions must take place every 3 to 4 weeks. Subcutaneous infusions slowly release the product underneath the skin, again through a needle, and must take place every week. Patients can be trained in both kinds of techniques and self-administer their infusions at home. Intramuscular infusions are not widely used anymore, as they can be painful and are at higher risk of reaction. Dosage is always adjusted on the basis of weight and of the individual response of patients to therapy.

Reactions to treatment

Patients may sometimes experience reactions to immunoglobulin infusions, including:

• swelling at the insertion site (common in SCIG)
• chills
• headache
• nausea (common in IVIG)
• fatigue (common in IVIG)
• muscle aches and pain, or joint pain
• fever (common in IVIG and rare in SCIG)
• hives (rare)
• thrombotic events (rare)
• aseptic meningitis (rare, more common in patients with SLE)
• anaphylactic shock (very rare)

Patients should not receive therapy if they are fighting an active infection as this increases the risk of reaction. Also, patients changing from one brand of product to another may be at higher risk of reaction for the first couple of treatments on the new brand. Reactions can be minimized by taking an antihistamine and/or hydrocortisone and some paracetamol/acetaminophen/anti-inflammatory (naproxen, advil, aspirin) prior to treatment; patients should also be well hydrated and continue to drink water before, after and during treatment. Use of a heating pad or warm blanket can help alleviate chills.

Research

Funding for research in the US is provided by the National Institutes of Health. Key research in the UK was previously funded by the Primary Immunodeficiency Association (PiA) until its closure in January 2012,^[9] and funding is raised through the annual Jeans for Genes campaign.

History

Charles Janeway, Sr. is generally credited with the first description of a case of CVID in 1953.^[10]

References

• Moris G., Garcia-Monco JC (1999). "The Challenge of Drug-Induced Aseptic Meningitis". Archives of Internal Medicine 159 (11): 1185–1194. doi:10.1001/archinte.159.11.1185. PMID 10371226.  (IVIG and Aseptic Meningitis, association with SLE)

External links

• Immune Deficiency Foundation (US)
• Michigan Immunodeficiency Foundation (US)
• Immune Deficiencies Foundation of Australia
• Immune Deficiencies Foundation of New Zealand
• IPOPI (International Patient Organisation for Patients with Primary Immunodeficiency)
• Canadian Immunodeficiencies Patient Organization (Canada)
• Dutch Patient Organisation for Primary Immunodeficiencies (SAS)
• GeneReviews/NCBI/NIH/UW entry on Common Variable Immune Deficiency Overview
• Maker of SCIG product
• Support and Discussion Forum for Primary Immunodeficiency including CVID, XLA, SCID, IgA Deficiency, Neutropenia, Goods Syndrome and Other Primary Immunodeficiencies