Common variable immunodeficiency is the most commonly diagnosed primary
immunodeficiency. It is characterized by low antibody levels and recurrent
infections. Signs and 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 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, idiopathic thrombocytopenic purpura, 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, of the spleen and of the liver,
as well as the formation of granulomas. Anxiety and depression can occur, as a
result of dealing with the other symptoms.
Causes 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. Susceptibility to
CVID may also be linked to the Major Histocompatibility Region of the genome,
particularly to DR-DQ haplotypes. 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.
Diagnosis As per the criteria laid out by ESID and
PAGID, 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. = 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, and has a poorer prognosis
than classic CVID. = Types =
Types include: 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: subcutaneously;
intramuscularly. 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. = Side effects =
Patients may sometimes experience reactions to immunoglobulin infusions,
including: swelling at the insertion site
chills headache
nausea fatigue
muscle aches and pain, or joint pain fever
hives thrombotic events
aseptic meningitis anaphylactic shock
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 paracetamolanti-inflammatory 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. Epidemiology
CVID has an estimated prevalence of about 1:50,000 in caucasians. The
disease seems to be less prevalent amongst Asians and African-Americans.
Males and females are equally affected. History
Charles Janeway, Sr. is generally credited with the first description of a
case of CVID in 1953. 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 until its closure in January 2012, and funding is
raised through the annual Jeans for Genes campaign.
References Moris G., Garcia-Monco JC. "The
Challenge of Drug-Induced Aseptic Meningitis". Archives of Internal
Medicine 159: 1185–1194. doi:10.1001/archinte.159.11.1185. PMID
10371226. External links
Immune Deficiency Foundation Michigan Immunodeficiency Foundation
Immune Deficiencies Foundation of Australia
Immune Deficiencies Foundation of New Zealand
IPOPI Canadian Immunodeficiencies Patient
Organization Primary Immunodeficiency UK
Dutch Patient Organisation for Primary Immunodeficiencies
GeneReviewsNIH/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