Common Variable Immunodeficiency

Author: Robert A Schwartz, MD, MPH; Chief Editor: Dirk M Elston, MD

Updated: May 31, 2012Background

Common variable immunodeficiency (CVID) is a disorder that involves the following:
(1) low levels of most or all of the immunoglobulin (Ig) classes, (2) a lack of B
lymphocytes or plasma cells that are capable of producing antibodies, and (3) frequent
bacterial infections. A diagnosis of CVID is reserved for those with an undefined B-cell
dysfunction.[1]
CVID is diverse, both in its clinical presentation and in the types of deficiency. Although
decreased serum levels of immunoglobulin G (IgG) and immunoglobulin A (IgA) are
characteristic, approximately 50% of patients with the deficiency also have diminished
serum immunoglobulin M (IgM) levels and T-lymphocyte dysfunction. About 20% of
those with CVID develop an autoimmune disease.[2]
Also see the Pediatrics article Common Variable Immunodeficiency.

Pathophysiology
In patients with common variable immunodeficiency (CVID), numerous immune-system
abnormalities are reported, the most common of which is defective antibody formation.
Consequently, both humoral and cell-mediated lymphocytic responses are affected. Some
CVID patients may have a defect in the T-cell ability to help B cells, and/or B-cell
response to T-cell help.[3]

Changes in the humoral response

The basic pathophysiologic process in CVID is a simple failure in the differentiation of B
lymphocytes. However, evidence shows that this defect in the pathway is not common
among patients. One study showed that, when B lymphocytes were stimulated with
pokeweed mitogen in vitro, plasma cells failed to differentiate, even in the presence of
normal T cells. This finding suggests a defect in B-cell expression in surface molecules.
Such cellular deficits have been traced to the second messenger and translocation
pathways of B cells. These deficits include problems with protein kinase C activation and
tyrosine phosphorylation. Findings from other studies suggest the complete absence of
IgG and IgA production, an increased rate of spontaneous apoptosis, impaired DNA
repair, and the presence somatic mutations affecting B-cell regulation.

Changes in the cell-mediated response

A number of factors and cofactors stimulate Ig secretion from B cells harvested from
patients with CVID. These factors include B-cell mitogens, soluble T-cell factors, specific
B-cell differentiation factors, the Epstein-Barr virus, interleukin 2 (IL-2), interleukin 4
(IL-4), and interleukin 10 (IL-10). Perhaps the most potent stimulant is the CD40 ligand,
which is expressed by activated CD4+ cells. In fact, in 40% of patients with CVID, the
CD40 ligand is expressed in low levels on activated T cells. In these patients, decreased
IL-2 production after T-cell receptor stimulation is also present.
A common defect is the response to antigens by CD4+ T lymphocytes. After
immunization, some patients with CVID have decreased numbers of circulating
responsive CD4+ T cells. Other patients have an increased number of CD4+ T cells, but
they also have an increased rate of apoptosis of these cells. Signal transduction appears to
be the primary defect in these T cells. Rezaei et al report on the meningococcal
vaccination response in CVID patients. They suggest it may help define subgroups of
patients, which may lead to better monitoring and new therapeutic strategies.[4]
Of all patients with CVID, 25-30% often have increased numbers of CD8+ T cells and a
reduced CD4/CD8 ratio (< 1). The cause is an increase in cyclic adenosine
monophosphate levels and the increased activation of protein kinase A. On physical
examination, patients with this subtype often have splenomegaly and bronchiectasis. In
addition, 60% of patients with CVID have a diminished response to T-cell receptor
stimulation and expression of receptors for IL-2, IL-4, interleukin 5 (IL-5), and interferon
gamma. However, the T-cell receptors show no evidence of abnormality; in fact, genetic
findings indicate normal heterogeneity of the genetic rearrangements. Therefore, most
patients with CVID can be said to have antibody deficiency secondary to T-cell signaling
abnormalities, as well as defective interactions between T and B lymphocytes. Laino et al
report that the prevalence of distinct clinical complications of CVID is higher in patients
with B- and T-cell abnormalities.[5]
Both the transient and permanent recovery of Ig production has been reported in both
patients with HIV and in patients with hepatitis C infection. This finding may indicate
that CVID is associated with potentially reversible defects in humoral and/or cellular
immunoregulatory factors.
TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor)
mediates isotype switching in B cells. One series found that 4 of 19 unrelated individuals
with CVID and 1 of 16 individuals with IgA deficiency had a missense mutation in 1
allele of TNFRSF13B (encoding TACI).[6] TTACI mutations can result in CVID and IgA
deficiency. Four genes have been documented to be mutated in CVID patients: ICOS,
TNFRSF13B (encoding TACI), TNFRSF13C (encoding BAFF-R) and CD19.[7]
Heterozygous mutations in TNFRSF13B are also associated with CVID,[1] whereas the
other 3 genes are recessive.[8, 9] Those with a mutation in the TNFRSF13B gene may
require further investigation.

Autosomal dominant CVID has been linked to chromosome 4q.[10] One study supports the
existence of a disease-causing gene for autosomal dominant CVID/IgA deficiency on
chromosome 4q. Other possible loci for dominant CVID genes are on chromosomes 5p
and 16q.

Epidemiology
Frequency

United States
The prevalence of common variable immunodeficiency (CVID) is approximately 1 case
per 50,000 population.

International
The international prevalence is similar to that in the United States.

Mortality/Morbidity

A 20-year survival rate is 64% for male patients and 67% for female patients.
In general, the expected survival rate for male and female patients is 92% and
94%, respectively.
Death may result from various causes (see Complications).

Race
CVID does not show a predilection for any specific race.

Sex
CVID equally affects males and females.

Age
CVID can occur in infants, young children, adolescents, or even those aged 20-40 years
or older.

CVID can become evident at any time from infancy to after the fourth decade of
life.
Peaks of onset occur in children aged 1-5 years and in persons aged 16-20 years.
More than two thirds of patients are aged 21 years or older when CVID is
diagnosed.

History

Five distinct clinical phenotypes have

been delineated for common variable
immunodeficiency (CVID): no
complications, autoimmunity, polyclonal
lymphocytic infiltration, enteropathy, and
lymphoid malignancy. In any patient with a past medical history
[11]

of CVID, 3 complications must be considered: recurrent infections, autoimmune

phenomena, and malignancy (see Physical).

Patients with CVID often have a history of

recurrent infections.
The recurrent infections commonly affect the upper and lower respiratory tracts. Patients
come to medical attention due to infectious diseases at the time of onset, the most
common being otitis media, diarrhea, pneumonia, and sinusitis.[12] Almost all have acute
and recurrent infections.

Persistent diarrhea and malabsorption

caused by Giardia lamblia infection occur
in patients with CVID. Symptoms generally resolve after treatment
with metronidazole. Infectious and autoimmune etiologies are the most likely causes for
severe chronic diarrhea. Malignancies of the gastrointestinal tract do not cause diarrhea.
Young children may fail to thrive because of the frequent infections or gastrointestinal
tract disease.

Physical
Generally, the physical examination findings are correlated to the history, and they
depend on the clinical presentation and specific organs involved.

Splenomegaly and generalized lymphadenopathy are

present in many patients with common variable
immunodeficiency (CVID).

Recurrent infections
Permanent damage to the bronchi may occur, resulting in bronchiectasis.
Common infective organisms include Haemophilus influenzae, Streptococcus
pneumoniae, Moraxella catarrhalis, and Staphylococcus aureus.
In some patients with CVID, uncommon infectious agents such as Pneumocystis carinii
and Mycoplasma pneumoniae may be detected first.
In addition to pulmonary infection, M pneumoniae can also cause primary infection in the
urinary tract and joints.
Infection with G lamblia may cause persistent diarrhea and malabsorption.
Recurrent infections with herpes simplex virus are reported. Herpes zoster infection may
develop in as many as 20% of patients with CVID.
Enterovirus infection has been reported in association with CVID.[13]

Autoimmune phenomena
As many as 20% of patients with CVID develop autoimmune complications.[14]
Rheumatoid arthritis, vitiligo, hemolytic anemia, thrombocytopenia, and neutropenia
have all been associated with CVID.[15]
Gastrointestinal diseases include pernicious anemia, a spruelike malabsorption disorder,
autoimmune hepatitis, primary biliary cirrhosis, intestinal nodular lymphoid hyperplasia,
atrophic gastritis, aphthous stomatitis, and inflammatory bowel disease.[16]

Malignancy
In patients with CVID, the risk of certain malignancies is high.
Lymphomas of a B-cell phenotype are of particular concern.
Malignancy is most likely associated with the Epstein-Barr virus.
The risk of gastric carcinoma is almost 50 times greater in patients with CVID than in
other individuals.
Malignant melanomas are reported.
Dermatologic manifestations [17]

Alopecia areata and alopecia universalis may occur.[18] Any time a person presents with
recurrent infections and alopecia, CVID should be considered in the differential
diagnosis. In one case study from the Hacettepe University in Turkey, Kili et al[19]
reported a 12-year-old boy who had recurrent respiratory tract infections and chronic
diarrhea since age 2 years. At age 2.5 years, he had a bandlike localized loss of hair
(alopecia areata), and 1 year later, he had lost all body hair. His sister had similar findings
and died from a pulmonary infection at the age of 7 years. On further studies, the patient
was found to have decreased serum levels of IgG, IgA, and IgM and an increased number
of CD8 cells. In addition, a skin biopsy specimen showed a perifollicular infiltrate of
mononuclear cells.
Cutaneous infections may be serious too, with necrotizing fasciitis described in one
patient.[20]
In patients with CVID, both non-necrotizing granulomas (sarcoidlike) and necrotizing
granulomas (tuberculoid) have been observed.[21, 22, 23, 24]
In one case report by Pujol et al,[25] histopathologic biopsy showed perivascular lymphoid
infiltrates in the upper and mid dermis, with central necrosis and a palisading granuloma.
A syndrome similar to sarcoidosis can affect patients with CVID. This syndrome is
characterized by noninfectious cutaneous granulomas, with underlying visceral
granulomas of the lungs, liver, spleen, or conjunctiva in most patients. These cutaneous
granulomas are nonspecific in patients with CVID and can appear as a maculopapular
rash; as infiltrated erythematous papules, plaques, excoriated papules, and ulcers; or as
nodules with ulcerations. On histologic analysis, such granulomas are noncaseating and
involve the dermis or subcutaneous fat. These nonsarcoidal, nontuberculoid
asymptomatic cutaneous granulomas often appear as multiple, nontender subcutaneous
nodules, predominantly juxta-articular, and the skin overlying the nodules was either
normal or slightly erythematous.[26]
Lesions frequently appear on the face and extremities and are always sterile. They often
resolve with treatment of the underlying disease.
Residual hyperpigmentation may be observed.
The increased incidence of malignancy in patients with CVID is well known. In 1992,
Green and Moschella[27] reported the first known case of a patient with CVID who
developed multiple squamous cell carcinomas. Many other cases have been published
since then. Patients with CVID have an increased risk for actinic keratosis and squamous
cell carcinoma. This risk is not surprising given the increased incidence of skin cancer
with prolonged iatrogenic immunosuppression, as in transplant recipients.
Other dermatologic manifestations of CVID include atopic dermatitis and polymorphic
light eruption.[28] However, these are not specific markers of CVID, and they are not

indications for a workup for CVID unless other implicating factors (eg, recurrent
infections) are present.

Causes
The primary cause of common variable immunodeficiency (CVID) remains unknown
despite 40 years of research. Part of the problem is the heterogeneity of the disease.
Genetic factors may be involved. In approximately 20% of patients with CVID, a firstdegree family member has a selective IgA deficiency. This finding may indicate that the
genes are linked.
When more than one family member is affected with CVID, approximately 5% of the
patients have a concurrent IgA deficiency.
Further results reveal specific localization to the C4A gene and, rarely, to the C2 gene in
the class III region of the major histocompatibility complex on chromosome 6.
No clear pattern of inheritance has been observed. Because most patients represent
sporadic cases and because they have no family history of immunodeficiency, different
modes of inheritance such as autosomal dominant with variable penetrance, autosomal
recessive, and X-linked forms have been reported.[29]
An autosomal recessive pattern of inheritance is suggested when more than one family
member is affected.
CVID is associated with the use of antirheumatic or antiepileptic drugs. If such an
association is later proven to be a causal relationship, the genetic etiology may turn out to
be a genetic predisposition to the disease. A common insult to the B-cell differentiation
pathway may be involved.

Differential Diagnoses

Bruton Agammaglobulinemia
Severe Combined Immunodeficiency

Laboratory Studies
Common variable immunodeficiency (CVID) can be diagnosed after defective functional
antibody formation is obtained. Usually, patients have decreased (not absent) serum IgA
and IgG levels and, occasionally, decreased serum IgM levels in the absence of other
known causes of antibody deficiency.
Compared with patients with X-linked agammaglobulinemia, patients with CVID
generally have higher serum Ig levels; however, the levels are consistently depressed. The
reference range for serum Ig varies with the patient's age, and the Ig results must be
evaluated on the basis of these age-dependent ranges.

Although electrophoresis and immunoelectrophoresis are not acceptable techniques for

the quantification of Ig levels, radial immunodiffusion or immunoturbidimetric methods
remain valuable.
An assessment of functional antibody production in response to natural antigens or
antigens to which the population is commonly exposed may be helpful. Similarly, an
evaluation of the antibody response after active immunization with polysaccharide or
protein antigens is possible.
However, because the nonresponse rate to hepatitis B is so high, especially among
persons older than 40 years, these antigens remain unreliable in the testing of immune
competence.
Circulating T and B lymphocytes can be assessed by using monoclonal antibodies for
immunofluorescence staining. CD19 and CD20 (B cells), CD3 (T cells), CD4 (helper T
cells), and CD8 (suppressor T cells) are all commonly used.
Natural killer (NK) cells also express CD3 and CD8 surface proteins. Therefore, NK cells
and T cells can be further enumerated by using monoclonal antibodies against CD16,
CD56, and CD57, though they are not lineage specific.
The in vivo measurement of T-cell function is possible by using an anergy panel to assess
localized immunologic skin responses.
The antigens most commonly used include mumps (1 mg/mL), although availability of
this antigen has varied; trichophytin (1:30 dilution); purified protein derivative (PPD) (210 IU); Candida antigen (1:100 dilution); and tetanus fluid toxoid (1:1000 dilution). An
intradermal injection of 0.1 mL of antigen is necessary to perform the test.
The results should be read 48-72 hours after the injection to ensure an induration of
maximal diameter. A positive test result indicates intact delayed-type hypersensitivity. A
negative test result to all antigens suggests impaired type IV immunity. Erythema around
the injection site does not indicate a positive result.
To assess the functional activity of the lymphocytes in vitro, they must be isolated and
stimulated with a variety of agents. One class of activators is the mitogens, which
includes phytohemagglutinin and concanavalin A, both of which stimulate T cells.
Pokeweed mitogen promotes proliferation of both T and B lymphocytes.
Another class of stimulators includes antigens. PPD, streptokinase, Candida antigen, and
tetanus toxoid all activate lymphocytes, if the patient has had a prior exposure to the
antigen or superantigen.
Allogeneic cells can also act as activators. They stimulate T-cell proliferation in mixed
lymphocyte cultures. The proliferation of lymphocytes can be activated by in vitro

antibodies to T-cell surface molecules that are important in signal transduction. These
molecules include CD3, CD2, CD28, and CD43.
T-cell activity can be directly studied. T lymphocytes express certain antigens after
activation. These antigens include CD69, IL-2 receptor (CD25), transferring receptors
(CD71), and major histocompatibility complex class II molecules (human leukocyte
antigen DR).
Measuring the levels of mediators and cytokines such as IL-2, IL-4, IL-5, interleukin 6
(IL-6), interferon gamma, and tumor necrosis factor in the culture supernatant is another
useful tool.
Another method is the measurement of levels of secreted Ig in the culture supernatant.
The complete blood count and autoantibody testing may be helpful as well. Anemia
secondary to an autoimmune process may be detected. Severe lymphopenia may indicate
that the patient has severe combined immunodeficiency disease or other primary T-cell
defects.

Imaging Studies

For the detection of pulmonary abnormalities in patients with common variable

immunodeficiency (CVID), high-resolution computed tomography of the chest
may be more useful than plain chest radiography or pulmonary function testing.

Other Tests

Excluding an infectious etiology is important.

The periodic monitoring of pulmonary function is crucial in any patient who is
able to perform the forced expiratory maneuvers.

Procedures

Biopsy should be considered to exclude infection or malignancy in enlarging

lymph nodes.
Bronchoscopy or endoscopy can provide information regarding specific lesions or
infectious processes.

Histologic Findings
Villous atrophy or infection with cryptosporidia or G lamblia can be reflected in the
histologic changes of the intestine. Submucosal tissue can be examined for the presence
of plasma cells.
Histologic changes may be observed in the lymph nodes of patients with CVID. The
findings may include reactive follicular hyperplasia, atypical hyperplasia, and
granulomatous inflammation.

Nonsarcoidal, nontuberculoid asymptomatic cutaneous granulomas seen in CVID show

well-demarcated areas of fibrinoid degeneration of collagen that stain homogeneously
and are surrounded by histiocytes in a palisading arrangement, suggestive of granuloma
annulare; no microorganisms could be detected.[26]

Staging
Any malignancies complicating CVID are staged by using conventional guidelines.

Medical Care

The mainstay of treatment for

Common variable immunodeficiency
(CVID) is Ig replacement therapy. Although
expensive, Ig replacement therapy stops the cycle of recurrent infections.
Ig may be administered intravenously or subcutaneously. Solutions of 3-12% intravenous
immunoglobulin (IVIG) can be used on a regular basis to maintain a trough level of 400500 mg/dL in adults. A

dose of 400-600 mg/kg every

2-4 weeks is usually required. In patients with structural
lung damage, a trough level of 700-800 mg/dL is required.
A solution of 16% subcutaneous injection of IV immunoglobulin (SCIG) is also an
effective treatment in patients with poor intravenous access. As expected, the volume
required to achieve adequate trough levels is much higher with SCIG than with IVIG. A
dose of 160 mg/kg/wk is comparable to an IVIG dose of 400 mg/kg/mo.
Adverse reactions to Ig administration must be monitored during therapy. The most
common reactions include backache, nausea, vomiting, chills, low-grade fever, myalgias,
and fatigue. Adverse effects occur within 30 minutes of the infusion and usually last for
several hours. Slowing the rate of infusion or interrupting the infusion for a few minutes
greatly helps in preventing symptoms. The effects can be treated with antipyretics,
diphenhydramine, and/or corticosteroids. Although anaphylactic reactions to IVIG are
uncommon, patients with IgA deficiency have an increased risk for these effects. Longterm intravenous access is not recommended because it can increase the risk of infection.
The transmission of infectious agents during infusion has caused problems in the past.
Although no cases of HIV infection have been linked to Ig therapy, the transmission of
hepatitis C virus has been reported. Current methods of viral inactivation help prevent
transmission. These methods include treatment with organic solvents and detergents,
pasteurization, and storage at a low pH. In the United States, Ig products are derived from
pooled human plasma, which undergoes a manufacturing process that includes cold
ethanol fractionation and viral inactivation steps.

In most patients, CVID responds well to Ig therapy. The recurrence of infections, arthritic
symptoms, and the severity and/or incidence of the autoimmune disease are reduced.
Gastrointestinal disease shows little improvement with IVIG. In some patients with
severe autoimmune disease, the concurrent use of steroids or other immunosuppressive
drugs may be needed.
Cyclosporin A has been successfully used in patients with CVID and lymphoid interstitial
pneumonitis. The administration of anti-CD20 monoclonal antibody has been used to
treat autoimmune thrombocytopenia and neutropenia. Studies are underway to evaluate
the efficacy of IL-2 administration in conjunction with polyethylene glycol. Results of
early in vitro studies show an increase in Ig production by B lymphocytes.
Antimicrobial therapy should be initiated at the first sign of infection. A narrow spectrum
of drugs should be used when culture and sensitivity results are available. The
prophylactic use of antibiotics should be avoided because of an increased risk of infection
with fungi or other resistant organisms.
Specific therapy is often necessary to target the organ system involved. For instance,
patients with chronic lung disease often develop airway obstructive disease that requires
treatment with inhaled corticosteroids and other asthma medications.

Surgical Care
Surgery is required to treat the complications of common variable immunodeficiency
(CVID).

Chronic sinusitis may require endoscopic sinus surgery.

Severe autoimmune thrombocytopenia or hemolytic anemia can be treated with
splenectomy.
Biopsy should be considered to exclude infection or malignancy in enlarging
lymph nodes.

Consultations
A specialist should be consulted whenever necessary.

Medication Summary
The goals of pharmacotherapy for common variable immunodeficiency (CVID) are to
reduce morbidity and prevent complications. Treatment with rapamycin has been
suggested, but this therapy awaits proper evaluation.[31] Rituximab has been used to treat
associated hemolytic anemia and thrombocytopenia.[32] Additionally, Lin et al reported on
the treatment of CVID-associated cutaneous granuloma using etanercept.[33]
The American Academy of Allergy, Asthma and Immunology has published guidelines
that may be helpful.[34]

Immunoglobulins
Class Summary
Ig passively supplies recipients with a broad spectrum of IgG antibodies against bacteria,
viruses, and parasites.
View full drug information

Immune globulin intravenous (Gamimune, Gammar-P, Sandoglobulin,

Gammagard S/D)
Neutralizes circulating myelin antibodies with anti-idiotypic antibodies. Down-regulates
proinflammatory cytokines, including interferon-gamma. Blocks Fc receptors on
macrophages and blocks the complement cascade. Suppresses inducer T and B cells and
augments suppressor T cells. Promotes remyelination. May increase CSF IgG levels by
10%.

Further Inpatient Care

Inpatient care may be necessary, depending on the severity of the clinical

manifestations secondary to common variable immunodeficiency (CVID).

Further Outpatient Care

The mainstay of outpatient care is the prevention of secondary medical

conditions. IVIG should be administered every 2-4 weeks to keep the level of
serum antibodies in the reference range.
Patients should see their physicians annually, unless they develop associated
infections, which warrant immediate treatment. Physicians should obtain a
thorough history and perform a thorough physical examination. Patients should be
evaluated for associated conditions such infection, autoimmune disease, and
malignancy.

Inpatient & Outpatient Medications

IVIG remains the mainstay of treatment.

IVIG can be administered on either an inpatient basis or an outpatient basis.
Although long-term intravenous access is often required, it is not recommended.
The use of a plastic cannula should be avoided because it can increase the risk of
venous sclerosis. Butterfly needles should be used in their place. Alternatives to
implantable venous access devices should be sought, although such devices have
been used for long periods without problems.

Deterrence/Prevention

Because at least some CVID patients can produce protective antibody titers, one
should consider the inclusion of polysaccharide vaccine in an immunization
program for them.[35]

Complications
In any patient with a past medical history of common variable immunodeficiency
(CVID), the 3 following complications must be considered (see Physical):

Recurrent infections
Autoimmune phenomena
Malignancy

Death may result. A common cause of death in patients with CVID is lymphoma. Other
causes include cor pulmonale secondary to chronic pulmonary infection, liver failure
caused by viral or autoimmune hepatitis, malnutrition resulting from gastrointestinal tract
disease, and other viral infections. Factors associated with mortality include low levels of
IgG, poor T-cell responses to antigens, and a low percentage of peripheral B cells.
Other complications include chronic sinusitis, severe autoimmune thrombocytopenia, and
hemolytic anemia.

Prognosis

The prognosis depends on the presence of severe autoimmune disease, recurrent

infections causing structural lung damage, and the development of a malignancy.
Other major factors in determining the prognosis is the extent of end-organ
damage and the success of prophylaxis against future infections.
Polyclonal lymphocytic infiltration is a clinical predictor associated with a 5-fold
increased risk of lymphoid malignancy.[11]
Elevated serum IgM and reduced circulating CD8 proportions may be predictive
markers for polyclonal lymphocytic infiltration and autoimmunity.[11]

Patient Education

Patients and their families should be educated about the early signs of infection so
that aggressive treatment is not delayed.
One helpful organization is the Immune Deficiency Foundation, which provides a
wealth of information to health care providers and patients and their families.