Common variable immunodeficiency
Jonathan S. Tam, M.D., and John M. Routes, M.D.
Common variable immunodeficiency (CVID) is a common primary immunodeficiency characterized by a failure in B-cell differentiation with defective
immunoglobulin production. Affected patients are uniquely susceptible to recurrent infection with encapsulated organisms and have an increased propensity
for the development of inflammatory and autoimmune manifestations. The diagnosis of CVID is commonly delayed and the underlying cause of the disorder
is not understood. Replacement antibody therapy reduces the risk of serious infections. However, optimal treatment regimens for the uncommon manifestations
associated with this disease, such as granulomatous lymphocytic interstitial lung disease, require further research.
(Am J Rhinol Allergy 27, 260–265, 2013; doi: 10.2500/ajra.2013.27.3899)
impaired B-cell differentiation leading to defective immunoglobulin
production. CVID is the most common clinically significant primary
immunodeficiency disease. It is not a single disease, but rather a
clinical syndrome that represents a family of disorders exhibiting a
common phenotype. The age of onset of CVID is variable, presenting
in both children and adults. The diagnosis is generally made between
20 and 40 years of age, but up 20% may present before the age of 20
years.1Depending on the ethnicity of the population, it affects an
estimated 1 in 25,000–50,000 subjects.2–4The true incidence of CVID
may be much higher because the disease is largely underappreciated
and underdiagnosed, which is reflected in the common delay in
diagnosis of up to 5–10 years.1,2,5–8
ommon variable immunodeficiency (CVID) is a heterogeneous
disorder characterized by recurrent bacterial infections and
Nearly all patients present with recurrent upper and/or lower
respiratory tract infections including bronchitis, sinusitis, otitis me-
dia, and pneumonia. Encapsulated bacteria (Haemophilus influenzae
and Streptococcus pneumoniae) are the most commonly discovered
pathogens.1,6,8–10In addition, patients with CVID appear to be partic-
ularly susceptible to infections with atypical bacteria such as Myco-
plasma sp. and Ureaplasma sp.8–11Therefore, when deciding on empiric
antimicrobial therapy of respiratory tract infections, agents such as
macrolides or fluoroquinolones should be considered because they
cover both encapsulated and atypical organisms. Pulmonary infec-
tions with Gram-negative rods should also be considered, in partic-
ular in patients with impaired cellular immunity or longstanding
CVID. Opportunistic infections are rare and occur in ?10% of pa-
Unlike congenital forms of agammaglobulinemia, such as X-linked
agammaglobulinemia, T-cell abnormalities are common in patients
with CVID and contribute to the more variable clinical manifestations
of this disease.1,8,12A subgroup of CVID patients termed late-onset
combined immune deficiency is defined by opportunistic infections
and/or severe T-cell lymphopenia (CD4 ? 200 cells/mm3).13This
subgroup of patients is also more likely to have a severe clinical
phenotype (gastrointestinal disease, granulomatous disease, spleno-
megaly, and lymphomas).
Gastrointestinal tract infections with pathogens similar to those
found in X-linked agammaglobulinemia (Campylobacter jejuni, Salmo-
nella sp, and Giardia lamblia) are also common.1,8The prevalence of
hepatitis is also increased in CVID, occurring in ?12% of patients. The
prognosis due to hepatitis secondary to infection with hepatitis C is
poor and may be rapidly progressive in patients with CVID.14,15Other
forms of liver disease such as nodular regenerative hyperplasia are an
increasingly recognized complication of CVID.1
The etiology of the vast majority of cases of CVID is unknown. In
a small subset of patients, however, specific molecular defects have
been identified. Most of these genetic abnormalities are rare with the
exception of mutations in TNFRSF13B, which encodes for transmem-
brane activator and calcium modulator and cyclophilin ligand
(TACI). Mutations in TACI occur in ?8–10% of patients with
CVID.16,17Patients with heterozygous mutation in TACI are at high
risk to develop CVID, whereas homozygous mutations of TACI al-
ways result in CVID.18Patients with mutations in TACI are also more
likely to have both autoimmune disease and splenomegaly.19–21
Other genetic defects leading to a CVID phenotype include muta-
tions in inducible T-cell costimulator (ICOS), CD19, CD81, CD20,
CD21, and B-cell activating factor of the tumor necrosis factor family
receptor (BAFF-R).16,17,22–28Some of these genetic mutations are likely
to be disease causing (ICOS, CD19, CD20, and CD81) and others
(BAFF-R) may require additional genetic contributions to lead to the
CVID phenotype.12Collectively, mutations in ICOS, CD19, CD81,
CD20, CD21, BAFF-R, and TACI account for ?10–15% of all cases of
Acute and chronic infections are a major cause of morbidity in
patients with CVID.7,12The occurrence of recurrent upper respiratory
tract infections can result in chronic sinusitis and hearing loss. Recur-
rent lower respiratory tract infections (i.e., pneumonia) may lead to
the development of bronchiectasis (Fig. 1), which is reported to be
present in up to 20% of patients with CVID.29,30In addition to infec-
tious complications in the lung, parenchymal and interstitial changes
may be found leading to both obstructive and restrictive defects
Of particular concern, is a restrictive interstitial lung disease, which
on biopsy reveals granulomatous and lymphoproliferative histo-
pathologic patterns (lymphocytic interstitial pneumotis, follicular
bronchiolitis, and lymphoid hyperplasia). The term granulomatous
and lymphocytic lung disease (granulomatous lymphocytic intersti-
tial lung disease [GLILD]) has been used to characterize this disor-
der30and occurs in ?10–25% of patients with CVID.29–35Progressive
pulmonary impairment due to GLILD appears to be an important
cause of morbidity and mortality in CVID30and shows a shortened
median survival (13.7 years versus 28.8 years in those without this
From the Section of Allergy and Immunology, Department of Pediatrics, Medical
College of Wisconsin, Milwaukee, Wisconsin
Presented at the North American Rhinology and Allergy Conference, February 4, 2013,
JM Routes has received research grants from the National Institutes of Health. The
remaining author has no conflicts of interest to declare pertaining to this article
Address correspondence to John M. Routes, M.D., Medical College of Wisconsin,
MACC Fund Research Center, Room 5064, 8701 Watertown Plank Road, Milwaukee,
E-mail address: firstname.lastname@example.org
Copyright © 2013, OceanSide Publications, Inc., U.S.A.
260July–August 2013, Vol. 27, No. 4
complication).1,12,30,36This noncaseating granulomatous disease is sys-
temic in nature and may be present in the lung, bone marrow, liver,
and lymph nodes.37Consequently, this disease process is often con-
fused with sarcoidosis; but unlike sarcoid, these lesions do not remit
spontaneously or resolve with steroid administration.30,31In addition
to granuloma, polyclonal lymphocytic infiltration or nonmalignant
hyperplasia of the lymph nodes (cervical, mediastinal, and abdominal
lymph nodes as well as the spleen) are found in at least 20% of CVID
subjects.2,8,30,31,36,38,39Lymphoid infiltrates can occur in the lungs or
other organs such as the liver and kidneys. Enlarged lymph nodes
usually show atypical or reactive hyperplasia, with or without pres-
ervation of germinal center boundaries.37
Patients with CVID are also at high risk to develop malignancy,
which occurs in up to 15% of patients. In particular, the prevalence of
non-Hodgkin’s lymphomas and gastric carcinoma are increased in
CVID and are a major cause of morbidity and mortality.1,38,40–42When
lymphomas appear in CVID, they are usually extranodal, B cell
in origin, negative for Epstein-Barr virus, and are more common
in subjects in the 4th to 7th decades of life.1,8,43
Interestingly, although patients with CVID are unable to make
antibodies to foreign antigens, they show a propensity to make au-
toantibodies; the overall prevalence of autoimmune disease is ?20–
25%.8,44They are susceptible to a wide range of autoimmune diseases,
but autoimmune thrombocytopenia and autoimmune hemolytic ane-
mia are the most commonly reported cytopenias occurring in 11–12%
The most common gastrointestinal manifestation of CVID is tran-
sient or persistent diarrhea, found in 21–57% of patients.44,46,47In
addition to bacterial and parasitic infections, chronic gastritis and
inflammatory bowel disease are significant problems for patients with
CVID.1,44Small bowel enteropathy in CVID resembles celiac disease
with short villi, crypt hyperplasia, and intraepithelial lymphocyto-
sis.47This small bowel enteropathy can lead to diarrhea, weight loss,
and malabsorption. Large bowel enteropathy resembling Crohn’s
disease and ulcerative colitis has also been described in CVID,47
although it is not clear if these have the same pathogenesis as classic
inflammatory bowel disease. Furthermore, a subset of individuals
(8% in one cohort)7with CVID exhibit nodular lymphoid hyperplasia
on biopsy—most commonly presenting as cholestasis or portal hy-
Based on the European Society for Immunodeficiency CVID regis-
try and recently reproduced in additional cohorts,49efforts have been
made to divide patients into five distinct phenotypes based on
intrinsic disease-related complications: no complications, autoim-
munity, polyclonal lymphocytic infiltration, enteropathy, and lym-
phoid malignancy.2The outcome of individual patients appears to
be dependent on the presence or absence of some of these specific
complications.2These phenotypes are not exclusive because the
lymphoproliferative phenotype (GLILD, splenomegaly, and ade-
nopathy) is frequently accompanied by autoimmune cytopenias, gas-
trointestinal, and hepatic disease.19,30,34,36,47,48,50,51
As treatments for infection have improved, complications such
chronic lung disease, malignancy, and autoimmune disease are now
the most common causes of mortality in CVID.1,2,30,31,37,42,43In a recent
analysis of 411 subjects with CVID in which 19% had died, the
Figure 1. (A) High-resolution computed
tomography (HRCT) scans showing bron-
chiectasis related to CVID in the context of
a normal chest radiograph (not shown).
(B) HRCT scans showing granulomatous
(GLILD) related to CVID in the context of
a normal chest radiograph (not shown).
Table 1 Common complications of CVID
Upper respiratory tract infections
Lower respiratory tract infections
Autoimmune hemolytic anemia
Cryptogenic organizing pneumonia
Inflammatory bowel disease (Crohn’s disease and ulcerative
Nodular regenerative hyperplasia
CVID ? common variable immunodeficiency; GLILD ? granulomatous and
lymphocytic interstitial lung disease.
American Journal of Rhinology & Allergy261
predominant causes of death included respiratory failure from
chronic lung disease, lymphoid or other malignancy, and liver dis-
ease.1Interestingly, not all complications were shown to be associated
with reduced mortality. Risk factors for early mortality included
gastrointestinal disease, liver disease, chronic lung disease, and lym-
phoma whereas autoimmunity and cancer other than lymphoma
were not associated with early mortality.
The diagnostic criteria for CVID include52
• Decreased serum IgG level, AND decreased serum IgA or IgM
• Decreased ability to make specific antibodies in response to immu-
• Exclusion of primary immunodeficiencies leading to decreased IgG
• Exclusion of secondary causes of decreased serum IgG
• Greater than 2 years of age
In patients with CVID, IgG levels are reduced by ?2 standard
deviations from the mean in all patients and ?450 mg/dL in 94.2% of
patients at diagnosis.2Almost all cases of CVID have a decrease in
IgA (usually ?5 mg/dL) and reductions in IgM in about one-half of
cases.1,2,5,6,8,52Specific antibody responses, which are impaired in
CVID, are shown by measuring specific antibodies 3–4 weeks after the
administration of a protein (i.e., tetanus, diphtheria toxoid, H. influ-
enzae B) and polysaccharide (pneumococcal vaccine) vaccines.53Early
in life CVID is not always discernible from transient hypogam-
maglobulinemia of infancy or congenital forms of agammaglobuline-
mia. Therefore, the general consensus is that this diagnosis of CVID
should not be made until after a patient reaches the age of 2 years.12
Exclusion of other secondary causes of hypogammaglobuline-
mia is especially important in patients with isolated low IgG
(Table 2).2,12,54–56Protein loss from protein losing enteropathy or
nephrotic syndrome can present as hypogammaglobulinemia and is
not uncommon. Chronic oral corticosteroid use can also lead to re-
duced IgG levels and is a common cause of hypogammaglobulinemia
in patients with severe asthma or chronic obstruction pulmonary
disease. The decrease in serum IgG occurs is relatively selective with
a relative sparing of the IgA and IgM and normal specific antibody
production.57,58The magnitude of the reduction of serum IgG after
corticosteroid therapy is dependent on the dose and duration of
steroid therapy. Although corticosteroid therapy typically does not
reduce serum IgG to ?400 mg/dL, reduction below this level may be
seen in patients receiving high doses of corticosteroids over a long
period of time.57,58Other common medications associated with hy-
pogammaglobulinemia include rituximab, azathioprine, sulfasala-
zine, and several anticonvulsants (carbamazepine, levetiracetam, ox-
carbazepine, and phenytoin).59–63
The physical examination of a patient with a suspected CVID
requires an in-depth focus on the involved organ systems. The chest
examination often may reveal wheezing, rhonchi, or crackles in pa-
tients with CVID-associated lung disease. The clinician should ob-
serve specifically for clubbing or cyanosis and use of accessory mus-
cles for respiration. Careful periodic examination of the lymph nodes
(cervical, axillary, or inguinal) and spleen is important, because pa-
tients with CVID also frequently have adenopathy and splenomegaly,
which can be quite profound.
Laboratory evaluation would include quantitative immunoglobu-
lins (IgG, IgA, and IgM) and functional antibody testing. Flow cy-
tometry should enumerate the total numbers of T cells, T-cell subsets
(CD4 and CD8), B cells, B-cell subsets, and NK cells. B-cell subset
analysis should include the percentage of total memory B cells,
switched memory B cells, and CD21(lo) B cells.31,64–67
B-cell numbers are variable in CVID, and if reduced may indicate a
poorer prognosis.1,8Low numbers of switched memory B cells
(CD27[?]IgM[?]IgD[?]) in the peripheral blood are frequently
found in patients with a more severe phenotype of CVID (e.g.,
GLILD)31,68and may portend a worse prognosis. T-cell abnormalities
occur in ?40% of patients and include anergy, T-cell lymphopenia,
and poor proliferative responses to mitogens and antigens.
At initial evaluation sinus, chest, abdomen, and pelvis CT should
be performed. Sinus CT is helpful in evaluation of sinus disease and
in deciding if any additional antibiotic treatments may be of benefit.
Abdominal CT scans are used to assess spleen size, and/or the
presence of intraabdominal and retroperitoneal adenopathy. Because
of the complexity of the pulmonary pathology in patients with CVID,
in addition to high-resolution computed tomography (HRCT) scans
of the chest, x rays, and full pulmonary function tests (including lung
volumes, spirometry and diffusion capacity) should be obtained as
part of the initial evaluation. HRCT scan of the chest is much more
sensitive than a standard chest radiograph in detecting pulmonary
parenchymal abnormalities such as interstitial lung disease or bron-
Serologic assays that measure specific antibody are inappropriate
to identify pathogens responsible for infection in patients with CVID.
Diagnosis of specific pathogens in this patient population must be
made by culture, polymerase chain reaction, or other direct methods
of pathogen detection. Screening for human immunodeficiency virus
and hepatitis B and C should be performed at the initial evaluation by
polymerase chain reaction. Abnormalities in liver function tests are
not uncommon and may be abnormal in as high as 43% of pa-
The primary treatment of CVID is antibody replacement with either
i.v. or subcutaneous immunoglobulin with an initial dose of 400–600
mg/kg of gammaglobulin per month.2,70This dose can be divided
every 3–4 weeks for i.v. administration or every 1–2 weeks for sub-
cutaneous administration. Both i.v. and subcutaneous methods have
been shown to be safe and effective for replacement.12,70–73
Subsequent dosing should not be based on IgG immunoglobulin
level, but rather on preventing infection. Although trough IgG levels
should be drawn before initial administration and may be used to
help guide therapy, recent studies have shown that individualized
dose adjustments based on clinical course may be preferable to blan-
ket goal IgG trough levels.74,75Furthermore, higher doses are required
for patients with significant pulmonary disease (i.e., bronchiectasis),
sinus disease, GLILD, or splenomegaly.75Once patients are estab-
lished on immunoglobulin replacement therapy, IgG trough levels
are measured every 6–12 months to ensure adequate dosing with a
minimum trough level of 500 mg/gL.
There is no convincing evidence that one brand of gammaglobulin
is better than others in reducing infections. However, products do
differ in their preparation, and when choosing a product one must
consider osmolality, pH, sodium, sugar, and IgA content. A full
Table 2 Causes of hypogammaglobulinemia to exclude before
diagnosis of CVID
Other primary immunodeficiency
Medications (corticosteroids, azathioprine, cyclosporine,
d-penicillamine, gold, sulfasalazine, carbamazepine,
levetiracetam, oxcarbazepine, and phenytoin)
Protein loss via gastrointestinal tract, lymphatics, or kidneys
Bone marrow failure
CVID ? common variable immunodeficiency; XLP ? X-linked lymphopro-
262July–August 2013, Vol. 27, No. 4
in-depth comparison of gammaglobulin formulations is beyond the
scope of this discussion, but a summary of available brands of im-
munoglobulin and their characteristic can be found at the Immune
Deficiency Foundation website.76
Additives in the preparations used to prevent protein aggrega-
tions77—such as amino acids, sorbitol, salt, or sucrose—may lead to
adverse effects in certain clinical settings. For example, sugar content
should be considered in a patient with diabetes or prediabetes. Fur-
thermore, sucrose content has been associated with renal failure or
insufficiency.78,79Because of the large protein load, patients with renal
dysfunction might want to avoid intravenous immunoglobulin (IVIg)
entirely, using subcutaneous immunoglobulin instead. The major
contributors to osmolality in IVIg are sodium and sugar content.
Reconstitution of lyophilized preparations can also result in hyper-
osmolar solutions. Osmolality is an important concern because hy-
perosmotic states have been implicated in thrombotic complications.80
Although the mortality of CVID caused by common infectious
pathogens has declined with the increased use of high-dose immu-
noglobulin replacement,81patients may continue to develop obstruc-
tive, restrictive, or bronchiectatic changes.7In fact, GLILD is refrac-
tory to gammaglobulin replacement therapy and bronchiectasis may
develop despite antibody replacement therapy.29–35
For the most part, many of the complications of CVID may be
treated in the same manner as immunocompetent patients with sim-
ilar diseases. Oral corticosteroids, immunomodulatory dosages of
IVIg (2 g/kg per month), and rituximab have been used to treat
autoimmune hemolytic anemia or autoimmune thrombocytopenia in
patients with CVID.19,45,82–84Splenectomy is to be avoided, because
severe infections have occurred.8,85Treatment of bronchiectasis in
patients with CVID is similar to the therapy of idiopathic bronchiec-
tasis. Mobilization of pulmonary secretions through the use of med-
ications such as ?2-agonists along with chest physiotherapy is fre-
quently used, although there are few trials that show the effectiveness
of pulmonary hygiene.86,87
The optimal treatment for GLILD in CVID is unknown, but these
patients appear to have a high mortality rate if left untreated. GLILD
is resistant to corticosteroid therapy so alternative treatment regimens
should be considered. Steroid sparing agents such as azathioprine,
6-mercaptopurine, cyclosporine A, mycophenolate mofetil, or meth-
otrexate have been tried with inconsistent results.50TNF inhibitors
have also been tried and some success has been reported.88,89How-
ever, the low prevalence of this complication in CVID patients makes
controlled or open trials difficult. Recent data from a retrospective
analysis of seven CVID patients with biopsy-proven GLILD aged
18–43 years suggests that combination chemotherapy with rituximab
and azathioprine may be beneficial in this select patient population.68
Patients showed statistically significant improvement in HRCT score
(p ? 0.011) and pulmonary function testing (forced expiratory volume
in 1 second, p ? 0.04 and forced vital capacity, p ? 0.036). These
findings are encouraging but highlight the urgent need for similar
prospective studies to ascertain the most effective medications, opti-
mal timing, duration of therapy, and effect on long-term morbidity
CVID is a complex, multifocal disease with a large array of clinical
manifestations and complications. Treatment with gammaglobulin
and improved antibiotic coverage have vastly improved the outlook
for patients; however, as infections and infectious complications be-
come less prominent, morbidities from disordered inflammation or
immune dysregulation have become greater areas of concern. Con-
tinued studies are needed to illuminate the many causes of this
disease and possibly therapeutic targets.
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