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Common Variable Immunodeficiency
and the Gastrointestinal Tract
Ishaan Kalha, MD and Joseph H. Sellin, MD
Address
Division of Gastroenterology, University of Texas Medical Branch,
301 University Boulevard, Route 0764, Galveston, TX 77555, USA.
E-mail: jhsellin@utmb.edu
Current Gastroenterology Reports 2004, 6:377–383
Current Science Inc. ISSN 1522-8037
Copyright © 2004 by Current Science Inc.
Common variable immunodeficiency (CVID) is the second
most prevalent primary immunodeficiency disorder but
clinically the most important. It causes a wide spectrum
of symptoms and signs affecting many systems of the body.
CVID is a combination of humoral and cell-mediated deficiency, which explains not only why so many systems are
affected but also why standard therapy in the form of intravenous immunoglobulin is not always effective. The gastrointestinal tract is the largest immune organ in the body, and
it is therefore expected that this immunodeficiency will
affect it in some way. The gastrointestinal manifestations of
CVID are variable and tend to mimic known diseases, such
as celiac sprue, pernicious anemia, and inflammatory bowel
disease, but show significant differences on the microscopic
level. Many studies continue to confirm a high prevalence
of inflammatory, malignant, and infectious gastrointestinal
disorders in patients with CVID. The T-cell–mediated
defects of this immunodeficiency disorder are thought
to be the cause of the majority of the gastrointestinal
disorders in CVID and not the antibody deficiency. Therefore, intravenous immunoglobulin alone may be ineffective.
Combination therapy with immunomodulators, such as
azathioprine and 6-mercaptopurine, may be needed to
treat these gastrointestinal manifestations of CVID.
Introduction
Common variable immunodeficiency (CVID) is the
second most common primary immunodeficiency
disorder (second to selective immunoglobulin A [IgA]
deficiency) but the most clinically significant. It affects
several thousand patients in the United States and Europe
[1]. Gastroenterologists are rarely involved in the initial
diagnosis and care of these patients; however, gastroenterologists need to be familiar with primary immunodeficiency disorders because of their multiple effects on the
gastrointestinal tract.
Common variable immunodeficiency relates to a
spectrum of abnormalities in the immune response manifested primarily by hypogammaglobulinemia and
recurrent sinopulmonary infections, chronic diarrhea, and
an enhanced risk of malignancy and granulomatous
disease [2••]. CVID is diverse in its clinical presentation
and in the types of immunodeficiency it manifests as.
Deficiencies previously known as late-onset hypogammaglobulinemia and adult-onset hypogammaglobulinemia
are now considered to be part of CVID [3•].
Typically, the immune system is a balance and
combination of two complicated, sometimes overlapping
sets of mechanisms. One of these is antigen specific and
the other is not antigen specific, or innate. These two
systems are necessary for the efficient removal of foreign
antigens and malignant cells while at the same time
avoiding inappropriate self recognition and self-tissue
damage. The non–antigen specific or innate mechanism
responds initially through activated macrophages and
neutrophils. The innate immune system is able to eliminate pathogens via nonspecific mechanisms before a more
focused antigen-specific T- and B-cell response is initiated.
CVID relates to the latter mechanism, which is characterized by an impaired antibody response [4].
Common variable immunodeficiency is characterized by low levels of most or all of the immunoglobulin
(Ig) classes, a lack of B lymphocytes or plasma cells
that are capable of producing antibodies, and frequent
bacterial infections [5••]. Although decreased serum
levels of IgG and IgA are characteristic, approximately
50% of patients with the deficiency also have diminished
serum IgM levels [5••,6].
The gastrointestinal tract is an important barrier to
infection. It is the largest immune organ in the body and
produces the greatest amount of IgA. It exists in a perpetual
state of physiologic inflammation because of continuous
exposure to ingested foreign antigens. Therefore, it is not
unexpected that defects in the immune system should
result in gastrointestinal manifestations. These manifestations include celiac-like sprue and diseases similar to
but different from ulcerative colitis, ulcerative jejunoileitis,
and lymphocytic colitis, as well as nodular lymphoid
hyperplasia (NLH), and autoimmune enteropathy. In this
overview we focus on the manifestations of CVID in the
gastrointestinal tract.
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Small Intestine
Epidemiology
Genetics
The estimated incidence of CVID in the United States is one
case per 10,000 to 50,000 population [1]. The prevalence
may be higher among individuals of northern European
descent. CVID has been reported in many different races
and affects male and female patients equally [7]. Approximately 10% of patients have a coexisting thymoma (Good’s
syndrome) [8]. A family history of primary immunodeficiency is typical. CVID tends to present later than the
other primary immunodeficiencies, typically in the second
and third decades of life.
The mortality rate from CVID remains high despite
therapy with intravenous Ig [9]. Because diagnosis tends to
be delayed, and the immune defects involve the humoral
and cell-mediated systems, the morbidity and mortality
rates with CVID are quite high relative to other primary
immunodeficiency disorders. In one large series, the most
frequent cause of death was lymphoma. Other causes of
death relate to cor pulmonale, liver failure, respiratory
insufficiency, and malnutrition [10•].
Identification of the gene(s) that underlie CVID has been
difficult because of its heterogeneity. Most patients with
CVID present as sporadic cases, although familial cases
with various inheritance modes have been reported [17].
A common genetic basis for CVID and selective IgA
deficiency (sIgAD) has been suspected because these
disorders occur in first-degree relatives of patients [18].
Family studies have suggested the existence of two susceptibility loci within the major histocompatibility complex
on the short arm of chromosome 6. One locus is near the
class II region, and the other is located near the junction
between the class III and class I regions [5••,18,19].
Pathophysiology
The pathophysiology of CVID is poorly understood. Studies
on the cells of the immune system in patients with CVID
have revealed a myriad of lymphocyte defects. Most patients
appear to have normal numbers of B lymphocytes, but these
lymphocytes fail to undergo proper maturation into plasma
cells and therefore remain incapable of making the different
types of Ig and antibodies [5••]. Other patients lack helper
T lymphocytes, which are necessary for a normal antibody
response [11]. Approximately 60% of patients with CVID
have diminished proliferative responses to T-cell receptor
stimulation and decreased expression for interleukin (IL)-4,
IL-5, and interferon (IFN)-γ [12,13]. Patients have relative
CD4+ lymphopenia, decreased lymphocyte proliferation,
and reduced production or expression of IL-2 [14].
Upregulation of tumor necrosis factor (TNF)-α has also
been reported, particularly in a subgroup of patients
with granulomas, and an excessive number of cytotoxic
T lymphocytes [15]. IFN-γ levels are decreased, but TNF-α
levels are increased. Typically, they go together in a coordinated TH-1 inflammatory-type pattern. This discrepancy
highlights the possibility that alternative inflammatory and
T-cell responses may be occurring. The T-cell receptor shows
no evidence of an abnormality; T-cell receptor gene analyses
indicate normal heterogeneity of gene rearrangements.
Therefore, CVID probably has a variety of causes, and a
single molecular or genetic defect is unlikely.
An interesting phenomenon relates to the recovery of
Ig production (mostly IgG and IgM) transiently or permanently following HIV or hepatitis C virus infection (HCV)
[16]. These cases suggest that CVID is associated with
potentially reversible defects in humoral or cellular
immunoregulatory factors and may have some remnant
intact backup B-cell system.
Diagnosis and Laboratory Investigations
Diagnosis of CVID is based on the exclusion of known causes
of humoral immune system defects. Typically, identification
of all the genetic defects of the primary immunodeficiency
disorders is complex and ultimately requires referral to a
tertiary center. However, an initial attempt at diagnosis can be
made if the following criteria are met. CVID is defined by 1) a
low total serum concentration of IgG; 2) poor or absent
response to immunization; and 3) exclusion of other primary
immunodeficiencies, such as X-linked agammaglobulinemia
(XLA), IgA deficiency, and T-cell defect syndromes, such as
DiGeorge’s syndrome and ataxia telangiectasia (Table 1)
[20,21]. Assessment of T-cell stimulation is subnormal in up
to 50% of patients with CVID. These results support the
hypothesis that most patients with CVID have antibody
deficiency and abnormalities in T-cell function.
Extragastrointestinal Manifestations
Clinical manifestations of CVID include recurrent infections, autoimmune disease, granulomatous diseases, and
malignancy. Although CVID may resemble HIV infection
in that it can cause weight loss, generalized lymphadenopathy, splenomegaly, diarrhea, and lymphoma, the opportunistic infections characteristic of HIV and AIDS are
rare in CVID [16]. Recurrent pyogenic infections of the
respiratory tract are the main clinical manifestations of
CVID. Bronchiectasis can develop if therapy is delayed.
Hemophilus influenzae, Moraxella catarrhalis, Streptococcus
pneumoniae, and Staphylococcus aureus are the most
commonly implicated organisms.
In contrast to XLA, CVID is associated with a higher
frequency of autoimmune and granulomatous diseases.
Ironically, although patients with CVID have a depressed
antibody response, some of the antibodies that are
produced appear to be autoantibodies that may attack
their own tissues. Granulomas have been reported
in approximately 5% to 10% of patients with CVID.
These patients are more likely to have deficient T-cell
proliferation and higher levels of TNF-α. A small group of
patients have CVID and “sarcoidosis.” The granulomas are
Common Variable Immunodeficiency and the Gastrointestinal Tract • Kalha and Sellin
Table 1. Diagnostic criteria for common variable
immunodeficiency
Marked decrease (<2 SDs below mean for age) in serum IgG
or IgA, in patients who fulfill the following criteria
Onset of immunodeficiency at age >2 years
Absent isohemaglutinins and/or poor response
to vaccines
Defined causes of hypogammaglobulinemia excluded
indistinguishable from those of classic sarcoidosis and are
found in the lung, liver, spleen, and conjunctivae. Dermatologic manifestations also occur and include alopecia
areata and universalis. Any time a patient presents with
recurrent infections and alopecia, CVID should be considered in the differential diagnosis.
Gastrointestinal Manifestations
Among the primary immunodeficiency disorders, gastrointestinal complaints are seen most frequently in CVID
[5••]. This may be the case because both B cells and T cells
are defective. CVID affects different areas of the gastrointestinal tract differently and to varying degrees.
Mouth and esophagus
The mouth and esophagus are not commonly involved in
antibody deficiency syndromes. Mouth ulcers and fungal
infections, typically with Candida species, are more
associated with neutropenic states. Typically, patients with
CVID need long-term antibiotics, which can lead to oral
candidiasis as a common side effect.
Stomach
Approximately 50% of patients have achlorhydria due
to atrophic gastritis, as evidenced by an abnormal
Schilling’s test, gastric atrophy with antral involvement,
reduced serum gastrin levels, and a pernicious anemialike syndrome. The gastritis carries a risk for gastric
carcinoma [2••,22].
This pernicious anemia-like syndrome often complicates CVID. It was first recognized in 1969 and involves
achlorhydria, atrophic gastritis, absence of intrinsic
factor, absence of antibodies to gastric parietal cells and
intrinsic factor, and malabsorption of vitamin B12. This
syndrome can be distinguished from classical pernicious
anemia by its earlier onset, absent autoantibodies,
and atrophic gastritis without a plasma cell infiltrate
in the lamina propria. The exact mechanism for this
syndrome is unclear, though it is thought to be secondary
to T-cell defects [22].
An abnormal gastrin response to food and stimulation with bombesin, a potent gastrin-releasing agent,
occurs in patients with CVID [23]. The mechanism for
this response is unclear, but it is seen in chronic atrophic
gastritis primarily in the antrum, a pattern observed
379
in Helicobacter pylori infection. Mucosal biopsies of
the antrum typically show low gastrin content. Impairment in gastrin secretion is unique to CVID and is
not seen in XLA or other conditions with hypogammaglobulinemia [24,25].
Abnormalities on biopsy have a wide spectrum of
morphologies. They range from nonspecific changes
to lymphocytic infiltration with single-cell necrosis and
apoptosis, resembling the pattern of acute gastric graftversus-host disease (GVHD) [26••].
Pa t i e n t s w i t h CV I D h ave a n i n c r e a s e d r i s k o f
malignancy, particularly adenocarcinoma. The gastric
cancer risk may be increased as much as 50-fold [27]. This
risk has been associated with H. pylori infection, impaired
gastrin secretion, atrophic gastritis, or an increased rate of
mutation in the tumor suppressor gene p53, which has
been observed in patients with CVID [27].
Small intestine
Approximately 50% of patients with CVID of the
small intestine exhibit diarrhea and malabsorption [7].
The cause may be related to villous atrophy, which
occurs as part of a sprue-like disorder; Giardia infection;
bacterial overgrowth; and small bowel lymphoma. The
diarrhea can be protracted or present as repeated episodes
of acute diarrhea.
The most common pathologic finding in the small
intestine is villous flattening that grossly resembles
celiac sprue (Fig. 1). However, several key differences are
apparent between the villous flattening of CVID and
classic celiac sprue. The first is that plasma cells are absent
from the intestinal biopsy specimens of patients with
CVID. In classic celiac sprue, there is a plasma cell infiltrate with increased amounts of IgM and IgA. In CVID,
because there is no antibody production, this cannot be
the cause of the villous flattening. In CVID it is thought
that the villous atrophy is T-cell mediated. In addition, no
antigliadin, antireticulin, or anti-endomysial antibodies
are present in CVID, but these antibodies are almost
pathognomonic in classic celiac sprue. Another key difference is the role of gluten. In classic celiac sprue, removal
of gluten from the diet almost always leads to recovery of
normal villous architecture. However, in CVID, removal
of gluten from the diet improves villous flattening in only
approximately 50% of patients [5••,28]. Clearly, alternative mechanisms are needed to explain why, although
the celiac sprue antibodies are not involved, a similar
pathologic lesion is present.
Microscopically, the changes in the small bowel are
diverse, ranging from marked villous atrophy and increased
intraepithelial lymphocytes resembling celiac sprue to NLH
and lymphoma. In villous atrophy, enterocyte maturation is
relatively normal, unlike celiac sprue, and the brush border
is preserved but with enzyme concentrations (alkaline phosphatase, gammaglutamyl transferase, and α-glucosidase)
significantly reduced. Goblet cells may also be seen near
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Small Intestine
Figure 1. Small bowel biopsy showing marked villous atrophy,
destruction of crypts, and occasional single-cell necrosis.
the tips of the villi [29]. Apoptosis is typically seen in
association with the villous atrophy and intraepithelial
lymphocytes and resembles acute GVHD [26••].
In another variation of small bowel CVID, numerous
foamy macrophages are evident in association with
distended villi with an appearance similar to that of
Whipple’s disease; however, the macrophages do not
contain periodic-acid-Schiff–positive bacilli. The crypts
may also contain numerous apoptotic bodies, and the
patient may exhibit clinical malabsorption.
The most common infection and cause of malabsorption
in the small intestine is Giardia lamblia. The course of
G. lamblia infection in patients with CVID is typically
protracted despite chronic therapy. Up to 30% of patients
with CVID are positive for G. lamblia infection. These
patients present with abdominal cramps, bloating, and
watery diarrhea. Mucosal involvement and histologic
changes vary in severity, from mild abnormal villous
architecture to total villous atrophy. This is an important
consequence of G. lamblia infection that can result in
malabsorption and steatorrhea. Giardia organisms can
mimic active celiac sprue and may account for the lack of
response to gluten withdrawal from the diet in suspected
sprue cases. This infection must be completely ruled out
in such a clinical scenario [30]. Other infectious agents,
including Cryptosporidium parvum, can cause some degree of
villous flattening. G. lamblia infection can be diagnosed
readily by enzyme-linked immunosorbent assay of the stool.
G. lamblia trophozoites or cysts can also be visualized directly
by microscopy of the stool. The infection has a tendency to
recur despite adequate therapy [5••]. Because the incidence
of G. lamblia infection in CVID is so high, empiric therapy
with metronidazole at the onset of diarrhea is a common
strategy. If patients show no improvement, further work-up
is needed. With metronidazole treatment, the complications
of G. lamblia infection, which include lactose intolerance,
steatorrhea, and protein-losing enteropathy, can resolve and
abnormal villous morphology can be reversed [2••]. The
prevalence of G. lamblia infection has decreased over the past
several years for reasons that remain unclear, but patients
still need to be tested for this infection.
Whether the incidence of common intestinal infections, such as Salmonella, Shigella, and Campylobacter, is
higher than in the normal population is unclear. Aerobic
and anaerobic bacterial overgrowth can occur in the
upper small intestine of patients with CVID but tends
not to result in gastrointestinal symptoms, malabsorption,
or intestinal lesions [5••]. Although antibiotics are used
widely and chronically in patients with CVID, the
incidence of Clostridium difficile infection is not significantly higher than in the normal population.
Au t o i m m u n e e n t e r o p a t hy i s a n o t h e r d i s t i n c t
expression of CVID in the small bowel. This entity is
associated with other autoimmune disorders, such as
rheumatoid arthritis and hemolytic anemia. Mucosal
changes resemble those seen in celiac sprue, such as villous
flattening and intraepithelial lymphocytes, and changes
seen in lymphocytic colitis. The distinguishing feature of
CVID autoimmune enteritis is the presence of antibodies
directed against enterocytes [31].
Nodular lymphoid hyperplasia occurs as a result of
failed B-cell follicle formation and may be found in up to
60% of patients with CVID. NLH presents as multiple
polyps or nodules typically in the small intestine
but also in the stomach and colon [26••]. NLH also occurs
in immunocompetent patients, nearly always in the
distal ileum and proximal colon; however, in immunodeficient patients, NLH tends to occur throughout the
small intestine, including the upper tract. Microscopically,
the nodules appear within the lamina propria and consist
of lymphoid follicles. They have large germinal centers and
prominent mitotic figures. The villi of overlying mucosa
may become effaced, but they do not atrophy and they
retain their architecture. The cause of NLH is unclear, and
its relationship to lymphoma is equally ambiguous.
Large intestine
Evidence continues to grow of a close relationship between
CVID and inflammatory bowel disease (IBD). The prevalence
of IBD is increased within CVID patients, which suggests that
patients with CVID may be predisposed to develop IBD. The
underlying mechanism for this relationship is thought to be
T-cell mediated, as are the majority of CVID manifestations in
the gastrointestinal tract [5••].
Colitis associated with CVID is thought to be a distinct
entity, separate from ulcerative colitis. This “CVID colitis”
shares features with GVHD, lymphocytic colitis, and
ulcerative colitis, including increased lymphocytes at the
epithelial surface, increased macrophages, acute inflammation in the crypt epithelium and lamina propria, and loss
of crypts [26••,32]. Plasma cells are decreased or absent
in contrast to ulcerative colitis. Granulomas and giant
cells are typically not seen. Some investigators believe
that CVID colitis may be an autoimmune phenomenon
Common Variable Immunodeficiency and the Gastrointestinal Tract • Kalha and Sellin
because of the tendency of an increased prevalence of other
autoimmune disorders.
An ongoing debate concerns whether CVID colitis can
be classified as part of an established diagnostic category,
such as ulcerative colitis. However, although the changes
seen in CVID colitis resemble the endoscopic appearance
and distribution of ulcerative colitis, the microscopic features
differentiate the two entities. Microscopically, the lack of
crypt distortion and plasma cell infiltrate makes the union
between CVID colitis and ulcerative colitis difficult.
Liver
Common variable immunodeficiency does not typically
result in a “hepatitic” condition. However, as a result of
receiving contaminated intravenous Ig, patients with CVID
have been infected with HCV. The rate of transmission is
high—up to 85%—and the natural history of the infection
in these patients tends to be more aggressive. In one series
of 71 HCV-infected patients, rapid progression was
observed, with end-stage liver disease seen in approximately 40%. Ten percent of patients spontaneously cleared
the virus, and approximately 30% were asymptomatic [33].
These patients may develop cirrhosis more rapidly than
those who are immunocompetent, typically within 3 to 10
years. Data on the response to IFN-α therapy is limited.
Although a virologic response may be seen, even if it is
sustained, disease progression still occurs, albeit more
slowly, and the viral load does not seem to relate to the rate
of progression [34].
Summary
Common variable immunodeficiency disorder appears to
manifest its own expression of gastrointestinal inflammation
that does not reliably fit into established diagnostic groups.
This applies to its attempts to mimic ulcerative colitis,
pernicious anemia, or sprue. Gastrointestinal manifestations
of CVID cannot be explained by antibody deficiency alone.
There is clearly a pivotal role for the T-cell defects associated
with CVID, highlighted by the fact that in many instances
intravenous IgG therapy alone is ineffective.
A common thread in the CVID histopathology
throughout the gastrointestinal tract is an increase
in apoptosis. Apoptosis is seen in CVID colitis and is
clearly a manifestation of immune dysfunction, because
the other entities in which apoptosis can be seen are
GVHD and immunodeficiency states such as HIV and
cytomegalovirus infection. Similar increases in apoptosis
can be seen in diarrhea associated with radiotherapy,
chemotherapy, and some drugs. The number of apoptotic
bodies in CVID colitis is increased relative to the normal
population but less than that seen in GVHD [26••].
This raises the possibility of an “apoptotic enterocolopathy” as a common underlying mechanism. Increased
apoptosis may change permeability, alter surface area,
and shift the balance between proliferating and mature
epithelial cells. Further studies are needed to determine
381
the role of apoptosis in gastrointestinal pathophysiology
and clinical disease.
Risk of Malignancy
The most common cause of death in patients with
CVID is related to developing cancer. A higher rate of
gastrointestinal malignancy has been reported, whether
adenocarcinoma or lymphoma, in patients with CVID
than in patients with XLA. Overall, a fivefold increase
in malignancy has been reported, mainly due to an excessively large risk for gastric cancer and lymphoma [35,36].
The risk of gastric carcinoma is approximately 50-fold
in patients with CVID. Potential risk factors include the
presence of achlorhydria, intestinal metaplasia, and
pernicious anemia. The risk of lymphoma is 30-fold
greater in patients with CVID [36]. The majority of the
lymphomas that develop are of B-cell immunophenotype,
with a frequent association with Epstein-Barr virus
infection [37,38]. These malignant lymphomas are usually
extranodal and are histologically graded as intermediateto high-grade non-Hodgkin’s lymphomas. The onset of
worrisome symptoms, such as weight loss, anorexia, or
rapidly enlarging lymph nodes, should prompt an evaluation for malignancy [35,39]
Therapy
The goal of therapy is to maintain a serum trough level of
IgG greater than 500 mg/dL. Typically, IgG is given intravenously on a monthly basis. The prognosis for patients
with CVID is reasonably good if they do not have
bronchiectasis and chronic lung damage or severe autoimmune disease or malignancy. Treatment of CVID is
similar to that of other disorders characterized by hypogammaglobulinemia, such as XLA. In the absence of a
significant T-lymphocyte defect, intravenous IgG almost
always brings improvement of symptoms.
Treatment with intravenous IgG typically does not
affect the rate of gastrointestinal infections, such as
G. lamblia, or any other gastrointestinal manifestations of
CVID, such as chronic diarrhea. Such gastrointestinal
symptoms as diarrhea do not correlate with levels of
IgG, IgA, IgM, or the immunologic status [5••,10•].
This may be related to the fact that intravenous IgG does
not reach the gut lumen and intravenous preparations
do not contain IgA or IgM, which are important in the gut
to deal with infections. Oral preparations of IgG have not
been successful.
In patients with CVID sprue who show no response to
gluten restriction, and if all infectious causes have been
ruled out by biopsy and culture, then steroid therapy has a
role. The aim of steroid therapy is to reduce the inflammatory response. It may seem counterintuitive to give an
immunosuppressive agent to an immunodeficient individual, but steroids are given only when patients are receiving
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concomitant intravenous IgG. This combination is also
used in therapy for colitis or NLH, for which steroids or
other immunosuppressive agents are considered [5••].
The use of intravenous IL-2 replacement has been
considered since the discovery of IL-2 deficiency in CVID.
Improvement in T-cell function and formation of atypical
antibodies have been observed, but no patient has
been placed into complete remission. IL-2 replacement is
viewed as an adjunctive therapy to intravenous IgG.
In contrast to decreased IL-2 levels are increased levels of
TNF-α. TNF-α inhibitors have been considered for control
of some manifestations of CVID. One report of treatment
with an anti-TNF agent involved a young man with sarcoidlike granulomas, skin-scarring alopecia, and rheumatoid
arthritis. This patient did not respond to intravenous IgG
but responded to anti-TNF therapy over a 3-month period
[40]. Typically, TNF levels are elevated in granulomatous
disorders of CVID, but there is little granulomatous
involvement of the gastrointestinal tract in patients with
CVID. TNF levels are also increased in chronic inflammatory conditions, such as IBD. For gastroenterologists, the
best known TNF-α blocker is the monoclonal receptor
antagonist infliximab. No studies have looked at the role
of infliximab in CVID colitis or in patients with IBD in the
setting of CVID.
Conclusions
Common variable immunodeficiency is characterized by
defective production of antibodies and T-cell defects,
causing an increased risk of infection. Most patients
with CVID experience acute, recurring bacterial infections,
including pneumonia, bronchitis, and sinusitis. Gastrointestinal diseases also occur in patients with CVID. The
gastrointestinal disorders are primarily related to T-cell
defects and result in a wide spectrum of disorders in the
gastrointestinal tract—more than in any other primary
immunodeficiency. Patients with CVID are at increased
risk of cancer and inflammatory conditions in the gastrointestinal tract. The aim of treatment is to keep patients
free of infections and to minimize the effect of chronic
conditions, such as CVID-related sprue, pernicious anemia,
and colitis.
References and Recommended Reading
Papers of particular interest, published recently, have been
highlighted as:
•
Of importance
•• Of major importance
1.
Hammarstrom L, Vorechovsky I, Webster D: Selective IgA
deficiency (SIgAD) and common variable immunodeficiency
(CVID). Clin Exp Immunol 2000, 120:225–131.
2.•• Cunningham-Rundles C, Bodian C: Common variable immunodeficiency: clinical and immunological features of 248
patients. Clin Immunol 1999, 92:34–48.
In this study, 248 consecutive patients were followed for a period of
up to 25 years. The mean age of diagnosis was 23 years in males and
28 years in female patients. Parameters found to be associated with
mortality were lower levels of serum IgG, poor T-cell response, and a
low proportion of peripheral B cells, which was statistically significant.
3.• McCabe RP, Washington K, Stenzel TT, et al.: Gastrointestinal
manifestations of non-AIDS immunodeficiency. Curr Treat
Options Gastroenterol 2002, 5:17–25.
This article discusses the manifestations of CVID and gives a good
overview of the other primary immunodeficiencies. It discusses
defects in antigen presentation and the relationship between phagocytic diseases and Crohn’s disease.
4. Saiki O, Ralph P, Cunningham-Rundles C, et al.: Three distinct
stages of B-cell defects in common varied immunodeficiency.
Proc Natl Acad Sci U S A 1982, 79:6008–6012.
5.•• Lai Ping So A, Mayer L: Gastrointestinal manifestations of
primary immunodeficiency disorders. Semin Gastrointest Dis
1997, 8:22–32.
This review article outlines the definition, pathophysiology, and
clinical presentation of CVID in the gastrointestinal tract. It divides
the clinical disorders into either inflammatory or infectious etiology.
It summarizes the risk of malignancy and the therapeutic options
available for treating CVID.
6. Bryant A, Calver NC, Toubi E, et al.: Classification of patients
with common variable immunodeficiency by B cell secretion
of IgM and IgG in response to anti-IgM and interleukin-2.
Clin Immunol Immunopathol 1990, 56:239–248.
7. Strober W, Chua K: Common variable immunodeficiency.
Clin Rev Allergy Immunol 2000, 19:157–181.
8. Verne GN, Amann ST, Cosgrove C, et al.: Chronic diarrhea
associated with thymoma and hypogammaglobulinemia
(Good's syndrome). South Med J 1997, 90:444–446.
9. Hermaszewski RA, Webster AD: Primary hypogammaglobulinaemia: a survey of clinical manifestations and complications.
Q J Med 1993, 86:31–42.
10.• Cunningham-Rundles C: Clinical and immunologic analyses
of 103 patients with common variable immunodeficiency.
J Clin Immunol 1989, 9:22–33.
An important review of one of the largest series of patients with
CVID. It underscores our understanding of CVID in terms of pathophysiology and clinical presentation.
11. Fischer MB, Hauber I, Eggenbauer H, et al.: A defect in the early
phase of T-cell receptor-mediated T-cell activation in patients
with common variable immunodeficiency. Blood 1994,
84:4234–4241.
12. Ferrer JM, Iglesias J, Hernandez M, et al.: Alterations in interleukin secretion (IL-2 and IL-4) by CD4 and CD4 CD45RO
cells from common variable immunodeficiency (CVI)
patients. Clin Exp Immunol 1995, 102:286–289.
13. Fritsch A, Junker U, Vogelsang H, et al.: On interleukins 4, 6
and 10 and their interrelationship with immunoglobulins G
and M in common variable immunodeficiency. Cell Biol Int
1994, 18:1067–1075.
14. Kruger G, Welte K, Ciobanu N, et al.: Interleukin-2 correction
of defective in vitro T-cell mitogenesis in patients with
common varied immunodeficiency. J Clin Immunol 1984,
4:295–303.
15. Aukrust P, Lien E, Kristoffersen AK, et al.: Persistent activation of
the tumor necrosis factor system in a subgroup of patients
with common variable immunodeficiency: possible immunologic and clinical consequences. Blood 1996, 87:674–681.
16. Jolles S, Tyrer M, Johnson M, et al.: Long term recovery of IgG
and IgM production during HIV infection in a patient with
common variable immunodeficiency (CVID). J Clin Pathol
2001, 54:713–715.
17. Nijenhuis T, Klasen I, Weemaes CM, et al.: Common variable
immunodeficiency (CVID) in a family: an autosomal dominant
mode of inheritance. Neth J Med 2001, 59:134–139.
Common Variable Immunodeficiency and the Gastrointestinal Tract • Kalha and Sellin
18.
Vorechovsky I, Cullen M, Carrington M, et al.: Fine mapping
of IGAD1 in IgA deficiency and common variable immunodeficiency: identification and characterization of haplotypes
shared by affected members of 101 multiple-case families.
J Immunol 2000, 164:4408–4416.
19. Schroeder HW Jr, Schroeder HW III, Sheikh SM: The complex
genetics of common variable immunodeficiency. J Investig
Med 2004, 52:90–103.
20. Conley ME, Notarangelo LD, Etzioni A: Diagnostic criteria
for primary immunodeficiencies. Representing PAGID
(Pan-American Group for Immunodeficiency) and ESID
(European Society for Immunodeficiencies). Clin Immunol
1999, 93:190–197.
21. Primary immunodeficiency diseases: report of a WHO scientific
group. Clin Exp Immunol 1997, 109(Suppl 1):1–28.
22. Moriuchi H, Takayanagi T, Yamasaki S, et al.: Pernicious anemia
in a patient with hypogammaglobulinemia. Acta Paediatr Jpn
1990, 32:311–314.
23. Alonso Falcon F, Codoceo Alquinta R, Polanco Allue I, et al.:
Study of gastrointestinal polypeptides controlling gastric
acid secretion in patients with primary antibody deficiency.
Rev Esp Enferm Dig 1999, 91:54–60.
24. den Hartog G, van der Meer JW, Jansen JB, et al.: Decreased
gastrin secretion in patients with late-onset hypogammaglobulinemia. N Engl J Med 1988, 318:1563–1567.
25. den Hartog G, Jansen JB, van der Meer JW, et al.: Gastric abnormalities in humoral immune deficiency syndromes. Scand J
Gastroenterol Suppl 1992, 194:38–40.
26.•• Washington K, Stenzel TT, Buckley RH, et al.: Gastrointestinal
pathology in patients with common variable immunodeficiency and X-linked agammaglobulinemia. Am J Surg
Pathol 1996, 20:1240–1252.
In this review of 43 patients with CVID the gastrointestinal pathology
was systematically evaluated. A pattern resembling graft-versus-host
disease was seen. Apoptosis was seen throughout the gastrointestinal
tract. A variant of Whipple’s disease was seen in one patient’s small
bowel biopsies. This paper is a detailed summary of the various
manifestations of CVID in the gastrointestinal tract.
27. Zullo A, Romiti A, Rinaldi V, et al.: Gastric pathology in
patients with common variable immunodeficiency. Gut 1999,
45:77–81.
28. Heneghan MA, Stevens FM, Cryan EM, et al.: Celiac sprue and
immunodeficiency states: a 25-year review. J Clin Gastroenterol
1997, 25:421–425.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
383
Abonia JP, Castells MC, McCabe RP, et al.: Common variable
immunodeficiency: gastrointestinal manifestations of nonAIDS immunodeficiency. Allergy Asthma Proc 2002, 23:53–57.
Iglesias Alzueta J, Matamoros Flori N: Common variable
immunodeficiency [in Spanish]. Allergol Immunopathol (Madr)
2001, 29:113–118.
Catassi C, Mirakian R, Natalini G, et al.: Unresponsive enteropathy associated with circulating enterocyte autoantibodies in
a boy with common variable hypogammaglobulinemia and
type I diabetes. J Pediatr Gastroenterol Nutr 1988, 7:608–613.
Strauss RG, Ghishan F, Mitros F, et al.: Rectosigmoidal colitis in
common variable immunodeficiency disease. Dig Dis Sci
1980, 25:798–801.
Quinti I, Pierdominici M, Marziali M, et al.: European surveillance of immunoglobulin safety: results of initial survey
of 1243 patients with primary immunodeficiencies in
16 countries. Clin Immunol 2002, 104:231–236.
Bjoro K, Skaug K, Haaland T, et al.: Long-term outcome of
chronic hepatitis C virus infection in primary hypogammaglobulinaemia. QJM 1999, 92:433–441.
Zenone T, Souillet G: Cancer and primary humoral immunodeficiency [in French]. Bull Cancer 1997, 84:813–821.
Kinlen LJ, Webster AD, Bird AG, et al.: Prospective study of
cancer in patients with hypogammaglobulinaemia. Lancet
1985, 1:263–266.
Brindicci D, Grimaldi F, Fracella MR, et al.: Radiologic evaluation and prognosis of lymphoid nodular hyperplasia of the
mesenteric intestine [in Italian]. Radiol Med (Torino) 1993,
86:622–625.
Chiaramonte C, Glick SN, Rodriguez Maria R, et al.: Nodular
lymphoid hyperplasia of the small bowel complicated
by jejunal lymphoma in a patient with common variable
immune deficiency syndrome. AJR Am J Roentgenol 1994,
163:1118–1119.
Mellemkjaer L, Hammarstrom L, Andersen V, et al.: Cancer risk
among patients with IgA deficiency or common variable
immunodeficiency and their relatives: a combined Danish
and Swedish study. Clin Exp Immunol 2002, 130:495–500.
Smith KJ, Skelton H: Common variable immunodeficiency
treated with a recombinant human IgG, tumour necrosis
factor-alpha receptor fusion protein. Br J Dermatol 2001,
144:597–600.