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: [email protected] 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 . 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 . 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. 378 Small Intestine Epidemiology Genetics The estimated incidence of CVID in the United States is one case per 10,000 to 50,000 population . 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 . Approximately 10% of patients have a coexisting thymoma (Good’s syndrome) . 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 . 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 . A common genetic basis for CVID and selective IgA deficiency (sIgAD) has been suspected because these disorders occur in first-degree relatives of patients . 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 . 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 . 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 . 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) . 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 . 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 . An abnormal gastrin response to food and stimulation with bombesin, a potent gastrin-releasing agent, occurs in patients with CVID . 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 . 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 . Small intestine Approximately 50% of patients with CVID of the small intestine exhibit diarrhea and malabsorption . 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 380 Small Intestine Figure 1. Small bowel biopsy showing marked villous atrophy, destruction of crypts, and occasional single-cell necrosis. the tips of the villi . 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 . 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 . 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 . 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 . 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 . 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 382 Small Intestine 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 . 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. 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