Common Variable Immunodeficiency Enteropathy Research Articles

Characterization of infectious and non-infectious gastrointestinal disease in common variable immunodeficiency: analysis of 114 patient cohort.

Common Variable Immunodeficiency (CVID), a complex primary immunodeficiency syndrome defined by defective B cell responses to infection and vaccination, has heterogeneous clinical manifestations. Gastrointestinal (GI) complications in CVID, both infectious and non-infectious, can cause significant impairment leading to malabsorption and frank malnutrition. In order to better characterize the spectrum of GI disease associated with CVID, we describe 114 patients with GI disease (15.6%) from our 728 patient single center CVID cohort. Norovirus, Giardia and Cytomegalovirus were the most frequently isolated infectious pathogens. CVID enteropathy was the most encountered GI diagnosis based on endoscopy, with only a minority of patients having Crohn's disease (6.1%) or ulcerative colitis/proctitis (4.5%). Concurrent autoimmunity (30.7%), lung disease (18.4%) and malignancy (8.7%) were also present in significant proportion of subjects. Lastly, 16 of 47 (34%) who underwent whole exome sequencing demonstrated a culprit gene defect associated with CVID.

CVID Colopathy: An Important Clinical Diagnosis with a Broad Differential

Abstract Introduction/Objective Colonic injury with increased epithelial cell apoptosis can be sometimes seen in colonic biopsies; raising a broad differential diagnosis. The possible etiologies include graft-versus-host disease and, drug- induced injury (including but not limited to mycophenolate mofetil, checkpoint inhibitors, antimetabolites, and tumor necrosis alpha inhibitors), infections (particularly cytomegalovirus and adenovirus), and immune disorders (common variable immune deficiency and autoimmune enterocolopathy). Hence, the umbrella term “apoptotic colopathy” was coined as a broad-spectrum diagnosis for further workup. Methods/Case Report Herein, we report a case of a 36-year-old Caucasian male who presented for follow-up of ulcerative pancolitis with additional history of decompensated liver cirrhosis. The patient has a past history of Common variable immunodeficiency (CVID) with CVID enteropathy and CMV gastritis. The patient’s long-term medications included Entyvio, IVIG, and Valcyte. Surveillance colonoscopy was performed and revealed portal colopathy, otherwise was unremarkable. Both right and left colon were biopsied. Microscopic examination showed marked epithelial cell apoptosis with no granulomas, dysplasia, or malignancy. No history of mycophenolate or stem cell transplant was noted. No viral cytopathic effect was seen, supported by CMV stain. Apoptotic colopathy with the possible differential diagnosis was rendered as the final diagnosis; mentioning the given clinical history of the patient for CVID, the histological picture is compatible with CVID colopathy. Results (if a Case Study enter NA) NA. Conclusion It is pertinent to be aware of all above mentioned possible etiologies in such cases. Correlation with detailed clinical history, medications, laboratory findings, and other histopathological findings (including judicial use of immunohistostains) is warranted to reach a definitive diagnosis that would drive patient management accordingly and help provide optimal patient care.

Interferon-Driven Immune Dysregulation in Common Variable Immunodeficiency–Associated Villous Atrophy and Norovirus Infection

PurposeAbout 15% of patients with common variable immunodeficiency (CVID) develop a small intestinal enteropathy, which resembles celiac disease with regard to histopathology but evolves from a distinct, poorly defined pathogenesis that has been linked in some cases to chronic norovirus (NV) infection. Interferon-driven inflammation is a prominent feature of CVID enteropathy, but it remains unknown how NV infection may contribute.MethodsDuodenal biopsies of CVID patients, stratified according to the presence of villous atrophy (VA), IgA plasma cells (PCs), and chronic NV infection, were investigated by flow cytometry, multi-epitope-ligand cartography, bulk RNA-sequencing, and RT-qPCR of genes of interest.ResultsVA development was connected to the lack of intestinal (IgA+) PC, a T helper 1/T helper 17 cell imbalance, and increased recruitment of granzyme+CD8+ T cells and pro-inflammatory macrophages to the affected site. A mixed interferon type I/III and II signature occurred already in the absence of histopathological changes and increased with the severity of the disease and in the absence of (IgA+) PCs. Chronic NV infection exacerbated this signature when compared to stage-matched NV-negative samples.ConclusionsOur study suggests that increased IFN signaling and T-cell cytotoxicity are present already in mild and are aggravated in severe stages (VA) of CVID enteropathy. NV infection preempts local high IFN-driven inflammation, usually only seen in VA, at milder disease stages. Thus, revealing the impact of different drivers of the pathological mixed IFN type I/III and II signature may allow for more targeted treatment strategies in CVID enteropathy and supports the goal of viral elimination.Graphical abstract

S3415 Gastroenterological Manifestations in a Patient With Common Variable Immunodeficiency

Introduction: Gastrointestinal manifestation of common variable immunodeficiency (CVID) can present with protein-losing enteropathy (PLE). A wide spectrum of liver injuries can occur with CVID, including nodular regenerative hyperplasia (NRH). Case Description/Methods: 41 y.o. female with PMH of CVID on IgG, chronically elevated LFTs, and nutritional deficiencies. Patient presented with 8-year history of diarrhea, bloating, weight loss, abdominal pain, hepatic encephalopathy (HE), new ascites, and shock. Previously was diagnosed with celiac disease and has strictly followed a gluten-free diet with no improvement. EGD on the current presentation showed visible changes in duodenal mucosa including villous flattening. Biopsies this time revealed villous flattening and absence of plasma cells consistent with CVID enteropathy. Liver biopsy 5 years prior to admission showed no liver disease. Serologic workups, including anti-gp210 and anti-sp100, were negative. Biopsy showed nodular regenerative hyperplasia and non-cirrhotic portal hypertension, which was confirmed by reticulin stain. Patient was started on budesonide 9 mg daily for treatment of PLE, and marked improvement of diarrhea was noted. Non-cirrhotic portal hypertension was managed with furosemide and spironolactone. HE was managed with oral lactulose. The patient was started on enteral and parenteral supplements. Discussion: Duodenal villous atrophy which is a diagnostic criterion for celiac disease can be seen in multiple other conditions including immune disorders such as CVID. In CVID patients with gastrointestinal symptoms, up to 80% of biopsies from different sites in the GI tract will show histological abnormalities. Given their common presentation, celiac disease can be initially diagnosed. The absence of plasma cells and apoptosis presence in duodenal biopsy can suggest PLE diagnosis. Serological studies are not reliable for celiac disease diagnosis due to deficiency of immunoglobulin production in CVID. Steroids can be used for the treatment of PLE in CVID. Hepatic manifestations in CVID are extremely varied and often misdiagnosed given they can mimic other diseases. NRH is a potentially fatal complication of CVID. Recognition of this complication allowed for symptom resolution within two days of starting lactulose therapy. NRH in CVID represents an autoimmune-like liver disease that might be driven by a local vasculopathy, and thus severe cases can warrant a trial of immunosuppression.

Long Term Norovirus Infection in a Patient with Severe Common Variable Immunodeficiency.

Norovirus is the most common cause of acute non-bacterial gastroenteritis. Immunocompromised patients can become chronically infected, with or without symptoms. In Europe, common variable immunodeficiency (CVID) is one of the most common inborn errors of immunity. A potentially severe complication is CVID-associated enteropathy, a disorder with similar histopathology to celiac disease. Studies suggest that chronic norovirus infection may be a contributor to CVID enteropathy, and that the antiviral drug ribavirin can be effective against norovirus. Here, a patient with CVID-like disease with combined B- and T-cell deficiency, had chronic norovirus infection and enteropathy. The patient was routinely administered subcutaneous and intravenous immunoglobulin replacement therapy (SCIg and IVIg). The patient was also administered ribavirin for ~7.5 months to clear the infection. Stool samples (collected 2013–2016) and archived paraffin embedded duodenal biopsies were screened for norovirus by qPCR, confirming a chronic infection. Norovirus genotyping was done in 25 stool samples. For evolutionary analysis, the capsid (VP1) and polymerase (RdRp) genes were sequenced in 10 and 12 stool samples, respectively, collected before, during, and after ribavirin treatment. Secretor phenotyping was done in saliva, and serum was analyzed for histo-blood group antigen (HBGA) blocking titers. The chronic norovirus strain formed a unique variant subcluster, with GII.4 Den Haag [P4] variant, circulating around 2009, as the most recent common ancestor. This corresponded to the documented debut of symptoms. The patient was a secretor and had HBGA blocking titers associated with protection in immunocompetent individuals. Several unique amino acid substitutions were detected in immunodominant epitopes of VP1. However, HBGA binding sites were conserved. Ribavirin failed in treating the infection and no clear association between ribavirin-levels and quantity of norovirus shedding was observed. In conclusion, long term infection with norovirus in a patient with severe CVID led to the evolution of a unique norovirus strain with amino acid substitutions in immunodominant epitopes, but conservation within HBGA binding pockets. Regularly administered SCIg, IVIg, and ~7.5-month ribavirin treatment failed to clear the infection.

VEDOLIZUMAB AS TREATMENT FOR COMMON VARIABLE IMMUNE DEFICIENCY (CVID): A CASE SERIES AND BRIEF REVIEW OF THE LITERATURE

Common variable immunodeficiency (CVID) is the most common symptomatic immunodeficiency, frequently presenting as recurrent upper respiratory infections. A portion of these patients develop non-specific gastrointestinal symptoms with a smaller subset developing CVID enteropathy, characterized by chronic diarrhea with absence of plasma cells and aggregates of T cells on intestinal pathology. We describe two cases of steroid refractory CVID enteropathy who were started on Vedolizumab (VDZ) with clinical remission.

CVID enteropathy is characterized by exceeding low mucosal IgA levels and interferon-driven inflammation possibly related to the presence of a pathobiont

Common variable immunodeficiency (CVID), the most common symptomatic primary antibody deficiency, is accompanied in some patients by a duodenal inflammation and malabsorption syndrome known as CVID enteropathy (E-CVID).The goal of this study was to investigate the immunological abnormalities in CVID patients that lead to enteropathy as well as the contribution of intestinal microbiota to this process.We found that, in contrast to noE-CVID patients (without enteropathy), E-CVID patients have exceedingly low levels of IgA in duodenal tissues. In addition, using transkingdom network analysis of the duodenal microbiome, we identified Acinetobacter baumannii as a candidate pathobiont in E-CVID. Finally, we found that E-CVID patients exhibit a pronounced activation of immune genes and down-regulation of epithelial lipid metabolism genes. We conclude that in the virtual absence of mucosal IgA, pathobionts such as A. baumannii, may induce inflammation that re-directs intestinal molecular pathways from lipid metabolism to immune processes responsible for enteropathy.

Total and High Molecular Weight Adiponectin Expression Is Decreased in Patients with Common Variable Immunodeficiency: Correlation with Ig Replacement Therapy.

Adiponectin (Acrp30) is an adipokine widely studied for its beneficial metabolic properties. It circulates as low molecular weight (LMW), medium molecular weight (MMW), and high molecular weight (HMW) oligomers. The latter exerts the most potent biological effects. Acrp30 attracted renewed interest with the finding that it was associated with the development and progression of immune disorders. The mechanisms underlying this association and the role of Acrp30 in the pathophysiology of immune-mediated conditions remain unknown. Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by chronic activation of the immune system, impaired antibody production, and imbalanced cytokine production. In the attempt to shed light on the expression of Acrp30 in CVID, we: (a) investigated total Acrp30 and its oligomerization state in CVID patients undergoing maintenance Ig replacement therapy; (b) assessed the effects of Ig replacement therapy on Acrp30 expression in treatment-naïve CVID patients, namely, patients not treated before diagnosis, before and after the first Ig administration; and (c) evaluated the correlation between Acrp30 levels and clinical phenotypes of the disease. As controls, we analyzed healthy subjects and patients affected by a non-immunodeficiency chronic inflammatory demyelinating polyneuropathy (CIDP), before and after Ig infusion. We found that total Acrp30 and HMW oligomers were decreased in CVID but not in CIDP patients versus controls. Moreover, Acrp30 levels were correlated with IgA levels and were associated with two CVID phenotypes, namely, autoimmune cytopenia and enteropathy. Receiver operating characteristic curve analysis indicated that Acrp30 modulation is specific for CVID patients. Acrp30 and HMW levels quickly and dramatically increased after Ig infusion only in eight treatment-naïve CVID patients but not in five CIDP patients. This finding indicates that Ig administration per se is not able to induce an increase of Acrp30, but the specific cellular and/or molecular background proper of CVID seems to be essential. In conclusion, our data indicate that Acrp30 is specifically related to CVID activity. Further studies are required to understand the biological role of Acrp30 and its possible use as disease biomarker in CVID.

Chronic Diarrhea in Hypogammaglobulinemia: A Case Report of Immunodeficiency

Introduction: Common variable immunodeficiency (CVID) or acquired hypogammaglobulinemia is the most common primary antibody deficiency which leads to lymphocytic dysfunction. CVID is not related to gender and can affect the person at any age, but the peaks of onset are the first and the third decades of life. CVID presents with various manifestations, which can obscure the proper diagnosis of the disease based on broad non-specific presentations. In this report, we describe a case of refractory chronic diarrhea secondary to underlying CVID disease without recurring bacterial infections. Case Presentation: A 31 year old woman with a chief complaint of persistent diarrhea and weight loss for five years. She did not complain of anysymptoms until the age of 26 when she started having several episodes of semi-solid diarrhea per day. Despite dietary and additional interventions, symptoms were persistent during a 5 year course of the disease and worsened in the last 2 months, with significantincrease in volume and frequency of diarrhea and associated weight loss of 10 kilograms. Several work-ups were inconclusive and she was referred to us for evaluation of CVID enteropathy. Discussion: Chronic diarrhea is considered one of the most common clinical manifestations of CVID. More than half of patients present with diarrhea and 10% develop idiopathic malabsorption associated with weight loss. This case report presents gastrointestinal manifestation of CVID as the only presentation during 5 years, which led to exhaustive diagnostic studies without definitive diagnosis or effective management. This report signifies the importance of early diagnosis of CVID, and the need to improve physicians’ general awareness of manifestations of the disease.

A Cross-Sectional Study of the Prevalence of Gastrointestinal Symptoms and Pathology in Patients With Common Variable Immunodeficiency.

The objective of this study was to study the prevalence of gastrointestinal (GI) symptoms and histopathology in patients with common variable immunodeficiency (CVID) as well as linking the findings to GI infections and markers of systemic immune activation. In this cross-sectional study, we addressed GI symptoms in 103 patients and GI histopathological findings in 53 patients who underwent upper and lower endoscopic examination. The most frequent histopathological findings were linked to GI symptoms, B-cell phenotype, and markers of systemic immune activation (soluble (s)CD14, sCD25, and sCD163). Microarray analysis compared "celiac-like disease" in CVID to celiac disease. Screening for selected bacterial and viral infections in fecal samples and gut mucosal biopsies was performed. The main findings of this study were as follows: most common GI symptoms were bloating (34%), pain (30%), and diarrhea (26%). The most frequent histopathological findings were increased intraepithelial lymphocytes in the descending part of the duodenum, i.e., "celiac-like disease" (46% of patients), decreased numbers of plasma cells in GI tract mucosa (62%), and lymphoid hyperplasia (38%), none of which were associated with GI symptoms. Reduced plasma cells in GI mucosa were associated with B-cell phenotypic characteristics of CVID, and increased serum levels of sCD14 (P=0.025), sCD25 (P=0.01), and sCD163 (P=0.04). Microarray analyses distinguished between CVID patients with "celiac-like disease" and celiac disease. Positive tests for bacterial and viral infections were scarce both in fecal samples and gut mucosal biopsies, including PCR test for norovirus in biopsy specimens (0 positive tests). In conclusion, GI pathology is common in CVID, but does not necessarily cause symptoms. However, reduced plasma cells in GI mucosa were linked to systemic immune activation, "celiac-like disease" in CVID and true celiac disease appear to be different disease entities, as assessed by gene expression, and infections (including norovirus) are rarely a cause of the CVID enteropathy.

Deciphering the Different Types of Refractory Celiac Disease

Universite Paris Descartes-Sorbonne Paris Centre Gastroenterology department, Hopital Europeen Georges Pompidou APHP, Paris Inserm U989, Hopital Europeen Georges Pompidou APHP Paris, France Fifteen years ago has emerged the concept of refractory celiac disease (RCD). [1,2] RCD is defined by persisting malabsorption and villous atrophy after one year of strict GFD ascertained by a dietician. RCD has been subdivided into two subgroups according to the normal (type I RCD (RCDI)) or abnormal phenotype of intraepithelial lymphocytes (IEL) (type II RCD (RCDII). RCDI is indistinguishable from active CD and is characterized by a polyclonal repertoire. Survival of patients with RCDI is slightly inferior to that of those with celiac disease. [3,4] In contrast, RCDII is a severe enteropathy with frequent intractable ulcerative duodeno-jejunitis. RCDII is characterized by a clonal repertoire and is considered as a low-grade intraepithelial lymphoma. [1,2] The five year survival rate of patients with RCDII is around 50%. This poor prognosis is due to severe malnutrition and increased risk of overt lymphoma. One of the current challenges in RCD is to ascertain the type of RCD. Indeed, diagnosis of RCD has become highly specialized. It requires small bowel endoscopic specialized investigations such as capsule endoscopy and double balloon enteroscopy. [5,6] Intestinal biopsy needs to be studied by different complementary techniques such as immunohistochemistry, flow cytometry, and Multiplex PCR, all necessary to ascertain the precise diagnosis. Recent studies have reported case series of chronic intestinal diseases mimicking the both types of RCD. RCDI needs to be distinguished from other causes of non clonal villous atrophy such as enteropathy associated with common variable immunodeficiency (CVID). [7] Demonstration of HLA haplotypes encoding HLA-DQ2 or DQ8 can be useful as their absence excludes CD or RCD as a cause of villous atrophy. [8] Nevertheless, genotypes HLA-DQ2/DQ8 are also found in 77% of CVID patients with enteropathy mimicking CD defined by intestinal intra-epithelial lymphocytosis. [7] So evidence of serum hypogammaglobulinemia and histopathological features such as intestinal plasmocytic rarefaction or nodular lymphoid hyperplasia appear essential to distinct CVID enteropathy from RCDI. [7] RCDII needs to be distinguished from other cases of clonal enteropathy with villous atrophy. Flow cytometry allows to tell the difference between RCDII and other intestinal clonal malignancies with villous atrophy. Indeed, demonstration of excess of CD4+IEL with a specific Vbeta repertoire is essential for diagnosis of intestinal CD4 lymphoproliferations. [9] Diagnosis may be particularly tricky when CD4 lymphoproliferation [9] or large granular lymphocytic leukemia (LGL) [10] complicate an authentic CD. Consequently, spectrum of RCD has been recently substantially extended. Advances in accuracy of diagnostic tools could reduce the number of undiagnosed RCD and increase the frequency of RCD currently estimated to 1 to 2% of CD patients. [11,12] Besides epidemiological interest, improvement of diagnostic tools allowed precise diagnosis of RCD type and appropriate treatment. By example, distinction between RCDII and CD complicated by LGL is crucial as cyclosporin, inefficient in RCDII, is in contrast very useful for treating LGL. Indeed, treatment of RCD remains another challenge particularly in case of RCDII patients who have poor prognosis and for whom referral treatment does not yet exist. Immunosuppressors are poorly efficient and may possibly trigger overt lymphoma. [13] Purine analogues such pentostatine or cladribine (2 CDA) have been largely used in the past with slight therapeutic effect. [4,14,15] Autologous haematopoietic stem cells transplantation represents an interesting alternative but when combined to chemotherapy for hopping sustained reduction of abnormal IEL. [16,17] We are currently evaluating this strategy in a prospective phase II trial. Many advances in the understanding of the pathogenesis of RCDII were made by deciphering the anti-apoptotic signaling pathway of the cytokine IL-15 which prevents the elimination of IEL in CD and RCDII. [18] The IL-15 induced antiapoptotic signaling pathway includes activation of IL15Rβγ, Jak3, STAT5 and Bcl-xL [19] which represent so many therapeutic targets. Blocking the effect of IL-15 appears of a particular interest in RCDII but may probably be useful in other types of RCD with possible involvement of IL-15 such as RCDI or LGL-complicated CD. [20] Continuing the characterization of the different forms of RCD will probably guide next pathogenic studies and permit to increase our therapeutic efficacy in the future.

The role of chronic norovirus infection in the enteropathy associated with common variable immunodeficiency.

A severe enteropathy of unknown etiology can be associated with common variable immunodeficiency (CVID). S tool and archived small intestinal mucosal biopsies from patients with CVID enteropathy were analyzed by PCR for the presence of Norovirus RNA. The PCR products were sequenced to determine the relationship of viral isolates. Stool samples from 10 patients with CVID but no enteropathy served as controls. All eight patients in our CVID cohort with enteropathy showed persistent fecal excretion of Norovirus. Analysis of archived duodenal biopsies revealed a strong association between the presence of Norovirus and villous atrophy over a period of up to 8 years. Analysis of the viral isolates from each patient revealed distinct strains of genogroup II.4. Sequence analysis from consecutive biopsy specimens of one patient demonstrated persistence of the same viral strain over a 6-year period. CVID patients without enteropathy showed no evidence of Norovirus carriage. Viral clearance occurred spontaneously in one patient and followed oral Ribavirin therapy in two further patients, and resulted in complete symptomatic and histological recovery. However, Ribavirin treatment in two further patients was unsuccessful. Norovirus is an important pathogen for patients with CVID and a cause of CVID enteropathy, as viral clearance, symptom resolution, and histological recovery coincide. Ribavirin requires further evaluation as a potential therapy.

Successful treatment of enteropathy associated with common variable immunodeficiency

Successful treatment of enteropathy associated with common variable immunodeficiency

Chronic Diarrhea, Malabsorption, Villous Blunting, and Microscopy Colitis due to Common Variable Immunodeficiency Syndrome

Introduction: While the most common diagnosis associated with chronic diarrhea and villous atrophy is celiac sprue, Common Variable Immunodeficiency (CVID) can also present similarly. Here we present a case of enteropathy with CVID that had been treated as refractory celiac disease. Case Report: A 42-year-old female with history of iron deficiency anemia, B12 deficiency and chronic diarrhea presented with intermittent abdominal cramping and watery diarrhea. Her symptoms dated back to age 18 after a trip to Indonesia. She was diagnosed with IBS and treated without improvement. Upper endoscopy at outside hospital initially showed mild villous blunting in duodenum consistent with celiac sprue. Gluten free diet was started, and she had minimal response after 2 years. Celiac panel later showed normal endomycial IgA and tissue transglutaminase IgA/IgG with low immunoglobulin A. Further evaluation showed hypogammaglobulinemia which was consistent with CVID. IVIG and Budesonide were started without improvement of her GI symptoms. Prednisone was subsequently started, which led to significant improvement of her GI symptoms. Colonoscopy showed increased intraepithelial hyperlymphocytosis and preserved crypt architecture consistent with lymphocytic colitis. Conclusion: CVID is a rare disease which can mimic GI symptoms and pathology of celiac disease. Although villous atrophy is present in both CVID and celiac disease, milder intraepithelial hyperlymphocytosis, lack of intestinal plasma cells and diffuse follicular lymphoid hyperplasia are more common in CVID. Microscopic colitis has also been reported in CVID enteropathy. This case suggests that it is important to consider alternative diagnosis such as CVID in patients labeled as refractory celiac disease.

CVID Enteropathy- A Rare Cause of Chronic Diarrhea in a Child

Common variable immunodeficiency (CVID) is a rare primary immunodeficiency disease characterized by hypogammaglobulinemia and recurrent bacterial infections especially in respiratory and gastrointestinal systems. The authors present here a case of CVID with uncommon gastrointestinal manifestation in the form of CVID enteropathy. Based upon the clinical presentation and histopatholic findings the patient was diagnosed as CVID enteropathy and treated with intravenous antibiotics and 3-4 wkly intravenous immunoglobulin infusion and he had responded poorly to gastrointestinal symptoms but the frequency of respiratory and skin infection reduced. CVID has heterogenous gastrointestinal manifestations; among them the CVID enteropathy is an uncommon presentation which responds poorly to the mainstay therapy of intravenous immunoglobulin infusion and represents a diagnostic as well as therapeutic challenge for treating physician.

The Enteropathy Associated With Common Variable Immunodeficiency: The Delineated Frontiers With Celiac Disease

The enteropathy associated with common variable immunodeficiency (CVID) is poorly characterized, and its possible relationships with well-defined causes of enteropathy, such as celiac sprue (CS), remain debated. We aimed to assess the clinical and histopathological features of the enteropathy associated with CVID. The medical files of 50 CVID patients with gastrointestinal symptoms were analyzed retrospectively. Histological, phenotypic, and molecular analysis of intestinal endoscopic specimens was centrally performed. Chronic diarrhea was the most frequent gastrointestinal symptom (92%), and biological evidence of malabsorption was observed in 54% of patients. Chronic gastritis associated or not with pernicious anemia and microscopic colitis were the most frequently observed histopathological features in gastric and colonic mucosa, respectively. Small-bowel biopsies available in 41 patients showed moderate increase in intestinal intraepithelial lymphocytes in 31 patients (75.6%) and villous atrophy in 21 patients (51%). Distinctive features from CS were a profound depletion in plasma cells and follicular lymphoid hyperplasia. Presence of peripheral blood CD8+ hyperlymphocytosis was predictive of intestinal intraepithelial hyperlymphocytosis. Intravenous (i.v.) immunoglobulin (Ig) therapy had no effect on enteropathy-related symptoms. Gluten-free diet improved only two out of 12 patients with villous atrophy, whereas all patients (7/7) responded to steroid therapy. Several distinctive features differentiate CVID enteropathy from other causes of enteropathy including CS. Replacement i.v. Ig therapy is insufficient to improve gastrointestinal symptoms. Steroids are effective in reducing inflammation and restoring mucosal architecture.

CLINICAL AND HISTOLOGIC IMPROVEMENT OF ENTEROPATHY ASSOCIATED WITH COMMON VARIABLE IMMUNODEFICIENCY WITH BUDESONIDE THERAPY

Common variable immunodeficiency (CVID) is an immunologic disorder characterized by defective antibody production. CVID has been associated with an enteropathy that has similarities to gluten-sensitive enteropathy with villous atrophy in the small bowel resulting in malabsorption. It does not respond to gluten avoidance and there are no proven therapies, though use of oral prednisone has been described. However, long-term immunosuppressive therapy in CVID might increase a patient's risk of infectious and systemic complications. This report describes an alternative approach to improve symptoms and histology in CVID enteropathy. Case: A 41 year-old male with CVID presented with progressive diarrhea and weight loss, describing up to 20 steatorrheic bowel movements a day over the past year. He denied fevers, chills, hematochezia, or other systemic complaints, excepting a 30 pound weight loss. His only significant medical problem was CVID, treated with regular IV immunoglobulin (IVIG) infusions for the previous three years. The patient took no medications and denied recent travel or sick contacts. Examination showed wasting, but was otherwise normal. Labs showed evidence of malabsorption and malnutrition. All stool studies were negative. Transglutaminase Ab. was negative, but small bowel biopsy revealed villous blunting. Colonoscopy and abdominal CT scan were normal. Though empirically started on a gluten-free diet, symptoms and villous blunting persisted. The patient was diagnosed with CVID enteropathy while on IVIG, so prednisone was added to treat the enteropathy-improving both his diarrhea and villous blunting. When the prednisone was tapered below 10 mg per day, the diarrhea and villous blunting recurred. So, prednisone with oral budesonide was started. The patient was weaned off prednisone over 3 months, remaining solely on oral budesonide for the past year without recurrence of diarrhea. Prealbumin and body weight have normalized. Villous blunting has improved. Discussion: There are limited therapeutic options for CVID enteropathy. Given the risks associated with long-term systemic steroids, this case report defines a viable Treatment option. Treatment of CVID enteropathy with oral budesonide has not been previously published.

COBALAMIN DEFICIENCY and SMALL BOWEL BACTERIAL OVERGROWTH: A COMMON ASSOCIATION

Background Bacterial overgrowth may cause cobalamin deficiency through competition for dietary cobalamin in the small intestine. The objective of this study was to prospectively determine the prevalence of small bowel bacterial overgrowth in patients with documented cobalamin deficiency in a tertiary referral centre.Methods Patients identified with cobalamin deficiency underwent diagnostic investigations including: Endoscopy (with gastric antrum, gastric body and duodenal biopsies and duodenal aspirate), 14C‐D‐Xylose breath test, intrinsic factor antibody, anti‐endomysial antibody and red cell folate level. ‘Definite’ small bowel bacterial overgrowth was defined as either a positive 14C‐D‐Xylose breath test or > 100 000 CFU/mL of culture of duodenal aspirate. ‘Suspected’ small bowel bacterial overgrowth was defined as an elevated red cell folate in the absence of supplemental folate therapy.Results Over a 2‐year period, 62 patients with cobalamin deficiency were identified, of whom, 26 (42%) had ‘definite’ small bowel bacterial overgrowth, whilst a further nine (15%) had ‘suspected’ small bowel bacterial overgrowth. Nineteen (31%) had pernicious anaemia, and no cause for cobalamin deficiency could be found in eight (13%) patients. The diagnosis found in the remaining patients included coeliac disease (4), Crohn's Disease (1), gastric resection (2), vegan (2), homozygotes of the MTHFR gene (C677T) mutation (2), and one had enteropathy associated with common variable immunodeficiency (CVID). ‘Definite’ small bowel bacterial overgrowth was found to coexist with nine of the 19 cases of pernicious anaemia, two coeliac subjects, one CVID enteropathy and one patient with the MTHFR gene mutation.Conclusion Small bowel bacterial overgrowth is commonly associated with cobalamin deficiency.