Silje F Jørgensen1,2,3, Henrik M Reims4, Didrik Frydenlund4, Kristian Holm1,5, Vemund Paulsen6, Annika E Michelsen1,7, Kristin K Jørgensen5,8, Liv T Osnes9, Jorunn Bratlie1, Tor J Eide4,7, Christen P Dahl1, Ellen Holter10, Rune R Tronstad11,12, Kurt Hanevik11, Hans-Richard Brattbakk11,13, Fatemeh Kaveh14, Torunn Fiskerstrand11,13, Anne-Marte B Kran7,15, Thor Ueland1,16, Tom H Karlsen1,3,5,7, Pål Aukrust1,2,3,7, Knut E A Lundin6,7,17, Børre Fevang1,2,7. 1. Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway. 2. Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway. 3. K. G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. 4. Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway. 5. Norwegian PSC Research Center, Oslo University Hospital Rikshospitalet, Oslo, Norway. 6. Department of Transplantation Medicine, Section of Gastroenterology, Oslo University Hospital Rikshospitalet, Oslo, Norway. 7. Institute of Clinical Medicine, University of Oslo, Oslo, Norway. 8. Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway. 9. Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, Norway. 10. Department of Microbiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway. 11. Department of Clinical Science, University of Bergen, Bergen, Norway. 12. Department of Pediatrics, Haukeland University Hospital, Bergen, Norway. 13. Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway. 14. Medical Genetics Department, Oslo University Hospital, Ullevål, Oslo, Norway. 15. Department of Microbiology, Oslo University Hospital, Ullevål, Oslo, Norway. 16. K.G. Jebsen Thrombosis Research and Expertise Center, University of Tromsø, Tromsø, Norway. 17. Centre for Immune Regulation, University of Oslo, Oslo, Norway.
Abstract
OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
OBJECTIVES: 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. METHODS: 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. RESULTS: 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 CVIDpatients 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). CONCLUSIONS: 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.
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