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Welcome to the April, 2013 edition of SciEP newsletter, providing monthly summaries of articles on science & education related topics of interest to scientist and professionals. The mission of our journals is to provide an open access forum for publishing new findings on issues pertinent to scientific and academic field. We also invite you to submit original research papers, review articles, short reports, or case studies are considered for publication in our Multidisciplinary Journals.

American Journal of Public Health Research
DOI: 10.12691/ajphr-1-1-3

The Implementation of a Tele-Homecare System with Service Oriented Architecture and HL7 Message Transmission Standard
Ching-Sung Wang

American Journal of Medical and Biological Research
DOI: 10.12691/ajmbr-1-1-2

The Influence of Ethanol on Pyruvate Kinases Activity in Vivo, in Vitro, in Silico
Lelevich Sergey Vladimirovich, Khrustalev Vladislav Victorovich, Barkovsky Eugene Victorovich, Shedogubova Tatyana Aleksandrovna

American Journal of Medical Sciences and Medicine
DOI: 10.12691/ajmsm-1-1-1

Clinical and Histological Features in Wegener Granulomatosis
Li Cavoli Gioacchino, Passantino Rita, Bono Luisa, Tortorici Calogera, Ferrantelli Angelo, Giammarresi Carlo, Rotolo Ugo

American Journal of Infectious Diseases and Microbiology
DOI: 10.12691/ajidm-1-1-2

The Curse of Lymphatic Filariasis: Would the Continual Use of Diethylcarbamazine Eliminate this Scourge in Papua New Guinea?
Anne Lanham, Lillian Mwanri

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American Journal of Infectious Diseases and Microbiology
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American Journal of Biomedical Research
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Label_Title

Dear Label_Name,

Greetings! I hope you are well.

I am writing on behalf of an international publishing house, Science and Education Publishing, USA (http://www.sciepub.com).

Science and Education Publishing (SciEP) is a multidisciplinary open access publisher of Journals covering the fields of Science, Technology and Medicine. All SciEP publications are subject to high-quality peer review, editorial and production processes and are freely available online.

Welcome to the April, 2013 edition of SciEP newsletter, providing monthly summaries of articles on science & education related topics of interest to scientist and professionals. The mission of our journals is to provide an open access forum for publishing new findings on issues pertinent to scientific and academic field. We also invite you to submit original research papers, review articles, short reports, or case studies are considered for publication in our Multidisciplinary Journals.

American Journal of Public Health Research
DOI: 10.12691/ajphr-1-1-3

The Implementation of a Tele-Homecare System with Service Oriented Architecture and HL7 Message Transmission Standard
Ching-Sung Wang

American Journal of Medical and Biological Research
DOI: 10.12691/ajmbr-1-1-2

The Influence of Ethanol on Pyruvate Kinases Activity in Vivo, in Vitro, in Silico
Lelevich Sergey Vladimirovich, Khrustalev Vladislav Victorovich, Barkovsky Eugene Victorovich, Shedogubova Tatyana Aleksandrovna

American Journal of Medical Sciences and Medicine
DOI: 10.12691/ajmsm-1-1-1

Clinical and Histological Features in Wegener Granulomatosis
Li Cavoli Gioacchino, Passantino Rita, Bono Luisa, Tortorici Calogera, Ferrantelli Angelo, Giammarresi Carlo, Rotolo Ugo

American Journal of Infectious Diseases and Microbiology
DOI: 10.12691/ajidm-1-1-2

The Curse of Lymphatic Filariasis: Would the Continual Use of Diethylcarbamazine Eliminate this Scourge in Papua New Guinea?
Anne Lanham, Lillian Mwanri

We have released issues of some journals on February 2013.
American Journal of Public Health Research
American Journal of Medical Sciences and Medicine
American Journal of Medical and Biological Research
American Journal of Pharmacological Sciences
American Journal of Clinical Medicine Research
American Journal of Nursing Research
American Journal of Cancer Prevention
American Journal of Medicine Studies
American Journal of Infectious Diseases and Microbiology
American Journal of Cardiovascular Disease Research
American Journal of Biomedical Research
American Journal of Mechanical Engineering
American Journal of Microbiological Research
Journal of Preventive Medicine
American Journal of Food and Nutrition
American Journal of Hypertension Research
American Journal of Sports Science and Medicine
Journal of Cancer Research and Treatment
American Journal of Zoological Research
Journal of Biomedical Engineering and Technology
American Journal of Microbiological Research
Biomedical Science and Engineering

We are pleased to announce that submissions are now being accepted for peer review for all the journals across all our subject areas in SciEP.

Please submit your manuscript via our online submission system:
http://www.sciepub.com/author/signin

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Sprue-Like and Other Intestinal Diseases in the Common Variable Immunodeficiency (Cvid) Spectrum

Hugh James Freeman

Department of Medicine (Gastroenterology), University of British Columbia, Vancouver, BC, Canada

Abstract: Many forms of immunodeficiency have been described. There may be about 150 different types, some with inherited or genetic causes, some with recognized specific molecular defects. Most can be classified as affecting the humoral or cellular, sometimes both, immune systems. In adults, the most common symptomatic form, albeit rare, is common variable immunodeficiency, or CVID. In recent years, it has also been suggested that rather than a single disease, CVID represents a heterogeneous group marked by panhypogammaglobulinemia and variable clinical features. In most, intestinal symptoms predominate, including, but not limited to sprue-like intestinal disease, a disorder that fails to respond to a gluten-free diet. Also, several types of colonic disease may occur similar to ulcerative colitis, Crohn’s disease and, most recently reported, collagenous colitis. Treatment of these disorders remains largely empirical and based on disease seen in the absence of CVID. Added molecular genetic studies are needed to more fully characterize the immune defects in CVID and, ultimately, to provide more evidence-based treatments.

Keywords: immunodeficiency, common variable immune deficiency, celiac disease, sprue-like intestinal disease

Received November 14, 2024; Revised December 16, 2024; Accepted December 22, 2024

Citation: Hugh James Freeman, Sprue-Like and Other Intestinal Diseases in the Common Variable Immunodeficiency (Cvid) Spectrum. International Journal of Celiac Disease, 12 (1). 19-21. January 2024. doi:10.12691/ijcd-12-1-4

1. Introduction

The primary immunodeficiency syndromes refer to an increasingly large and heterogeneous group of disorders that now number more than 150, many being inherited or genetically-based, some due to specific intrinsic defects in the immune system [1,2,3,4,5,6]. In recent decades, much added information has appeared with most immunodeficiency syndromes being popularly classified as largely humoral (B cell), some cellular (T cell), or both. The most common symptomatic form of primary immunodeficiency disease identified in adults, although still very rare, is common variable immunodeficiency (CVID), or, alternatively labeled, late-onset immunodeficiency. Rather than a single disease, some have characterized CVID as a “collection of hypogammaglobulinemic syndromes resulting from various molecular (genetic) defects” and “variable” because of its numerous heterogeneous clinical manifestations. However, in most, respiratory and/or intestinal symptoms predominate. Indeed, since the intestinal mucosa contains more immunological cells than any other organ system, it may be anticipated that significant intestinal changes would occur during its long-term natural history, especially in the presence of an immunodeficiency disorder.

2. Prevalence and Clinical Features

Estimates for prevalence of CVID have ranged from 1 in 25,000 to 1 in 50,000 [2,3]. Although it has been suggested that genetic factors play a role, the pathogenesis of CVID remains unclear despite decades of research investigation and definition of a number of specific gene mutations in development of B-cells [1]. Interestingly, CVID patients commonly have a first-degree family member with an immunodeficiency syndrome, such as IgA deficiency (i.e., about 20%) so inherited factors are likely candidates in performing a critical role in onset and progression of the disease [3].

Most of these patients present clinically with repeated upper and lower bacterial respiratory tract infections, sometimes leading to bronchiectasis along with a high frequency of gastrointestinal infections. Other major clinical features include autoimmune diseases, particularly immune thrombocytopenic purpura or autoimmune hemolytic anemia. Granulomatous and lymphoid infiltrative disorders may also occur along with an enhanced risk of malignancy [4].

3. Diagnosis and IgG Infusions

Diagnosis of CVID is generally based on quantified reductions in serum immune globulin (IgG, IgA and/or IgM) levels along with reduced, even absent, antibody responses to vaccines made with tetanus or diphtheria toxoid, Hemophilus influenza type b conjugate along with measles, mumps, rubella and pneumococcal polysaccharide vaccines. Others [7] have historically included lymphocyte transformation in vitro having markedly reduced responses to phytohemagglutinin, conconavalin A and pokeweed mitogen [8,9]. In addition, skin testing for delayed hypersensitivity may be impaired to purified protein derivatives, mumps, streptokinase-streptodornase and Candida. Finally, sensitivity to dinitrochlorobenzene may be impaired despite repeated applications [10] along with reduced formation of T-cell rosettes [11]. Together, these findings implicate a defective B-cell response (and also T-cell) in the pathogenesis of its immunological reaction to most infections. Interestingly, patients fail to also

produce antibodies to transglutaminase, endomysium or gliadin [12]. Most patients are initially diagnosed in the third to fifth decades, sometimes later, but, in retrospect, even after diagnosis, most have had previous recurrent symptoms, often over many years. Treatment with IgG infusions were historically used and may have been helpful, however, limited numbers with CVID make definitive recommendations difficult, particularly for such a heterogeneous disorder and further evaluation in future seems warranted.

4. Sprue-like Intestinal Disease

The high frequency (i.e., up to 60% or more) of intestinal changes in CVID, especially in those with chronic or persistent diarrhea, were noted from the outset, even dating back to its earliest recognition and description [3,4,5,6].

A commonly reported finding in mucosal biopsy material, particularly from the small intestine, has been the distinctive absence or a remarkable reduction in

mucosal (lamina propria) plasma cells [13]. However, this needs more critical evaluation since some have normal plasma cell numbers. These changes may also be reported in biopsies from stomach, colon or rectum. In the small bowel, biopsy changes may have a superficially similar appearance to celiac disease with villous flattening as in so-called “sprue-like intestinal disease”. An improved histopathological response to a strict gluten-free diet fails to occur as reflected in careful histopathological studies with repeated and sequential biopsies [7]. In some with CVID, however, crypt epithelial mitotic figures may be reduced in numbers (i.e., hypoplastic crypts) in contrast to the hyperplastic crypt epithelium of celiac disease. As well, the mucosal lesion is often associated with diminished serum IgG, IgA and IgM levels. In addition, trophozoites (and cysts) of Giardia lamblia may be commonly detected in biopsies along with other bacterial and viral agents (eg., cytomegalovirus) [7]. These infectious agents may, in part, also contribute to the some of the histopathologic changes observed. Often, the resultant diarrhea, malabsorption and/or steatorrhea associated with giardiasis may be responsive to treatment courses of metronidazole, but sometimes repeated courses of the antibiotic may be required to eradicate organisms as demonstrated in follow-up biopsy material. In addition to mucosal architectural changes, some patients may develop extensive, benign-appearing lymphoid nodular hyperplasia. This may occur throughout the intestinal tract, particularly in small intestine, but in some, also diffusely in stomach and large intestine.

Massive involvement may sometimes result in intestinal intussusception and obstruction. Others have suggested that definitive evidence for presentation with lymphoma or, specifically, progression to lymphoma is still required [4,14].

5. Inflammatory Bowel Diseases

Another reported presentation of CVID is the development of inflammatory bowel disease, superficially resembling Crohn’s disease or ulcerative colitis. In some, presentation with diarrhea and/or weight loss may occur similar those presenting with small bowel mucosal changes. Biopsy specimens from the large bowel mucosa have also been reported to show an absence or paucity of lamina propria plasma cells [12], an increase in intra-epithelial lymphocytes, altered crypt architecture with occasional sporadic mucosal granulomas and giant cells. In addition, histopathological appearances of graft-versus-host disease may occur [12].

For most patients, immunoglobulin infusions may limit infections but the colitis persists [12]. Most have been treated with similar pharmacological and biological agents compared to types of colitis (without immunodeficiency) but evidence to support their use is limited, largely in case reports. Moreover, in those with significant T-cell defects treated with steroids, immunosuppressant drugs or biological agents (eg., infliximab), there may be a high risk for other opportunistic infections.

In recent years, CVID has also been associated with rare reports of collagenous infiltration in the mucosa [14,15,16,17,18], extending the usual list of enumerated gastrointestinal mucosal histopathological changes described in most reports. In one recent clinical series [18], a paucity of plasma cells was not evident in most patients. Of interest, most patients with CVID and collagenous colitis were usually under age 50 years, much different from the typical older age spectrum of patients with collagenous colitis, but without CVID. It is conceivable that this simply reflects a form of early mortality bias with CVID so collagenous colitis would not have sufficient time to appear and be recognized.

6. Summary

In summary, CVID is a rare immunological disorder of unknown cause, usually presenting with recurrent respiratory and intestinal infections in middle-aged and more senior adults. Perhaps, 20% have a family history of IgA deficiency. In small bowel, changes of sprue-like intestinal disease may be present with histologic features reminiscent of celiac disease but no response occurs with a strict gluten-free diet. In colon, a variety of different patterns of inflammatory bowel disease have been reported, including ulcerative colitis-like disease, Crohn’s-like disease and, most recently, collagenous colitis. Most often, the prescribed treatments have been similar to disease in the absence of CVID along with gamma-globulin infusions. Further studies are needed to more optimally describe and classify the different forms of CVID, their specific clinical manifestations and their treatment.

References

[1]   | Agarwal S, Mayer L. Diagnosis and treatment of gastrointestinal disorders in patient with primary immunodeficiency. Clin Gastroenterol Hepatol 2013; 11: 1050-1063.

[2]  
Bousfiha A, Moundir A, Tangye SG, Picard C, Jeddane L, Al-Herz W, Rundles CC, Franco JL, Holland SM, Klein C, Morio T, Oksenhendler E, Puel A, Puck J, Seppanen MR, Somech R, Su HC, Sullivan KE, Torgerson TR, Meyts I. The 2022 update of IUIS phenotypical classification of human inborn errors of immunity. J Clin Immunol 2022; 42: 1508-1520.

[3]   | Hammarstrom L, Vorechovsky I, Webster D. Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID). Clin Exp Immunol 2000; 120: 225-231.
[4]   | Resnick ES, Moshier EL, Godbold JH, Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood 2012; 119: 1650-1657.
[5]   | Ruschel MA, Vagar S. Common variable immunodeficiency. NCBI Bookshelf, National Library of Medicine, National Institutes of Health, Stat Pearls Publishing, Treasure Island, Florida, 2023 [NBK549787].
[6]   | Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol 1999; 92: 34-48.
[7]   | Freeman HJ, Shnitka TK, Piercey JR, Weinstein WM. Cytomegalovirus infection of the gastrointestinal tract in a patient with late-onset immunodeficiency syndrome. Gastroenterology 1977; 73: 1397-1403.
[8]   | Foad BS, Adams LE, Yamauchi Y, Litwin A. Phytomitogen responses of peripheral blood lymphocytes in young and older subjects. Clin Exp Immunol 1974; 17: 657-664.
[9]   | Hagen C, Froland A. Analysis of variation in lymphocyte response to PHA in normal subjects. Acta Pathol Microbiol Scand [B] 1973; 81: 253-258.
[10]   | Eilber FR, Mizze JA, Morton DL. Sequential evaluation of general immune competence in cancer patients: correlation with clinical course. Cancer 1975; 35: 660-665.
[11]   | Weiner MS, Bianco C, Nussenzweig V. Enhanced binding of neuraminidase-treated sheep erythrocytes to human T-lymphocytes. Blood 1973; 42: 939-946.
[12]   | Agarwal S, Cunningham-Rundles C. Gastrointestinal manifestations and complications of primary immunodeficiency disorders. Immunol Allergy Clin North Am 2019; 39: 81-94.
[13]   | Perera DR, Weinstein WM, Rubin CE. Symposium on pathology of the gastrointestinal tract—-Part II. Small intestinal biopsy. Hum Pathol 1975; 6: 157-217.
[14]   | Washington K, Stenzel TT, Buckley RR, Gottfried MR. Gastrointestinal pathology in patients with common variable immunodeficiency and X-linked agammaglobulinemia. Am J Surg Pathol 1996; 20: 1240-1252.
[15]   | Byrne MF, Royston D, Patchett SE. Association of common variable immuno-deficiency with atypical collagenous colitis. Eur J Gastroenterol Hepatol 2003; 15: 1051-1053.
[16]   | Freeman HJ. Collagenous mucosal inflammatory disorders of the gastrointestinal tract. Gastroenterology 2005; 129: 338-350.
[17]   | Narsal T, Su H, Braxton D, Gupta S. Collagenous gastritis in primary selective IgM deficiency: transition to EBV+ gastric adenocarcinoma. Case Rep Immunol 2021; 5574944.
[18]   | Mandaliya R, Burkart AL, DiMarino AJ, Rattan S, Cohen S. Association between common variable immunodeficiency and collagenous infiltrative disorders of the gastrointestinal tract: a series of four patients. Indian J Gastroenterol 2016; 35: 133-138.