Colon
Noninfectious colitis
Common variable immunodeficiency (CVID)
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PubMed Search: Colon common variable immunodeficiency
Table of Contents
Definition / general | Essential features | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Case reports | Treatment | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Van Treeck BJ, Hartley C. Common variable immunodeficiency (CVID). PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/coloncvid.html. Accessed April 25th, 2024.
Definition / general
- Common variable immunodeficiency disorders (CVID) are uncommon conditions of primary B cell dysfunction or T cell impairment leading to hypogammaglobulinemia and IgA or IgM deficiency
- Immunoglobulin deficiency elicits an immunodeficiency state with increased susceptibility to recurrent infections, inflammatory diseases, autoimmune diseases and malignancy (J Allergy Clin Immunol Pract 2016;4:38)
Essential features
- CVID is due to B cell impairment causing hypogammaglobulinemia with either IgA or IgM deficiency
- Infectious, inflammatory, autoimmune and malignant gastrointestinal manifestations can occur in approximately 15% of patients with CVID
- CVID histology in the colon may include one or more of the following: inflammatory bowel disease-like pattern, microscopic colitis pattern, granulomatous inflammation, increased apoptosis, lymphoid aggregates and infections such as cytomegalovirus and herpes simplex virus
- Presence of plasma cells does not rule out CVID because approximately 33% of CVID cases will have plasma cells
Epidemiology
- Second most common immunodeficiency disorder after selective IgA deficiency (Am J Surg Pathol 2007;31:1800)
- True incidence or prevalence is unknown but estimated prevalence is 1:100,000 to 1:10,000 in the general population (J Allergy Clin Immunol Pract 2016;4:38, Br J Haematol 2009;145:709)
- Age of onset varies from childhood to adulthood with a bimodal peak age of onset in the first and third decades of life (J Allergy Clin Immunol Pract 2016;4:38, J Allergy Clin Immunol 2014;134:116, Clin Immunol 1999;92:34)
- Males and females are equally affected (J Allergy Clin Immunol 2014;134:116)
Sites
- All organ systems including the colon can be affected (J Allergy Clin Immunol Pract 2016;4:38)
Pathophysiology
- All patients have B cell loss of function due to an intrinsic defect or lack of extrinsic activation by another immune cell (J Allergy Clin Immunol Pract 2016;4:38)
- T cell loss of function may also contribute to B cell impairment (J Allergy Clin Immunol Pract 2016;4:38)
- B cell impairment leads to reduced or absent IgG, IgA or IgM immunoglobulin levels (J Allergy Clin Immunol Pract 2016;4:38)
- Reduced immunoglobulin levels leads to increased susceptibility to recurrent infections especially of the sinopulmonary and gastrointestinal tract
- Gastrointestinal tract involvement is a manifestation of CVID due to its large surface area and presence of numerous immunoglobulin producing plasma cells; if the plasma cells become dysfunctional, immune dysregulation and infection can result
- Altered immunity can also lead to infection, autoimmune disease, inflammatory disease and malignancy
Etiology
- > 98% of cases do not have an identifiable etiology (J Allergy Clin Immunol Pract 2016;4:38)
- Predominantly sporadic genetic disease with 5 - 25% of cases being familial (J Allergy Clin Immunol Pract 2016;4:38)
- Familial cases are most commonly inherited in an autosomal dominant pattern (J Allergy Clin Immunol Pract 2016;4:38)
- Examples of genes involved in CVID include CD19, CD20, CD21, CD27, CD81, CTLA4, ICOS, IL21 and IL21R (J Allergy Clin Immunol Pract 2016;4:38)
Clinical features
- Infectious, inflammatory, autoimmune and malignant gastrointestinal tract manifestations can occur in approximately 15% of individuals with CVID (Blood 2012;119:1650)
- Symptoms of gastrointestinal tract manifestations in CVID patients include: weight loss, anemia, chronic diarrhea, chronic abdominal discomfort, bloody diarrhea (Dig Dis Sci 2007;52:2977, Am J Gastroenterol 2019;114:648)
- Colonoscopy and biopsy reports from 63 Finnish patients with CVID identified (Am J Gastroenterol 2019;114:648):
- Nonspecific colitis in 14%
- Ulcerative colitis in 8%
- Microscopic colitis in 10%
- Crohn's disease 2%
- Colonic polyps (types not specified) in 30%
- GI malignancies (types not specified) in 3%
- Cytomegalovirus colitis in 2%
- Herpes simplex virus colitis in 2%
Diagnosis
- CVID is diagnosed in the proper clinical situation with the following criteria (J Allergy Clin Immunol Pract 2016;4:38):
- Presentation with immunodeficiency at greater than 2 years of age
- Decreased serum IgG (≥ 2 standard deviations below the mean for age) and decreased serum IgA or IgM
- Absent isohemagglutinins or inability to develop antibodies to vaccines
- Acquired hypogammaglobulinemia is ruled out
- Colonoscopy and biopsy are helpful in the assessment of lower gastrointestinal tract involvement by inflammatory, autoimmune, infectious and malignant sequelae of CVID
Laboratory
- Low serum IgG (≥ 2 standard deviations below the mean for age)
- Low serum IgA or IgM
- Circulating B cells may be normal (54% of cases), increased (19% of cases), decreased (12% of cases) or undetectable (12% of cases) (Blood 2008;112:277)
- Circulating T cells and natural killer cells are usually within normal limits (Clin Immunol 1999;92:34)
- Important to remember: serology may be falsely negative or falsely positive due to the patient's inability to mount a humoral response and due to intravenous immunoglobulin (IVIG) administration, respectively
Case reports
- 31 year old man with nodular lymphoid hyperplasia of stomach, small intestine and large intestine mimicking familial adenomatous polyposis (Indian J Pathol Microbiol 2009;52:530)
- 39 year old man with CVID associated with inflammatory bowel disease and diabetes mellitus type 1 (Clin Med Case Rep 2009;2:67)
- 69 year old woman with CVID and herpes simplex type 1 colitis (Eur J Gastroenterol Hepatol 2006;18:541)
- A case series of 4 patients, ages 19 - 69, with CVID associated with collagenous colitis, gastritis and sprue (Indian J Gastroenterol 2016;35:133)
Treatment
- IVIG may be insufficient to treat inflammatory and autoimmune conditions associated with CVID (J Allergy Clin Immunol Pract 2016;4:38)
- Infections, autoimmune diseases, inflammatory diseases and malignancies need to be treated when they are identified
Microscopic (histologic) description
- Numerous colonic histologic patterns can be seen in CVID including the following (Am J Surg Pathol 2007;31:1800, Am J Gastroenterol 2019;114:648):
- Ulcerative colitis-like pattern and Crohn's disease-like pattern
- Some cases may have active colitis but without features of chronicity such as crypt atrophy / loss and crypt branching
- Lymphocytic colitis pattern and collagenous colitis pattern
- Unclear whether these patterns of injury are mimicking or are true cases of lymphocytic colitis and collagenous colitis
- Granulomatous inflammation
- Etiology may be infectious or inflammatory, fungal and mycobacterial stains are important to rule out infection
- Viral infection (CMV, HSV, etc.)
- Important to thoroughly evaluate for viral inclusions as serology may be negative due to hypoglobulinemia associated with CVID
- Increased apoptosis can occur in colonic epithelium mimicking graft versus host disease, viral infection (CMV) and drug effect (mycophenolate)
- Lymphoid aggregates are a common finding in the colon of CVID patients
- Ulcerative colitis-like pattern and Crohn's disease-like pattern
- Presence of plasma cells does not rule out CVID as reduced plasma cells were identified in 63% of colonic CVID biopsies / resection specimens (Am J Surg Pathol 2007;31:1800)
Microscopic (histologic) images
Contributed by Benjamin J. Van Treeck, M.D and Christopher Hartley, M.D.
Lamina propria neutrophils
Absence of plasma cells
Increased crypt apoptosis
Mild active colitis
Reduced mucosal plasma cells
Increased lamina propria eosinophils
Increased lamina propria neutrophils
Mild to moderate active chronic colitis
CD138
Sample pathology report
- Colon, biopsy:
- Colonic mucosa with mild active chronic colitis, increased apoptosis and absence of plasma cells (evaluated with CD138); negative for dysplasia (see comment)
- Comment: These features are consistent with the patient’s history of common variable immunodeficiency. Clinicopathologic correlation is recommended.
Differential diagnosis
- Crohn's colitis:
- Reduced to absent plasma cells is not a feature of Crohn's colitis
- Common variable immunodeficiency disorders (CVID) injury pattern can mimic Crohn's disease to the extent that patients may be diagnosed with Crohn's disease prior to being diagnosed with CVID (Am J Surg Pathol 2007;31:1800)
- Clinical history of CVID is helpful in distinguishing Crohn’s colitis from CVID
- Ulcerative colitis:
- Reduced to absent plasma cells is not a feature of ulcerative colitis
- Clinical history of CVID is helpful in distinguishing ulcerative colitis from CVID
- Lymphocytic colitis:
- Reduced to absent plasma cells is not a feature of lymphocytic colitis
- Clinical history of CVID is helpful in distinguishing lymphocytic colitis from CVID
- Collagenous colitis:
- Reduced to absent plasma cells is not a feature of collagenous colitis
- Clinical history of CVID is helpful in distinguishing collagenous colitis from CVID
- Cytomegalovirus (CMV) colitis:
- Evaluate for CMV viral inclusions
- CMV immunohistochemical stain can be helpful
- CVID can coexist with CMV infection
- Herpes simplex virus (HSV) colitis:
- Evaluate for HSV viral inclusions
- HSV immunohistochemical stain can be helpful
- CVID can coexist with HSV infection
- Acute self limited colitis:
- Reduced to absent plasma cells is not a feature of acute self limited colitis
- Clinical history of CVID and microbiology tests are helpful in distinguishing acute self limited colitis from CVID
- Acute self limited colitis may coexist with CVID
- Lymphoma such as mantle cell lymphoma, follicular lymphoma and others:
- Clonal population of lymphocytes is not a feature of CVID
- CVID may predispose to lymphoma
- Graft versus host disease (GVHD):
- Clinical history of transplant is necessary to diagnosis GVHD
- Reduced to absent plasma cells is not a feature of GVHD
- Sarcoidosis:
- Clinical history may be helpful in differentiating sarcoidosis from CVID
- Sarcoidosis can coexist with CVID (Am J Surg Pathol 2007;31:1800)
Board review style question #1
A patient with chronic diarrhea, recurrent sinopulmonary infections and reduced serum IgG and IgA levels undergoes colonoscopy. The colonic biopsies demonstrate rare lamina propria plasma cells. Which one of the following statements is correct?
- Presence of rare plasma cells does not rule out the possibility of common variable immunodeficiency (CVID) in this patient and should be mentioned in the pathology report
- Presence of rare plasma cells is secondary to chronic diarrhea and is not related to common variable immunodeficiency (CVID) in this patient
- Presence of rare plasma cells rules out the possibility of common variable immunodeficiency (CVID) in this patient
- Presence of rare plasma cells should not be reported and a diagnosis of normal colonic mucosa should be included in the pathology report
Board review style answer #1
A. Presence of rare plasma cells does not rule out the possibility of common variable immunodeficiency (CVID) in this patient and should be mentioned in the pathology report
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Reference: Common variable immunodeficiency (CVID)
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Reference: Common variable immunodeficiency (CVID)
Board review style question #2
A patient with chronic diarrhea, recurrent sinopulmonary infections and reduced IgG and IgA levels is diagnosed with common variable immunodeficiency (CVID). Which of the following histologic patterns can be seen in colonic biopsies from patients with CVID?
- Inflammatory bowel disease-like pattern, increased apoptosis pattern, colonic mucosal prolapse-like pattern
- Inflammatory bowel disease-like pattern, increased apoptosis pattern, lymphocytic colitis pattern
- Inflammatory bowel disease-like pattern, increased apoptosis pattern, radiation induced colitis-like pattern
- Inflammatory bowel disease-like pattern, ischemic colitis-like pattern, lymphocytic colitis pattern
Board review style answer #2
B. Inflammatory bowel disease-like pattern, increased apoptosis pattern, lymphocytic colitis pattern
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Reference: Common variable immunodeficiency (CVID)
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Reference: Common variable immunodeficiency (CVID)
