Definition/General
Introduction:
Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency in adults, characterized by hypogammaglobulinemia and recurrent infections
It represents a heterogeneous group of disorders with variable B cell dysfunction
The diagnosis is one of exclusion after ruling out other specific immunodeficiencies.
Origin:
Results from multiple genetic defects affecting B cell function and antibody production
Monogenic forms (20% cases): mutations in ICOS, CD19, CD20, CD21, CD81, BAFF-R, TACI, PIK3CD
Polygenic forms (80% cases): complex inheritance
Leads to impaired antibody responses and B cell dysfunction.
Classification:
Classified by clinical phenotypes: Infection-only phenotype
Autoimmune/inflammatory phenotype
Lymphoproliferative phenotype
Enteropathy phenotype
Granulomatous disease
Malignancy-associated
Based on EUROclass system.
Epidemiology:
Prevalence 1 in 25,000-50,000
Most common adult primary immunodeficiency
Peak onset 20-40 years
Slight female predominance
Family history in 20% cases
Variable clinical course.
Clinical Features
Presentation:
Recurrent sinopulmonary infections
Chronic diarrhea and malabsorption
Autoimmune manifestations
Lymphadenopathy and splenomegaly
Granulomatous disease
Increased malignancy risk.
Symptoms:
Recurrent pneumonia and bronchitis
Chronic sinusitis
Gastrointestinal infections
Autoimmune cytopenias
Arthritis
Granulomatous hepatitis
Lymphoma development.
Risk Factors:
Family history (20% cases)
Certain HLA types
Environmental triggers
Infections (EBV)
Autoimmune diseases
Immunosuppressive treatments.
Screening:
Immunoglobulin levels (low IgG, ±IgA/IgM)
Vaccine responses (impaired)
B cell subsets (flow cytometry)
T cell function
Genetic testing (selected cases)
Exclusion of other PIDs.
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Gross Description
Appearance:
Bone marrow aspirate shows variable cellularity
B cells present but functionally abnormal
Plasma cells reduced or absent
Normal T cells and other lineages
Reactive changes possible.
Characteristics:
Variable B cell numbers
Reduced plasma cell differentiation
Normal bone marrow architecture
Possible granulomatous infiltrates
Reactive lymphoid aggregates.
Size Location:
Lymphadenopathy common
Splenomegaly frequent
Hepatomegaly (granulomatous)
Normal bone marrow distribution
Multi-organ involvement.
Multifocality:
Systemic immune dysfunction
Variable organ involvement
Progressive complications
Autoimmune manifestations
Malignancy development.
Microscopic Description
Histological Features:
Variable B cell numbers (normal to reduced)
Reduced plasma cells
Normal T cells
Possible granulomatous infiltrates
Reactive changes in response to infections.
Cellular Characteristics:
B cells morphologically normal but functionally impaired
Reduced plasma cell differentiation
Normal T cell morphology and numbers
Increased activated lymphocytes
Granulomatous inflammation (subset).
Architectural Patterns:
Preserved bone marrow architecture
Variable lymphoid cellularity
Possible granuloma formation
Reactive follicular hyperplasia (lymph nodes)
No specific pattern.
Grading Criteria:
Diagnosis by hypogammaglobulinemia: IgG <7 g/L (adults)
Poor vaccine responses
Exclusion criteria met
Clinical manifestations present
B cell dysfunction demonstrated.
Immunohistochemistry
Positive Markers:
CD19 and CD20 show variable B cells
CD3 shows normal T cells
CD138 shows reduced plasma cells
CD68 marks macrophages (granulomas)
MPO shows normal granulopoiesis.
Negative Markers:
Immunoglobulin heavy chains reduced
Memory B cell markers often reduced
Plasma cell markers decreased
Viral markers variable.
Diagnostic Utility:
Demonstrates B cell dysfunction
Shows reduced plasma cells
Identifies granulomatous inflammation
Assesses T cell populations
Excludes other immunodeficiencies
Monitors disease progression.
Molecular Subtypes:
Monogenic CVID (specific mutations)
Polygenic CVID (complex)
EUROclass B+ (normal B cells)
EUROclass B- (reduced B cells)
Different phenotypes.
Molecular/Genetic
Genetic Mutations:
Monogenic forms (20%): ICOS, CD19, CD20, CD21, CD81, BAFF-R, TACI, PIK3CD, PIK3R1, PLCG2, NFKB1, NFKB2, IRF2BP2
Polygenic forms (80%): multiple loci
HLA associations
Copy number variants.
Molecular Markers:
Hypogammaglobulinemia (all isotypes)
Poor specific antibody responses
B cell dysfunction
Variable T cell abnormalities
Inflammatory markers elevated
Autoantibodies (subset).
Prognostic Significance:
Variable prognosis
Infection-only better outcome
Granulomatous disease more severe
Autoimmunity complicates management
Malignancy risk 50-fold increased
Early treatment improves outcomes.
Therapeutic Targets:
Immunoglobulin replacement (IVIG/SCIG)
Antimicrobial prophylaxis
Immunosuppression (autoimmune complications)
Rituximab (lymphoproliferation)
TNF inhibitors (granulomatous disease)
Supportive care.
Differential Diagnosis
Similar Entities:
X-linked agammaglobulinemia
Hyper-IgM syndromes
Good syndrome
Secondary immunodeficiency
Selective IgA deficiency
Specific antibody deficiency.
Distinguishing Features:
CVID: Variable B cells
CVID: Adult onset
CVID: Autoimmune features
XLA: Absent B cells
XLA: Early onset
HIGM: Elevated IgM
Good syndrome: Thymoma present
Secondary: Identifiable cause.
Diagnostic Challenges:
Excluding secondary causes
Identifying monogenic forms
Distinguishing from other PIDs
Phenotype classification
Prognosis prediction
Treatment selection.
Rare Variants:
Late-onset CVID
CVID with normal IgG
Granulomatous-lymphocytic interstitial lung disease
CVID-like disorder
Autoimmune-predominant.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Bone marrow aspirate and biopsy from [site], adequate for evaluation
Diagnosis
Common Variable Immunodeficiency
Classification
Classification: Primary immunodeficiency with B cell dysfunction
Bone Marrow Cellularity
Cellularity: [X]% for age, with variable B cell numbers and reduced plasma cells
Lineage Assessment
B cells: variable numbers, functionally impaired. Plasma cells: reduced. T cells: normal
Morphological Features
Shows variable B cell numbers with reduced plasma cell differentiation
Special Studies
Flow cytometry: recommend B cell subset analysis
Functional studies: vaccine responses, antibody levels
Genetic testing: consider in selected cases
Clinical Correlation
Findings consistent with common variable immunodeficiency
Final Diagnosis
Bone marrow showing B cell dysfunction consistent with common variable immunodeficiency