Basics
Description
- Common variable immunodeficiency is the most common clinically important primary immunodeficiency syndrome, characterized by
- Low IgG, IgA, and/or IgM
- Recurrent infections
- A wide spectrum of immunologic abnormalities, including autoimmune disease, inflammatory conditions, and the development of lymphomas
- Other terminology for this disease include the following:
- Acquired hypogammaglobulinemia
- Adult-onset hypogammaglobulinemia
- Dysgammaglobulinemia
- Common variable hypogammaglobulinemia
- Diagnosis of exclusion, requiring low IgG and variable reduction in IgA and/or IgM, impaired specific antibody responses
Epidemiology
- Prevalence is estimated to be 1 in 25,000 to 1 in 66,000 in the general population.
- Can present at any age
- Most diagnosed between 20 and 40 years old
- Diagnosis is usually made several years after the onset of recurrent infections (pneumonia, sinusitis, otitis).
- A subgroup of children has been described in which the onset of disease was most often <5 years of age. This group was characterized by a relapsing and remitting course in which autoimmune disease predominated.
- About 20-25% of patients with common variable immunodeficiency have 1 or more autoimmune conditions at time of diagnosis.
- Affects males and females equally
Risk Factors
Genetics
- Complex genetics, likely multifactorial
- Rare recessive mutations described in
- T-cell inducible costimulatory (ICOS) in one kindred, <1% of patients
- CD19 in a few unrelated families
- B-cell activating factor (BAFF)
- CD20 and CD81
- Transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI, TNFRSF13B) in 8% of patients, associated with autoimmunity and lymphoid hyperplasia; heterozygous mutation more common than homozygous; significance not clear due to similar mutation found in healthy family members
- IgA deficiency more likely in offspring of parents with common variable immunodeficiency
- Incidence of IgA deficiency, autoimmune disease, and malignancies is increased in family members of patients with common variable immunodeficiency.
Pathophysiology
- Main characteristic is hypogammaglobulinemia.
- Impaired immunoglobulin and specific antibody production despite normal B cell numbers
- Often increased proportion of immature B cells
- Deficiency of class-switched memory B cells associated with more complex disease (autoimmunity, granulomatous disease, hypersplenism, and lymphoid hyperplasia)
- Functional defects of both B and T lymphocytes are described.
Etiology
- The primary immunologic defect(s) leading to this syndrome is unknown.
- Multiple defects have been associated with common variable immunodeficiency, including the following:
- Lack of somatic mutation within variable region genes
- Lack of memory B cells
- Impaired maturation, IL-12 secretion, and upregulation of costimulatory molecules by antigen-presenting cells may impair T cells, which are important for providing help to B cells for antibody production.
- Toll-like receptor 9 (TLR9) response and expression by B cells may also be impaired. TLR signaling pathways are being investigated for their potential role in pathogenesis of common variable immunodeficiency.
- Some genetic defects have been described but do not account for the majority of cases.
Diagnosis
History
- Recurrent sinopulmonary infections, especially sinusitis and pneumonia, with encapsulated bacteria
- Autoimmune diseases such as autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, thyroid disease, and chronic active hepatitis
- Localized or systemic granulomatous disease that can be diagnosed years before low IgG is discovered. Lungs, spleen, and lymph nodes are most commonly affected; can be misdiagnosed as sarcoidosis
- Persistent diarrhea of infectious (e.g., Giardia lamblia) or noninfectious causes
- Inflammatory bowel disease-like disorder in 6-10% of patients
- Noninfectious, diffuse pulmonary complications described as granulomatous-lymphocytic interstitial lung disease (GLILD) exhibit granulomatous and lymphoproliferative histologic patterns (lymphocytic interstitial pneumonia [LIP], follicular bronchiolitis, and lymphoid hyperplasia).
- Severe or unusual viral infections with herpes simplex, cytomegalovirus, and varicella, such as pneumonitis, hepatitis, or encephalitis. Chronic meningoencephalitis can be seen with enteroviral infection.
Physical Exam
- Evaluation should focus on the presence of infection.
- 30% of patients will have lymphadenopathy and/or splenomegaly.
Diagnostic Tests & Interpretation
Lab
- IgG, IgA, IgM below age-appropriate norms
- CBC with differential: Examine smear for evidence of hemolysis in autoimmune hemolytic anemia.
- Autoimmune antibody screen: antinuclear antibody, autoantibody panel
- Stool culture for bacteria and ova/parasites to evaluate chronic diarrhea
- Isohemagglutinins as well as functional antibody titers to bacterial antigens such as tetanus, diphtheria, and pneumococcus are usually low to absent.
- Spirometry may be helpful in following chronic lung disease.
- Mitogen/antigen stimulation studies will help assess lymphocyte function.
- T- and B-lymphocyte enumeration by flow cytometry
- B-cell phenotyping becoming more available
- Absent B lymphocytes in males suggests X-linked agammaglobulinemia rather than common variable immunodeficiency.
- Appropriate cultures based on site of infection
Imaging
Chest and sinus x-ray studies/CT scans may be warranted for evaluation of bronchiectasis and chronic disease.
Diagnostic Procedures/Other
- GI endoscopy with biopsies for cases of idiopathic persistent diarrhea
- Lymph node biopsy in suspected malignancy
Differential Diagnosis
- Other primary antibody deficiency disorders: X-linked agammaglobulinemia, transient hypogammaglobulinemia of infancy, and selective antibody deficiency
- Severe malabsorption with protein-losing enteropathy
- HIV infection
- Chronic lung disease: cystic fibrosis, immotile cilia syndrome, and α1-antitrypsin deficiency
- Primary autoimmune diseases: immune idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, systemic lupus erythematosus, thyroiditis
Treatment
Medication
First Line
Immunoglobulin replacement therapy
Second Line
Antibiotics as needed for infection may also be used as adjunct to immunoglobulin replacement as prophylaxis.
Additional Treatment
General Measures
- Monthly IV immunoglobulin replacement
- Starting dose is usually 400-600 mg/kg/month IV to maintain a trough IgG level of at least 500 mg/dL or FDA-approved formulation(s) for SC administration, given weekly or biweekly following the establishment of intravenous immunoglobulin (IVIG) dosage.
- Appropriate antibiotics for acute infections
- Prophylactic antibiotics may be helpful in chronic/recurrent infections.
- Cautious use of corticosteroids may be necessary in the treatment of GI and autoimmune manifestations.
Issues for Referral
- Autoimmune manifestations
- GI: chronic abdominal pain or signs of possible lymphoid hyperplasia
Inpatient Considerations
Nursing
- Supervision during IVIG administration
- Monitor for side effects of therapy.
- Have anaphylaxis medications available.
Ongoing Care
Follow-up Recommendations
- Close and frequent follow-up is warranted for patients with severe, recurrent symptoms. It may be as frequent as monthly, depending on symptoms.
- Signs and symptoms suggesting malignancy (e.g., persistent adenopathy in absence of infection, significant weight loss, or abdominal mass) should be evaluated expeditiously.
- Abdominal pain may indicate infection or lymphoid hyperplasia.
Patient Monitoring
CBC with differential, ALT, creatinine, IgG level
Patient Education
Several Web sites available to patients and families:
- Immune Deficiency Foundation: http://primaryimmune.org
- International Patient Organisation for Primary Immunodeficiencies: www.ipopi.org
- The Jeffrey Modell Foundation: www.jmfworld.org
- National Institute of Allergy and Immunology: www.niaid.nih.gov
Prognosis
- Immunoglobulin replacement therapy, prophylactic antibiotics when necessary, and close follow-up by immunology have greatly improved the overall prognosis.
- The newer challenge with this disease is detection and management of autoimmune and other disease-associated complications.
- Phenotypic classifications based on memory B cell numbers divide patients into two major categories: those that do well with IgG replacement alone and others with more likely autoimmune and granulomatous complications.
Complications
- Autoimmune disease in 20% of common variable immunodeficiency patients; most common are autoimmune hemolytic anemia and idiopathic thrombocytopenia purpura.
- GI complications include chronic diarrhea, malabsorption, and weight loss. Inflammatory bowel disease and Helicobacter pylori infection have also been observed.
- Granulomatous infiltrations may mimic sarcoidosis.
- Lymphoproliferative disease: Overall risk is 8-10%. The most common are lymphomas, usually non-Hodgkin lymphoma, well differentiated, mostly Epstein-Barr virus negative.
- Chronic sinusitis and lung disease with abnormal pulmonary function tests
- Progressive decline in T-lymphocyte function
Additional Reading
- Agarwal S, Cunningham-Rundles C. Autoimmunity in common variable immunodeficiency. Curr Allergy Asthma Rep. 2009;9(5):347-352. [View Abstract]
- Ballow M. Primary immunodeficiency disorders: antibody deficiencies. J Allergy Clin Immunol. 2002;109(4):581-591. [View Abstract]
- Brant D, Gershwin M. Common variable immune deficiency and autoimmunity. Autoimmun Rev. 2006;5(7):465-470. [View Abstract]
- Castigli E, Geha R. Molecular basis of common variable immunodeficiency. J Allergy Clin Immunol. 2006;117(4):740-746. [View Abstract]
- Cunningham-Rundles C. How I treat common variable immunodeficiency. Blood. 2010;116(1):7-15. [View Abstract]
- Cunningham-Rundles C. Immune deficiency: office evaluation and treatment. Allergy Asthma Proc. 2003;24(6):409-415. [View Abstract]
- Moratto D, Gulino AV, Fontana S, et al. Combined decrease of defined B and T cell subsets in a group of common variable immunodeficiency patients. Clin Immunol. 2006;121(2):203-214. [View Abstract]
- Orange JS, Glessner JT, Resnick E, et al. Genome-wide association identifies diverse causes of common variable immunodeficiency. J Allergy Clin Immunol. 2011;127(6):1360-1367.e6. [View Abstract]
- Park JH, Levinson AI. Granulomatous-lymphocytic interstitial lung disease (GLILD) in CVID. Clin Immunol. 2010;134(2):97-103. [View Abstract]
- Salzer U, Grimbacher B. Common variable immunodeficiency: the power of costimulation. Semin Immunol. 2006;18(6):337-346. [View Abstract]
- Simonte S, Cunningham-Rundles C. Update on primary immunodeficiency: defects of lymphocytes. Clin Immunol. 2003;109(2):109-118. [View Abstract]
- Warantz K, Schlesier M. Flowcytometric phenotyping of common variable immunodeficiency. Cytometry B Clin Cytom. 2008;74(5):261-271. [View Abstract]
Codes
ICD09
- 279.06 Common variable immunodeficiency
- 279.00 Hypogammaglobulinemia, unspecified
- 279.10 Immunodeficiency with predominant T-cell defect, unspecified
- 279.06 Common variable immunodeficiency
ICD10
- D83.0 Common variable immunodeficiency with predominant abnormalities of B-cell numbers and function
- D83.2 Common variable immunodeficiency with autoantibodies to B- or T-cells
- D83.9 Common variable immunodeficiency, unspecified
- D83.1 Com variab immunodef w predom immunoreg T-cell disorders
- D83.8 Other common variable immunodeficiencies
SNOMED
- 23238000 common variable agammaglobulinemia (disorder)
- 191011000 Common variable immunodeficiency with predominant abnormalities of B-cell numbers and functions (disorder)
- 191013002 Common variable immunodeficiency with autoantibodies to B- or T-cells (disorder)
- 191012007 Common variable immunodeficiency with predominant immunoregulatory T-cell disorders (disorder)
FAQ
- Q: What is the life expectancy of patients with the diagnosis of common variable immunodeficiency?
- A: Because the clinical presentations and symptoms are variable, it is difficult to predict the life expectancy in individual patients. IVIG replacement, in addition to antibiotic therapy, has greatly improved the outlook for these patients. However, despite adequate therapy, a large percentage of patients with common variable immunodeficiency have a progressive decline in immune function. Major morbidity and mortality usually result from the associated complications of malignancy, chronic lung disease, and severe autoimmune disease. In one study, the mortality is estimated at 23-27% over a median follow-up of 7 years (0-25 years). The 20-year survival after diagnosis for males is 64% and for females 67% versus 92% and 94%, respectively, for the general population. Main causes of death include respiratory complications, granulomatous disease of organs, liver disease, malnutrition due to GI pathology, uncontrolled autoimmune manifestations, and lymphoma.
- Q: Should patients with common variable immunodeficiency receive live viral vaccines?
- A: In general, patients receiving IVIG replacement therapy do not require any vaccinations. Live viral vaccines should be avoided in these patients, especially if they have deteriorating immune function.
- Q: Can common variable immunodeficiency be diagnosed prenatally?
- A: Because there are no clear genetic inheritance patterns, prenatal diagnosis is unavailable.