eMedicine Specialties > Dermatology > Allergy & Immunology

Common Variable Immunodeficiency

Author: Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Coauthor(s): Rohit M Modak, MD, MBA, Staff Physician, Department of Infectious Diseases, Virginia Hospital Center; Prema Modak, MD, Attending Physician, Department of Ophthalmology, Martinsburg West Virginia Veterans Affairs Medical Center
Contributor Information and Disclosures

Updated: Jun 12, 2009

Introduction

Background

Common variable immunodeficiency (CVID) is a disorder that involves the following: (1) low levels of most or all of the immunoglobulin (Ig) classes, (2) a lack of B lymphocytes or plasma cells that are capable of producing antibodies, and (3) frequent bacterial infections.

CVID is a common immune disorder and is, in fact, the most prevalent primary immunodeficiency. However, it is diverse, both in its clinical presentation and in the types of deficiency. Although decreased serum levels of immunoglobulin G (IgG) and immunoglobulin A (IgA) are characteristic, approximately 50% of patients with the deficiency also have diminished serum immunoglobulin M (IgM) levels and T-lymphocyte dysfunction. About 20% of those with CVID develop an autoimmune disease.1

The eMedicine Pediatrics article, Common Variable Immunodeficiency, may be of interest.

Pathophysiology

In patients with common variable immunodeficiency (CVID), numerous immune-system abnormalities are reported, the most common of which is defective antibody formation. Consequently, both humoral and cell-mediated lymphocytic responses are affected.

Changes in the humoral response

The basic pathophysiologic process in CVID is a simple failure in the differentiation of B lymphocytes. However, evidence shows that this defect in the pathway is not common among patients. One study showed that, when B lymphocytes were stimulated with pokeweed mitogen in vitro, plasma cells failed to differentiate, even in the presence of normal T cells. This finding suggests a defect in B-cell expression in surface molecules.

Such cellular deficits have been traced to the second messenger and translocation pathways of B cells. These deficits include problems with protein kinase C activation and tyrosine phosphorylation. Findings from other studies suggest the complete absence of IgG and IgA production, an increased rate of spontaneous apoptosis, impaired DNA repair, and the presence somatic mutations affecting B-cell regulation.

Changes in the cell-mediated response

A number of factors and cofactors stimulate Ig secretion from B cells harvested from patients with CVID. These factors include B-cell mitogens, soluble T-cell factors, specific B-cell differentiation factors, the Epstein-Barr virus, interleukin 2 (IL-2), interleukin 4 (IL-4), and interleukin 10 (IL-10). Perhaps the most potent stimulant is the CD40 ligand, which is expressed by activated CD4+ cells. In fact, in 40% of patients with CVID, the CD40 ligand is expressed in low levels on activated T cells. In these patients, decreased IL-2 production after T-cell receptor stimulation is also present.

A common defect is the response to antigens by CD4+ T lymphocytes. After immunization, some patients with CVID have decreased numbers of circulating responsive CD4+ T cells. Other patients have an increased number of CD4+ T cells, but they also have an increased rate of apoptosis of these cells. Signal transduction appears to be the primary defect in these T cells. Rezaei et al report on the meningococcal vaccination response in CVID patients. They suggest it may help define subgroups of patients, which may lead to better monitoring and new therapeutic strategies.2

Of all patients with CVID, 25-30% often have increased numbers of CD8+ T cells and a reduced CD4/CD8 ratio (<1). The cause is an increase in cyclic adenosine monophosphate levels and the increased activation of protein kinase A. On physical examination, patients with this subtype often have splenomegaly and bronchiectasis. In addition, 60% of patients with CVID have a diminished response to T-cell receptor stimulation and expression of receptors for IL-2, IL-4, interleukin 5 (IL-5), and interferon gamma. However, the T-cell receptors show no evidence of abnormality; in fact, genetic findings indicate normal heterogeneity of the genetic rearrangements. Therefore, most patients with CVID can be said to have antibody deficiency secondary to T-cell signaling abnormalities, as well as defective interactions between T and B lymphocytes. Laino et al report that the prevalence of distinct clinical complications of CVID is higher in patients with B- and T-cell abnormalities.3

Both the transient and permanent recovery of Ig production has been reported in both patients with HIV and in patients with hepatitis C infection. This finding may indicate that CVID is associated with potentially reversible defects in humoral and/or cellular immunoregulatory factors.

TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) mediates isotype switching in B cells. One series found that 4 of 19 unrelated individuals with CVID and 1 of 16 individuals with IgA deficiency had a missense mutation in 1 allele of TNFRSF13B (encoding TACI).4 TTACI mutations can result in CVID and IgA deficiency. Four genes have been documented to be mutated in CVID patients: ICOS, TNFRSF13B (encoding TACI), TNFRSF13C (encoding BAFF-R) and CD19.5 Heterozygous mutations in TNFRSF13B are also associated with CVID, whereas the other 3 genes are recessive.6,7

Autosomal dominant CVID has been linked to chromosome 4q.8 One study supports the existence of a disease-causing gene for autosomal dominant CVID/IgA deficiency on chromosome 4q. Other possible loci for dominant CVID genes are on chromosomes 5p and 16q.

Frequency

United States

The prevalence of common variable immunodeficiency (CVID) is approximately 1 case per 50,000 population.

International

The international prevalence is similar to that in the United States.

Mortality/Morbidity

  • A 20-year survival rate is 64% for male patients and 67% for female patients.
  • In general, the expected survival rate for male and female patients is 92% and 94%, respectively.
  • Death may result from various causes (see Complications).

Race

CVID does not show a predilection for any specific race.

Sex

CVID equally affects males and females.

Age

CVID can occur in infants, young children, adolescents, or even those aged 20-40 years or older.

  • CVID can become evident at any time from infancy to after the fourth decade of life.
  • Peaks of onset occur in children aged 1-5 years and in persons aged 16-20 years.
  • More than two thirds of patients are aged 21 years or older when CVID is diagnosed.

Clinical

History

Five distinct clinical phenotypes have been delineated for common variable immunodeficiency (CVID): no complications, autoimmunity, polyclonal lymphocytic infiltration, enteropathy, and lymphoid malignancy.9 In any patient with a past medical history of CVID, 3 complications must be considered: recurrent infections, autoimmune phenomena, and malignancy (see Physical).

Patients with CVID often have a history of recurrent infections.

  • The recurrent infections commonly affect the upper and lower respiratory tracts. Patients come to medical attention due to infectious diseases at the time of onset, the most common being otitis media, diarrhea, pneumonia, and sinusitis.10 Almost all have acute and recurrent infections.
  • Persistent diarrhea and malabsorption caused by Giardia lamblia infection occur in patients with CVID.
    • Symptoms generally resolve after treatment with metronidazole.
    • Infectious and autoimmune etiologies are the most likely causes for severe chronic diarrhea.
    • Malignancies of the gastrointestinal tract do not cause diarrhea.
  • Young children may fail to thrive because of the frequent infections or gastrointestinal tract disease.

Physical

Generally, the physical examination findings are correlated to the history, and they depend on the clinical presentation and specific organs involved.

Splenomegaly and generalized lymphadenopathy are present in many patients with common variable immunodeficiency (CVID).

  • Recurrent infections
    • Permanent damage to the bronchi may occur, resulting in bronchiectasis.
    • Common infective organisms include Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, and Staphylococcus aureus.
    • In some patients with CVID, uncommon infectious agents such as Pneumocystis carinii and Mycoplasma pneumoniae may be detected first.
    • In addition to pulmonary infection, M pneumoniae can also cause primary infection in the urinary tract and joints.
    • Infection with G lamblia may cause persistent diarrhea and malabsorption.
    • Recurrent infections with herpes simplex virus are reported. Herpes zoster infection may develop in as many as 20% of patients with CVID.
    • Enterovirus infection has been reported in association with CVID.11
  • Autoimmune phenomena
  • Malignancy
    • In patients with CVID, the risk of certain malignancies is high.
    • Lymphomas of a B-cell phenotype are of particular concern.
    • Malignancy is most likely associated with the Epstein-Barr virus.
    • The risk of gastric carcinoma is almost 50 times greater in patients with CVID than in other individuals.
    • Malignant melanomas are reported.
  • Dermatologic manifestations13
    • Alopecia areata and alopecia universalis may occur.14 Any time a person presents with recurrent infections and alopecia, CVID should be considered in the differential diagnosis. In one case study from the Hacettepe University in Turkey, Kiliç et al15 reported a 12-year-old boy who had recurrent respiratory tract infections and chronic diarrhea since age 2 years. At age 2.5 years, he had a bandlike localized loss of hair (alopecia areata), and 1 year later, he had lost all body hair. His sister had similar findings and died from a pulmonary infection at the age of 7 years. On further studies, the patient was found to have decreased serum levels of IgG, IgA, and IgM and an increased number of CD8 cells. In addition, a skin biopsy specimen showed a perifollicular infiltrate of mononuclear cells.
    • In patients with CVID, both non-necrotizing granulomas (sarcoidlike) and necrotizing granulomas (tuberculoid) have been observed.16,17,18,19
    • In one case report by Pujol et al,20 histopathologic biopsy showed perivascular lymphoid infiltrates in the upper and mid dermis, with central necrosis and a palisading granuloma.
    • A syndrome similar to sarcoidosis can affect patients with CVID. This syndrome is characterized by noninfectious cutaneous granulomas, with underlying visceral granulomas of the lungs, liver, spleen, or conjunctiva in most patients. These cutaneous granulomas are nonspecific in patients with CVID and can appear as a maculopapular rash; as infiltrated erythematous papules, plaques, excoriated papules, and ulcers; or as nodules with ulcerations. On histologic analysis, such granulomas are noncaseating and involve the dermis or subcutaneous fat. These nonsarcoidal, nontuberculoid asymptomatic cutaneous granulomas often appear as multiple, nontender subcutaneous nodules, predominantly juxta-articular, and the skin overlying the nodules was either normal or slightly erythematous.21
    • Lesions frequently appear on the face and extremities and are always sterile. They often resolve with treatment of the underlying disease.
    • Residual hyperpigmentation may be observed.
    • The increased incidence of malignancy in patients with CVID is well known. In 1992, Green and Moschella22 reported the first known case of a patient with CVID who developed multiple squamous cell carcinomas. Many other cases have been published since then. Patients with CVID have an increased risk for actinic keratosis and squamous cell carcinoma. This risk is not surprising given the increased incidence of skin cancer with prolonged iatrogenic immunosuppression, as in transplant recipients.
    • Other dermatologic manifestations of CVID include atopic dermatitis and polymorphic light eruption.23 However, these are not specific markers of CVID, and they are not indications for a workup for CVID unless other implicating factors (eg, recurrent infections) are present.

Causes

The primary cause of common variable immunodeficiency (CVID) remains unknown despite 40 years of research. Part of the problem is the heterogeneity of the disease.

  • Genetic factors may be involved.
    • In approximately 20% of patients with CVID, a first-degree family member has a selective IgA deficiency.
    • This finding may indicate that the genes are linked.
    • When more than one family member is affected with CVID, approximately 5% of the patients have a concurrent IgA deficiency.
    • Further results reveal specific localization to the C4A gene and, rarely, to the C2 gene in the class III region of the major histocompatibility complex on chromosome 6.
    • No clear pattern of inheritance has been observed.
    • Because most patients represent sporadic cases and because they have no family history of immunodeficiency, different modes of inheritance such as autosomal dominant with variable penetrance, autosomal recessive, and X-linked forms have been reported.24
    • An autosomal recessive pattern of inheritance is suggested when more than one family member is affected.
  • CVID is associated with the use of antirheumatic or antiepileptic drugs.
    • If such an association is later proven to be a causal relationship, the genetic etiology may turn out to be a genetic predisposition to the disease.
    • A common insult to the B-cell differentiation pathway may be involved.

More on Common Variable Immunodeficiency

Overview: Common Variable Immunodeficiency
Differential Diagnoses & Workup: Common Variable Immunodeficiency
Treatment & Medication: Common Variable Immunodeficiency
Follow-up: Common Variable Immunodeficiency
References
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References

  1. Cunningham-Rundles C. Autoimmune manifestations in common variable immunodeficiency. J Clin Immunol. May 2008;28 Suppl 1:S42-5. [Medline].

  2. Rezaei N, Aghamohammadi A, Siadat SD, et al. Serum bactericidal antibody responses to meningococcal polysaccharide vaccination as a basis for clinical classification of common variable immunodeficiency. Clin Vaccine Immunol. Apr 2008;15(4):607-11. [Medline].

  3. Lanio N, Sarmiento E, Gallego A, Carbone J. Immunophenotypic profile of T cells in common variable immunodeficiency: is there an association with different clinical findings?. Allergol Immunopathol (Madr). Jan-Feb 2009;37(1):14-20. [Medline].

  4. Castigli E, Wilson SA, Garibyan L, et al. TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat Genet. Aug 2005;37(8):829-34. [Medline].

  5. Schaffer AA, Salzer U, Hammarström L, Grimbacher B. Deconstructing common variable immunodeficiency by genetic analysis. Curr Opin Genet Dev. Jun 2007;17(3):201-12. [Medline].

  6. Neumann C, Grimbacher B. [Molecular basis of common variable immunodeficiency]. Dtsch Med Wochenschr. Apr 20 2007;132(16):885-7. [Medline].

  7. Salzer U, Chapel HM, Webster AD, et al. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet. Aug 2005;37(8):820-8. [Medline].

  8. Finck A, Van der Meer JW, Schaffer AA, et al. Linkage of autosomal-dominant common variable immunodeficiency to chromosome 4q. Eur J Hum Genet. Jul 2006;14(7):867-75. [Medline].

  9. Chapel H, Lucas M, Lee M, et al. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood. Jul 15 2008;112(2):277-86. [Medline].

  10. Aghamohammadi A, Farhoudi A, Moin M, et al. Clinical and immunological features of 65 Iranian patients with common variable immunodeficiency. Clin Diagn Lab Immunol. Jul 2005;12(7):825-32. [Medline].

  11. Le Cleach L, Benchikhi H, Liedman D, Boumsel L, Wolkenstein P, Revuz J. [Hand-foot-mouth syndrome recurring during common variable deficiency]. Ann Dermatol Venereol. Mar 1999;126(3):251-3. [Medline].

  12. Khodadad A, Aghamohammadi A, Parvaneh N, et al. Gastrointestinal manifestations in patients with common variable immunodeficiency. Dig Dis Sci. Nov 2007;52(11):2977-83. [Medline].

  13. Lassoued K. [Humoral immune deficits and the skin]. Ann Dermatol Venereol. Mar 1999;126(3):215-22. [Medline].

  14. Boonyaleepun S, Boonyaleepun C, Schlactus JL. Effect of IVIG on the hair regrowth in a common variable immune deficiency patient with alopecia universalis. Asian Pac J Allergy Immunol. Mar 1999;17(1):59-62. [Medline].

  15. Kilic S, Ersoy F, Sanal O, Turkbay D, Tezcan I. Alopecia universalis in a patient with common variable immunodeficiency. Pediatr Dermatol. Jul-Aug 1999;16(4):305-7. [Medline].

  16. Alvarez-Cuesta C, Molinos L, Cascante JA, Soler T, Perez-Oliva N. Cutaneous granulomas in a patient with common variable immunodeficiency. Acta Derm Venereol. Jul 1999;79(4):334. [Medline].

  17. Krupnick AI, Shim H, Phelps RG, Cunningham-Rundles C, Sapadin AN. Cutaneous granulomas masquerading as tuberculoid leprosy in a patient with congenital combined immunodeficiency. Mt Sinai J Med. Sep-Oct 2001;68(4-5):326-30. [Medline].

  18. Levine TS, Price AB, Boyle S, Webster AD. Cutaneous sarcoid-like granulomas in primary immunodeficiency disorders. Br J Dermatol. Jan 1994;130(1):118-20. [Medline].

  19. Mitra A, Pollock B, Gooi J, Darling JC, Boon A, Newton-Bishop JA. Cutaneous granulomas associated with primary immunodeficiency disorders. Br J Dermatol. Jul 2005;153(1):194-9. [Medline].

  20. Pujol RM, Nadal C, Taberner R, Diaz C, Miralles J, Alomar A. Cutaneous granulomatous lesions in common variable immunodeficiency: complete resolution after intravenous immunoglobulins. Dermatology. 1999;198(2):156-8. [Medline].

  21. Abdel-Naser MB, Wollina U, El Hefnawi MA, Habib MA, El Okby M. Non-sarcoidal, non-tuberculoid granuloma in common variable immunodeficiency. J Drugs Dermatol. Apr 2006;5(4):370-2. [Medline].

  22. Green HA, Moschella S. Multiple invasive squamous cell carcinomas and common variable immunodeficiency. Arch Dermatol. Mar 1992;128(3):412-3. [Medline].

  23. Creamer D, McGregor JM, Hawk JL. Polymorphic light eruption occurring in common variable hypogammaglobulinaemia, and resolving with intravenous immunoglobulin therapy. Clin Exp Dermatol. Jul 1999;24(4):273-4. [Medline].

  24. Nijenhuis T, Klasen I, Weemaes CM, Preijers F, de Vries E, van der Meer JW. Common variable immunodeficiency (CVID) in a family: an autosomal dominant mode of inheritance. Neth J Med. Sep 2001;59(3):134-9. [Medline].

  25. Modrzewska K, Wiatr E, Langfort R, Oniszh K, Roszkowski-Sliz K. [Common variable immunodeficiency in a patient with suspected sarcoidosis]. Pneumonol Alergol Pol. 2009;77(1):91-6. [Medline].

  26. Simonson WT, Markovina S, Grossman WJ, et al. Common variable immunodeficiency with regulatory T-cell deficiency treated with rapamycin. Ann Allergy Asthma Immunol. Feb 2009;102(2):170-1. [Medline].

  27. Shabbat S, Aharoni J, Sarid L, Ben-Harush M, Kapelushnik J. Rituximab as monotherapy and in addition to reduced CHOP in children with primary immunodeficiency and non-Hodgkin lymphoma. Pediatr Blood Cancer. May 2009;52(5):664-6. [Medline].

  28. Lin JH, Liebhaber M, Roberts RL, Dyer Z, Stiehm ER. Etanercept treatment of cutaneous granulomas in common variable immunodeficiency. J Allergy Clin Immunol. Apr 2006;117(4):878-82. [Medline].

  29. [Guideline] Bonilla FA, Bernstein IL, Khan DA, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol. May 2005;94(5 Suppl 1):S1-63. [Medline].

  30. Andres E, Limbach FX, Kurtz JE, et al. Primary humoral immunodeficiency (late-onset common variable immunodeficiency) with antinuclear antibodies and selective immunoglobulin deficiency. Am J Med. Oct 15 2001;111(6):489-91. [Medline].

  31. Ariatti C, Rossi D, Vivenza D, et al. Molecular characterization of common variable immunodeficiency-related lymphomas. Ann Ital Med Int. Jul-Sep 2001;16(3):163-9. [Medline].

  32. Bayry J, Hermine O, Webster DA, Levy Y, Kaveri SV. Common variable immunodeficiency: the immune system in chaos. Trends Mol Med. Aug 2005;11(8):370-6. [Medline].

  33. Goldes JA, Filipovich AH, Neudorf SM, et al. Epidermodysplasia verruciformis in a setting of common variable immunodeficiency. Pediatr Dermatol. Oct 1984;2(2):136-9. [Medline].

  34. Kuribayashi JS, Bombardieri CR, Baracho GV, et al. Slower rescue of ER homeostasis by the unfolded protein response pathway associated with common variable immunodeficiency. Mol Immunol. May 2008;45(10):2990-7. [Medline].

  35. Marzano AV, Berti E, Alessi E, Caputo R. Clonal CD8 infiltration of the skin in common variable immunodeficiency: a prelymphomatous stage?. J Am Acad Dermatol. Apr 2001;44(4):710-3. [Medline].

  36. Pierson JC, Camisa C, Lawlor KB, Elston DM. Cutaneous and visceral granulomas in common variable immunodeficiency. Cutis. Oct 1993;52(4):221-2. [Medline].

  37. Smith KJ, Skelton H. Common variable immunodeficiency treated with a recombinant human IgG, tumour necrosis factor-alpha receptor fusion protein. Br J Dermatol. Mar 2001;144(3):597-600. [Medline].

  38. Spickett GP. Current perspectives on common variable immunodeficiency (CVID). Clin Exp Allergy. Apr 2001;31(4):536-42. [Medline].

  39. Ziegler EM, Seung LM, Soltani K, Medenica MM. Cutaneous granulomas with two clinical presentations in a patient with common variable immunodeficiency. J Am Acad Dermatol. Sep 1997;37(3 Pt 1):499-500. [Medline].

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Further Reading

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Keywords

CVID, primary immunodeficiencies, immunoglobulin deficiency, immunoglobulin G, IgG, immunoglobulin A, IgA, immunoglobulin M, IgM, B lymphocytes, T lymphocytes

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Contributor Information and Disclosures

Author

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Coauthor(s)

Rohit M Modak, MD, MBA, Staff Physician, Department of Infectious Diseases, Virginia Hospital Center
Disclosure: Nothing to disclose.

Prema Modak, MD, Attending Physician, Department of Ophthalmology, Martinsburg West Virginia Veterans Affairs Medical Center
Prema Modak, MD is a member of the following medical societies: American Academy of Ophthalmology
Disclosure: Nothing to disclose.

Medical Editor

Takeji Nishikawa, MD, Emeritus Professor, Department of Dermatology, Keio University School of Medicine; Director, Samoncho Dermatology Clinic; Managing Director, The Waksman Foundation of Japan Inc
Disclosure: Nothing to disclose.

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Managing Editor

Jeffrey P Callen, MD, Professor of Medicine, Chief, Division of Dermatology, University of Louisville School of Medicine
Jeffrey P Callen, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and American College of Rheumatology
Disclosure: Amgen Honoraria Consulting; Abbott Honoraria Consulting; Electrical Optical Sciences Honoraria Consulting; Centocor Honoraria Consulting; Medicis Honoraria Consulting; Celgene Honoraria Consulting

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
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