eMedicine Specialties > Dermatology > Allergy & Immunology

Common Variable Immunodeficiency: Differential Diagnoses & Workup

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

Differential Diagnoses

Bruton Agammaglobulinemia
Severe Combined Immunodeficiency

Other Problems to Be Considered

Omenn syndrome
X-linked hypogammaglobulinemia
Protein-losing enteropathy
Thymoma
Transient hypogammaglobulinemia secondary to infection
Common variable immunodeficiency (CVID) can mimic sarcoidosis.25

Workup

Laboratory Studies

  • Common variable immunodeficiency (CVID) can be diagnosed after defective functional antibody formation is obtained.
    • Usually, patients have decreased (not absent) serum IgA and IgG levels and, occasionally, decreased serum IgM levels in the absence of other known causes of antibody deficiency.
    • Compared with patients with X-linked agammaglobulinemia, patients with CVID generally have higher serum Ig levels; however, the levels are consistently depressed.
    • The reference range for serum Ig varies with the patient's age, and the Ig results must be evaluated on the basis of these age-dependent ranges.
    • Although electrophoresis and immunoelectrophoresis are not acceptable techniques for the quantification of Ig levels, radial immunodiffusion or immunoturbidimetric methods remain valuable.
  • An assessment of functional antibody production in response to natural antigens or antigens to which the population is commonly exposed may be helpful.
    • Similarly, an evaluation of the antibody response after active immunization with polysaccharide or protein antigens is possible.
    • However, because the nonresponse rate to hepatitis B is so high, especially among persons older than 40 years, these antigens remain unreliable in the testing of immune competence.
  • Circulating T and B lymphocytes can be assessed by using monoclonal antibodies for immunofluorescence staining.
    • CD19 and CD20 (B cells), CD3 (T cells), CD4 (helper T cells), and CD8 (suppressor T cells) are all commonly used.
    • Natural killer (NK) cells also express CD3 and CD8 surface proteins. Therefore, NK cells and T cells can be further enumerated by using monoclonal antibodies against CD16, CD56, and CD57, though they are not lineage specific.
  • The in vivo measurement of T-cell function is possible by using an anergy panel to assess localized immunologic skin responses.
    • The antigens most commonly used include mumps (1 mg/mL), although availability of this antigen has varied; trichophytin (1:30 dilution); purified protein derivative (PPD) (2-10 IU); Candida antigen (1:100 dilution); and tetanus fluid toxoid (1:1000 dilution). An intradermal injection of 0.1 mL of antigen is necessary to perform the test.
    • The results should be read 48-72 hours after the injection to ensure an induration of maximal diameter.
    • A positive test result indicates intact delayed-type hypersensitivity. A negative test result to all antigens suggests impaired type IV immunity.
    • Erythema around the injection site does not indicate a positive result.
  • To assess the functional activity of the lymphocytes in vitro, they must be isolated and stimulated with a variety of agents.
    • One class of activators is the mitogens, which includes phytohemagglutinin and concanavalin A, both of which stimulate T cells. Pokeweed mitogen promotes proliferation of both T and B lymphocytes.
    • Another class of stimulators includes antigens. PPD, streptokinase, Candida antigen, and tetanus toxoid all activate lymphocytes, if the patient has had a prior exposure to the antigen or superantigen.
    • Allogeneic cells can also act as activators. They stimulate T-cell proliferation in mixed lymphocyte cultures. The proliferation of lymphocytes can be activated by in vitro antibodies to T-cell surface molecules that are important in signal transduction. These molecules include CD3, CD2, CD28, and CD43.
  • T-cell activity can be directly studied.
    • T lymphocytes express certain antigens after activation. These antigens include CD69, IL-2 receptor (CD25), transferring receptors (CD71), and major histocompatibility complex class II molecules (human leukocyte antigen DR).
    • Measuring the levels of mediators and cytokines such as IL-2, IL-4, IL-5, interleukin 6 (IL-6), interferon gamma, and tumor necrosis factor in the culture supernatant is another useful tool.
    • Another method is the measurement of levels of secreted Ig in the culture supernatant.
    • The complete blood count and autoantibody testing may be helpful as well.
    • Anemia secondary to an autoimmune process may be detected.
    • Severe lymphopenia may indicate that the patient has severe combined immunodeficiency disease or other primary T-cell defects.

Imaging Studies

  • For the detection of pulmonary abnormalities in patients with common variable immunodeficiency (CVID), high-resolution computed tomography of the chest may be more useful than plain chest radiography or pulmonary function testing.

Other Tests

  • Excluding an infectious etiology is important.
  • The periodic monitoring of pulmonary function is crucial in any patient who is able to perform the forced expiratory maneuvers.

Procedures

  • Biopsy should be considered to exclude infection or malignancy in enlarging lymph nodes.
  • Bronchoscopy or endoscopy can provide information regarding specific lesions or infectious processes.

Histologic Findings

Villous atrophy or infection with cryptosporidia or G lamblia can be reflected in the histologic changes of the intestine. Submucosal tissue can be examined for the presence of plasma cells.

Histologic changes may be observed in the lymph nodes of patients with CVID. The findings may include reactive follicular hyperplasia, atypical hyperplasia, and granulomatous inflammation.

Nonsarcoidal, nontuberculoid asymptomatic cutaneous granulomas seen in CVID show well-demarcated areas of fibrinoid degeneration of collagen that stain homogeneously and are surrounded by histiocytes in a palisading arrangement, suggestive of granuloma annulare; no microorganisms could be detected.21

Staging

Any malignancies complicating CVID are staged by using conventional guidelines.

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
[ CLOSE WINDOW ]

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].

[ CLOSE WINDOW ]

Further Reading

[ CLOSE WINDOW ]

Keywords

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

[ CLOSE WINDOW ]

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.

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.