Differential Diagnosis in Hypogammaglobulinemia

  • Isabella QuintiEmail author
  • Cinzia Milito
  • Rossella Carello
  • Federica Pulvirenti
Part of the Rare Diseases of the Immune System book series (RDIS)


Hypogammaglobulinemia is defined as an impaired production of antibodies. This condition represents a diagnostic challenge for clinicians, due to its association with many pathological entities with different manifestations and outcomes. Primary hypogammaglobulinemia is caused by defects in B-cell number and maturation, reduced survival and activation of B cells, and faulty interaction between B and T cells and is commonly observed in many primary immunodeficiencies. However, hypogammaglobulinemia secondary to cancer, chemotherapy, immunosuppressive therapy, chromosomal alterations, and protein-losing diseases is a widely recognized condition. The clinical relevance of secondary hypogammaglobulinemias has been increasingly recognized. Differential diagnosis could be puzzling because of similar clinical aspects in primary and secondary forms of hypogammaglobulinemias. Thus, for all patients with a low immunoglobulin serum level at the initial evaluation, defined causes of secondary hypogammaglobulinemias should be extensively ruled out. In particular, B-cell malignancies (mainly chronic lymphocytic leukemia) and plasma cell dyscrasias should be excluded in patients with low immunoglobulin serum levels.


Hypogammaglobulinemia Secondary hypogammaglobulinemia Lymphoproliferative diseases Drug-induced hypogammaglobulinemia Diagnostic work-up 


  1. 1.
    Bonilla FA, Barlan I, Chapel H, Costa-Carvalho BT, Cunningham-Rundles C, de la Morena MT, Espinosa-Rosales FJ, Hammarström L, Nonoyama S, Quinti I, Routes JM, Tang MLK, Warnatz K. International Consensus Document (ICON): common variable immunodeficiency disorders. J Allergy Clin Immunol Pract. 2016;4:38–59. Scholar
  2. 2.
    Dorsey MJ, Orange JS. Impaired specific antibody response and increased B-cell population in transient hypogammaglobulinemia of infancy. Ann Allergy Asthma Immunol. 2006;97:590–5.CrossRefGoogle Scholar
  3. 3.
    Moschese V, Cavaliere FM, Graziani S, Bilotta C, Milito C, Chini L, Quinti I. Decreased IgM, IgA, and IgG response to pneumococcal vaccine in children with transient hypogammaglobulinemia of infancy. J Allergy Clin Immunol. 2016;137:617–9. Scholar
  4. 4.
    Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol. 1999;93:190–7.CrossRefGoogle Scholar
  5. 5.
    Al-Herz W, Bousfiha A, Casanova JL, Chapel H, Conley ME, Cunningham-Rundles C, et al. Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency. Front Immunol. 2011;2:54.CrossRefGoogle Scholar
  6. 6.
    Calvo Campoverde K, Gean E, Piquer Gibert M, Martinez Valdez L, Deyà-Martínez A, Rojas Volquez M, Esteve-Sole A, Juan M, Plaza AM, Alsina L. Humoral deficiency in three paediatric patients with genetic diseases. Allergol Immunopathol (Madr). 2016;44:257–62. Scholar
  7. 7.
    Finley SC, Cooper MD, Finley WH, Uchida IA, Noto TA, Roddam RF. Immunological profile in a chromosome 18 deletion syndrome with IgA deficiency. J Med Genet. 1969;6:388–93.CrossRefGoogle Scholar
  8. 8.
    Cody JD, Sebold C, Heard P, Carter E, Soileau B, Hasi-Zogaj M, Hill A, Rupert D, Perry B, O’Donnell L, Gelfond J, Lancaster J, Fox PT, Hale DE. Consequences of chromsome18q deletions. J Med Genet C Semin Med Genet. 2015;169:265–80. Scholar
  9. 9.
    Yu HR, Yang MY, Yeh WT, Yang KD. Common variable immunodeficiency with mosaic trisomy 8: report of one case. Acta Paediatr Taiwan. 2000;41:331–5.PubMedGoogle Scholar
  10. 10.
    Valentini D, Marcellini V, Bianchi S, Villani A, Facchini M, Donatelli I, Castrucci MR, Marasco E, Farroni C, Carsetti R. Generation of switched memory B cells in response to vaccination in Down syndrome children and their siblings. Vaccine. 2015;33:6689–96. Scholar
  11. 11.
    Kerr J, Quinti I, Eibl M, Chapel H, Späth PJ, Sewell WA, Salama A, van Schaik IN, Kuijpers TW, Peter HH. Is dosing of therapeutic immunoglobulins optimal? A review of a three-decade long debate in europe. Front Immunol. 2014;12(5):629. Scholar
  12. 12.
    Forconi F, Moss P. Perturbation of the normal immune system in patients with CLL. Blood. 2015;126:573–81. Scholar
  13. 13.
    Visentin A, Compagno N, Cinetto F, Imbergamo S, Zambello R, Piazza F. Clinical profile associated with infections in patients with chronic lymphocytic leukemia. Protective role of immunoglobulin replacement therapy. Haematologica. 2015;100:e515–8. Scholar
  14. 14.
    Zemble RM, Takach PA, Levinson AI. The relationship between hypogammaglobulinemia, monoclonal gammopathy of undetermined significance and humoral immunodeficiency: a case series. J Clin Immunol. 2011;31:737–43. Scholar
  15. 15.
    Compagno N, Cinetto F, Boscaro E, Semenzato G, Agostini C. Serum free light chains in the differential diagnosis and prognosis of primary and secondary hypogammaglobulinemia. J Allergy Clin Immunol. 2015;135:1075–7.CrossRefGoogle Scholar
  16. 16.
    Holtick U, Albrecht M, Chemnitz JM, Theurich S, Skoetz N, Scheid C, von Bergwelt-Baildon M. Bone marrow versus peripheral blood allogeneic haematopoietic stem cell transplantation for haematological malignancies in adults. Cochrane Database Syst Rev. 2014;4:CD010189. Scholar
  17. 17.
    Pastori D, Esposito A, Mezzaroma I. Immunomodulatory effects of intravenous immunoglobulins (IVIGs) in HIV-1 disease: a systematic review. Int Rev Immunol. 2011;30:44–66. Scholar
  18. 18.
    Pahwa S, Kirkpatrick D, Ching C, Lopez C, Pahwa R, Smithwick E, O’Reilly R, August C, Pasquariello P, Good RA. Persistent cytomegalovirus infection: association with profound immunodeficiency and treatment with interferon. Clin Immunol Immunopathol. 1983;28:77–89.CrossRefGoogle Scholar
  19. 19.
    Greenberger PA, Walker CL, Fitzsimons TE, Roberts M. Hypogammaglobulinemia associated with cytomegalovirus pneumonia. J Infect Dis. 1991;163:631–3.CrossRefGoogle Scholar
  20. 20.
    Hügle B, Suchowerskyj P, Hellebrand H, Adler B, Borte M, Sack U, Overberg-Schmidt US, Strnad N, Otto J, Meindl A, Schuster V. Persistent hypogammaglobulinemia following mononucleosis in boys is highly suggestive of X-linked lymphoproliferative disease—report of three cases. J Clin Immunol. 2004;24:515–22.CrossRefGoogle Scholar
  21. 21.
    Ameratunga R, Barker RW, Steele RH, Deo M, Woon ST, Yeong ML, Koopmans W. Profound reversible hypogammaglobulinemia caused by celiac disease in the absence of protein losing enteropathy. J Clin Immunol. 2015;35:589–94. Scholar
  22. 22.
    Sadat MA, Moir S, Chun TW, Lusso P, Kaplan G, Wolfe L, Memoli MJ, He M, Vega H, Kim LJ, Huang Y, Hussein N, Nievas E, Mitchell R, Garofalo M, Louie A, Ireland DC, Grunes C, Cimbro R, Patel V, Holzapfel G, Salahuddin D, Bristol T, Adams D, Marciano BE, Hegde M, Li Y, Calvo KR, Stoddard J, Justement JS, Jacques J, Long Priel DA, Murray D, Sun P, Kuhns DB, Boerkoel CF, Chiorini JA, Di Pasquale G, Verthelyi D, Rosenzweig SD. Glycosylation, hypogammaglobulinemia, and resistance to viral infections. N Engl J. 2014;370:1615–25. Scholar
  23. 23.
    Wirsum C, Glaser C, Gutenberger S, Keller B, Unger S, Voll RE, Vach W, Ness T, Warnatz K. Secondary antibody deficiency in glucocorticoid therapy clearly differs from primary antibody deficiency. J Clin Immunol. 2016;36:406–12. Scholar
  24. 24.
    Fassbinder T, Saunders U, Mickholz E, Jung E, Becker H, Schlüter B, Jacobi AM. Differential effects of cyclophosphamide and mycophenolate mofetil on cellular and serological parameters in patients with systemic lupus erythematosus. Arthritis Res Ther. 2015;17:92. Scholar
  25. 25.
    Farr M, Struthers GR, Scott DG, Bacon PA. Fenclofenac-induced selective IgA deficiency in rheumatoid arthritis. Br J Rheumatol. 1985;24:367–9.CrossRefGoogle Scholar
  26. 26.
    Farr M, Tunn E, Bacon PA, Smith DH. Hypogammaglobulinaemia and thrombocytopenia associated with sulphasalazine therapy in rheumatoid arthritis. Ann Rheum Dis. 1985;44:723–4.CrossRefGoogle Scholar
  27. 27.
    Snowden N, Dietch DM, Teh LS, Hilton RC, Haeney MR. Antibody deficiency associated with gold treatment: natural history and management in 22 patients. Ann Rheum Dis. 1996;55:616–21.CrossRefGoogle Scholar
  28. 28.
    Williams A, Scott DL, Greenwood A, Huskisson EC. The clinical value of measuring immunoglobulins when assessing penicillamine therapy in rheumatoid arthritis. Clin Rheumatol. 1988;7:347–53.CrossRefGoogle Scholar
  29. 29.
    Pereira LF, Sanchez JF. Reversible panhypogammaglobulinemia associated with phenytoin treatment. Scand J Infect Dis. 2002;34:785–7.CrossRefGoogle Scholar
  30. 30.
    Hoshino C, Hoshi T. Carbamazepine-induced agammagloblinaemia clinically mimicking diffuse panbronchiolitis. BMJ Case Rep. 2011; Scholar
  31. 31.
    Eom TH, Lee HS, Jang PS, Kim YH. Valproate-induced panhypogammaglobulinemia. Neurol Sci. 2013;34:1003–4. Scholar
  32. 32.
    De Angelis F, Tosti ME, Capria S, Russo E, D’Elia GM, Annechini G, Stefanizzi C, Foà R, Pulsoni A. Risk of secondary hypogammaglobulinaemia after Rituximab and Fludarabine in indolent non-Hodgkin lymphomas: A retrospective cohort study. Leuk Res. 2015;39:1382–8. Scholar
  33. 33.
    Diwakar L, Gorrie S, Richter A, Chapman O, Dhillon P, Al-Ghanmi F, et al. Does rituximab aggravate pre-existing hypogammaglobulinaemia? J Clin Pathol. 2010;63:275–7. Scholar
  34. 34.
    Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, Stevens RM, Shaw T. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004;350:2572–81.CrossRefGoogle Scholar
  35. 35.
    Witzig TE, Flinn IW, Gordon LI, Emmanouilides C, Czuczman MS, Saleh MN, Cripe L, Wiseman G, Olejnik T, Multani PS, White CA. Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin’s lymphoma. J Clin Oncol. 2002;20:3262–9.CrossRefGoogle Scholar
  36. 36.
    Evans SS, Clemmons AB. Obinutuzumab: a novel anti-CD20 monoclonal antibody for chronic lymphocytic leukemia. J Adv Pract Oncol. 2015;6:370–4.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Österborg A, Wierda WG, Mayer J, Hess G, Hillmen P, Schetelig J, Schuh A, Smolej L, Beck C, Dreyfus B, Hellman A, Kozlowski P, Pfreundschuh M, Rizzi R, Spacek M, Phillips JL, Gupta IV, Williams V, Jewell RC, Nebot N, Lisby S, Dyer MJ. Ofatumumab retreatment and maintenance in fludarabine-refractory chronic lymphocytic leukaemia patients. Br J Haematol. 2015;170:40–9. Scholar
  38. 38.
    Kappos L, Li D, Calabresi PA, O’Connor P, Bar-Or A, Barkhof F, Yin M, Leppert D, Glanzman R, Tinbergen J, Hauser SL. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet. 2011;378:1779–87. Scholar
  39. 39.
    Lutalo PM, D’Cruz DP. Update on belimumab for the management of systemic lupus erythematosus. Expert Opin Biol Ther. 2014;14:1701–8. Scholar
  40. 40.
    Genovese MC, Silverman GJ, Emery P, Gupta RC, Gill A, Veenhuizen M, Xie L, Komocsar WJ, Berclaz PY, Lee C. Efficacy and safety of Tabalumab, an anti-B-cell-activating factor monoclonal antibody, in a heterogeneous rheumatoid arthritis population: results from a randomized, placebo-controlled, Phase 3 Trial (FLEX-O). J Clin Rheumatol. 2015;21:231–8. Scholar
  41. 41.
    Furie RA, Leon G, Thomas M, Petri MA, Chu AD, Hislop C, Martin RS, Scheinberg MA, PEARL-SC Study. A phase 2, randomised, placebo-controlled clinical trial of blisibimod, an inhibitor of B cell activating factor, in patients with moderate-to-severe systemic lupus erythematosus, the PEARL-SC study. Ann Rheum Dis. 2013;74:1667–75. Scholar
  42. 42.
    Topp MS, Kufer P, Gökbuget N, Goebeler M, Klinger M, Neumann S, Horst HA, Raff T, Viardot A, Schmid M, Stelljes M, Schaich M, Degenhard E, Köhne-Volland R, Brüggemann M, Ottmann O, Pfeifer H, Burmeister T, Nagorsen D, Schmidt M, Lutterbuese R, Reinhardt C, Baeuerle PA, Kneba M, Einsele H, Riethmüller G, Hoelzer D, Zugmaier G, Bargou RC. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol. 2011;29:2493–8. Scholar
  43. 43.
    Micallef IN, Maurer MJ, Wiseman GA, Nikcevich DA, Kurtin PJ, Cannon MW, Perez DG, Soori GS, Link BK, Habermann TM, Witzig TE. Epratuzumab with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy in patients with previously untreated diffuse large B-cell lymphoma. Blood. 2011;118:4053–61. Scholar
  44. 44.
    Kantarjian H, Thomas D, Jorgensen J, Kebriaei P, Jabbour E, Rytting M, York S, Ravandi F, Garris R, Kwari M, Faderl S, Cortes J, Champlin R, O’Brien S. Results of inotuzumab ozogamicin, a CD22 monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia. Cancer. 2013;119:2728–36. Scholar
  45. 45.
    Sullivan-Chang L, O’Donnell RT, Tuscano JM. Targeting CD22 in B-cell malignancies: current status and clinical outlook. Bio Drugs. 2013;27:293–304. Review.CrossRefGoogle Scholar
  46. 46.
    Maude SL, Teachey DT, Porter DL, Grupp SA. CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood. 2015;125:4017–23. Scholar
  47. 47.
    Kappos L, Wiendl H, Selmaj K, Arnold DL, Havrdova E, Boyko A, Kaufman M, Rose J, Greenberg S, Sweetser M, Riester K, O’Neill G, Elkins J. Daclizumab HYP versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2015;373:1418–28. Scholar
  48. 48.
    Obermann M, Ruck T, Pfeuffer S, Baum J, Wiendl H, Meuth SG. Simultaneous early-onset immune thrombocytopenia and autoimmune thyroid disease following alemtuzumab treatment in relapsing-remitting multiple sclerosis. Mult Scler. 2016;22:1235–41. Scholar
  49. 49.
    Furst DE, Keystone EC, Braun J, Breedveld FC, Burmester GR, De Benedetti F, Dörner T, Emery P, Fleischmann R, Gibofsky A, Kalden JR, Kavanaugh A, Kirkham B, Mease P, Sieper J, Singer NG, Smolen JS, Van Riel PL, Weisman MH, Winthrop K. Updated consensus statement on biological agents for the treatment of rheumatic diseases. Ann Rheum Dis. 2011;2:i2–45. Scholar
  50. 50.
    Nixon AE, Chen J, Sexton DJ, Muruganandam A, Bitonti AJ, Dumont J, Viswanathan M, Martik D, Wassaf D, Mezo A, Wood CR, Biedenkapp JC, TenHoor C. Fully human monoclonal antibody inhibitors of the neonatal fc receptor reduce circulating IgG in non-human primates. Front Immunol. 2015;6:176. Scholar
  51. 51.
    Hartung HP, Kieseier BC. Atacicept: targeting B cells in multiple sclerosis. Ther Adv Neurol Disord. 2010;3:205–16. Scholar
  52. 52.
    Kerr J, Quinti I, Eibl M, Chapel H, Späth PJ, Sewell WA, Salama A, van Schaik IN, Kuijpers TW, Peter HH. Is dosing of therapeutic immunoglobulins optimal? A review of a three-decade long debate in europe Front Immunol. 2014 Dec 12;5:629. eCollection 2044.

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Isabella Quinti
    • 1
    Email author
  • Cinzia Milito
    • 1
  • Rossella Carello
    • 1
  • Federica Pulvirenti
    • 1
  1. 1.Department of Molecular MedicineSapienza University of RomeRomeItaly

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