Hypogammaglobulinemia (serum IgG lower than 2 SD below the age-matched mean) and clinical symptoms such as increased susceptibility to infection, autoimmune manifestations, granulomatous disease, and unexplained polyclonal lymphoproliferation are considered to be diagnostic hallmarks in patients with common variable immunodeficiency (CVID), the most frequent clinically severe primary immunodeficiency syndrome. In the present study, we investigated patients with hypogammaglobulinemia and no clinical or immunological signs of defective cell-mediated immunity and differentiated two groups on the basis of their IgG antibody formation capacity against a variety of different antigens (bacterial toxins, polysaccharide antigens, viral antigens). Patients with hypogammaglobulinemia and intact antibody production (HIAP) displayed no or only mild susceptibility to infections, while CVID patients showed marked susceptibility to bacterial infections that normalized following initiation of IVIG or subcutaneous immunoglobulin replacement therapy. There was a substantial overlap in IgG serum levels between the asymptomatic HIAP group and the CVID patients examined before immunoglobulin treatment. HIAP patients showed normal levels of switched B-memory cells (CD19(+)CD27(+)IgD(-)), while both decreased and normal levels of switched B-memory cells could be found in CVID patients. IgG antibody response to a primary antigen, tick-borne encephalitis virus (TBEV), was defective in CVID patients, thus confirming their substantial defect in IgG antibody production. Defective IgG antibody production against multiple antigens could also be demonstrated in an adult patient with recurrent infections but normal IgG levels. To facilitate early treatment before recurrent infections may lead to organ damage, the antibody formation capacity should be examined in hypogammaglobulinemic patients and the decision to treat should be based on the finding of impaired IgG antibody production.

Department of Clinical Immunology and Allergology Faculty of Medicine Masaryk University Brno Czech Republic ; Department of Clinical Immunology and Allergology St Anne's University Hospital Brno Czech Republic

Immunology Outpatient Clinic Vienna Austria

See more in PubMed

Chee L, Graham SM, Carothers DG, Ballas ZK. Immune dysfunction in refractory sinusitis in a tertiary care setting. Laryngoscope (2001) 111:233–5.10.1097/00005537-200102000-00008 PubMed DOI

Sethi DS, Winkelstein JA, Lederman H, Loury MC. Immunologic defects in patients with chronic recurrent sinusitis: diagnosis and management. Otolaryngol Head Neck Surg (1995) 112:242–7.10.1016/S0194-5998(95)70244-X PubMed DOI

Ameratunga R, Woon S-T, Gillis D, Koopmans W, Steele R. New diagnostic criteria for common variable immune deficiency (CVID), which may assist with decisions to treat with intravenous or subcutaneous immunoglobulin. Clin Exp Immunol (2013) 174:203–11.10.1111/cei.12178 PubMed DOI PMC

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) 93:190–710.1006/clim.1999.4799 PubMed DOI

Available from: http://esid.org/Working-Parties/Registry/Diagnosis-criteria

Rosen FS, Eibl M, Roifman C, Fischer A, Volanakis J, Aiuti F, et al. Primary immunodeficiency diseases report of an IUIS scientific committee. Clin Exp Immunol (1999) 118(Suppl 1):1–2810.1046/j.1365-2249.1999.00109.x PubMed DOI PMC

Goldacker S, Draeger R, Warnatz K, Huzly D, Salzer U, Thiel J, et al. Active vaccination in patients with common variable immunodeficiency (CVID). Clin Immunol (2007) 124:294–303.10.1016/j.clim.2007.04.011 PubMed DOI

Plebani A, Soresina A, Rondelli R, Amato GM, Azzari C, Cardinale F. Clinical, immunological, and molecular analysis in a large cohort of patients with X-linked agammaglobulinemia: an Italian multicenter study. Clin Immunol (2002) 104(3):221–30.10.1006/clim.2002.5241 PubMed DOI

Al-Herz W, Bousfiha A, Casanova J-L, 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) 2:54.10.3389/fimmu.2011.00054 PubMed DOI PMC

Eibl N, Spatz M, Fischer GF, Mayr WR, Samstag A, Wolf HM, et al. Impaired primary immune response in type-1 diabetes: results from a controlled vaccination study. Clin Immunol (2002) 2002(103):249–59.10.1006/clim.2002.5220 PubMed DOI

Warnatz K, Denz A, Dräger R, Braun M, Groth C, Wolff-Vorbeck G, et al. Severe deficiency of switched memory B cells (CD27(+)IgM(-)IgD(-)) in subgroups oif patients with common variable immunodeficiency: a new approach to classify a heterogeneous disease. Blood (2002) 99:1544–51.10.1182/blood.V99.5.1544 PubMed DOI

Yong PL, Orange JS, Sullivan KE. Pediatric common variable immunodeficiency: immunologic and phenotypic associations with switched memory B cells. Pediatr Allergy Immunol (2010) 21:852–8.10.1111/j.1399-3038.2010.01004.x PubMed DOI

van de Ven AAJM, van de Corput L, van Tilburg CM, Tesselaar K, van Gent R, Sanders EAM, et al. Lymphocyte characteristics in children with common variable immunodeficiency. Clin Immunol (2010) 135:63–7110.1016/j.clim.2009.11.010 PubMed DOI

McGill JW, Tukey W, Larsen A. Variations of box plots. Am Stat (1978) 32:12–610.1080/00031305.1978.10479236 DOI

Rabel PO, Planitzer CB, Farcet MR, Kreil TR. Tick-borne encephalitis virus-neutralizing antibodies in different immunoglobulin preparations. Clin Vaccine Immunol (2012) 19:623–5.10.1128/CVI.05705-11 PubMed DOI PMC

Seidel MG, Grohmann E, Sadeghi K, Pollak A, Heitger A, Förster-Waldl E. Vaccination against tick-borne encephalitis virus tests specigic IgG production ability in patients under immunoglobulin substitution therapy. Vaccine (2010) 28:6621–6.10.1016/j.vaccine.2010.07.027 PubMed DOI

Chovancova Z, Vlkova M, Litzman J, Lokaj J, Thon V. Antibody forming cells and plasmablasts in peripheral blood in CVID patients after vaccination. Vaccine (2011) 29:4142–50.10.1016/j.vaccine.2011.03.087 PubMed DOI

Umetsu DT, Ambrosino DM, Quinti I, Siber GR, Geha RS. Recurrent sinopulmonary infection and impaired antibody response to bacterial capsular polysaccharide antigen in children with selective IgG-subclass deficiency. New Engl J Med (1985) 313:1247–5110.1056/NEJM198511143132002 PubMed DOI

Ambrosino DM, Siber GR, Chilmonczyk BA, Jernberg JB, Finberg RW. An immunodeficiency characterized by impaired antibody responses to polysaccharides. New Eng J Med (1987) 316:790–310.1056/NEJM198703263161306 PubMed DOI

Silk HJ, Ambrosino D, Geha RS. Effect of intravenous gammaglobulin therapy in IgG2 deficient and IgG2 sufficient children with recurrent infections and poor response to immunization with Hemophilus influenzae type b capsular polysaccharide antigen. Ann Allergy (1990) 64:21–5. PubMed

When to initiate immunoglobulin replacement therapy (IGRT) in antibody deficiency: a practical approach