Primary antibody deficiencies (PAD) constitute the majority of all primary immunodeficiency diseases (PID) and immunoglobulin replacement forms the mainstay of therapy for many patients in this category. Secondary antibody deficiencies (SAD) represent a larger and expanding number of patients resulting from the use of a wide range of immunosuppressive therapies, in particular those targeting B cells, and may also result from renal or gastrointestinal immunoglobulin losses. While there are clear similarities between primary and secondary antibody deficiencies, there are also significant differences. This review describes a practical approach to the clinical, laboratory and radiological assessment of patients with antibody deficiency, focusing on the factors that determine whether or not immunoglobulin replacement should be used. The decision to treat is more straightforward when defined diagnostic criteria for some of the major PADs, such as common variable immunodeficiency disorders (CVID) or X-linked agammaglobulinaemia (XLA), are fulfilled or, indeed, when there is a very low level of immunoglobulin production in association with an increased frequency of severe or recurrent infections in SAD. However, the presentation of many patients is less clear-cut and represents a considerable challenge in terms of the decision whether or not to treat and the best way in which to assess the outcome of therapy. This decision is important, not least to improve individual quality of life and reduce the morbidity and mortality associated with recurrent infections but also to avoid inappropriate exposure to blood products and to ensure that immunoglobulin, a costly and limited resource, is used to maximal benefit.

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

Department of Clinical Immunology University of Oxford UK

Immunodeficiency Centre for Wales Department of Immunology University Hospital of Wales Cardiff UK

Zobrazit více v PubMed

Gathmann B, Grimbacher B, Beauté J PubMed PMC

Picard C, Al‐Herz W, Bousfiha A PubMed PMC

Jolles S. The variable in common variable immunodeficiency: a disease of complex phenotypes. J Allergy Clin Immunol Pract 2013; 1:545–56. PubMed

Bonilla FA, Barlan I, Chapel H PubMed 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; 93:190–7. PubMed

Ameratunga R, Woon ST, Gillis D, Koopmans W, Steele R. New diagnostic criteria for CVID. Expert Rev Clin Immunol 2014; 10:183–6. PubMed

Wolf HM, Thon V, Litzman J, Eibl MM. Detection of impaired IgG antibody formation facilitates the decision on early immunoglobulin replacement in hypogammaglobulinemic patients. Front Immunol 2015; 6:32. PubMed PMC

Driessen GJ, Dalm VA, van Hagen PM PubMed PMC

Lucas M, Lee M, Lortan J, Lopez‐Granados E, Misbah S, Chapel H. Infection outcomes in patients with common variable immunodeficiency disorders: relationship to immunoglobulin therapy over 22 years. J Allergy Clin Immunol 2010; 125:1354–60 e4 . PubMed

Resnick ES, Moshier EL, Godbold JH, Cunningham‐Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood 2012; 119:1650–7. PubMed PMC

Espanol T, Catala M, Hernandez M, Caragol I, Bertran JM. Development of a common variable immunodeficiency in IgA‐deficient patients. Clin Immunol Immunopathol 1996; 80:333–5. PubMed

Aghamohammadi A, Mohammadi J, Parvaneh N PubMed

Orange JS, Ballow M, Stiehm ER PubMed

Wall LA, Dimitriades VR, Sorensen RU. Specific antibody deficiencies. Immunol Allergy Clin North Am 2015; 35:659–70. PubMed

Dhalla F, Misbah SA. Secondary antibody deficiencies. Curr Opin Allergy Clin Immunol 2015; 15:505–13. PubMed

Chapel HM, Lee M, Hargreaves R, Pamphilon DH, Prentice AG. Randomised trial of intravenous immunoglobulin as prophylaxis against infection in plateau‐phase multiple myeloma. The UK Group for Immunoglobulin Replacement Therapy in Multiple Myeloma. Lancet 1994; 343:1059–63. PubMed

Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia . Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia. A randomized, controlled clinical trial. Cooperative group for the study of immunoglobulin in chronic lymphocytic leukemia. N Engl J Med 1988; 319:902–7. PubMed

Friman V, Winqvist O, Blimark C, Langerbeins P, Chapel H, Dhalla F. Secondary immunodeficiency in lymphoproliferative malignancies. Hematol Oncol 2016; 34:121–32. PubMed

Sanchez‐Ramon S, Dhalla F, Chapel H. Challenges in the role of gammaglobulin replacement therapy and vaccination strategies for hematological malignancy. Front Immunol 2016; 7:317. PubMed PMC

Hamblin AD, Hamblin TJ. The immunodeficiency of chronic lymphocytic leukaemia. Br Med Bull 2008; 87:49–62. PubMed

Kaminsky P, Lesesve JF, Jonveaux P, Pruna L. IgG deficiency and expansion of CTG repeats in myotonic dystrophy. Clin Neurol Neurosurg 2011; 113:464–8. PubMed

Kim J, Hayton WL, Robinson JM, Anderson CL. Kinetics of FcRn‐mediated recycling of IgG and albumin in human: pathophysiology and therapeutic implications using a simplified mechanism‐based model. Clin Immunol 2007; 122:146–55. PubMed PMC

Casulo C, Maragulia J, Zelenetz AD. Incidence of hypogammaglobulinemia in patients receiving rituximab and the use of intravenous immunoglobulin for recurrent infections. Clin Lymph Myeloma Leuk 2013; 13:106–11. PubMed PMC

van Vollenhoven RF, Emery P, Bingham CO III PubMed PMC

Venhoff N, Effelsberg NM, Salzer U PubMed PMC

Davila ML, Riviere I, Wang X PubMed PMC

Maude SL, Frey N, Shaw PA PubMed PMC

Jolles S, Borrell R, Zouwail S PubMed PMC

Braamskamp MJ, Dolman KM, Tabbers MM. Clinical practice. Protein‐losing enteropathy in children. Eur J Pediatr 2010; 169:1179–85. PubMed PMC

Duraisingham SS, Buckland MS, Grigoriadou S, Longhurst HJ. Secondary antibody deficiency. Expert Rev Clin Immunol 2014; 10:583–91. PubMed

Dominguez‐Pinilla N, Benitez EM, Gonzalez‐Tome MI, Ruiz‐Contreras J, Gonzalez‐Granado LI. Invasive pneumococcal infection secondary to hypogammaglobulinemia due to Menetrier disease. Pediatr Infect Dis J 2013; 32:578. PubMed

Hodge D, Misbah SA, Mueller RF, Glass EJ, Chetcuti PA. Proteus syndrome and immunodeficiency. Arch Dis Child 2000; 82:234–5. PubMed PMC

Boddana P, Webb LH, Unsworth J, Brealey M, Bingham C, Harper SJ. Hypogammaglobulinemia and bronchiectasis in mycophenolate mofetil‐treated renal transplant recipients: an emerging clinical phenomenon? Clin Transplant 2011; 25:417–9. PubMed

Kawano T, Matsuse H, Obase Y PubMed

Abe S, Suzuki T, Hori T, Baba A, Shiraishi H. Hypogammaglobulinemia during antipsychotic therapy. Psychiatry Clin Neurosci 1998; 52:115–7. PubMed

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. PubMed PMC

van Rossum MA, Fiselier TJ, Franssen MJ PubMed

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. PubMed

Santachiara R, Maffei R, Martinelli S PubMed

Ginzler EM, Wax S, Rajeswaran A PubMed PMC

Kappos L, Hartung HP, Freedman MS PubMed

Hargreaves RM, Lea JR, Griffiths H PubMed PMC

Kyle RA, Gertz MA, Witzig TE PubMed

Kyle RA, Therneau TM, Rajkumar SV PubMed

Perez‐Persona E, Vidriales MB, Mateo G PubMed

McGrath EE, Blades Z, Anderson PB. Chylothorax: aetiology, diagnosis and therapeutic options. Respir Med 2010; 104:1–8. PubMed

Nair SK, Petko M, Hayward MP. Aetiology and management of chylothorax in adults. Eur J Cardiothorac Surg 2007; 32:362–9. PubMed

Ashrafi M, Hosseini SA, Abolmaali S PubMed

Hayman G, Bansal A. Antibody deficiency associated with carbamazepine. BMJ 2002; 325:1213. PubMed PMC

Kaplan B, Kopyltsova Y, Khokhar A, Lam F, Bonagura V. Rituximab and immune deficiency: case series and review of the literature. J Allergy Clin Immunol Pract 2014; 2:594–600. PubMed

Levy R, Mahevas M, Galicier L PubMed

Sarmiento E, Diez P, Arraya M PubMed

Berger M, Jolles S, Orange JS, Sleasman JW. Bioavailability of IgG administered by the subcutaneous route. J Clin Immunol 2013; 33:984–90. PubMed PMC

Jolles S, Orange JS, Gardulf A PubMed PMC

Hlavackova E, Liska M, Jicinska H, Navratil J, Litzman J. Secondary combined immunodeficiency in pediatric patients after the fontan operation: three case reports. Int Arch Allergy Immunol 2016; 170:251–6. PubMed

Jolles S, Carne E, Brouns M, El‐Shanawany T, Williams P, Marshall C, Fielding P. FDG PET‐CT imaging of therapeutic response in granulomatous lymphocytic interstitial lung disease (GLILD) in common variable immunodeficiency (CVID). Clin Exp Immunol 2017; 187:138–45. PubMed PMC

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. PubMed

Holding S, Jolles S. Current screening approaches for antibody deficiency. Curr Opin Allergy Clin Immunol 2015; 15:547–55. PubMed

Holding S, Khan S, Sewell WA, Jolles S, Dore PC. Using calculated globulin fraction to reduce diagnostic delay in primary and secondary hypogammaglobulinaemias: results of a demonstration project. Ann Clin Biochem 2015; 52:319–26. PubMed

Jolles S. Subclinical infection and dosing in primary immunodeficiencies. Clin Exp Immunol 2014; 178(Suppl.1):67–9. PubMed PMC

B cell subsets reconstitution and immunoglobulin levels in children and adolescents with B non-Hodgkin lymphoma after treatment with single anti CD20 agent dose included in chemotherapeutic protocols: single center experience and review of the literature

Consensus Recommendations for the Clinical Management of Hematological Malignancies in Patients with DNA Double Stranded Break Disorders

Antibodies against Pneumococcal Capsular Polysaccharides and Natural Anti-Galactosyl (Alpha-Gal) in Patients with Humoral Immunodeficiencies