Clinical Medicine 2016 Vol 16, No 6: 571–6 CME IMMUNOLOGY AND ALLERGY Secondary antibody deficiency – causes and approach to diagnosis Authors: S a p n a S r i v a s t a v a A a n d P h i l i p W o o d A Antibody defi ciencies can occur in the context of primary patients who could be potentially affected are fully assessed and disorders due to inherited genetic defects; however, secondary monitored for antibody deficiency and prophylactic measures, immune disorders are far more prevalent and can be caused such as antibiotics or immunoglobulin replacement therapy by various diseases and their treatment, certain medications (IgRT), are promptly instituted to prevent end organ damage. and surgical procedures. Immunoglobulin replacement Not all forms of secondary hypogammaglobulinaemia are ABSTRACT therapy has been shown to be effective in reducing infections, thought to confer an increased risk of infections, but this has morbidity and mortality in primary antibody defi ciencies not been well studied for the majority of conditions.2 but secondary antibody defi ciencies are in general poorly defi ned and there are no guidelines for the management of M e d i c a t i o n s patients with this condition. Clinical decisions are based on experience from primary antibody defi ciencies. Both primary There are many classes of drugs that can cause antibody and secondary antibody defi ciencies can be associated with deficiency and, therefore, a complete drug history is infections, immune dysregulation and end-organ damage, mandatory. Both long- and short-term systemic treatment causing signifi cant morbidity and mortality. Therefore, it is with corticosteroids have been associated with decreased 4 important to diagnose and treat these patients promptly to immunoglobulin levels but not increased infection rates. minimise adverse effects and improve quality of life. We focus on secondary antibody defi ciency and describe the causes, diagnosis and treatment of this disorder. Key points Secondary antibody deficiency is most commonly caused by Definition and causes lymphoproliferative disorders and drugs Antibody deficiency is defined quantitatively by an immunoglobulin (IgG) level significantly below the These patients have an increased risk of infection, which may be normal range or a failure of immunoglobulin function life-threatening because of quantitative and qualitative defects (hypogammaglobulinaemia). Primary antibody deficiencies are in the humoral immune response caused by genetic defects that usually affect B-cell development 1 and/or function. The majority of these are likely to have a A full immunological work-up, including measurement of specific polygenic aetiology. Hypogammaglobulinaemia can also be antibody responses, IgG subclasses and frequency of infections, due to conditions that result in immunoglobulin loss or affect is required to assess potential susceptibility to infections in B-cell numbers and/or function. Causes of secondary antibody hypogammaglobulinaemic patients deficiencies include protein losing states – such as nephrotic syndrome – and protein-losing enteropathy, hematologic In patients with low immunoglobulin levels, vaccination malignancies, chemotherapy, solid-organ transplantation, response to the pneumococcal polysaccharide vaccine should be infectious diseases and the adverse effects of specific therapeutic 2,3 checked to give an indication regarding immune function, even drugs ( Table 1 ). if the patient has not suffered with infections, as they may be at The clinical significance of this condition is the risk of risk of severe sepsis life-threatening infections by encapsulated organisms, such as streptococcus and Haemophilus influenzae (normally dealt There are no clear guidelines for the management of secondary with by antibody responses), which makes it crucial that antibody deficiency. KEYWORDS: antibody deficiency, immunodeficiency, immunoglobulin replacement, malignancy, secondary A Authors: consultant clinical immunologist, Department of Clinical hypogammaglobulinaemia Immunology and Allergy, St James’s University Hospital, Leeds, UK . © Royal College of Physicians 2016. All rights reserved. 571 CMJv16n6-CME_Wood_Johnston.indd 571 21/11/16 12:26 PM CME Immunology and allergy Patients with asthma and hypogammaglobulinaemia Table 1. Conditions causing secondary antibody secondary to corticosteroid use retain specific antibody deficiency responses and, thus, are not necessarily candidates ≥ Malignancy Chronic lymphocytic leukaemia for IgRT. Patients who take daily doses of 12.5 mg prednisone for 1 year or more are more likely to have Multiple myeloma hypogammaglobulinaemia and IgG levels are inversely Good's syndrome correlated with corticosteroid dose. 4 Non-Hodgkin lymphoma Immunosuppressants combined with corticosteroids may create an even greater propensity toward hypogammaglo- Immunoglobulin loss Protein losing enteropathy bulinaemia. Biological drugs can cause secondary Nephrotic syndrome hypogammaglobulinaemia and this should be borne in Plasma exchange mind when commencing these drugs ( Fig 1 , Table 2 ). Such treatments are commonly used in patients with autoimmune Severe dermatitis and neoplastic diseases. An example is rituximab, which is Drugs an anti-CD20 monoclonal antibody. Rituximab may cause Anticonvulsants Phenytoin, carbamazepine, hypogammaglobulinaemia, particularly if given in multiple valproate, lamotrigine cycles and in those patients with lower antibody levels pre- treatment. It is particularly associated with infections when Immunomodulatory Long-term or frequent combined with other chemotherapeutic agents.4 R i t u x i m a b corticosteroids Gold, targets peripheral B-cells and can deplete them for several penicillamine, sulfasalazine months. Although usually transient, hypogammaglobulinaemia cyclophosphamide, can be persistent and clinically significant, requiring azathioprine mycophenolate intravenous immunoglobulin therapy to control infections. 5 (in allogeneic and solid organ Rituximab illustrates the point that transient or permanent transplantation) derangement of humoral immune function can be caused by Anti-B-cell antibodies Rituximab biological treatment; vigilance for this is essential. Belimumab Periodic monitoring after rituximab therapy for recovery of B-cell numbers, serum immunoglobulins and vaccine Infections Epstein-Barr virus, responses may help identify patients that develop persistent cytomegalovirus, HIV, parvovirus hypogammaglobulinaemia and would benefit from IgRT B19, congenital rubella before they have significant infections. Rituximab-induced Table 2. Biological drugs causing secondary hypogammaglobulinaemia Mechanism of action Target Drug Use B-cell depleting Anti-CD20 Rituximab Haematological B-cell malignancies, lupus Ocrelizumab nephritis, ANCA-associated vasculitis Ofatumumab Veltuzumab Obinutuzumab Anti-CD52 Alemtuzumab Chronic lumphocytic leukaemia, multiple sclerosis, T-cell lymphoma, conditioning regimen for transplant Anti-CD74 Milatuzumab Non-Hodgkin lymphoma, chronic lymphocytic leukaemia, multipke myeloma Inhibiting B-cell survival Anti-BAFF Belimumab Clinical trials for autoimmune disease and Tabalumab haematological malignancies Atacicept (also antagonises effect of APRIL) Inhibiting B-cell activation Anti-CD22 Epratuzumab Proteosome Bortezomib Multiple myeloma, mantle cell lymphoma inhibition Anti-TKI Imatinib Chronic myelogenous leukaemia, gastric Dasatinib stromal tumour Inhibiting T-cell/B-cell interaction Anti-CD80/86 Abatacept Rheumatoid arthritis ANCA = anti-neutrophil cytoplasmic antibody; APRIL = a proliferation inducing ligand; BAFF = B-cell activating factor; CD = cluster of differentiation TKI = angiogenic tyrosine kinase inhibitor 572 © Royal College of Physicians 2016. All rights reserved. CMJv16n6-CME_Wood_Johnston.indd 572 21/11/16 12:26 PM CME Immunology and allergy Hypogammaglobulinaemia Clinical history/secondary cause • Clinical signs/symptoms of lymphoproliferave disorder • Corcosteroids/immunosuppressants, anconvulsants • Previous cytotoxic chemotherapy for malignancy, treatment for autoimmune disease • Protein loss – diarrhoea, oedema, low albumin, elevated protein/creanine rao Tests • FBC with differenal, renal and liver funcaon, bone profile, inflammatory markers • Lymphocyte subsets • Immunoglobulin levels with serum electrophoresis and immunofixaon • Urine for Bence-Jones protein • Specific anbodies to pneumococcus, tetanus and Haemophilus influenzae B (including test vaccinaon and post vaccinaon response if low) • IgG subclasses • Urine protein/creanine rao Infecons? Yes** No Consider IgRT IgG levels <4?* Fig 1. Investigation and management of secondary antibody defi ciency. *Patients with Yes No secondary antibody defi ciencies may have a Consider IgRT Poor specific normal IgG level but poor specifi c antibody anbody responses? responses making them susceptible to infections; immunoglobulin replacement therapy should be considered. **Consider a trial of prophylactic antibiotics before resorting to No Yes immunoglobulin therapy. FBC = full blood count; No IgRT Consifer IgRT IgG = immunoglobulin G; IgRT = immunoglobulin Monitor replacement therapy hypogammaglobulinaemia may persist for a prolonged period M a l i g n a n c i e s of at least 2 years, likely because of the different mechanisms involved. 6 It is currently unclear whether antibody levels ever Malignancies, especially lymphoproliferative disorders (chronic 9 recover in some patients after chemotherapy treatments such as lymphocytic leukaemia (CLL) and myeloma), are commonly rituximab.