Antibody deficiencies

A two-year-old boy is on his fourth course of antibiotics this year for otitis media and has just had his second pneumonia. His immunoglobulins come back with a total IgG well below the age-adjusted reference range. Two doors open from that single result. Through one door sits a child with X-linked agammaglobulinaemia who will need lifelong immunoglobulin replacement and genetic counselling for his mother's carrier relatives. Through the other sits a thriving toddler with transient hypogammaglobulinaemia of infancy who will be normal by age four and needs only a watchful plan. Telling those two children apart — without over-investigating one and under-treating the other — is the whole skill of this topic. [1] [2]

Overview & Definition

An antibody deficiency is a state in which the body cannot produce adequate functional antibody to clear the organisms that antibody normally handles — chiefly encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae, and enteric viruses. The defect may sit anywhere along B-cell development, from the stem-cell stage through to the class-switched plasma cell. Wherever it sits, the clinical fingerprint is the same: recurrent, persistent, severe, or unusual infection, most often of the sinopulmonary tract. [2]

The headline distinction for a general paediatrician is between quantitative defects (the immunoglobulin levels are low) and functional defects (the levels are normal but the antibody does not work). Specific antibody deficiency is the classic functional defect — a child with normal total IgG who nevertheless fails to respond to polysaccharide antigens. This is why a functional vaccine challenge belongs in every work-up, not only when the numbers look low. [4] [10]

Primary antibody deficiencies sit within the International Union of Immunological Societies (IUIS) classification of inborn errors of immunity, most of them in the category of predominantly antibody deficiencies. The 2022 update lists the agreed clinical and laboratory phenotypes, and it is this framework — not a single test — that a fellowship answer is built on. [2]

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1. [1]Boyle JM, Buckley RH. Population prevalence of diagnosed primary immunodeficiency diseases in the United States. J Clin Immunol, 2007.PMID 17577648
2. [2]Bousfiha A, Moundir A, Tangye SG, et al. The 2022 Update of IUIS Phenotypical Classification for Human Inborn Errors of Immunity. J Clin Immunol, 2022.PMID 36198931
3. [3]Winkelstein JA, Marino MC, Lederman HM, Jones SM, Sullivan K, Burks AW, et al. X-linked agammaglobulinemia: report on a United States registry of 201 patients. Medicine (Baltimore), 2006.PMID 16862044
4. [4]Ameratunga R, Gillis D, Steele R Diagnostic criteria for common variable immunodeficiency disorders. J Allergy Clin Immunol Pract, 2016.PMID 27587325
5. [5]Bonilla FA. Personalized therapy for common variable immunodeficiency. Allergy Asthma Proc, 2020.PMID 31888779
6. [6]Seidel MG, Kindle G, Gathmann B, Quinti I, Buckland M, van Montfrans J, et al. The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity. J Allergy Clin Immunol Pract, 2019.PMID 30776527
7. [7]Schütz K, Alecsandru D, Grimbacher B, et al. Imaging of Bronchial Pathology in Antibody Deficiency: Data from the European Chest CT Group. J Clin Immunol, 2019.PMID 30547383
8. [8]Eldeniz FC, Gul Y, Yorulmaz A, et al. Evaluation of the 10 Warning Signs in Primary and Secondary Immunodeficient Patients. Front Immunol, 2022.PMID 35634313
9. [9]Lankisch P, Schiffner J, Ghosh S, et al. The Duesseldorf warning signs for primary immunodeficiency: is it time to change the rules? J Clin Immunol, 2015.PMID 25749910
10. [10]Ameratunga R, Longhurst H, Steele R, et al. Comparison of Diagnostic Criteria for Common Variable Immunodeficiency Disorders (CVID) in the New Zealand CVID Cohort Study. Clin Rev Allergy Immunol, 2021.PMID 34236581