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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.01541

The natural history of untreated primary hypogammaglobulinemia in adults: Implications for the diagnosis and treatment of Common Variable Immunodeficiency Disorders.

 Rohan Ameratunga1*,  Yeri Ahn1, Richard Steele1 and  See-Tarn Woon1
  • 1Auckland City Hospital, New Zealand

Background
Adults with hypogammaglobulinemia are frequently encountered by clinicians. Where IgG levels are markedly decreased, most patients are treated with subcutaneous or intravenous immunoglobulin (SCIG/IVIG), because of the presumed risk of severe infections. The natural history of untreated severe asymptomatic hypogammaglobulinemia is thus unknown. Similarly, there are no long-term prospective studies examining the natural history of patients with moderate reductions in IgG.
Methods
In 2006, we began a prospective cohort study of patients with symptomatic and asymptomatic reductions in IgG who were not immediately commenced on SCIG/IVIG. Over the course of twelve years, one hundred and twenty patients were enrolled in the NZ hypogammaglobulinemia study (NZHS) including fifty-nine who were asymptomatic.
Results
Five patients with profound hypogammaglobulinemia (IgG < 3 g/l), who were not on regular SCIG/IVIG have remained well for a mean duration of 139 months. This study has also shown most asymptomatic patients with moderate hypogammaglobulinemia (IgG 3.0-6.9 g/l) have been in good health for a mean observation period of 96 months. Only one asymptomatic patient with moderate hypogammaglobulinemia experienced progressive decline in IgG levels to < 3 g/l and was accepted for IVIG replacement. None have suffered catastrophic infections or any of the severe autoimmune or inflammatory sequelae associated with Common Variable Immunodeficiency Disorders (CVID). Unexpectedly, 18.1% of asymptomatic and 41.6% of symptomatic hypogammaglobulinemic patients spontaneously increased their IgG into the normal range (≥ 7.0 g/l) on at least one occasion, which we have termed transient hypogammaglobulinemia of adulthood (THA). In this study, vaccine challenge responses have correlated poorly with symptomatic state and long-term prognosis.
Conclusions
In spite of our favourable experience, we recommend patients with severe asymptomatic hypogammaglobulinemia are treated with SCIG/IVIG because of the potential risk of severe infections. Patients with moderate asymptomatic hypogammaglobulinemia have a good prognosis. Patients with symptomatic hypogammaglobulinemia are a heterogeneous group where some progress to SCIG/IVIG replacement, while many others spontaneously recover. This study has implications for the diagnosis and treatment of CVID.

Keywords: CVID, Hypogammaglobinaemia, IVIG = intravenous immunoglobulin, SCIG, HGUS

Received: 28 Apr 2019; Accepted: 20 Jun 2019.

Edited by:

Menno C. Van Zelm, Monash University, Australia

Reviewed by:

Jiri Litzman, St. Anne's University Hospital Brno, Czechia
Virgil Dalm, Erasmus Medical Center, Erasmus University Rotterdam, Netherlands  

Copyright: © 2019 Ameratunga, Ahn, Steele and Woon. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Rohan Ameratunga, Auckland City Hospital, Auckland, New Zealand, immunology@xtra.co.nz