Medicina

Immunol Allergy Clin N Am
28 (2008) 367–386

Common Variable Immunodeficiency:
An Update on Etiology
and Management
Patrick F.K. Yong, MRCPa,b, Michael Tarzi, MRCPb,
Ignatius Chua, MRCPb, Bodo Grimbacher, MDb,*,
Ronnie Chee, MRCP, MRCPathb
a

Department of Clinical Immunology, Kings College Hospital, London SE5 9RS, UK
Department of Immunology and Molecular Pathology, UCL ImmunologyConsortium,
Royal Free Hospital and University College London, Pond Street, London NW3 2QG, UK
b

Common variable immunodeficiency (CVID) is the commonest symptomatic primary immunodeficiency and represents a heterogeneous group
of primary antibody deficiency disorders that on the whole do not yet
have an identified molecular or genetic basis. Patients who have CVID
are prone to recurrentinfections primarily affecting the respiratory tract
and gut, although other atypical presentations and unusual organisms
have been reported. In addition, a significant proportion of patients also
manifest features of immune dysregulation, including autoimmune disease
and granulomatous inflammation, as well as malignant disease. Although
the principal defect is thought to result in failure of B-celldifferentiation
and antibody secretion, multiple abnormalities in almost all other components of the immune system have been described.
Janeway and colleagues [1] have been credited with the first description of
CVID in 1953. In more recent years, significant advances in elucidating
some of the underlying genetic defects and molecular mechanisms in
CVID have contributed to the understanding of humanimmunology and
are likely to have implications beyond the scope of primary immunodeficiency diseases. Clinical care of these patients has also improved with
attempts to classify these patients more accurately to help guide prognosis,
better treatment modalities, and a push toward greater awareness of the
condition and the need for early diagnosis to prevent complications.
* Correspondingauthor.
E-mail address: b.grimbacher@medsch.ucl.ac.uk (B. Grimbacher).
0889-8561/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.iac.2008.01.001
immunology.theclinics.com

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YONG

et al

The exact prevalence of CVID is unknown, although estimates of between
1:10,000 and 1:50,000 have been made [2]. CVID has been defined clinically
by the presence ofrecurrent infection and a reduction in IgG (of at least
2 SD below the mean) and at least one other immunoglobulin isotype, as
well as by a failure to mount a significant specific antibody response to
challenge with vaccination or natural infection [2,3]. For diagnosis, other
known causes of hypogammaglobulinemiadgenetic or acquireddmust be
excluded [3].
The disease occurs equally in bothgenders, and onset of symptoms can
occur at any age, with peaks in the first and third decades [4]. There usually
is a significant interval of 4 to 9 years from onset of symptoms to diagnosis
[4–6], potentially contributing to increased morbidity and poorer outcomes.
CVID usually is sporadic, although familial clustering has been documented
in approximately 10% of patients [7]. In addition, it hasalso been noted that
IgA deficiency occurs in family members of patients who have CVID
[8], consistent with the observation that IgA deficiency can progress to
CVID [9].
Genetic advances
There has been intensive research to identify genetic defects in CVID. To
date, mutations in five genes have been identified that are associated with
a CVID phenotype. Not surprisingly, all are molecules involvedin some
element of B-cell biology. The genetic mutations identified to date result
in defective inducible costimulator (ICOS) on T cells [10], transmembrane
activator and calcium-modulator and cyclophilin ligand interactor (TACI,
encoded by TNFRSF13B) [11,12], CD19 [13], and B-cell activating factor receptor (BAFF-R, encoded by TNFRSF13C) [14] on B cells; as well as a deficiency in MSH5...