360
U N I T 4
Infection and Immunity
media and sinus and pulmonary infections), but the
onset of infections occurs much later, usually between
the ages of 15 and 35 years. In contrast to X-linked
agammaglobulinemia, the sex distribution in CVID is
almost equal. Most persons with CVID have no iden-
tified molecular diagnosis. Because the disorder occurs
in first-degree relatives of persons with IgA deficiency,
and some persons with IgA deficiency develop agam-
maglobulinemia, these disorders may have a common
genetic basis.
Persons with CVID often have autoantibody for-
mation and normal-sized or enlarged tonsils and
lymph nodes, and approximately 25% have spleno-
megaly.
35
They have an increased tendency toward
development of interstitial lung disease, autoim-
mune disorders, hepatitis, and chronic diarrhea with
associated intestinal malabsorption. There is also an
increased risk of gastric cancer and non-Hodgkin
B-cell lymphoma.
Treatment methods for CVID are similar to those
used for X-linked agammaglobulinemia, with IVIG
being the cornerstone of therapy. Anaphylaxis to IgA
in the IVIG can occur in persons with CVID who are
IgA deficient. The use of IgA-depleted IVIG has greatly
reduced this risk.
Selective Immunoglobulin A Deficiency.
Selective
IgA deficiency is the most common type of immuno-
globulin deficiency.
2
The syndrome is characterized by
moderate to marked reduction in levels of serum and
secretory IgA, probably due to a block in the path-
way that promotes terminal differentiation of mature
B cells to IgA-secreting plasma cells. The occurrence of
IgA deficiency in both men and women and in mem-
bers of successive generations within families suggests
autosomal inheritance with variable expressivity. The
disorder has also been noted in persons treated with
certain drugs (e.g., phenytoin, sulfasalazine), sug-
gesting that environmental factors may trigger the
disorder.
35
Although an IgA deficiency can occur in apparently
healthy persons, it is commonly associated with repeated
infections in the respiratory, gastrointestinal, and uro-
genital systems. Persons with IgA deficiency also can
develop antibodies against IgA, which can lead to severe
anaphylactic reactions when blood components con-
taining IgA are given.
5
Therefore, only specially washed
erythrocytes from normal donors or erythrocytes from
IgA-deficient donors should be used.
There is no specific treatment available for selective
IgA deficiency unless there is a concomitant reduction
in IgG levels. Administration of IgA immune globulin is
of little benefit because IgA has a short half-life and is
not secreted across the mucosa. There also is the risk of
anaphylactic reactions associated with IgA antibodies in
the immune globulin.
Immunoglobulin G Subclass Deficiency.
An IgG
subclass deficiency can affect one or more of the IgG
subtypes, despite normal levels or elevated serum con-
centrations of IgG. In general, antibodies directed
against protein antigens belong to the IgG
1
and IgG
3
subclasses, and antibodies directed against carbohy-
drate and polysaccharide antigens are primarily from
the IgG
2
subclass. As a result, persons who are deficient
in IgG
2
subclass antibodies can be at greater risk for
development of sinusitis, otitis media, and pneumonia
caused by polysaccharide-encapsulated microorgan-
isms such as
S. pneumoniae, H. influenzae
type b, and
N. meningitidis.
Children with mild forms of the deficiency can be
treated with prophylactic antibiotics to prevent repeated
infections. Intravenous immunoglobulin can be given to
children with severe manifestations of this deficiency.
The use of polysaccharide vaccines conjugated to pro-
tein carriers can provide protection against some of
these infections, whereas protein vaccines conjugated to
protein carriers would stimulate an IgG
1
response.
X-linked Immunodeficiency with Hyperimmuno
globulinemia M.
Hyper-IgM syndrome
is character-
ized by low IgG and IgA levels with normal or, more
frequently, high IgM concentrations.
35
Being predomi-
nantly an X-linked recessive disorder, the disease is
primarily seen in boys. Formerly classified as a B-cell
defect, it now has been traced to a T-cell defect. The
disorder results from the inability of T cells to signal B
cells to undergo isotype switching to IgG and IgA; thus,
they produce only IgM.
35,39
Like those with X-linked agammaglobulinemia,
affected individuals become symptomatic during the
first and second years of life. They have recurrent pyo-
genic infections, including otitis media, sinusitis, tonsil-
litis, and pneumonia. Persons with the syndrome are
also at increased risk for development of autoimmune
diseases of the formed elements of the blood, includ-
ing hemolytic anemia, thrombocytopenia, and recurrent
severe neutropenia.
35,39
Cellular (T-Cell) Immunodeficiency Disorders
Unlike B cells, in which a well-defined series of differ-
entiation steps ultimately leads to the production of
immunoglobulins, mature T lymphocytes consist of dis-
tinct subpopulations with diverse immunologic assign-
ments.
39
They protect against fungal, protozoan, viral,
and intracellular bacterial infections; control malignant
cell proliferation; and are responsible for coordinating
the overall immune response.
In general, persons with T-cell–mediated immu-
nodeficiency disorders have infections or other clini-
cal problems that are more severe than those seen
with antibody disorders. Children with defects in this
branch of the immune response rarely survive beyond
infancy or childhood unless immunologic reconstitu-
tion is achieved.
35
However, exceptions are being rec-
ognized as newer T-cell defects, such as the X-linked
hyper-IgM syndrome, are identified.
35
Other recently
identified primary T-cell immunodeficiency disorders
result from defective expression of the TCR complex,
defective cytokine production, and defects in T-cell
activation.
