Page 501 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHAPtER 34 Primary Antibody Deficiencies 481

concentrations to IgA deficiency to IgA deficiency with IgG
subclass deficits to frank CVID have been documented in both
sporadic and familial cases. 2
CVID is a diagnostic category of primary immunodeficiencies
that includes a number of immune disorders. Most patients of
Northern European descent with CVID exhibit a distinctive
phenotype characterized by a broad deficiency of Ig isotypes in
spite of the presence of normal numbers of surface Ig bearing
B-cell precursors in peripheral blood. Almost all of these patients
are IgA deficient and, by definition, demonstrate total serum
IgG levels of <500 mg/dL. Some IgG subclasses are more affected
than others, with the sequential order of involvement being IgG4
> IgG2 > IgG1 > IgG3. Most patients are also deficient in IgM
and IgE.
Patients with uncomplicated conditions demonstrate normal
cell-mediated immunity, although a minority of patients may fIG 34.4 Hypogammaglobulinemic Sprue in a 41-Year-Old
have evidence of T-cell dysfunction as well as other hematopoietic White Male With Common Variable Immune Deficiency (CVID)
cell types. In some cases, B-cell numbers are reduced, although and Insulin-Dependent Diabetes Mellitus. The patient suffered
not to the extent exhibited by disorders of pre-BCR formation from intractable diarrhea. Shown is a hematoxylin and eosin
or BTK signaling. (H&E) stain of a duodenal biopsy obtained by endoscopy. The
IgAD and CVID have been associated with congenital infection villi are blunted, and there is a marked increase in intraepithelial
with rubella virus, CMV, and T. gondii. The administration of lymphocytes. However, unlike typical celiac disease, the villi are
certain drugs has also been linked to a depression in serum Ig not completely blunted, and few plasma cells are seen. The
levels (see Table 34.1). Several medications used to treat epilepsy patient is homozygous for the HLA-DQ2, -DR17(3), -B8 haplotype.
have been associated with the development of antibody deficien- Although the patient failed to respond to a gluten-free diet, the
cies. For example, up to 20% of patients treated with phenytoin diarrhea resolved with corticosteroid therapy.
develop a mild decrease in serum IgA levels, and a minority may
progress to a CVID-like phenotype. Medications used for the
treatment of rheumatoid arthritis, inflammatory bowel disease,
and chronic myelogenous leukemia can also decrease production species and thus require antibiotic therapy. Paradoxically, antigen-
of antibody. Persistence of antibody deficiency usually requires specific IgE can be produced in sufficient quantities to enable
choosing between discontinuation of the drug and persisting anaphylactic reactions.
infection with the virus or parasite. Recovery of Ig production Patients with CVID are often anergic, but only a minority
may take months to years. suffers infections characteristic of cell-mediated immune dysfunc-
tion, including mycobacteria, P. jiroveci, and fungi. CD8 T-cell
Clinical Manifestations numbers may be depressed in such patients. Most viral infections
Although some patients with CVID have reduced numbers of are cleared normally. Exceptions include enteroviral infections,
circulating B cells, the majority has normal quantities of IgA, including meningoencephalitis, as well as hepatitis B and C,
IgG, and IgM-bearing B-cell precursors in the blood. Defects in which can progress to chronic active hepatitis. Lack of humoral
+
B-cell survival, number of circulating CD27 memory B cells immunity enhances susceptibility to viral reactivation. Untreated
+
+
(including IgM CD27 B cells), B-cell activation after antigen patients often complain of recurrent herpes zoster (shingles).
receptor cross-linking, T-cell signaling, and cytokine expression Autoimmune diseases are common in CVID. Coombs-positive
have been observed. Both increases and decreases in the relative hemolytic anemia with idiopathic thrombocytopenic purpura,
numbers of CD4 to CD8 T cells are common, and cutaneous a combination known as Evans syndrome, may predate the
anergy is a frequent finding. diagnosis of CVID.
The clinical manifestations of CVID are similar but more Noncaseating granulomas in the lungs, lymph nodes, skin,
severe than the ones seen in IgAD. Respiratory symptoms often bone marrow, and liver reminiscent of or indistinguishable from
begin with recurrent sinusitis, otitis media, and mild bronchitis. sarcoid-like syndrome is more common in African Americans
The frequency and severity of the upper respiratory infections but can be seen in up to one-fifth of all patients. Occasionally
worsen in the young adult, and lower respiratory infections, the granulomas result from mycobacterial and fungal infections.
such as pneumonia, become common. Apparently asymptomatic, In the majority of cases, the cause remains unclear, and the
untreated patients may suffer recurrent subclinical pulmonary granulomas resolve spontaneously.
infections that can lead to irreversible chronic lung damage with There is an increased risk for the development of GI and
bronchiectasis, unilateral hyperlucent lung, emphysema, and cor lymphoid malignancies, especially non-Hodgkin lymphomas.
pulmonale. Recurrent cellulitis, boils, folliculitis, impetigo, or Confounding the diagnosis of malignancy is the patients’
erythroderma can be presenting complaints. propensity to develop benign lymphoproliferative disorders.
Intermittent or chronic diarrhea due to G. lamblia is a common Lymphadenopathy, splenomegaly, or a combination of both is
complaint. Patients can develop a malabsorption syndrome that common in untreated patients.
resembles celiac sprue but is unresponsive to gluten avoidance
(Fig. 34.4). Untreated patients often complain of asymmetrical, Origin and Pathogenesis
oligoarticular arthralgias or frank arthritis, which in some cases The typical presenting manifestation of CVID is hypogamma-
reflect infections with encapsulated organisms or with Mycoplasma globulinemia, not agammaglobulinemia, suggesting a partial or