Page 504 - Clinical Immunology_ Principles and Practice ( PDFDrive )

484 PARt fouR Immunological Deficiencies

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and decreased levels of vitamin A and carotene. The cause of SELECTIVE IGG SUBCLASS DEFICIENCIES
diarrhea and malabsorption in this latter patient subset remains
unclear, and treatment is limited to supportive measures, with Diagnosis
vitamin and mineral replacement as indicated. A diagnosis of clinical immunodeficiency should be supported
Patients with bronchiectasis should be treated aggressively by clear evidence of functional impairment. Most individuals
with replacement therapy. In severe cases, aggressive pulmonary with modest reductions in serum IgG subclass levels are function-
toilet will benefit the patient, including bronchodilator therapy, ally normal. Indeed, individuals with deletions of the heavy chain
position and postural drainage, or other physical therapies. The Ig gene locus, some of whom completely lack IgG1, IgG2, IgG4,
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use of corticosteroids should be avoided. and IgA have been reported to be asymptomatic.
Mothers with IgA deficiency may fail to secrete IgA in their The diagnosis of a functional IgG subclass deficiency can
colostrum. Although colostral IgM levels may be elevated in an thus be made with confidence only when there is both a significant
attempt to compensate for the lack of maternal IgA, the newborn decrease in the serum concentration of a specific isotype and
remains relatively unprotected against intestinal pathogens. Of there is clear evidence of abnormal specific antibody production.
greater concern is the fact that the babies of mothers with Up to 10% of normal males and 1% of normal females have
untreated CVID are born in a state of humoral immunodeficiency IgG4 deficiency, which makes a diagnosis of immunodeficiency
and thus are at risk for life-threatening sinopulmonary infection. as a result of an isolated IgG4 subclass deficiency problematic.
To compensate for the loss of IgG across the placenta and to Among patients with a deficiency of IgG1 or IgG3, documentation
provide the infant with the passive immunity that will be required, of the ability to produce protective titers of antitetanus toxin
the dose of replacement gammaglobulin therapy should be and antidiphtheria toxin antibodies following standard tetanus
increased by 50% during the third trimester of pregnancy. toxoid and diphtheria immunizations is a strong indication that
Splenomegaly is common in untreated patients. Hypersplenism replacement gammaglobulin therapy is likely unwarranted.
in most patients responds to aggressive therapy with antibiotics Similarly, documentation of a strong antipneumococcal polysac-
and IVIG. The presumption is that the hypersplenism is secondary charide response in patients with an apparent IgG2 deficiency
to reactive hyperplasia of lymphoid follicles within the spleen would suggest gammaglobulin replacement is likely not required.
attempting to respond to infection. Development of esophageal IgG2 levels normally begin to rise in childhood later than other
varices or other hematological manifestations of hypersplenism subclasses. Conversely, the lack of a response to vaccination calls
(refractory thrombocytopenia, anemia, neutropenia, and lym- for appropriate prophylactic antibiotic therapy before a trial of
phopenia) may require splenectomy as the therapy of last resort. IVIG is attempted.
The outcome for most such patients has been good, with resolu-
tion of symptoms, although patients with altered TACI alleles Clinical Manifestations
tend to do less well. The clinical spectrum of isolated IgG subclass deficiency is quite
The development of a constellation of pulmonary abnormali- variable, and deficiencies of each of the four IgG subclasses have
ties that include granulomatous and lymphoproliferative histo- been described. Some individuals are referred to the clinical
pathologic patterns (lymphocytic interstitial pneumonia [LIP], immunologist with only a mild reduction of total IgG, but most
follicular bronchiolitis, and lymphoid hyperplasia), termed symptomatic patients have marked deficiencies of one or more
granulomatous–lymphocytic interstitial lung disease (GLILD), IgG subclass despite normal total IgG concentrations. Since
can be an ominous sign. These patients appear more likely to IgG1 makes up the majority of serum IgG in most patients,
develop granulomatous liver disease, autoimmune hemolytic a deficiency of IgG1 tends to correlate with depressed serum
anemia, lymphoproliferative disease, and progressive pulmonary levels of total IgG.
disease. 37 Determination of IgG subclasses is rarely performed on
asymptomatic individuals; thus most patients with an isolated
IgG2 deficiency come to medical attention as a result of recurrent
sinusitis, otitis media, or pulmonary infections. Individuals may
have few residual symptoms between infections, but some have
tHERAPEutIC PRINCIPLES severe chronic inflammation with refractory sinusitis, pulmonary
fibrosis, or bronchiectasis. Because protective antibodies directed
• The primary goal of treatment is to keep the patient infection free. against carbohydrate antigens are usually of the IgG2 subclass,
• In patients whose respiratory mucosa is intact, intravenous or subcutane- many affected patients exhibit an impairment of their ability to
ous replacement immunoglobulin G (IgG) therapy is generally effective
in protecting the patient from pulmonary infections. mount specific protective responses to encapsulated pathogens.
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• For those patients who have developed bronchiectasis or who continue However, normal responses have also been described. Many
to subject themselves to environmental toxins (e.g., smoking), replace- clinicians would agree, however, that patients with IgG2 deficiency,
ment IgG will ameliorate but may not prevent all such infections. who suffer from recurrent sinopulmonary infections and who
• Because mucosal Ig cannot be replaced, even patients on adequate respond to less than half of the polysaccharide antigens with
IgG replacement therapy remain at risk for sinus or gastrointestinal which they have been challenged, meet the standard for functional
infections.
• Prophylactic antibiotics that are effective against encapsulated organisms immune deficiency and thus warrant aggressive prophylactic
can significantly reduce the frequency of upper respiratory tract therapy up to and including Ig replacement should the infections
infections in patients who continue to suffer in spite of replacement be severe.
therapy with intravenous immunoglobulin (IVIG). IgG3 deficiency can occur alone or in association with IgG1
• Prolonged diarrhea in patients with hypogammaglobulinemia is often deficiency. Recurrent infection of the respiratory tract with
caused by Giardia lamblia and responds well to metronidazole therapy. chronic lung disease has been reported. With a serum half-life
• Patients with primary antibody deficiencies should not receive live
vaccines. only 2 weeks, IgG3 levels may be consumed rapidly during the
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course of an active infection in an otherwise normal individual.