Page 1057 - Williams Hematology ( PDFDrive )

1032 Part VII: Neutrophils, Eosinophils, Basophils, and Mast Cells Chapter 66: Disorders of Neutrophil Function 1033

Most sophisticated procedures can identify the molecular defect. treatment with broad-spectrum parenteral antibiotics is required. Often
Cytochrome b content can be measured in extracts of deter- it is necessary to treat with antibiotics for a prolonged time until the ini-
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gent-disrupted neutrophils by a spectrophotometric assay. Once the tially elevated sedimentation rate approaches normal values. Aspergillus
diagnosis of CGD is made, the genotype can be determined. A mosaic spp. infection requires treatment with amphotericin B or, in refractory
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population of oxidation that has positive and negative neutrophils in cases, with granulocyte transfusions. Glucocorticoids also may be
a male patient’s mother and sister strongly suggests X-linked CGD. useful in the treatment of patients with antral and urethral obstruction.
Lack of a mosaic pattern among female relatives does not rule out the The risk of Aspergillus infection can be reduced by avoiding marijuana
X-linked mode of inheritance because the defect can arise spontane- smoke and decaying plant material, such as mulch and hay, both of
ously. Prenatal diagnosis of CGD is established by analysis of DNA from which contain numerous fungal spores. Long-term oral prophylaxis
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amniocytes or chorionic villus samples. with trimethoprim-sulfamethoxazole (5 mg/kg per day of trimethop-
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Differential Diagnosis Leukocytes from patients with CGD have rim) is an accepted practice in the management of patients with CGD.
normal glucose-6-phosphate dehydrogenase (G6PD) activity. However, Patients have prolonged infection-free periods, which result from the
a few individuals with apparent CGD have been described who have prevention of infections caused by S. aureus, without increasing the
neutrophils that lack or are almost lacking in G6PD activity. 421,422 The incidence of fungal infections. The use of itraconazole prophylactically
erythrocytes of these patients also lack the enzyme, and the patients has reduced the development of fungal infections. 427,428
have chronic hemolysis. In the cases of severe neutrophil G6PD defi- IFN-γ (50 mcg/m , three times per week, subcutaneously) can
2
ciency, an attenuated respiratory burst progressively decreases as a reduce the number of serious bacterial and fungal infections. 427,429
result of the depletion of intracellular NADPH, the primary substrate IFN-γ–enhanced neutrophil function in vitro has not been cor-
for the respiratory burst oxidase. CGD and G6PD deficiency can be related with improvement in the activity of the neutrophil respiratory
distinguished from each other by the hemolytic anemia seen in the lat- burst in patients totally lacking the ability to generate superoxide.
ter disorder and by the fact that erythrocyte G6PD activity is normal in On the other hand, its use increases the neutrophil expression of
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CGD and markedly reduced in G6PD deficiency. A variety of studies the high-affinity Fcγ receptor 1, as well as monocyte expression of
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indicate that the small GTPase Rac-2 plays an essential role in activity FcγRI, FcγRII, FcγRIII, CD11/CD18, and HLA-DR. The IFN-γ
of the NADPH and the actin cytoskeleton in human neutrophils. A protective effect in patients with CGD may involve improved micro-
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toddler has been described as presenting with a perirectal abscess at bial clearance, as suggested by the enhanced phagocytic activity by
5 weeks of age. This patient subsequently had necrosis of the perium- neutrophils of opsonized S. aureus. In rare, X-linked CGD patients
bilical skin and fascia, and his surgical wounds did not heal properly. able to generate some superoxide, IFN-γ programs granulocyte cells
Functionally his neutrophils had multiple defective components; for to increase their expression of cytochrome b, which results in nor-
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x
example, adhesion to ligands for sLe , chemotaxis, release of primary mal superoxide generation. With the use of current prophylactic
azurophil granules upon stimulation with chemotactic peptide, and treatments, the mortality in CGD has been reduced to two patient
failure to undergo the respiratory burst using the same stimulus. 423,424 deaths per year per 100 patients followed. 376
Molecular analysis identified the asparagine for aspartic acid mutation CGD patients with mutations that result in 5 to 10 percent of
at amino acid 57 of one allele of the Rac-2 gene. 423,424 Mutant Rac-2 did normal-functioning amounts of NADPH have a mild phenotype and
not bind GTP and it inhibited and behaved as a dominant negative better clinical prognosis than do patients with complete absence of
to impair Rac-2–mediated activation of the respiratory burst. Fortu- any NADPH-oxidase activity. Similarly, female carriers of X-linked
424
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nately, the youngster was successfully transplanted with marrow from CGD who have only 3 to 5 percent oxidase-normal neutrophils rarely
a HLA-identical older brother. 424 get serious infections suggestive of the CGD clinical phenotype. Thus,
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Therapy, Course, and Prognosis Allogeneic hematopoietic stem even low levels or partial correction by gene therapy of CGD is likely
cell transplantation is the only recognized curative treatment for CGD. to provide clinical benefits. In support of that hypothesis, mouse mod-
Reduced intensity conditioning stem cell transplantation from HLA- els of X-linked and p47 phox -deficient CGD have been developed by gene
matched donors performed in 56 patients with intractable infections targeting. 434,435 Studies in the gp91 phox - and the p47 phox -deficient mouse
and severe inflammation carried a 2-year overall survival of 96 per- models of CGD show that retrovirus-mediated gene-therapy-targeting
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cent. However, vigorous supportive care along with the use of recom- of marrow progenitor cells ex vivo can result in the correction of defects
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binant IFN continues to be the foundation of treatment. Cultures in oxidant production in vivo in blood neutrophils after radiation con-
must be obtained as soon as infection is suspected, as unusual organ- ditioning and transplantation of marrow stem cells. 436,437 Protection
isms are commonly the source of infection and may grow promptly from infection challenge occurred even when the oxidase-corrected
in vitro. Most abscesses require surgical drainage for therapeutic and cells comprised less than 10 percent of circulating neutrophils. These
diagnostic purposes, and prolonged use of antibiotics is often required. promising results suggest that somatic gene therapy can be employed to
If fever occurs, it is advisable to obtain certain studies that aid in the correct defective phagocyte oxidase function in selected patients with
management of septic episodes. These include roentgenograms of CGD. In a phase I clinical trial, gene therapy for p47 phox -deficiency CGD,
the chest and skeleton and a computed tomography (CT) scan of the five adult patients received intravenous infusions of autologous blood
liver because of the frequency of pneumonia, osteomyelitis, and liver stem cells that were ex vivo transduced using a retrovirus encoding nor-
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abscesses. Arrangements should be made for prompt medical atten- mal p47 phox 438
. Although conditioning therapy was not given prior to the
tion at the first signs of infection. With early intervention, many lesions stem cell infusion, functionally corrected neutrophils were detectable
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can be managed by conservative medical means. For example, enlarg- in blood for several months. In another study, long-term high-level
ing lymph nodes often regress when treated with local heat and orally clinical beneficial correction in ex vivo gene therapy of X-linked CGD
administered antistaphylococcal antibiotics. It is particularly important occurred in two adult patients. Nonablative busulfan conditioning
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to obtain a microbiologic diagnosis, and fine-needle aspiration may be was used to augment gene therapy correction. There needs to be cau-
helpful in this regard. In general, antibiotic therapy for the offending tion regarding the long-term stability and safety of gene therapy. For
organisms is indicated and purulent masses should be drained. The instance, there are concerns about gene insertion rendering patients
cause of fever and prostration cannot always be established, and empiric vulnerable to developing an hematological malignancy.

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