Page 814 - Hematology_ Basic Principles and Practice ( PDFDrive )

700 Part VI Non-Malignant Leukocytes

National Institutes of Health was recently reported to be only 36% not solve the problem because only 50% of the mother’s blood
because of either lack of access or because of side effects (fever, will match. Because of the difficulty in finding blood, transfusion
myalgia); the availability of more potent antifungals and oral antibiot- with non-McLeod blood is likely to occur. Although management is
ics may be a mitigating factor for reducing serious infectious compli- difficult and use of steroids is necessary, the hemolytic anemia can
cations in the absence of prophylactic rIFN-γ. be managed successfully.
One of the most frequent errors in the management of CGD Allogeneic BMT can be used to treat CGD, including using
patients is the failure to treat potentially serious infections promptly matched unrelated donors. 8,15 Because of the risks associated with this
and aggressively with appropriate parenteral antibiotics. Even the procedure, BMT is generally considered only for patients who have
best antibiotics can be rendered ineffective if given too late in the a fully human leukocyte antigen-matched sibling and frequent and
course of an infection in CGD. Therefore, early intervention is severe infections despite aggressive medical management. However,
advisable. Although many of the minor infections and low-grade reduced-intensity conditioning regimens for allogeneic transplanta-
fevers in CGD patients can be managed on an outpatient basis, tions have now been successfully used for BMT in CGD, including
episodes of consistently high fever over a 24-hour period or clearly several cases with ongoing fungal infections. 8,15 Despite improved
established infections (e.g., pneumonia or lymphadenitis) should be success rates and decreased complications, which patients with CGD
treated with parenteral antibiotics that cover, at least initially, S. should undergo transplantation remains an individualized decision,
aureus and enteric gram-negative organisms. Reasonable attempts to particularly for those with residual NADPH oxidase activity and little
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define the source of the infection and the responsible microbe should or no history of serious infection or other complications. Finally,
also begin promptly. Monitoring markers of inflammation such as the genetic therapies aimed at correcting the defective gene in BM stem
erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) cells hold promise for the future if obstacles can be solved to achieve
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can be very useful, both as a clue to the presence of a significant effective and safe gene delivery and their transplantation. Observa-
infection as well as following the patient’s response to therapy. If the tions on female carriers of X-linked CGD with skewed X-inactivation
patient fails to respond, then more aggressive diagnostic procedures and preclinical studies in murine CGD models suggest that com-
should be instituted (computed tomography, bone, and gallium plete correction of NADPH oxidase activity in 10% of circulating
scans; open biopsies if indicated) and empirical changes in the anti- neutrophils will lead to clinically relevant improvements in host
biotics used to broaden coverage to Pseudomonas cepacia. If fungus defense.
is identified or strongly suspected, amphotericin B has been the
drug of choice in the past, but newer azole antifungal agents such as
voriconazole are supplanting its use. Even with appropriate antibiot- Neutrophil Glucose-6-Phosphate
ics, certain types of infections respond slowly and may require many Dehydrogenase Deficiency
months of therapy. Surgical drainage or resection can sometimes
play a key role in accelerating healing of certain types of infec- NADPH, the primary substrate for the respiratory burst oxidase, is
tion such as lymphadenitis, osteomyelitis, and abscesses of visceral generated by the first two reactions of the hexose monophosphate
organs such as the liver or lung. Finally, granulocyte transfusions shunt pathway, which are catalyzed by G6PD (see Fig. 50.3, reaction
16
may be of benefit in the treatment of stubborn or life-threatening 8) and 6-phosphogluconate dehydrogenase (6PGD). The leukocyte
infections. 3,7,8 and erythrocyte G6PD are encoded by the same gene. Thus, a severe
Recurrent fever in CGD always raises the possibility of infection deficiency of G6PD in neutrophils can result in a greatly attenuated
in these patients; however, the macrophage activation syndrome respiratory burst because of low levels of NADPH. However, the vast
(MAS)–hemophagocytic lymphohistiocytosis (HLH) spectrum of majority of individuals with inherited G6PD deficiency do not have
disorders should be considered, especially if the patient has sple- problems with a decreased respiratory burst or recurrent infections.
nomegaly, leukopenia, or thrombocytopenia. As in inflammatory A CGD-like syndrome has very rarely been observed in G6PD-
disorders such as rheumatoid arthritis, secondary MAS-HLH has deficient patients who have congenital nonspherocytic hemolytic
been reported in CGD and is probably often overlooked. Specific anemia (CNSHA), in whom hemolysis occurs in the absence of redox
treatment may be indicated, especially if the patient has significant stress. 3,16 Even in CNSHA, most G6PD mutations cause the enzyme
cytopenias or evidence of hepatic dysfunction. to decay over a period of days and weeks, so that levels in the short-
Use of corticosteroids should generally be avoided, including lived neutrophil usually do not become critically low even in some
extensive topical use, except in cases of severe asthma, esophageal of the most unstable G6PD variants. A few rare and poorly under-
strictures, gastric antral narrowing, granulomatous cystitis, inflam- stood G6PD mutations that cause CNSHA are associated with
matory bowel disease, or certain cases of pneumonia. Clear evidence extremely low (<5% of normal) levels of G6PD in the neutrophil,
shows that corticosteroids are beneficial in these clinical settings resulting in a deficient respiratory burst and CGD-like symptoms.
because the steroids induce rapid regression of obstructive symptoms The combination of chronic, severe hemolytic anemia, recurrent
at low oral doses (e.g., 1 mg/kg/day of prednisone). Steroids can infections, and the laboratory demonstration of extremely low G6PD
be lifesaving in young children with airway obstruction because of levels in neutrophils and erythrocytes serves to distinguish this disease
inflammation. Because of the exaggerated inflammatory reaction from CGD. The treatment for neutrophil G6PD deficiency is the
seen in CGD, there can be significant swelling in the airway and same as for CGD, except that the efficacy of rIFN-γ has not been
compression by pulmonary nodes that can block air movement and demonstrated in the former. The chronic hemolytic anemia is treated
impede drainage. In these cases, the physician and patient should be by supportive means, including transfusions.
aware of the risks of the additional immunosuppression caused by
the corticosteroids.
Rare patients with X91° CGD have genomic deletions that span Disorders of Glutathione Metabolism
the gp91 phox gene and the Xk gene, which encodes a membrane
3
protein necessary for expression of the Kell genes. Absence of the As depicted in Fig. 50.3 (reaction 6), the reduced form of glutathione
Xk gene product results in the McLeod syndrome, in which red (GSH) serves to protect the neutrophil from the harmful effects of
blood cells have weak Kell antigens and variable acanthocytosis hydrogen peroxide on NADPH oxidase and other neutrophil pro-
along with nerve and muscle disorders related to its expression in teins. Adequate intracellular levels of GSH are maintained by recycling
nonerythroid tissues. Transfusion of patients with McLeod syndrome oxidized glutathione (GSSG) to GSH by glutathione reductase (see
poses a serious problem because they can develop alloantibodies of Fig. 50.3, reaction 7), as well as by de novo synthesis of glutathione
wide specificity that can preclude any further transfusions except with by glutathione synthetase (see Fig. 50.3, reaction 9). Severe deficien-
Kell-negative blood products. McLeod-matched blood is extremely cies in either of these enzymes are extremely rare and are apparently
3
rare, and patients with this syndrome should have their own blood inherited in an AR manner. In the case of glutathione reductase
frozen in case it is needed. Note that use of maternal blood does deficiency, the respiratory burst terminates prematurely, presumably