Page 813 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 50 Disorders of Phagocyte Function 699

these tests performed on appropriately handled blood samples and likely because of the effects of modifier genes; these patients may
by experienced laboratories to avoid inconclusive or false-normal warrant more aggressive treatment such as bone marrow transplanta-
results. tion (BMT; see later).
Genetic classification is useful primarily for purposes of genetic Several approaches can be used to prevent infections. Patients with
counseling and prenatal diagnosis. With the exception of classic CGD should receive all their routine immunizations on schedule
X-linked disease in a male whose mother is a carrier, determining the (including live virus vaccines), with influenza vaccine administered
specific oxidase gene affected in a given CGD patient (see Table 50.1) each year as well. Cuts and skin abrasions should be cleansed promptly
requires additional laboratory studies. Genetic testing for the four with soap and water and a topical antiseptic applied (2% hydrogen
most common genetic subgroups is commercially available. Labora- peroxide, Betadine ointment, or both). Frequent brushing, flossing,
tories specializing in neutrophil biochemistry can also perform use of antibacterial mouthwash, and professional cleaning of teeth
immunoblot analysis of neutrophil extracts, flavocytochrome b can help prevent gingivitis. Constipation should be avoided because
spectroscopy, or functional analysis of membrane and cytosol frac- it can lead to rectal or anal fissures and abscesses. Early anal infections
tions in the cell-free oxidase assay. In a male with absent flavocyto- can be treated with soaking in soapy water (with or without Betadine).
chrome b without clear evidence for a maternal carrier, it is necessary The frequency of pulmonary infections can be reduced by not using
to search for the mutation in both the gp91 phox and p22 phox genes by commercially available bedside humidifiers; avoiding smoking (ciga-
DNA sequencing or another method of analysis. rettes and marijuana); and refraining from handling decaying plant
Testing for the McLeod red cell phenotype should be done in all materials (e.g., hay, mulch, rotting sawdust), which often contain
patients diagnosed with X-linked CGD. This causes a mild hemo- numerous Aspergillus spp. Avoidance of construction sites, especially
lytic anemia. More importantly, there can be serious problems with demolition of old buildings that may harbor fungi, is recommended.
development of hemolytic antibodies if these patients are transfused. There have been clear outbreaks of Aspergillus pneumonias in immu-
nosuppressed children visiting hospitals undergoing renovation.
There is clear evidence that chronic prophylactic TMP-SMX can
Prognosis and Treatment decrease the number of bacterial infections in CGD patients by more
than half without a concomitant increased risk of fungal infection.
The cornerstones of therapy in CGD are currently (1) prevention In addition, itraconazole is an effective agent for prophylaxis for
and early treatment of infections, (2) aggressive use of parenteral fungal infections in CGD. Liver function tests should be monitored
antibiotics for most infections, (3) use of prophylactic TMP-SMX in patients receiving itraconazole.
(5 mg/kg/day of trimethoprim) or dicloxacillin (25–50 mg/kg/day) Prophylactic rIFN-γ has been another mainstay of current man-
3,8
for sulfa-allergic patients, (4) prophylactic itraconazole (200 mg/day agement of CGD. The clinical benefit of rIFN-γ is probably related
if 13 years of age or older or if weighing at least 50 kg, or 100 mg to generally enhanced phagocyte function and killing by nonoxida-
daily if younger than 13 years of age or weighing less than 50 kg), tive mechanisms because its use is not accompanied by any measur-
and (5) use of prophylactic recombinant human interferon-γ (rIFN-γ; able improvement in NADPH oxidase activity in the vast majority
2
2
0.05 mg/m or 0.0015 mg/kg if less than 0.5 m three times per of CGD patients. In the original multicenter trial, patients were
3,8
week). Using these guidelines, the prognosis for patients with CGD randomized in a double-blind fashion to receive either placebo or
2
has improved dramatically since the disorder was first described in rIFN-γ (0.05 mg/m three times per week). As summarized in Table
the 1950s, when almost all patients died in childhood. In a large 50.5, there was a substantial decrease in the number of serious infec-
study based on data collected by a CGD registry in the United States tions in the rIFN-γ arm. Side effects were observed in some of the
in the 1990s, the overall mortality rate was estimated to be 5% per patients but typically were restricted to mild fever and flu-like symp-
7
year for X-CGD and 2% per year for AR CGD, and a more recent toms. No additional adverse reactions, including any increased inci-
single-institution study on 76 patients reported an overall mortality dence of chronic inflammatory complications, have been noted with
8
rate of 1.5% per year. There is a general consensus that a large more prolonged courses of prophylactic rIFN-γ (more than 10 years),
majority of newly diagnosed children should survive well into their and the patients continued to have a substantial benefit, with fivefold
adult years with aggressive and careful management. As already noted, fewer serious infections compared with the placebo group in the
patients with deficiency of p47 phox have a tendency for milder disease phase III study in Table 50.5. On average, this group of patients
compared with those with flavocytochrome-negative CGD. On the averaged one serious infection per patient every 4 to 5 years. However,
other hand, some patients (usually X-linked) prove to have more rIFN-γ is used less frequently in Europe as nonrandomized data did
frequent serious infections or inflammatory complications (or both), not suggest much benefit, and the usage in a cohort followed at the

TABLE Efficacy of Interferon-γ in Preventing Serious Infections in Chronic Granulomatous Disease
50.5
Clinical Study
Variable Phase III Placebo a Phase III IFN-γ a Phase IV (US) IFN-γ b Phase IV (Europe) IFN-γ c Phase IV IFN-γ d
Patients (n) 65 63 30 28 76
Average duration of therapy on study (years) 0 0.83 1.03 2.4 4.3
Patient-years in study 50.9 52.1 31.10 67.2 328
Serious infections per patient-year 1.1 0.38 0.13 0.4 0.30
Number of hospital days per patient-year 28.2 8.6 2.2 15.0 Not reported
a Results from The International Chronic Granulomatous Disease Cooperative Study Group: A controlled trial of interferon gamma to prevent infection in chronic
granulomatous disease. N Engl J Med 324:509, 1991.
b Results from Weening RS, Leitz GJ, Seger RA: Recombinant human interferon-gamma in patients with chronic granulomatous disease—European follow up study. Eur J
Pediatr 154:295, 1995.
c Results from Bemiller LS, Roberts DH, Starko KM, et al: Safety and effectiveness of long-term interferon gamma therapy in patients with chronic granulomatous disease.
Blood Cells Mol Dis 21:239, 1995.
d Results from Marciano BE, Wesley R, De Carlo ES, et al: Long-term interferon-gamma therapy for patients with chronic granulomatous disease. Clin Infect Dis 39:692,
2004.
IFN, Interferon.