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1026 Part VII: Neutrophils, Eosinophils, Basophils, and Mast Cells Chapter 66: Disorders of Neutrophil Function 1027

including a prominent forehead, deep set eyes, a broad nasal bridge, a was found upon particle ingestion by phagocytes, which was not related
wide fleshly nasal tip, mild prognathism facial asymmetry, and hemi- to mitochondrial oxygen metabolism. Next, it was found that the
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hypertrophy. There is a high incidence of scoliosis, hyperextensible process of phagocytosis was accompanied by the formation of large
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joints, and delayed shedding of the primary teeth. Occasionally, unex- quantities of H O in the cell. Subsequently, it was reported that
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2
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plained osteopenia presents, which is often complicated by recurrent homogenates of phagocytes consume oxygen when incubated with
bone fractures. Additionally, there is an increased risk of both Hodgkin pyridine nucleotides. These observations indicated that an oxidase
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and non-Hodgkin lymphoma. enzyme or enzymes in the phagocytes were activated during phagocy-
Laboratory Features Blood and sputum eosinophilia have tosis to convert molecular oxygen into H O . It was then established
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been a consistent finding in all patients. Patient serum IgE levels that phagocytes from patients with CGD could ingest, but could not
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range from three to 80 times the upper limit of normal. The serum kill, the catalase-positive organisms. Building on previous studies that
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IgE usually rises above 2000 IU/mL and often is elevated at birth. a neutrophil oxidase mediates the increase in oxygen consumption, a
Upon reaching adulthood the IgE may decline over years, despite pyridine-dependent oxidase was found to be deficient in neutrophils of
the clinical abnormalities of STAT3 deficiency. Usually patients have patients with CGD, which led to their inability to reduce the dye nitrob-
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normal concentrations of IgG, IgA, and IgM, and may have elevated lue tetrazolium (NBT) during phagocytosis of particles. Collectively,
levels of IgD. Patients often have abnormally low anamnestic anti- these studies laid the groundwork for subsequent studies to unravel the
body response and poor antibody and cell-mediated responses to biochemical and genetic defects in CGD.
neoantigens. At times the neutrophils and monocytes of patients Epidemiology The incidence of CGD in the United States is 1 per
have a profound chemotactic defect. 200,000 livebirths, based on data from the National Institutes of Allergy
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Differential Diagnosis Autosomal recessive-HIES (AR-HIES) is a and Infectious Disease Registry. Data from the Registry indicates that
distinct clinical entity manifested by elevated IgE ligands, and recurrent 86 percent of patients are male and 14 percent female; 80 percent are
skin and cutaneous viral infections and mutations in DOCK8. 370,375 classified as white, 11 percent as black patients, and 3 percent Asians or
Fatal sepsis occurs in AR-HIES from both Gram-positive and mixed-race patients. Of the 340 patients in the Registry with adequate
Gram-negative bacteria. Patients with AR-HIES have more symp- information for determination genetic transmission, 70 percent had the
tomatic neurologic disease than STAT3 deficiency. Autoimmune X-linked recessive form of the disease.
hemolytic anemia may occur, but neutrophil chemotaxis is normal. Etiology and Pathogenesis Several laboratory tests are used
The genetic mutation underlying AR-HIES remain unclear. Therapy to classify forms of CGD and aid in understanding its pathogenesis
remains supportive. (Table 66–4). The diagnosis of CGD is based on a compatible clini-
Therapy No known therapy is curative, and management deci- cal history and demonstration of a defective respiratory burst. Sev-
sions are based on the clinical findings. Prophylactic trimethoprim- eral methods detect the production of reactive oxidants. The NBT
sulfamethoxazole is effective in reducing infections with S. aureus. method relies on the intracellular reduction of NBT by superoxide
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Type and route of antibiotic therapy are dictated by the results of the anion to a blue formazan precipitate that can be seen microscopi-
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Gram stain and culture in patients with acute bacterial infections. cally. More sensitive methods rely on the reaction of oxidants with
Incision and drainage are essential for the management of abscesses, specific chemiluminescent and fluorescent probes. The patients with
including superinfected pneumatoceles. Eczematoid dermatitis can be CGD may have heterogeneous array of regular symptoms and sever-
controlled with topical glucocorticoids to reduce inflammation and ity, depending on which subunit is defective and on the nature of the
antihistamines to control pruritus. Intravenous immunoglobulin may genetic mutation.
decrease the number of infections for some patients. Attention needs Nicotinamide Adenine Dinucleotide Phosphate-Oxidase Function
to be paid to the scoliosis, fractures and degenerative joints by orthope- Engulfment of microbes by phagocytic cells is associated with a
dists. Retention of primary teeth requires dental expertise. burst of oxygen consumption that is important for microbicidal
Course and Prognosis If the hyperimmunoglobulin E is recognized killing and digestion. The respiratory burst is accompanied, not by
early in life and the patient is maintained on chronic anti-Staphylococcal mitochondrial respiration, but by a unique electron transport chain
antibiotic therapy, the prognosis remains good. Many such patients called the NADPH oxidase. Prior to stimulation, the components of
have reached maturity, indicating that the syndrome is compatible the oxidase are physically separated into two major subcellular loca-
with prolonged survival. Conversely, if the diagnosis is delayed and the tions (Fig. 66–6). The membrane-bound portion of the NADPH oxi-
patient develops infected giant pneumatoceles, secondary fungal infec- dase contains a heterodimeric cytochrome b composed of a large,
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tions may occur, leading to a morbid state. heavily glycosylated subunit with a Mr of 91 kDa, known as a gp91 phox
(91-kDa glycoprotein of the phagocyte oxidase), and a 22-kDa pro-
.
DEFECTS IN MICROBICIDAL ACTIVITY tein known as p22 phox 376,384 Eighty to 90 percent of the cytochrome
b is found in specific and gelatinase granules and secretory ves-
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Chronic Granulomatous Disease icles of the neutrophil and following neutrophil activation translo-
Definition and History CGD is a genetic disorder affecting the function cates to the plasma membrane. 66,318 The heavy chain of cytochrome b
of neutrophils and monocytes. These phagocytic cells are able to ingest, contains sites for heme binding, flavin adenine dinucleotide (FAD)
but not kill, catalase-positive microorganisms because of an inability to groups, and NADPH binding. 385–388 The three-dimensional structure
generate antimicrobial oxygen metabolites (see Table 66–2). It is caused of cytochrome b indicates that the carboxyl-terminal half of the
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by mutations involving one of several genes encoding a component of peptide contains sequences for flavin and NADPH binding. The
the NADPH oxidase. 376 amino half of the molecule is hydrophobic and contains the histi-
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In 1957, two pediatric groups caring for six male infants reported dines that coordinate heme binding. The p22 phox also contains
a clinical disorder of chronic suppurative lymphadenitis and recurrent a site for heme binding. The synthesis of the p22 phox peptide is
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fevers leading to premature deaths in the children. 377,378 In the same absolutely required for stability of gp91 phox and for oxidase activity
time period, three observations assisted in providing the framework in the membrane. The p22 phox also contains proline-rich regions
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to understand the defect in the phagocytes of patients with CGD. Sci- that display consensus protein–protein interactions that provide a
entists described first that a striking increase in oxygen consumption binding site for p47 phox 391
. Three other proteins vital to the function

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