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1030 Part VII: Neutrophils, Eosinophils, Basophils, and Mast Cells Chapter 66: Disorders of Neutrophil Function 1031

H O 2 catalase O + H O H O 2
2
2
2
2
E. coli Strep.
H 2 O 2 H 2 O 2 H 2 O 2 H 2 O 2
H 2 O 2 E. coli H 2 O 2 E. coli H 2 O 2 Strep. H 2 O 2

H 2 O 2
H 2 O 2 H 2 O 2 H 2 O 2

Normal CGD
Figure 66–7. The pathogenesis of chronic granulomatous disease (CGD). The manner in which the metabolic deficiency of the CGD neutrophil
predisposes the host to infection is shown schematically. Normal neutrophils accumulate hydrogen peroxide (H O ) in the phagosome containing
2
2
ingested Escherichia coli. Myeloperoxidase is delivered to the phagosome by degranulation, as indicated by the closed circles, and in this setting,
H O acts as a substrate for myeloperoxidase to oxidize halide to hypochlorous acid and chloramines, which kill the microbes. The quantity of H O
2
2
2
2
produced by the normal neutrophils is sufficient to exceed the capacity of catalase, a H O -catabolizing enzyme of many aerobic microorganisms,
2
2
including most Gram-negative enteric bacteria, Staphylococcus aureus, Candida albicans, and Aspergillus spp. When organisms such as E. coli gain entry
into the CGD neutrophils, they are not exposed to H O because the neutrophils do not produce it, and the H O generated by microbes themselves
2
2
2
2
is destroyed by their own catalase. When CGD neutrophils ingest streptococci (Strep.) or pneumococci, these organisms generate enough H O to
2
2
result in a microbicidal effect. On the other hand, as indicated in the middle figure, catalase-positive microbes, such as E. coli, can survive within the
phagosome of the CGD neutrophil.
distant sites and released to establish new foci of infection. Acti- common clinical infections that afflict CGD patients and Table 66–6
405
vation of the oxidase also has a pronounced effect on the pH within cites their prevalence.
the phagocytic vacuole. It is controversial whether activation of the Among the various infections, only perirectal abscess, suppurative
respiratory burst is associated with an alkaline phase, but the pH adenitis, and bacteremia/fungemia differ significantly in prevalence in
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of the phagocytic vacuole becomes more acidic in CGD patients the X-linked recessive and autosomal recessive CGD patients. Each of
than in normal patients. 161,409 The alkaline phase may be important these conditions was twice as common in the X-linked form.
for the antimicrobial and digestive functions of the neutral hydro- The onset of clinical signs and symptoms may occur from early
lases released from the cytoplasmic granules into the vacuole upon infancy to young adulthood. Although the majority of patients with
phagocytosis. In CGD, the phagocytic vacuoles remain acidic and CGD (76 percent) are diagnosed before the age of 5 years, approx-
the bacteria are not digested properly. The impairment in the imately 10 percent are not diagnosed until the second decade of
410
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respiratory burst by CGD neutrophils leads to delayed neutrophil life, and on rare occasions, not until the third decade or later.
apoptosis and subsequent impaired clearance of degenerating neu- The organisms infecting CGD patients have changed considerably
trophils by CGD macrophages, which, in turn, predisposes the host from those initially reported between 1957 and 1976. Staphylococcus
to enhanced inflammation. CGD neutrophils are incapable of gen- caused most of the infections in the initial cases; Klebsiella and E.
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erating NETs and cannot trap microorganisms by this mechanism. coli were then the next most common pathogens. Now Aspergillus
The CGD macrophage is unable to clear CGD neutrophils because is the prominent organism causing pneumonia and is the leading
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of a deficiency of intrinsic IL-4 production, which occurs because cause of death in patients. Invasive aspergillosis can occur in the
of defective phosphatidylserine exposure on CGD neutrophils, that first few months of life in healthy infants as well as in those with
is a necessary requirement to engage CGD macrophage phosphati- CGD. Although aspergillosis is the most common infecting fungus
dylserine membrane receptors and subsequent macrophage activa- in CGD, Candida and several other fungal strains have been inva-
tion. In hematoxylin-and-eosin-stained sections from patients, sive in this disorder. Burkholderia cepacia is another leading cause
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macrophages eventually may contain a golden pigment, which of death in patients with CGD. Serratia marcescens is the third lead-
reflects the abnormal accumulation of ingested material and also ing organism that commonly infects patients with CGD. Infections
contributes to the diffuse granulomata that give CGD its descriptive are characterized by microabscesses and granuloma formation. The
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name. On the other hand, when CGD neutrophils ingest pneu- presence of pigmented histiocytes is helpful in establishing the diag-
mococci or streptococci, these organisms generate enough H O to nosis. Patients may suffer from the consequences of chronic infec-
2
2
result in a microbicidal effect. tions including the anemia of chronic disease, lymphadenopathy,
Clinical Features Although the clinical presentation is variable, hepatosplenomegaly, chronic purulent dermatitis, restrictive lung
several clinical features suggest the diagnosis of CGD. Any patient disease, gingivitis, hydronephrosis, and gastroenteric narrowing.
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with recurrent lymphadenitis should be considered to have CGD. Addi- Patients with CGD are also at risk for developing colitis and chorior-
tionally, patients with bacterial hepatic abscesses, osteomyelitis at mul- etinitis, and discoid lupus erythematosus. 383
tiple sites or in the small bones of the hands and feet, a family history of Several mothers of patients in whom X-linked inheritance was
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recurrent infections, or unusual catalase-positive microbial infections established had an illness resembling systemic lupus erythematosus.
all require clinical evaluation for this disorder. Table 66–5 lists the most Both X-linked and autosomal recessive patients with CGD also have a
Kaushansky_chapter 66_p1005-1042.indd 1030 9/21/15 10:48 AM