746 ■ Part XIV Immunology
neutrophil apoptosis and subsequent clearance of degenerating neutrophils by macrophages, which in turn leads to ongoing local tissue damage from release of proteases and other granule proteins.
Clinical Manifestations Although the clinical presentation is variable, several features suggest the diagnosis of CGD. Any patient with recurrent pneumonia, lymphadenitis, hepatic or other abscesses, osteomyelitis at multiple sites, a family history of recurrent infections, or any infection with an unusual catalase-positive organism requires evaluation. Residual NADPH oxidase may attenuate CGD. The onset of clinical signs and symptoms may occur from early infancy to young adulthood. The attack rate and severity of infections are exceedingly variable. The most common pathogen is S. aureus, although any catalase-positive microorganism may be involved. Other organisms frequently causing infections include Serratia marcescens, Burkholderia cepacia, Aspergillus, Candida albicans, Nocardia, and Salmonella. There may also be i ncreased susceptibility to mycobacterium including the BCG vaccine. Pneumonia, lymphadenitis, osteomyelitis, and skin infections are the most common illnesses encountered. Bacteremia or fungemia occur but are much less common than focal infections. Patients may suffer from the sequelae of chronic infection, including anemia of chronic disease, poor growth, lymphadenopathy, hepatosplenomegaly,, chronic purulent dermatitis, restrictive lung hepatosplenomegaly disease, gingivitis, hydronephrosis, and pyloric outlet narrowing. Perirectal abscesses and recurrent skin infections, including folliculitis, cutaneous granulomas, and discoid lupus erythematosus also suggest the possibility of CGD. Granuloma formation and inflammatory processes are a hallmark of CGD and may be the presenting symptoms that prompt testing for CGD if they cause pyloric outlet obstruction, bladder outlet or ureter obstruction, or rectal fistulae and granulomatous colitis simulating Crohn disease. Laboratory Findings The diagnosis is most often made by performing flow cytometry using dihydrorhodamine 123 (DHR) to m easure oxidant production through its increased fluorescence when oxidized by H 2O2. The nitroblue tetrazolium (NBT) dye test is frequently cited in the literature but is now only rarely used clinically. A few individuals have been described with apparent CGD due to severe glucose-6-phosphate dehydrogenase (G6PD) deficiency,, leading to insufficient NADPH substrate for the phagocyte ciency oxidase. The erythrocytes of these patients also lack the enzyme, leading to chronic hemolysis. Treatment HSCT is the only known cure for CGD. For supportive care, patients with CGD should be given daily oral trimethoprimsulfamethoxazole and an antifungal drug, such as itraconazole (see later), for prophylaxis of infections. Cultures must be obtained as soon as infection is suspected. Most abscesses require surgical drainage for therapeutic and diagnostic purposes. Prolonged use of antibiotics is often required. Aspergillus or Candida infection requires treatment with intravenous antifungal drugs. Granulocyte transfusions may be necessary if antibiotics are ineffective. If fever occurs without an obvious focus, it is advisable to consider the use of radiographs of the chest and skeleton as well as CT scans of the liver to determine if pneumonia, osteomyelitis, or liver abscesses are present. The cause of fever cannot always be established, and empirical treatment with broad-spectrum parenteral antibiotics is often required. The erythrocyte sedimentation rate (ESR) may be used to help determine the duration of antibiotic treatment. Corticosteroids may also be useful for the treatment of children with antral and urethral obstruction or severe granulomatous colitis. Granulomas may be sensitive to low doses of
prednisone (0.5 mg/kg/day); treatment should be tapered over several weeks. Inhibitors of tumor necrosis factor alpha pathways, such as infliximab, should be avoided if possible due to the very high risk of invasive fungal infection. Interferon- γ (IFN (IFN- γ ) 50 µg/m2 3 times/wk reduces the number of hospitalizations and serious infections. The mechanism of action of IFN-γ therapy in CGD is unknown. Itraconazole (200 mg/day for patients >50 kg and 100 mg/day for patients <50 kg and ≤5 yr of age) administered prophylactically reduces the frequency of fungal infections.
Genetic Counseling Identifying a patient’s specific genetic subgroup is useful primarily for genetic counseling and prenatal diagnosis. In cases of suspected X-linked CGD, further analysis is not necessary if the fetus is initially demonstrated to be a 46,XX female. Fetal blood sampling and oxidase function analysis of fetal neutrophils can be used for prenatal diagnosis of CGD. DNA analysis of amniotic fluid cells or chorionic villus biopsy is an option for early prenatal diagnosis in families in which the specific mutation is known. Prognosis The overall mortality rate for CGD is about 2 patient deaths/ yr/100 cases, with the highest mortality among young children. The development of effective infection prophylactic regimens, close surveillance for signs of infections, and aggressive surgical and medical interventions has improved the prognosis. BIBLIOGRAPHY
Please visit the Nelson Textbook of Pediatrics website at www.expertconsult. com for the complete bibliography bibliography .
Chapter 125
Leukopenia Peter E. Newburger and Laurence A. Boxer
Marked developmental changes in normal values for the total white blood cell (WBC) count occur during childhood ( Chapter 708). 708 ). The mean WBC count at birth is high, followed by a rapid fall beginning at 12 hr until the end of the 1st wk. Thereafter, values are stable until 1 yr of age. A slow, steady decline in the WBC count continues throughout childhood until reaching the adult value during adolescence. Leukopenia in adolescents and adults is defined as a total WBC count <4,000/µL. Evaluation of patients with leukopenia, neutropenia, or lymphopenia begins with a thorough history, physical examination, family history, and screening laboratory tests (Table ( Table 125-1). 125-1). NEUTROPENIA
Neutropenia is an absolute neutrophil count (ANC), calculated as the WBC count × % of neutrophils and bands, more than 2 standard deviations below the normal mean. Normal neutrophil counts must be stratified for age and race. For whites over the age of 12 mo, the lower limit of normal for the neutrophil count is 1,500/µL, and for blacks over 12 mo old, the lower limit of normal is 1,200/µL. The relatively lower limit in blacks probably reflects a relative decrease in neutrophils in the storage compartment of the bone marrow. Neutropenia may be characterized as mild neutropenia, with an ANC of 1,000-1,500/µL; moderate neutropenia, with an ANC of 500-1,000/µL; or severe neutropenia, with an ANC <500/µL. This stratification aids in predicting the risk of pyogenic infection; only patients with severe neutropenia have significantly increased susceptibility to lifethreatening infections.
