Chapter 18 Disorders of Phagocyte Function
Clinical Approach to Patients With Disorders of Phagocyte Function
Index of Suspicion
Patients with disorders of phagocyte function usually present at a young age with recurrent, deep-seated bacterial and fungal infections. Unlike patients with severe neutropenia caused by bone marrow failure, these patients usually do not have sepsis. Blood cultures are often negative. The major diagnostic problem faced by the clinician is to determine if the history of infection is unusual enough to warrant consideration of an underlying neutrophil dysfunction defect. The first point to remember is that primary immunodeficiency disorders are rare and primary neutrophil dysfunction syndromes form only a small percentage of all primary immunodeficiency syndromes. The patient is more likely to have recurrent community-acquired Staphylococcus infection than chronic granulomatous disease.
Specific features that may suggest a phagocytic defect are shown in Figure 18-2. Excellent discussions of this problem have been published (see Kyono and Coates1 and Dinauer and Newburger2). Four aspects of each patient’s infection history should be considered: frequency, severity, location, and responsible pathogen. Patients with unusual features in at least one of these aspects should alert the clinician to a possible underlying phagocyte disorder. When considering frequency, the patient’s age and associated medical conditions must be taken into account. For example, recurrent otitis media in a 2-year-old patient is far less worrisome than a similar history in a 40-year-old patient. The more unusual or severe the infections, the less frequently these have to occur before a phagocyte evaluation is indicated. Infections in unexpected anatomic locations, such as hepatic, pulmonary, and rectal abscesses, may indicate an underlying phagocyte defect. Childhood periodontal disease or gingivitis is distinctly uncommon, and in the absence of neutropenic conditions, strongly suggests underlying neutrophil dysfunction. The identification of certain pathogens (e.g., Serratia marcescens, Klebsiella spp., Aspergillus spp., Nocardia spp., Burkholderia cepacia, invasive candidiasis) in children and young adults can provide the strongest indications for pursuing further studies. A history of delayed separation of the umbilical cord is often mentioned as a sign of phagocytic defect. This is fairly common as an isolated finding and is usually of no significance. However, this is in conjunction with omphalitis or other pyogenic infections raises the possibility of LAD or chemotactic defects. A child with nystagmus, fair skin, and recurrent staphylococcal infections should be evaluated for CHS.
Evaluation
Performing a good history and physical examination to eliminate common causes of recurrent infection is important before looking for rare syndromes. For example, is the recurrent pneumonia caused by an aspirated foreign body in the bronchus? In general, patients should first be evaluated for lymphocyte or complement defects. A useful algorithm is presented in Figure 18-2. Note that testing described in this algorithm is not exhaustive, and patients with truly striking histories of unusual kinds of infections should be referred for further evaluation by specialized research laboratories.
Figure 18-1 STEPS IN THE RESPONSE OF CIRCULATION NEUTROPHILS TO INFECTION.
The adhesion molecule E-selectin is upregulated on endothelial cells in response to inflammatory mediators (interleukin-1 [IL-1], endotoxin, tumor necrosis factor-α [TNF-α]), resulting in rolling attachment and margination through interaction with sialyl Lewis carbohydrates on its surface. Chemoattractants such as IL-8 cause upregulation of neutrophil β2 integrins that, in turn, mediate tight adhesion to intercellular adhesion molecule 1 (ICAM-1) and platelet endothelial cell adhesion molecule 1 (PECAM-1) on endothelial cells. Activated neutrophils can detect as little as a 2% change in the chemoattractant gradient and move to the site of infection. Neutrophils phagocytose bacteria opsonized by antibody and complement. Both oxidative and nonoxidative antimicrobial mechanisms are then used to kill bacteria. Disorders of phagocyte function associated with each of these steps are noted. G6PD, Glucose-6-phosphate dehydrogenase; NADPH, nicotinamide adenine dinucleotide phosphate.
(Modified from Kyoto W, Coates TD: A practical approach to neutrophil disorders. Pediatr Clin North Am 49:929, 2002, with permission.)
Figure 18-2 EVALUATION OF PATIENTS WITH RECURRENT BACTERIAL OR FUNGAL INFECTIONS.
The history, physical examination, and infections episodes in patients with a possible primary neutrophil dysfunction syndrome are noted. The initial evaluation can be done in most clinical laboratories. A qualified reference laboratory with special expertise in this area should do the neutrophil evaluations. Chemotaxis is very difficult to evaluate clinically and should only be attempted in a qualified research laboratory with extensive experience.
CBC, Complete blood count; DHR, dihydrorhodamine; ESR, erythrocyte sedimentation rate; FACS, Fluorescence activated cell sorter; PHA, phytohemagglutinin; r/o, rule out.
Diagnosis of Chronic Granulomatous Disease
The diagnosis of CGD is easily established by doing an NBT slide test or flow cytometry of DHR 123 fluorescence to detect neutrophil NADPH oxidase activity. The NBT slide test is very easy to set up, as is DHR flow cytometry. However, because the probability of getting an abnormal result is very low, there may be confusion in interpretation because of a lack of experience. In the authors’ experience, incorrect positive and negative results have been reported for both assays. Thus, if the index of suspicion is high, consultation should be obtained from a center with extensive experience with the test and with the disorder.
Neutrophil respiratory burst activity is preserved in anticoagulated blood maintained at room temperature for several days; thus, DHR testing can be done 1 to 2 days later after shipping to a commercial laboratory. A normal control should always be shipped with the patient specimen to eliminate problems in specimen handling during transport.
NBT Slide Test
• No NBT reduction (absence of cells with dark blue formazan deposits) in both X-linked and AR forms of CGD (see Fig. 18-3, B).
• Usually no reduction in 50% of cells and normal in 50% for X-linked carrier. The percent positive cells can vary if there is unequal X inactivation and may appear normal or like CGD with extreme lyonization (see Fig. 18-3, C).
• False-positive results can occur (i.e., apparent failure to reduce NBT supporting the diagnosis of CGD) if the neutrophils do not adhere to the slide. This happens with greasy slides or with some cases of LAD. Using PMA to stimulate the cells will avoid this.
DHR Flow Cytometry
• This approach has replaced the NBT slide test in many laboratories. It has the advantage of assessing large numbers of cells and can give quantitation of the amount of oxidant production.
• The change in fluorescence channel number with stimulation is the critical number and not the percent positive cells.
• X-linked CGD patients will not respond at all and show no increase in fluorescence with stimulation (see Fig. 18-3, F).
• X-linked carriers will show about 50% of the cells that respond with a normal increase in fluorescence, and the other half will have no response. Degrees of unequal X inactivation are much more accurately quantified by this assay (see Fig. 18-3, G).
• AR patients, particularly those with absent p47phox, have some response to stimulation and show a small increase in fluorescence (see Fig. 18-3, H). This level of oxidant production is usually not visible on the NBT test.
Related posts:
Heme Biosynthesis and Its Disorders: Sideroblastic Anemia
Infectious Mononucleosis and Other Epstein-Barr Virus–Associated Diseases: Part 2
Thrombotic Thrombocytopenic Purpura and the Hemolytic Uremic Syndrome
Infectious Mononucleosis and Other Epstein-Barr Virus–Associated Diseases: Part 1
Disorders of Coagulation in the Neonate
Inherited Forms of Bone Marrow Failure
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
