Inherited and acquired clinical disorders of phagocyte function result from defects in one or more of the major steps leading to microbial killing—adhesion, chemotaxis, ingestion, degranulation, and pro duction of microbicidal oxidants (Fig.1). Patients with inherited disorders typically present in infancy or childhood with recurrent, unusual, or recalcitrant bacterial and fungal infections, and it is usually not difficult to determine that these are outside the range of normal. The presentation of these different inherited disorders can overlap, so that a specific diagnosis cannot be made on clinical grounds alone. Infections commonly seen include those of skin or mucosa, lung, lymph node, deep tissue abscesses, or childhood periodontitis. These can often have an indolent presentation with only low-grade fevers. Bacterial sepsis is an unusual initial symptom and usually reflects dis semination from an infected site. Inherited defects in phagocyte function are rare and represent only approximately 20% of the primary immunodeficiencies. Thus children with suspected disorders of host defense should also be screened for defects in humoral, cellular, and complement-mediated immunity. An approach to evaluating the patient with significant recurrent infections is shown in Fig. 2. Patients in whom a defect is identified should be referred to a center specialized in care of such patients.
Fig1. 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), 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 ICAM-1 and 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 phagocytize 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; ICAM-1, intercellular adhesion molecule 1; NADPH, nicotinamide adenine dinucleotide phosphate; PECAM-1, platelet endothelial cell adhesion molecule 1. (Courtesy Kyoto W, Coates TD. A practical approach to neutrophil disorders. Pediatr Clin North Am. 2002;49:929, with permission.)
Fig2. 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 carry out the neutrophil evaluations. Chemotaxis is very difficult to evaluate clinically and should be attempted only in a qualified research laboratory with extensive experience. CBC, Complete blood count; CRP, C-reactive protein; DHR, dihydrorhodamine; ESR, erythrocyte sedimentation rate; FACS, fluorescence-activated cell sorting; HIV, human immunodeficiency virus; IgE, immunoglobulin E; NBT, nitroblue tetrazolium; PHA, phytohemagglutinin; r/o, rule out; SED, sedimentation.
In clinical practice, although nearly all patients with well-characterized phagocyte abnormalities have recurrent or unusual infections, the majority of individuals with histories of persistent or recurrent infections do not have identifiable phagocyte disorders or other immune defects. In some cases, these reflect another underlying medical condition or nonimmunologic problem related to an anatomic or obstructive defect. This chapter focuses largely on disorders in which a good correlation exists between the clinical condition and an identifiable defect in phagocyte function.
