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.

NBT Slide Test

DHR Flow Cytometry