Primary phagocytic disorders of childhood.

Primary phagocytic disorders are rare and, usually but not invariably, first manifest during childhood, so pediatricians must be familiar with these disorders to enable early diagnosis and appropriate institution of therapy. When should a primary phagocytic disorder be considered? As a general rule, infections by common pathogens that are unusually severe or recurrent and infections by opportunistic pathogens should prompt consideration of an immunodeficiency. Multiple soft-tissue infections requiring surgical debridement, severe dental infections leading to premature tooth loss during childhood or adolescence, and recurrent anorectal infections are common harbingers of a phagocytic disorder. In contrast, relatively benign infections, such as paronychiae and furunculosis, are common and alone do not merit evaluation for an immunodeficiency. Patients with phagocytic disorders are prone to infections by bacteria and often by Candida sp. and filamentous fungi, although the spectrum of pathogens varies with different phagocytic disorders. For example, patients with chronic granulomatous disease (CGD) have infections primarily caused by five pathogens: Staphylococcus aureus, Burkholderia cepacia, Serratia marcescens, Nocardia sp., and Aspergillus sp. 43 In contrast, disseminated nontuberculous mycobacterial infection in a child without HIV infection may indicate a disorder of macrophage activation 57 (see article by Uzel and Holland, p. 1275). Knowledge of the spectrum of pathogens to which persons with phagocytic disorders are susceptible is key to guiding subsequent laboratory evaluation. Certain phagocytic disorders are associated with systemic features unrelated to immune function that may be clues for early diagnosis (Table 1). Patients with CGD may initially manifest with inflammatory complications, commonest granulomatous enteritis indistinguishable from Crohn disease. Chediak-Higashi syndrome (CHS), a disorder of fusion of intracellular granules, is associated with oculocutaneous albinism. Hyper-IgE syndrome with recurrent infections (HIES; Job syndrome) is characterized by atopic dermatitis first manifesting during infancy and craniofacial and skeletal abnormalities. A thorough family history and knowledge about the transmission of various phagocytic disorders are important in making an early diagnosis. For example, the possibility of X-linked CGD (X-CGD) should be considered in boys with inflammatory bowel disease with a maternal uncle who died at a young age of "pneumonia." Mutations can arise de novo during meiosis; thus, a negative family history for an X-linked or autosomal dominant disorder does not rule out the disease. Children from consanguineous parents are at increased risk for autosomal recessive (AR) disorders. Management of patients with phagocytic disorders is challenging. The authors have found that a few basic principles are of key importance. First, patients are often sicker than they appear. Signs of systemic infection, such as fever and peripheral leukocytosis, and signs of local infection, such as erythema, warmth, and tenderness, are often blunted. Thus, a high level of vigilance is required. Second, because the spectrum of pathogens in persons with phagocytic disorders is broad, a microbiologic diagnosis should be pursued expeditiously. Third, because of ineffective native host defense, systemic antimicrobial therapy of infections typically is prolonged to avoid recrudescence. Also, surgical debridement of localized disease should be performed early when feasible. Prophylactic antibiotics are used in several of the phagocytic disorders. Cytokine therapy, leukocyte transfusions, bone marrow transplantation (BMT), and gene therapy are used or are being evaluated in specific phagocytic disorders.