Invited Review Pediatric Clostridium difficile: A Phantom Menace or Clinical Reality? *†Lynne V. McFarland, *Sally A. Brandmarker, and ‡Stefano Guandalini *Department of Medicinal Chemistry, University of Washington, and †Biocodex, Inc., Seattle, Washington; ‡Department of Pediatrics, University of Chicago, Chicago, Illinois, U.S.A. Clostridium difficile is the leading cause of nosocomi- al gastrointestinal illness in adult patients in hospitals. Even though C. difficile disease in adults has been well studied, research on pediatric C. difficile disease is still in its infancy. For many years it has been believed that C. difficile was a disease that affected only adults and was not a problem for children. This erroneous belief arose from the observation that neonates acquire C. difficile quickly (within 48 hours of birth) but show no intestinal symptoms (1–4). More recent evidence has been docu- mented in case reports of pediatric C. difficile and out- breaks of C. difficile disease in pediatric populations (5– 7). Pediatric C. difficile disease has also been associated with the occurrence of severe complications and high mortality rates (8–10). The cascade of events in the pathogenesis of C. diffi- cile disease is similar in children and adults. Normal intestinal microflora are disrupted by antibiotic exposure, medications, or surgery. If the child is then exposed to C. difficile (or its spores), colonization may occur, with pro- duction of toxins A and B. These toxins act on entero- cytes, causing an inflammatory response and morpho- logic changes that lead to diarrhea or colitis. Host factors (age, diet, immune response) play an important role in determining whether C. difficile develops into asymp- tomatic carriage or active disease. Treatment for pediatric C. difficile disease usually re- lies on metronidazole or vancomycin, but clinical guide- lines have not been defined for the pediatric population (11). As in adults, recurrent C. difficile disease that does not respond to conventional therapy develops in a pro- portion of children treated with antibiotic therapy. EPIDEMIOLOGY Acquisition of Clostridium difficile During the first few weeks of life, as many as 67% of infants become colonized with C. difficile if they are delivered in the hospital (1,4,12,13). Older children and adults are protected from colonization by C. difficile by the ability of the normal intestinal microflora to inhibit the overgrowth of pathogenic organisms by a phenom- enon called colonization resistance (14,15). C. difficile disease does not usually occur in adults unless antibiotics or other factors disrupt this colonization resistance (16,17). However, because the neonatal intestine is im- mature and does not have the protective milieu of normal microflora established in adults, the neonate is suscep- tible to bacterial colonization and overgrowth. The source of the C. difficile is usually not the mother, but rather exposure to C. difficile spores in the hospital nurs- ery (1,18,19). Delmee et al. (2) found that 60% of neo- nates in a hospital nursery had C. difficile colonization, and 50% of the environmental surfaces were positive for C. difficile spores. Prevalence and Incidence The frequency of pediatric C. difficile is dependent on the age of the children (Table 1). Neonates (birth through 1 month of age) have high frequencies (up to 64%) of C. difficile colonization, but are usually asymptomatic car- riers (3,4,13). In infants (<2 years of age), the prevalence ranges from 3% to 62%, but more infants with coloni- zation have symptomatic disease (Fig. 1). In older chil- dren (3–18 years of age), the prevalence is similar to adult frequencies (5–8%), with similar distributions of symptomatic and asymptomatic carriers. Outbreaks Several outbreaks of pediatric C. difficile have been described in the literature (1,5,20,21). Delmee et al. (2) prospectively observed children admitted to one neonatal ward at a Belgian hospital for 6 months and found that 76 (67%) of 114 of the neonates acquired C. difficile (2). Once the isolates were identified, 83% of the strains were in one of two serogroup types and 85% of the environ- mental isolates were also of these two serotypes (2). No significant association was found between acquisition of C. difficile and the development of intestinal symptoms Received February 21, 2000; accepted June 8, 2000. Address correspondence and reprint requests to Dr. Lynne V. McFarland, 1910 Fairview Avenue E., Suite 208, Seattle, WA 98102, U.S.A. (e-mail lvmcfarl@u.washington.edu). Journal of Pediatric Gastroenterology and Nutrition 31:220–231 © September 2000 Lippincott Williams & Wilkins, Inc., Philadelphia 220