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The purpose of this study was to determine the age-related risks, disease-specific risks, and characteristics of serious pneumococcal infections in children with sickle cell disease (SCD) while penicillin prophylaxis was standard. The clinical experiences of three pediatric sickle cell programs spanning January 1, 1992, to May 31, 1998, were combined. Data were collected regarding the patients followed up and the characteristics of Streptococcus pneumoniae bacteremia and meningitis cases. Forty-seven pneumococcal infections (44 bacteremia, 3 meningitis) among 40 patients with SCD were observed. Forty infections occurred in children with homozygous hemoglobin S (SS) during 4108 patient-years at a median age of 22 months; 7 occurred in double heterozygous hemoglobin SC (SC) children during 1777 patient-years at a median age of 23 months. Ten infections occurred among 9 SS children 5 years or older. Most children in whom infections developed were reportedly taking prophylactic penicillin and when older than 24 months old had received Pneumovax (Merck & Co., Inc., West Point, PA, U.S.A.. The following pneumococcal serotypes were identified in 15 cases studied: 6A, 6B, 9V, 14, 15B, 18B, 18F, 19F, and 23F. Infections resulted in five deaths and two strokes. The observed severe pneumococcal infection rate in SS children younger than 5 years was less than that reported before penicillin prophylaxis, supporting routine penicillin prophylaxis in this specific population. The optimal duration of penicillin prophylaxis in older children with SCD remains unknown. The administration of 7-valent Prevnar (Wyeth Lederle Vaccines, Philadelphia, PA, U.S.A.) to children younger than 24 months old with SCD should be beneficial, based on the serotype data.