Pediatric hematology-oncology outreach for developing countries.

Health care in some developing countries is now at a level that makes programs for care of children with cancer feasible. Examples of successful international programs in this field include twinning programs, nongovernmental assistance organizations, such as the National Children's Cancer Society, and committees of professional organizations, such as the International Society of Pediatric Oncology (SIOP). The international outreach program at St. Jude Children's Research Hospital includes training programs within the hospital, partner sites in 13 countries, a school for Latin American nurses, a distance learning website, and telecommunications programs, which are described in detail. Future programs should be designed to maximize and evaluate impact, report accomplishments and failures, and avoid duplication.

Effect of malnutrition at the time of diagnosis on the survival of children treated for cancer in El Salvador and Northern Brazil.

PURPOSE: To investigate the relationship between survival and malnutrition at the time of diagnosis among children treated for cancer in two developing countries. PATIENTS AND METHODS: We studied 443 children treated for cancer between 1995 and 1998 at two centers in San Salvador, El Salvador, and Recife, Brazil. Median age at diagnosis was 4.9 years; 283 children had leukemia and 160 had solid tumors. Z-scores were calculated for weight for age (WAZ), height for age (HAZ), and weight for height (WHZ) at diagnosis. Z scores <-2 indicated malnutrition. Patients were also stratified by low-risk disease (solid tumors: stage I, stage II, or localized; acute lymphocytic leukemia: white blood cell count <25,000/microL, no central nervous system involvement, no mediastinal mass and age >1 and <10 yrs) and high-risk disease (all other patients, including those with acute or chronic myelocytic leukemia). RESULTS: Z-scores indicated malnutrition in 23.5% (WAZ), 22.8% (HAZ), and 15.7% (WHZ) of patients. Z-score was not significantly related to overall survival rates, to survival rates analyzed by type of malignancy or risk status, or to survival rates at the end of the first month of treatment. CONCLUSIONS: We found no relationship between nutritional status and survival in these patients. This implies that future protocols for use in developing countries can be designed to provide optimal treatment intensity despite the high incidence of malnutrition.

Granulocyte-macrophage colony-stimulating factor in the treatment of neonates with neutropenia and sepsis.

To evaluate the efficacy of granulocyte-macrophage colony-stimulating factor (GM-CSF) in improving neutrophil counts and survival of neutropenic septic neonates, the authors studied 8 neonates with gestational or postconceptional age at least 30 weeks; weight at least 1000 g; serious infection with concomitant neutropenia (absolute neutrophil count [ANC] < 3.0 x 10(9)/L) or leukopenia (white blood cell count < 5.0 x 10(9)/L) and anticipated survival at least 48 h. Patients received 5 micrograms/kg of GM-CSF intravenously for 5 consecutive days or until the ANC reached 20 x 10(9)/L. Clinical parameters and complete blood counts were monitored. Prestudy ANCs ranged from 0.05 to 2.7 x 10(9)/L. Four patients had positive blood cultures, 4 had necrotizing enterocolitis, and 1 was in septic shock. All patients had elevated C-reactive protein. All patients had resolution of neutropenia and survived the septic episodes. The use of GM-CSF in these patients merits further exploration.

Long-term follow-up of patients treated with primary radiotherapy for supradiaphragmatic Hodgkin's disease at St. Jude Children's Research Hospital.

OBJECTIVE: To assess disease control, patterns of relapse, factors predictive of relapse, and late effects of treatment, we reviewed all cases of supradiaphragmatic (SD) Hodgkin's disease (HD) treated with primary radiation therapy (RT) at our institution. METHODS: We retrospectively reviewed the disease characteristics, treatment history, and long-term outcome of the 106 patients with Stage I and II supradiaphragmatic HD who received definitive irradiation at St. Jude Children's Research Hospital between 1970 and 1995. As of the date of analysis, 95 patients are alive, with a median follow-up of 13.3 years (range, 1.9-24.2 years). RESULTS: The median age at diagnosis was 14.7 years (range, 3.7-22.7). Involved-field RT was given to 13 patients (12%), whereas 37 (35%) had mantle RT, 51 patients (48%) had subtotal nodal irradiation, and 5 (5%) had total nodal irradiation. Relapsed disease developed in 26 patients at a median of 1.8 years (range, 0.2-9.3 years). The 5- and 10-year estimated cumulative incidences of relapse were 20.9% +/- 4.0% and 25.1% +/- 4.3%, respectively. With a median dose of 36 Gy (range, 32-40), in-field failure rate was 6.2%, whereas subdiaphragmatic relapse in sites irradiated prophylactically was 1.5%. There was a trend toward an increased incidence of relapse with higher ESR (p = 0.088) and greater number of sites of disease (p = 0.087). Age, stage, histology, nodal disease > or = 6 cm, the presence of bulky mediastinal disease, and the method of staging did not affect the incidence of relapse. The pattern of failure could not be predicted based on the stage of disease, the extent of subdiaphragmatic staging, the extent of radiation therapy, or the sequence of RT fields-"ping pong" vs. sequential. Subset analysis of Stage II patients revealed significantly more relapses in clinically staged patients. Excluding Stage IA patients with high cervical disease or peripheral nodal disease, nodal extension failures were more common for patients undergoing limited-volume RT, whereas extranodal relapses were likely after STNI or TNI. The estimated 10- and 15-year cumulative incidences of second malignancies were 2.9% +/- 1.6% and 7.9% +/- 3.3%, respectively. Our patients are at increased risk of second malignancies (11-fold), and fatal cardiac (68-fold) and infectious (33-fold) complications. Overall survival at 10 years was 90.8% +/- 3.2%; event-free survival was 72.1% +/- 5.0%. CONCLUSIONS: The current analysis confirms the curative potential of RT for HD in children and adolescents. Despite successful salvage therapy, relapsed disease remained the principal cause of death in our cohort. Excess risk of septic death in asplenic patients, fatal heart disease, and second malignancies may further compromise the ultimate cure of HD in long-term survivors.

Pilot study of noninvasive detection of venous occlusions from central venous access devices in children treated for acute lymphoblastic leukemia.

BACKGROUND: Survivors of childhood acute lymphocytic leukemia (ALL) are at risk of venous occlusion induced by central venous access devices (CVADs). A sensitive, noninvasive screening technique to identify the magnitude of this problem is needed. Ultrasound (US) cannot always adequately image the innominate veins or the superior vena cava. Magnetic resonance angiography (MRA) can be noninvasive and may be useful for screening these patients. OBJECTIVE: We examined the suitability of US and MRA to identify venous occlusion. MATERIALS AND METHODS: We used MRA and ultrasound to examine 11 pediatric patients previously treated for ALL. CVADs had been in place a median of 2.5 years (range, 0.4-2.8 years) and removed a median of 2.1 years (range, 0.6-2.9 years) previously. We also performed 2D time-of-flight magnetic resonance angiography (TOF MRA) on two healthy young adult women with no history of venous abnormality or CVAD use. RESULTS: MRA suggested central venous abnormalities in 8 of the 11 ALL survivors and in both healthy control subjects. US results were negative in all 11 survivors. CONCLUSION: Further investigation is warranted to develop a sensitive and specific noninvasive method for identifying venous occlusion caused by prior CVAD use. Such a method would allow prospective studies of this complication in pediatric ALL survivors.

Factor V Leiden and other hypercoagulable state mutations are not associated with osteonecrosis during or after treatment for pediatric malignancy.

OBJECTIVE: Osteonecrosis (ON) is a debilitating complication of cancer treatment in children and is usually associated with systemic steroid therapy. Defects of coagulation may be important in the pathogenesis of ON. This study evaluated the prevalence of factor V Leiden (FVL, 1691G-->A), the most common inherited thrombophilic state, the prothrombin 20210G-->A polymorphism, and the thermolabile methylene tetrahydrofolate reductase (MTHFR, 677C-->T) variant in a group of children in whom ON developed during or after treatment for cancer. STUDY DESIGN: Children in whom ON developed during cancer treatment at St Jude Children's Research Hospital were studied (n = 24). Genomic DNA was isolated, and polymerase chain reaction was performed to identify the FVL, prothrombin 20210, and thermolabile MTHFR mutations. RESULTS: Sixteen of 24 patients had acute lymphoblastic leukemia. The mean age at ON diagnosis was 14.4 +/- 3. 7 years. The mean interval between cancer diagnosis and ON diagnosis was 27 +/- 21 months. Twenty-two patients had received steroids for a mean duration of 24 +/- 15 weeks before having development of ON. No patient had a history of thrombosis. Five (21%) patients had a family history of thrombosis. Genetic analysis revealed 0 (0%) of 24 FVL, 1 (4.5%) of 22 prothrombin 20210, and 3 (13.6%) of 22 thermolabile MTHFR. None of these mutation frequencies was significantly different from our control frequencies or published values. CONCLUSIONS: Although procoagulant abnormalities in general and FVL in particular have been detected in a significant number of patients with ON of the jaw and Legg-Perthes disease, we did not identify an increased prevalence of FVL or other hypercoagulable state mutations in a cohort of children with ON that developed during or after treatment for a variety of cancers.

Increased mortality after successful treatment for Hodgkin's disease.

PURPOSE: To determine the impact of treatment toxicity on long-term survival in pediatric Hodgkin's disease. PATIENTS AND METHODS: We studied late events in 387 patients treated for pediatric Hodgkin's disease on four consecutive clinical trials at St Jude Children's Research Hospital from 1968 to 1990. Relative risks, actuarial risks, and absolute excess risks for cause-specific deaths were calculated. RESULTS: As of April 1997, 316 (82%) of patients were alive, with a median follow-up of 15.1 (range, 2.9 to 28.6) years. In this cohort, which represented 5,623 person-years of follow-up, 71 fatal events resulted from Hodgkin's disease (n=36), second malignancies (n=14), infections (n=7), accidents (n=7), cardiac disease (n=6), and asphyxiation (n=1). The 5-year estimated event-free survival (EFS) for the entire cohort was 79.6%+/-2.1 %, which declined to 63.1%+/-4.4% by 20 years. Cumulative incidences of cause-specific deaths at 25 years were 9.8%+/-1.6% for Hodgkin's disease, 8.1%+/-2.6% for second malignancy, 4.0%+/-1.8% for cardiac disease, 3.9%+/-1.5% for infection, and 2.1%+/-0.8% for accidents. Standardized incidence ratios showed excess risk for all second malignancies (12; 95% confidence interval [CI], 8 to 17), acute myeloid leukemia (81; 95% CI, 16 to 237), solid tumors (11; 95% CI, 7 to 16), and breast cancer (33; 95% CI, 12 to 72). Standardized mortality ratios also showed excess mortality from cardiac disease (22; 95% CI, 8 to 48) and infection (18; 95% CI, 7 to 38). CONCLUSION: Compared with age- and sex-matched control populations, survivors of pediatric Hodgkin's disease who were treated before 1990 face an increased risk of early mortality related to second cancers, cardiac disease, and infection.

Abnormalities of the central nervous system in very young children with sickle cell anemia.

OBJECTIVE: To determine whether abnormalities of the CNS are present in very young children with sickle cell anemia. STUDY DESIGN: Thirty-nine children with hemoglobin SS between the ages of 7 and 48 months were examined with magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). No child had a history of clinical stroke, although 3 had a history of seizures (2 neonatal). Twenty-one patients underwent developmental testing with the Bayley or McCarthy Scales. RESULTS: The overall prevalence of CNS abnormalities in asymptomatic children was 4 of 36 (11%, confidence interval 3, 26%). One patient had a silent infarct observed on MRI and a stenotic lesion on MRA; 3 other patients had stenotic lesions on MRA. The 3 patients who had a history of seizures all had lesions consistent with infarcts on MRI. Of the asymptomatic patients who had psychometric testing, 1 of 18 was developmentally delayed. One of 3 with a history of seizures had mild developmental delay. CONCLUSIONS: Very young children with sickle cell anemia (and no history of clinical stroke) have infarction in the brain and/or stenosis of major cerebral arteries, similar to those reported in older children. These findings indicate a need for larger studies to define the incidence of CNS lesions in this age group and to determine the need for early therapeutic intervention to prevent CNS sequelae of sickle cell disease.

Mild hemophilia in children: prevalence, complications, and treatment.

PURPOSE: To review the natural history of mild hemophilia (factor VIII or IX level >5% and <50%), including presentation and diagnosis, characteristics of bleeding episodes, and therapy, at two hemophilia treatment centers. METHODS: Inpatient and outpatient records of 55 patients <17 years old with factor VIII or IX levels of 5 to 50% were reviewed and bleeding episodes for which medical attention was sought were analyzed. RESULTS: Five of the 55 patients were girls. Girls and patients with no family history of hemophilia were diagnosed at 5.5 and 5.3 years of age, respectively, compared to 2.8 years overall. Thirty-five patients were diagnosed because of a positive family history. No bleeding occurred in 18 patients; 190 bleeding episodes occurred in 37 patients. Most bleeding occurred in muscle/soft tissue (101 episodes) or joints (57 episodes) and were associated with trauma (174 episodes). CONCLUSIONS: Mild hemophilia may affect females more often than is appreciated. Delays in diagnosis and treatment may occur unless the variability in presentation is recognized.

Thrombopoietin level in young patients is related to megakaryocyte frequency and platelet count.

PURPOSE: To examine the relationships among platelet counts, bone marrow megakaryocyte frequency, and circulating thrombopoietin (TPO) levels. PATIENTS AND METHODS: TPO levels in 17 children and one young adult with chronic or recurrent thrombocytopenia were measured by ELISA and megakaryocyte frequency was analyzed by light microscopy. Three groups of patients were studied: Group I patients had aplastic anemia and absent or decreased megakaryocytes; Group II patients had intermittent periods of chemotherapy-induced thrombocytopenia; and Group III patients had normal or increased megakaryocytes. Controls consisted of 77 healthy adults. RESULTS: Patients in Group I had markedly increased TPO levels compared to normal controls. Their levels were significantly different (p = 0.03) from those of patients in Group III. The latter had normal or only mildly increased TPO levels except for one patient with myelodysplastic syndrome. Patients in Group II had markedly elevated TPO levels. After their bone marrow and platelet counts recovered from chemotherapy, their TPO levels decreased. In all three groups, a transient increase in platelet count (e.g., after platelet transfusion or anti-D immune globulin therapy) was associated with a moderate decrease in TPO. CONCLUSIONS: From this study, three conclusions can be made: 1) TPO levels are inversely related to megakaryocyte frequency; 2) platelet counts have a modest influence on TPO level; and 3) TPO levels may have clinical utility in diagnosis and management and further our understanding of the pathobiology of the disorders that cause thrombocytopenia.

Late vascular occlusion of central lines in pediatric malignancies.

OBJECTIVE: To determine whether thrombi or vascular occlusion represent a late complication persisting several years after removal of central venous lines (CVLs) in children and adolescents treated for childhood cancer. METHODS: Children whose treatment for malignancy included placement of a CVL that had been removed at least 2 months previously were studied during scheduled follow-up that included contrast-enhanced computed tomography. Spiral volume acquisition was used to obtain 3-mm images from the chest apices through the right hilum, and three-dimensional reconstruction of angiograms was performed. Thrombosis/occlusion was defined as narrowing, obstruction, or filling defect of the deep venous system, with or without the formation of collateral veins. Charts were reviewed to document patient characteristics, previous CVL complications, administration of hyperalimentation, use of urokinase, and family history of venous thrombosis. RESULTS: Twenty-three patients treated for solid tumors and 2 treated for B-cell acute lymphocytic leukemia or lymphoma were studied. Lines had been in place from 0.2 to 36 months (median, 7.4) and were removed at 2.3 to 121.8 months (median, 32.5) before study. Nine patients received hyperalimentation for periods ranging from 2 to 38 weeks (median, 12). Four patients had required urokinase instillations, and one developed superior vena cava syndrome; 4 had a CVL-related infection (two superficial and two Candida line infections). Occlusion was seen on computed tomography angiograms in 3 of the 25 patients (12%; 95% confidence interval: 4.5-31%). One of the patients with occlusion had superior vena cava syndrome; none had a family history of thrombosis, use of a double lumen CVL, or multiple instillations of urokinase. CONCLUSIONS: Persistent asymptomatic vascular occlusion does occur as a late complication of CVL placement for treatment of childhood malignancies, although the frequency appears low among patients treated primarily for solid tumors. Prospective studies of large numbers of patients with a broader spectrum of diagnoses are necessary to define the incidence of and risk factors for this complication and to assess the need for prevention with anticoagulation or other therapy. Pediatricians caring for patients with a history of cancer and CVLs should be aware that these patients may have persistent vascular occlusion that could predispose them to recurrent thrombosis or postphlebitic syndrome.

Use of chest computed tomography in the staging of pediatric Wilms' tumor: interobserver variability and prognostic significance.

PURPOSE: To determine the specificity and prognostic significance of computed tomography (CT) of the chest in pediatric Wilms' tumor. PATIENTS AND METHODS: Patients treated for newly diagnosed Wilms' tumor at St Jude Children's Research Hospital between December 1978 and July 1995 were included in the study if an initial chest radiograph and CT were available and if pulmonary involvement (determined by chest radiographs) was absent. For the 202 patients studied, radiographs and CT scans were reviewed blindly and independently by three experienced radiologists for the presence of pulmonary nodules. Outcome variables consisted of intraobserver variability (in a subsample of 40 cases) and concordance between ratings on radiographs and CT scans (both by McNemar's test), interrater variability (by logistic regression), and the cumulative incidence of pulmonary relapse for patients with and without positive CT scans, by reviewer. RESULTS: As expected, ratings of pulmonary involvement on radiographs were discordant with CT ratings. There was marked variability among reviewers in CT ratings (P = .0001). Of 202 CT scans, 78 were read as positive by at least one reviewer, 41 were rated positive by only one reviewer, 18 by two reviewers, and 19 by all three. Intrarater variability on repeat reviews was not significant. Patients with nodules identified on CT had a significantly higher pulmonary relapse rate when analyzed separately by reviewer. However, for the 14 patients who had pulmonary relapse, CT scans were rated positive by all three reviewers in only five cases and as negative by all three in another five cases. CONCLUSION: The variability in interpretation of chest CT scans in patients with Wilms' tumor limits the predictive utility of these studies. Optimal, standardized techniques and central review are essential if chest CT is to be used for staging in cooperative studies.

Recurrent Streptococcus pneumoniae sepsis in children with sickle cell disease.

Streptococcus pneumoniae sepsis is the most common invasive infection among patients with sickle cell disease. The risk of a recurrent episode of sepsis and subsequent death in those patients who have had a previous septic event is much higher. Patients with sickle disease who have had pneumococcal sepsis should continue penicillin prophylaxis indefinitely and should not be candidates for out-patient management of febrile episodes.

Nasopharyngeal carriage of penicillin-resistant Streptococcus pneumoniae in children with sickle cell disease.

OBJECTIVE: We studied the prevalence of nasopharyngeal (NP) carriage, antimicrobial susceptibilities, and serotypes of Streptococcus pneumoniae (SP) in children with sickle cell disease (SCD) in the Mid-South. In addition, we examined risk factors for NP carriage of penicillin-resistant SP (PRSP). STUDY DESIGN: Between July 1994 and December 1995, we obtained NP cultures from 312 children with SCD followed at the Mid-South Sickle Cell Center, 208 (67%) of whom were receiving penicillin prophylaxis. RESULTS: Among the 312 patients, colonization with SP occurred in 42 (13%), 30 (71%) of whom were receiving penicillin prophylaxis. Twenty-three of the 42 SP isolates (55%) were resistant to penicillin; 5 of the 23 (22%) were highly resistant. PRSP organisms were also resistant to cefotaxime (43%), trimethoprim-sulfamethoxazole (57%), and erythromycin (22%). Serotypes 6A, 6B, 14, 19A, and 23F accounted for 19 (90%) of 21 resistant strains. Children who were treated with antibiotics during the preceding month were more likely to carry PRSP than children who were not treated. CONCLUSIONS: There is a high prevalence of NP carriage of PRSP in children with SCD in the Mid-South, which raises concerns regarding the continued effectiveness of penicillin prophylaxis in these children. Further studies on the antimicrobial susceptibilities of resistant organisms and the relationship between NP carriage of SP and invasive disease are needed before developing new recommendations for prophylaxis and treatment.

Transdermal fentanyl administration in children and adolescents with sickle cell pain crisis.

PURPOSE: The purpose of this study was to determine the dose-concentration relationship and clinical effect of transdermal fentanyl (TF) in patients with sickle cell pain crisis (SCPC). PATIENTS AND METHODS: Ten patients aged 9-16 years were studied. Patients initially received a TF dose of 25 (n = 7) or 50 (n = 3) micrograms/h if morphine use was > 2.5 mg/h. Supplemental morphine usage via patient-controlled analgesia (PCA), sedation status, pain status, respiratory rate, pulse rate, oxygen saturation, and blood pressure were monitored. RESULTS: The average TF dose was 0.77 +/- 0.37 micrograms/kg/h on day 1 and 1.17 +/- 0.46 micrograms/kg/h on day 2. Fentanyl concentrations measured at 24 and 48 h were 0.60 +/- 0.31 and 1.18 +/- 0.44 ng/ml, respectively. A significant relationship existed between TF dose and fentanyl concentration (r2 = 0.56, p < 0.01). There was no difference in any of the clinical monitoring parameters between day 1 and day 2. However, 7 of 10 patients reported subjective improvement in pain control over that achieved with PCA alone. No adverse effects were noted. CONCLUSIONS: Improved understanding of the dose-effect relationship for TF in children and adolescents is necessary before adequate pain control can be achieved with this delivery system.

Outpatient therapy with ceftriaxone and oral cefixime for selected febrile children with sickle cell disease.

PURPOSE: Children with sickle cell disease are at increased risk for bacterial sepsis and, when febrile, are usually hospitalized for intravenous antibiotic therapy pending results of blood cultures. In this study, we prospectively identified a group of febrile patients with sickle cell disease who were at low risk for sepsis and treated them with outpatient therapy. PATIENTS AND METHODS: Children identified as low risk for sepsis were treated with an initial dose of intravenous ceftriaxone, followed by outpatient therapy with oral cefixime, and were monitored for 14 days after the initial visit. Compliance was assessed by phone calls to parents and by analysis of urine samples. RESULTS: In 107 eligible febrile episodes (80 patients) over a 21-month period, no patient developed sepsis. One child developed bacteremia 3 days after completing the course of cefixime, and one had splenic sequestration on the fourth study day. Both patients did well. Side effects of cefixime were modest, and overall compliance was excellent (approximately 95%), although urine samples were returned by only 56% of parents. CONCLUSION: We conclude that outpatient therapy is safe and effective in febrile patients with sickle cell disease who meet the criteria for a low risk of sepsis.

Antibiotic-resistant pneumococcal infection in children with sickle cell disease in the United States.

OBJECTIVE: The purpose of this report is to examine the increasing problem of antibiotic-resistant pneumococcal infection in children with sickle cell disease in the United States. PATIENTS AND METHODS: In this retrospective review, 16 children with sickle cell disease and penicillin-resistant pneumococcal invasive infection were identified. They had a median age of 2 years (range 1-15) and were treated in Memphis, Dallas, Los Angeles, and five other cities between 1987 and early 1995. RESULTS: At presentation, patients frequently had high fever (> or 40.0 degrees C in 75%) and a toxic appearance (44%). Meningitis was present initially in two and diagnosed on days 4 and 5 in two. All were treated with an intravenous cephalosporin and nine received vancomycin. The clinical course was variable: two died within 36 h of presentation. In 20-86% of cases the organisms were resistant to cephalosporins, chloramphenicol, trimethoprim/sulfamethoxazole, erythromycin, and clindamycin; none were resistant to vancomycin. CONCLUSIONS: (a) The increasing prevalence of antibiotic-resistant Streptococcus pneumoniae infection in the United States poses special problems for patients with sickle cell disease. (b) Prompt antibiotic susceptibility testing of pneumococcal isolates should be performed. (c) Initial antibiotic management for patients suspected of sepsis/meningitis should include intravenous cephalosporin and vancomycin. (d) No alternative to penicillin prophylaxis is currently available. (e) An effective conjugated pneumococcal vaccine is needed.

Penicillin- and cephalosporin-resistant strains of Streptococcus pneumoniae causing sepsis and meningitis in children with sickle cell disease.

OBJECTIVE: We investigated the possibility that antimicrobial-resistant pneumococci were causing invasive disease in children with sickle-cell disease (SCD). STUDY DESIGN: Records of all children with SCD observed at the Mid-South Sickle Cell Center (MSSCC) at LeBonheur Children's Medical Center were reviewed from January 1990 to June 1994. Children with SCD and pneumococcal sepsis were identified. The Streptococcus pneumoniae isolates from these children were examined for serotype and antimicrobial susceptibilities. Two additional children not observed in the MSSCC had pneumococcal sepsis caused by penicillin-resistant isolates and were also included. RESULTS: Antimicrobial susceptibility testing of the six penicillin-resistant isolates revealed that four were resistant to trimethoprim-sulfamethoxazole, two to erythromycin, and one to clindamycin. The two isolates that were resistant to ceftriaxone also were multiply resistant. From the MSSCC, 26 children had pneumococcal sepsis during the 4 1/2-year period studied. Five of these children (19%) died. Four (15%), including one who died, were infected with penicillin-resistant strains. CONCLUSION: Pneumococcal sepsis, meningitis, and infections of other foci in children with SCD may be caused by S. pneumoniae that is resistant to one or more antimicrobial agents, including penicillin. The addition of vancomycin to the antibiotics currently used for initial management should be considered in areas where the antibiotic resistance of S. pneumoniae is prevalent.

Higher activity of polymorphic thiopurine S-methyltransferase in erythrocytes from neonates compared to adults.

Thiopurine S-methyltransferase (TPMT) catalyses the S-methylation of aromatic and heterocyclic sulfhydryl compounds, including thiopurine antimetabolites (i.e. mercaptopurine and thioguanine). The activity of TPMT in erythrocytes and other tissues exhibits genetic polymorphism, which is inherited as an autosomal codominant trait. Although inheritance is the principal determinant of TPMT activity, other factors (e.g. renal function, race and thiopurine therapy) have been shown to influence erythrocyte TPMT activity. Because the TPMT polymorphism has not been established in early erythrocyte populations, and the activity of many enzymes differs in neonates, we determined the activity of TPMT in erythrocytes obtained from 60 full-term newborns. Median peripheral blood TPMT activity was 25.3 U per ml pRBC (range 9-52.8 U per ml pRBC), which was > 50% higher than race matched healthy adults (p < 0.001). Western blot analysis demonstrated higher TPMT protein content in erythrocytes from newborns compared to adults, and revealed a significant correlation between TPMT protein and TPMT activity in erythrocytes (rs = 0.63, p = 0.03). Although erythrocyte TPMT activity was significantly higher in newborns, the distribution of activity in newborns was consistent with the genetic polymorphism previously observed in adults.