Philippe Reinert

Impact of early transcranial Doppler screening and intensive therapy on cerebral vasculopathy outcome in a newborn sickle cell anemia cohort

Transcranial Doppler (TCD) is used to detect children with sickle cell anemia (SCA) who are at risk for stroke, and transfusion programs significantly reduce stroke risk in patients with abnormal TCD. We describe the predictive factors and outcomes of cerebral vasculopathy in the Créteil newborn SCA cohort (n = 217 SS/Sβ(0)), who were early and yearly screened with TCD since 1992. Magnetic resonance imaging/magnetic resonance angiography was performed every 2 years after age 5 (or earlier in case of abnormal TCD). A transfusion program was recommended to patients with abnormal TCD and/or stenoses, hydroxyurea to symptomatic patients in absence of macrovasculopathy, and stem cell transplantation to those with human leukocyte antigen-genoidentical donor. Mean follow-up was 7.7 years (1609 patient-years). The cumulative risks by age 18 years were 1.9% (95% confidence interval [95% CI] 0.6%-5.9%) for overt stroke, 29.6% (95% CI 22.8%-38%) for abnormal TCD, which reached a plateau at age 9, whereas they were 22.6% (95% CI 15.0%-33.2%) for stenosis and 37.1% (95% CI 26.3%-50.7%) for silent stroke by age 14. Cumulating all events (stroke, abnormal TCD, stenoses, silent strokes), the cerebral risk by age 14 was 49.9% (95% CI 40.5%-59.3%); the independent predictive factors for cerebral risk were baseline reticulocytes count (hazard ratio 1.003/L × 10(9)/L increase, 95% CI 1.000-1.006; P = .04) and lactate dehydrogenase level (hazard ratio 2.78/1 IU/mL increase, 95% CI1.33-5.81; P = .007). Thus, early TCD screening and intensification therapy allowed the reduction of stroke-risk by age 18 from the previously reported 11% to 1.9%. In contrast, the 50% cumulative cerebral risk suggests the need for more preventive intervention.

Bacterial Meningitis in Children: A French Prospective Study

From January 2001 through December 2003, a total of 1084 children with bacterial meningitis were enrolled in a prospective French nationwide survey. The most frequent pathogens found in children older than 28 days were Neisseria meningitis (55.3%) and Streptococcus pneumoniae (33.4%). S. pneumoniae was the most frequent pathogen found among infants aged 2-12 months (49.5%), whereas N. meningitidis was the most frequent pathogen among children >12 months old (69.7%). Approximately one-half of S. pneumoniae isolates had diminished susceptibility to penicillin. The case-fatality rates were 7.6% for children with N. meningitidis meningitis and 10.8% for children with S. pneumoniae infection.

Comparison of two dosages of azithromycin for three days versus penicillin V for ten days in acute group A streptococcal tonsillopharyngitis.

Background. Three-day, 10 mg/kg/day azithromycin (AZM) studies in pediatric acute group A streptococcal tonsillopharyngitis have shown contradictory bacteriologic results. This study investigates the efficacy and tolerability of two dosages of 3-day azithromycin (20 mg/kg/day and 10 mg/kg/day) compared with 10-day penicillin V. Methods. This was a prospective, comparative, randomized, multicenter trial. Children were scheduled to return for visits at 14 days (main end point) and 1 month after the onset of treatment for clinical and bacteriologic assessment. Molecular tools were used to compare pre- and posttreatment group A beta-hemolytic Streptococcus (GABHS) isolates. Results. Between November, 1997, and July, 1998, 501 patients (169 AZM 10 mg, 165 AZM 20 mg, 167 penicillin V) between 2 and 12 years old were enrolled; 500 were assessable for safety, 469 for intent to treat analysis and 420 for efficacy in the per protocol analysis. Before treatment 25 (7.9%) of 315 GABHS stains isolated from patients receiving AZM were resistant to this compound. On Day 14 pretreatment GABHS were eradicated from 78 (57.8%) of the 135 children receiving the AZM 10 mg regimen, 131 (94.2%) of the 139 receiving AZM 20 mg and 123 (84.2%) of the 146 taking penicillin. One month after the outset of treatment, bacteriologic relapses were observed in 40.5% (n = 30) of the children receiving AZM 10 mg, 14.8% (n = 18) of children taking AZM 20 mg and 13.2% (n = 15) of those treated with penicillin V. AZM 20 mg/kg/day was statistically superior to AZM 10 mg/kg/day microbiologically on Day 14 (P = 0.0001) and Day 30 (P = 0.0001) and clinically on Day 14 (P = 0.0035). AZM 20 mg/kg/day was statistically equivalent both microbiologically and clinically to standard therapy with penicillin V at all endpoints. The incidence of treatment-related adverse events was similar in the two azithromycin groups [AZM 10 mg, 31 of 169 (18.3%); AZM 20 mg, 37 of 164 (23%)] but significantly higher than those observed in the penicillin V group [5 of 166 (3%);P < 0.0001]. Most treatment-related adverse events were gastrointestinal and of mild-to-moderate severity. Fourteen patients withdrew from the trial because of adverse events (1 in the penicillin V group, 7 in the AZM 10 mg group and 6 in the AZM 20 mg group). Conclusion. This is the first study to demonstrate a daily dose-dependent difference in microbiologic efficacy of a regimen; 3-day AZM 20 mg/kg/day is a more effective regimen than 3-day AZM 10 mg/kg/day for pediatric GABHS tonsillopharyngitis.

Kinetics of Decline of Maternal Measles Virus-Neutralizing Antibodies in Sera of Infants in France in 2006

ABSTRACT The optimal age for measles vaccination is an important health issue, since maternal antibodies may neutralize the vaccine antigen before a specific immune response develops, while delaying vaccination may increase the risk of complicated diseases in infants. However, measles vaccination impacts the duration of protection afforded by transplacental transfer of maternal antibodies: vaccination-induced maternal antibodies disappear faster than disease-induced antibodies. In order to maintain protection against measles in infants, it is important to monitor the dynamics of this phenomenon in vaccinated populations. To assess the current situation in France, a multicenter, prospective seroepidemiological study was conducted in seven French hospitals between October 2005 and January 2007. Maternal measles antibody concentrations from 348 infants 0 to 15 months old were measured using the plaque reduction neutralization assay. Geometric mean concentrations and the percentage of infants with maternal measles antibody concentrations above the protection threshold (≥120 mIU/ml) were assessed according to age. Results show that after more than 20 years of routine measles vaccination in France, maternal measles-neutralizing antibodies decrease dramatically in French infants by 6 months of age, from 1,740 mIU/ml for infants 0 to 1 month old to 223 mIU/ml for infants 5 to 6 months old, and that 90% of infants are not protected against measles after 6 months of age. Infant protection against measles could be optimized both by increasing herd immunity through an increased vaccine coverage and by lowering the age of routine vaccination from 12 to 9 months.

Prevalence of Anti-Varicella-Zoster Virus Antibodies in French Infants under 15 Months of Age

ABSTRACT Varicella is a widespread disease of childhood resulting from primary infection with varicella-zoster virus (VZV). The objective of this study was to determine the kinetics of the decline of maternal anti-VZV antibodies in French infants between birth and the age of 15 months in order to estimate the duration of passively acquired maternal anti-VZV immunoglobulin G (IgG). This prospective multicenter study was conducted between October 2005 and January 2007 in the pediatric wards and/or pediatric emergency units of seven French hospitals scattered throughout the country. The level of anti-VZV IgG antibodies in serum was measured by a time-resolved fluorescence immunoassay (TRFIA) (the threshold considered positive is 150 mIU/ml). A total of 345 infants were included. Seventy-seven percent of mothers reported a history of varicella. A rapid decline in the prevalence of anti-VZV antibodies was observed during the first few months of life, with the mean antibody titer decreasing from 536 mIU/ml at birth and through 1 month to below the 150-mIU/ml threshold at 3 to 4 months. The half-life of passively acquired maternal immunoglobulins was around 6 weeks. Based on a large number of subjects, this study clearly demonstrated, for the first time in France, high levels of passively acquired maternal antibodies during the neonatal period, and it allowed us to estimate the duration of passively acquired maternal anti-VZV IgG in French infants. After 4 to 5 months, infants had very low levels of maternal anti-VZV IgG, below the 150-mIU/ml cutoff of the VZV IgG TRFIA.

Immunogenicity and safety of a pneumococcal conjugate 7-valent vaccine in infants with sickle cell disease.

Objectives: To evaluate safety and immunogenicity of the pneumococcal 7-valent conjugate vaccine (PCV7) when administered to infants with sickle cell disease (SCD) at 2, 3, and 4 months of age with a booster dose of a 23-valent pneumococcal polysaccharide vaccine (PS-23) at 15 to 18 months of age. Methods: This open-label multicenter study in France enrolled 2-month-old infants with SCD. Blood samples for the determination of antibody concentrations to vaccine serotypes were obtained immediately before and 1 month after the primary immunization, and before and 1 month after the PS-23 booster. Local and systemic reactions were recorded on diary cards. Results: Of the 51 infants enrolled, 49 received primary immunization and 46 received the booster dose. After primary immunization ≥95% of the subjects had antibody titers ≥0.35 μg/mL for the 7 serotypes. After boosting, geometric mean concentrations were high for all serotypes, ranging from 6.32 μg/mL (serotype 18C) to 29.49 μg/mL (serotype 4). Except for 1 case after administration of the booster dose, all fevers reported were less than 39°C. No vaccine-related serious adverse events were reported. Conclusions: PCV7 administered at 2, 3, and 4 months of age in infants with SCD was well-tolerated, highly immunogenic, and primed for immune memory as indicated by the dramatic response to the PS-23 dose administered at 15–18 months in this study. However, the current recommended schedule is to boost with the PCV7 at 12–15 months of age and for these high-risk children, to enlarge the protection with a subsequent PS-23 dose at 2 years of age.

Challenge with Hepatitis B Vaccine in Children Previously Vaccinated with a Hepatitis B-Containing Combination Vaccine

IntroductionThe World Health Organization (WHO) recommends universal infant hepatitis B virus (HBV) vaccination as the most effective preventive measure against HBV-induced disease in endemic areas. More than 160 countries have followed the WHO recommendations to incorporate HBV vaccination in their national infant immunization programs. While antibodies to hepatitis B surface antigen (anti-HBs) concentrations progressively decrease following vaccination in infancy, protection persists, probably due to lasting immune memory. Hence, it is thought that future exposure to wild-type virus or HBV vaccine will induce a protective secondary immune response.MethodsChildren aged 7–8 years old who had been vaccinated in infancy with a hexavalent DTacP-IPV-HB-Hib vaccine (Hexavac®; Sanofi Pasteur MSD, Lyon, France) and children aged 7–9 years vaccinated in infancy with a DT-HB vaccine (Primavax®; Sanofi Pasteur MSD), whose anti-HBs concentrations had fallen below the seroprotective threshold of 10 mIU/mL at age 4.5–6 years, received a challenge dose of monovalent HBV vaccine (HBVAXPRO®; Sanofi Pasteur MSD) to assess persistence of protection.ResultsOne month postchallenge, 54 of 61 (88.5%) Hexavac-primed seronegative children and 34 of 40 (85.0%) Primavax-primed seronegative children had anti-HBs concentrations ≥10 mIU/mL. The percentage of protected children would have been even higher if the children who still had protective antibody levels (who were not included in this challenge study) had been assessed (42.1% with Hexavac, 55.4% with Primavax).ConclusionVaccination with a HBV-containing multivalent vaccine during infancy induces a lasting immune memory that can be boosted, even in children with a decline in anti-HBs concentrations. The present results confirm that the full primary vaccination schedule in infancy seems to confer long-term protection via immune memory and that an additional HBV dose is not generally required.

Distribution of serum measles-neutralizing antibodies according to age in women of childbearing age in France in 2005-2006: impact of routine immunization.

Measles antibody titers were measured in 210 French women. Ninety-four percent had protective values (>120 mIU/mL). Geometric mean titers were significantly different (P < 0.001) between women born before and after 1983, when measles vaccination was recommended (731 and 1358 mIU/mL, respectively). geometric mean titers in 4 age cohorts decreased significantly (P < 0.001) with increasing birth year. These data may help identify the appropriate age for infant vaccination.

Manifestations pseudoneurologiques révélatrices d’une histiocytose langerhansienne

Langerhans cell histiocytosis (LCH) is a multisystemic disease, which may present with neurological involvement. We report the case of a 20-month-old girl with initial liver and skin involvement. Initial symptoms were recurrent episodes of trunk dystonia, lasting approximately 2 months prior to the diagnosis of LCH. No brain MRI abnormality was demonstrated at initial work-up and over 7 years of follow-up, except for a postpituitary involvement noted after 3 years of follow-up. These episodes of dystonia subsided during the first week of specific LCH chemotherapy (vinblastine and steroid), suggesting that they may have resulted from hepatalgia related to the histiocytic infiltration of the liver.