Loïc de Pontual

Clostridium difficile Carriage in Healthy Infants in the Community: A Potential Reservoir for Pathogenic Strains

BACKGROUND Clostridium difficile has long been considered to be a nosocomial pathogen but has emerged in the community in recent years. During infancy, asymptomatic C. difficile colonization is common. However, knowledge of colonization determinants and strain characteristics is limited. We studied the dynamics of C. difficile colonization in healthy infants from the community. Determinants of colonization and strain genotypes were also determined in a cohort of infants attending day nurseries. METHODS A 1-year follow-up study involving 10 healthy infants was performed to determine the incidence and kinetics of intestinal C. difficile colonization. In addition, a 1-point study involving 85 healthy infants (age, 0-3 years) from 2 day nurseries was performed. C. difficile isolates were typed by polymerase chain reaction-ribotyping and analyzed for the presence of toxin genes. RESULTS During the follow-up study, all infants acquired C. difficile and were colonized for several months. An early (neonatal) and a late (4-6 months of age) acquisition period were identified. In day nurseries, 38 infants (45%) carried C. difficile, with 11 (13%) carrying a toxigenic isolate. Age and several environmental factors were associated with the C. difficile carrier state. Strains causing disease in adults were identified in infants. Interestingly, no infant carried the common epidemic 027 or 078 strains. CONCLUSIONS This study provides information on the dynamics of colonization in infants in the community and on the genotype of involved strains. C. difficile colonization appears mainly as an age-dependent process. Pathogenic strains circulate in asymptomatic infants from the community, who represent a potential reservoir of pathogenic strains.

Invasive Pneumococcal Disease in Children Can Reveal a Primary Immunodeficiency

BACKGROUND About 10% of pediatric patients with invasive pneumococcal disease (IPD) die from the disease. Some primary immunodeficiencies (PIDs) are known to confer predisposition to IPD. However, a systematic search for these PIDs has never been carried out in children presenting with IPD. METHODS We prospectively identified pediatric cases of IPD requiring hospitalization between 2005 and 2011 in 28 pediatric wards throughout France. IPD was defined as a positive pneumococcal culture, polymerase chain reaction result, and/or soluble antigen detection at a normally sterile site. The immunological assessment included abdominal ultrasound, whole-blood counts and smears, determinations of plasma immunoglobulin and complement levels, and the evaluation of proinflammatory cytokines. RESULTS We included 163 children with IPD (male-to-female ratio, 1.3; median age, 13 months). Seventeen children had recurrent IPD. Meningitis was the most frequent type of infection (87%); other infections included pleuropneumonitis, isolated bloodstream infection, osteomyelitis, endocarditis, and mastoiditis. One patient with recurrent meningitis had a congenital cerebrospinal fluid fistula. The results of immunological explorations were abnormal in 26 children (16%), and a PID was identified in 17 patients (10%), including 1 case of MyD88 deficiency, 3 of complement fraction C2 or C3 deficiencies, 1 of isolated congenital asplenia, and 2 of Bruton disease (X-linked agammaglobulinemia). The proportion of PIDs was much higher in children aged >2 years than in younger children (26% vs 3%; P < .001). CONCLUSIONS Children with IPD should undergo immunological investigations, particularly those aged >2 years, as PIDs may be discovered in up to 26% of cases.

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.

A Mild Form of SLC29A3 Disorder: A Frameshift Deletion Leads to the Paradoxical Translation of an Otherwise Noncoding mRNA Splice Variant

We investigated two siblings with granulomatous histiocytosis prominent in the nasal area, mimicking rhinoscleroma and Rosai-Dorfman syndrome. Genome-wide linkage analysis and whole-exome sequencing identified a homozygous frameshift deletion in SLC29A3, which encodes human equilibrative nucleoside transporter-3 (hENT3). Germline mutations in SLC29A3 have been reported in rare patients with a wide range of overlapping clinical features and inherited disorders including H syndrome, pigmented hypertrichosis with insulin-dependent diabetes, and Faisalabad histiocytosis. With the exception of insulin-dependent diabetes and mild finger and toe contractures in one sibling, the two patients with nasal granulomatous histiocytosis studied here displayed none of the many SLC29A3-associated phenotypes. This mild clinical phenotype probably results from a remarkable genetic mechanism. The SLC29A3 frameshift deletion prevents the expression of the normally coding transcripts. It instead leads to the translation, expression, and function of an otherwise noncoding, out-of-frame mRNA splice variant lacking exon 3 that is eliminated by nonsense-mediated mRNA decay (NMD) in healthy individuals. The mutated isoform differs from the wild-type hENT3 by the modification of 20 residues in exon 2 and the removal of another 28 amino acids in exon 3, which include the second transmembrane domain. As a result, this new isoform displays some functional activity. This mechanism probably accounts for the narrow and mild clinical phenotype of the patients. This study highlights the ‘rescue’ role played by a normally noncoding mRNA splice variant of SLC29A3, uncovering a new mechanism by which frameshift mutations can be hypomorphic.

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.

Effect of Nebulized Hypertonic Saline Treatment in Emergency Departments on the Hospitalization Rate for Acute Bronchiolitis: A Randomized Clinical Trial

Importance Acute bronchiolitis is the leading cause of hospitalization among infants. Previous studies, underpowered to examine hospital admission, have found a limited benefit of nebulized hypertonic saline (HS) treatment in the pediatric emergency department (ED). Objective To examine whether HS nebulization treatment would decrease the hospital admission rate among infants with a first episode of acute bronchiolitis. Design, Setting, and Participants The Efficacy of 3% Hypertonic Saline in Acute Viral Bronchiolitis (GUERANDE) study was a multicenter, double-blind randomized clinical trial on 2 parallel groups conducted during 2 bronchiolitis seasons (October through March) from October 15, 2012, through April 15, 2014, at 24 French pediatric EDs. Among the 2445 infants (6 weeks to 12 months of age) assessed for inclusion, 777 with a first episode of acute bronchiolitis with respiratory distress and no chronic medical condition were included. Interventions Two 20-minute nebulization treatments of 4 mL of HS, 3%, or 4 mL of normal saline (NS), 0.9%, given 20 minutes apart. Main Outcomes and Measures Hospital admission rate in the 24 hours after enrollment. Results Of the 777 infants included in the study (median age, 3 months; interquartile range, 2-5 months; 468 [60.2%] male), 385 (49.5%) were randomized to the HS group and 387 (49.8%) to the NS group (5 patients did not receive treatment). By 24 hours, 185 of 385 infants (48.1%) in the HS group were admitted compared with 202 of 387 infants (52.2%) in the NS group. The risk difference for hospitalizations was not significant according to the mixed-effects regression model (adjusted risk difference, –3.2%; 95% CI, –8.7% to 2.2%; P = .25). The mean (SD) Respiratory Distress Assessment Instrument score improvement was greater in the HS group (–3.1 [3.2]) than in the NS group (–2.4 [3.3]) (adjusted difference, –0.7; 95% CI, –1.2 to –0.2; P = .006) and similarly for the Respiratory Assessment Change Score. Mild adverse events, such as worsening of cough, occurred more frequently among children in the HS group (35 of 392 [8.9%]) than among those in the NS group (15 of 384 [3.9%]) (risk difference, 5.0%; 95% CI, 1.6%-8.4%; P = .005), with no serious adverse events. Conclusions and Relevance Nebulized HS treatment did not significantly reduce the rate of hospital admissions among infants with a first episode of acute moderate to severe bronchiolitis who were admitted to the pediatric ED relative to NS, but mild adverse events were more frequent in the HS group. Trial Registration clinicaltrials.gov Identifier: NCT01777347

Conduite à tenir devant une diarrhée aiguë chez l’enfant

Diarrhea in childhood is very frequent (two episodes/year/children less of 5 years), rarely fatale (mostly mild) and not requiring additional exploration. But it can justify a hospitalization in case of dehydration (delay of care) or risk of dehydration. It is mainly of viral origin (rotavirus +++) and it has for main complication dehydration. Diagnosis and evaluation of the dehydration, in percentage of loss of weight, must be fast and lead (drive) to a premature correction of hypovolumic shock (or to an accurate fluid management). Main treatment is oral rehydration solutions (ORS), which considerably upset the morbi-mortality, associated with a premature refeeding. Breast-feeding must not be interrupted. Symptomatic treatments and especially antibiotics are not recommended. In case of failure of the rehydration by ORS, alternative is nasogastric tube or intraveinous infusion. Prevention includes essentially the respect of hygienic rules and antirotavirus vaccine.

Strains Responsible for Invasive Meningococcal Disease in Patients With Terminal Complement Pathway Deficiencies

Background Patients with terminal complement pathway deficiency (TPD) are susceptible to recurrent invasive meningococcal disease (IMD). Neisseria meningitidis (Nm) strains infecting these patients are poorly documented in the literature. Methods We identified patients with TPD and available Nm strains isolated during IMD. We investigated the genetic basis of the different TPDs and the characteristics of the Nm strains. Results We included 56 patients with C5 (n = 8), C6 (n = 20), C7 (n = 18), C8 (n = 9), or C9 (n = 1) deficiency. Genetic study was performed in 47 patients and 30 pathogenic variants were identified in the genes coding for C5 (n = 4), C6 (n = 5), C7 (n = 12), C8 (n = 7), and C9 (n = 2). We characterized 61 Nm strains responsible for IMD in the 56 patients with TPD. The most frequent strains belonged to groups Y (n = 27 [44%]), B (n = 18 [30%]), and W (n = 8 [13%]). Hyperinvasive clonal complexes (CC11, CC32, CC41/44, and CC269) were responsible for 21% of IMD cases. The CC23 predominates and represented 26% of all invasive isolates. Eleven of the 15 clonal complexes identified fit to 12 different clonal complexes belonging to carriage strains. Conclusions Unusual meningococcal strains with low level of virulence similar to carriage strains are most frequently responsible for IMD in patients with TPD.

Sudden death caused by Staphylococcus aureus carrying Panton–Valentine leukocidin gene in a young girl

Staphylococcus aureus carrying the Panton–Valentine leukocidin (PVL) gene could be the source of both recurrent furunculosis or abscesses and severe infections, mainly necrotising pneumonia. We present the case of a young girl from consanguineous parents who died suddenly. The postmortem examination revealed necrotising pneumonia due to a PVL producing Staphylococcus aureus strain, raising the question of the role of the host’s immune status in this infection.

Impact of Implementing National Guidelines on Antibiotic Prescriptions for Acute Respiratory Tract Infections in Pediatric Emergency Departments: An Interrupted Time Series Analysis

Background Many antibiotics are prescribed inappropriately in pediatric emergency departments (PEDs), but little data are available in these settings about effective interventions based on guidelines that follow the antimicrobial stewardship principle. Our aim was to assess the impact of implementing the 2011 national guidelines on antibiotic prescriptions for acute respiratory tract infection (ARTI) in PEDs. Method We conducted a multicentric, quasiexperimental, interrupted time series analysis of prospectively collected electronic data from 7 French PEDs. We included all pediatric patients who visited a participating PED during the study period from November 2009 to October 2014 and were diagnosed with an ARTI. The intervention consisted of local protocol implementation, education sessions, and feedback. The main outcome was the antibiotic prescription rate of discharge prescriptions for ARTI per 1000 PED visits before and after implementation, analyzed using the segmented regression model. Results We included 242534 patients with an ARTI. The intervention was associated with a significant change in slope for the antibiotic prescription rate per 1000 PED visits (-0.4% per 15-day period, P = .04), and the cumulative effect at the end of the study was estimated to be -30.9%, (95% CI [-45.2 to -20.1]), representing 13136 avoided antibiotic prescriptions. The broad-spectrum antibiotic prescription relative percentage decreased dramatically (-62.7%, 95% CI [-92.8; -32.7]) and was replaced by amoxicillin. Conclusion Implementation of the 2011 national French guidelines led to a significant decrease in the antibiotic prescription rate for ARTI and a dramatic drop in broad-spectrum antibiotic prescriptions, in favor of amoxicillin.