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.

European Society for Pediatric Gastroenterology, Hepatology, and Nutrition/European Society for Pediatric Infectious Diseases evidence-based guidelines for the management of acute gastroenteritis in children in Europe: update 2014.

OBJECTIVES: These guidelines update and extend evidence-based indications for the management of children with acute gastroenteritis in Europe. METHODS: The guideline development group formulated questions, identified data, and formulated recommendations. The latter were graded with the Muir Gray system and, in parallel, with the Grading of Recommendations, Assessment, Development and Evaluations system. RESULTS: Gastroenteritis severity is linked to etiology, and rotavirus is the most severe infectious agent and is frequently associated with dehydration. Dehydration reflects severity and should be monitored by established score systems. Investigations are generally not needed. Oral rehydration with hypoosmolar solution is the major treatment and should start as soon as possible. Breast-feeding should not be interrupted. Regular feeding should continue with no dietary changes including milk. Data suggest that in the hospital setting, in non-breast-fed infants and young children, lactose-free feeds can be considered in the management of gastroenteritis. Active therapy may reduce the duration and severity of diarrhea. Effective interventions include administration of specific probiotics such as Lactobacillus GG or Saccharomyces boulardii, diosmectite or racecadotril. Anti-infectious drugs should be given in exceptional cases. Ondansetron is effective against vomiting, but its routine use requires safety clearance given the warning about severe cardiac effects. Hospitalization should generally be reserved for children requiring enteral/parenteral rehydration; most cases may be managed in an outpatients setting. Enteral rehydration is superior to intravenous rehydration. Ultrarapid schemes of intravenous rehydration are not superior to standard schemes and may be associated with higher readmission rates. CONCLUSIONS: Acute gastroenteritis is best managed using a few simple, well-defined medical interventions.

[Pertussis worldwide. Vaccinating children and adults]. / La coqueluche dans le monde. Vacciner l'enfant et l'adulte.

Pertussis (whooping cough) is an important cause of morbidity and mortality in infants world-wide, and continues to be a public health concern despite high vaccination coverage. The disease, caused by bacterium Bordetella pertussis, is present in all countries. Before vaccines became widely available in the 1950s, pertussis was one of the most common childhood diseases worldwide. According to WHO, estimation of deaths was 4 millions/year in 1950 and 100 000/year in 2015. But morbidity remains important with a high circulation of the bacterium determining atypical clinical forms after whole cell or acellular vaccines use. This is due mainly to the absence of booster doses in adolescents and adults. Major progress are generalisation of PCR and vaccination of mother during pregnancy. A resurgence of pertussis is observed after generalisation of acellular vaccines use. In China the progression of allele ptxPl was found in all areas following the use of acellular vaccine. This allele, rare before acellullar vaccine, is linked to a macrolide resistance, and reaches more than 30% of strains isolated in hospitalised children.These evolutions must be evaluated in clinical forms and genotyping of all strains, in all areas.

X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production.

Germline mutations in five autosomal genes involved in interleukin (IL)-12-dependent, interferon (IFN)-gamma-mediated immunity cause Mendelian susceptibility to mycobacterial diseases (MSMD). The molecular basis of X-linked recessive (XR)-MSMD remains unknown. We report here mutations in the leucine zipper (LZ) domain of the NF-kappaB essential modulator (NEMO) gene in three unrelated kindreds with XR-MSMD. The mutant proteins were produced in normal amounts in blood and fibroblastic cells. However, the patients' monocytes presented an intrinsic defect in T cell-dependent IL-12 production, resulting in defective IFN-gamma secretion by T cells. IL-12 production was also impaired as the result of a specific defect in NEMO- and NF-kappaB/c-Rel-mediated CD40 signaling after the stimulation of monocytes and dendritic cells by CD40L-expressing T cells and fibroblasts, respectively. However, the CD40-dependent up-regulation of costimulatory molecules of dendritic cells and the proliferation and immunoglobulin class switch of B cells were normal. Moreover, the patients' blood and fibroblastic cells responded to other NF-kappaB activators, such as tumor necrosis factor-alpha, IL-1beta, and lipopolysaccharide. These two mutations in the NEMO LZ domain provide the first genetic etiology of XR-MSMD. They also demonstrate the importance of the T cell- and CD40L-triggered, CD40-, and NEMO/NF-kappaB/c-Rel-mediated induction of IL-12 by monocyte-derived cells for protective immunity to mycobacteria in humans.

Prediction of moderate and high grade vesicoureteral reflux after a first febrile urinary tract infection in children: construction and internal validation of a clinical decision rule.

PURPOSE: Urinary tract infection leads to a diagnosis of moderate or high grade (III or higher) vesicoureteral reflux in approximately 15% of children. Predicting reflux grade III or higher would make it possible to restrict cystography to high risk cases. We aimed to derive a clinical decision rule to predict vesicoureteral reflux grade III or higher in children with a first febrile urinary tract infection. MATERIALS AND METHODS: We conducted a secondary analysis of prospective series including all children with a first febrile urinary tract infection from the 8 European participating university hospitals. RESULTS: A total of 494 patients (197 boys, reflux grade III or higher in 11%) were included. Procalcitonin and ureteral dilatation on ultrasound were significantly associated with reflux grade III or higher and then combined into a prediction model with an ROC AUC of 0.75 (95% CI 0.69-0.81). Given the prespecified constraint of achieving at least 85% sensitivity, our model led to the clinical decision rule, for children with a first febrile urinary tract infection cystography should be performed in cases with ureteral dilatation and serum procalcitonin level 0.17 ng/ml or higher, or without ureteral dilatation (ie ureter not visible) when serum procalcitonin level is 0.63 ng/ml or higher. The rule had 86% sensitivity (95% CI 74-93) with 47% specificity (95% CI 42-51). Internal cross-validation produced 86% sensitivity (95% CI 79-93) and 43% specificity (95% CI 39-47). CONCLUSIONS: A clinical decision rule was derived to enable a selective approach to cystography in children with urinary tract infection. The rule predicts high grade vesicoureteral reflux with approximately 85% sensitivity and avoids half of the cystograms that do not find reflux grade III or higher. Further validation is needed before its widespread use.

Underestimation of influenza viral infection in childhood asthma exacerbations.

Bocavirus was found in 11.6% of hospitalized children and 13% of ambulatory patients with exacerbations of asthma, and respiratory syncytial virus was found in 13.5% and 17.7%, respectively. In addition, influenza A virus was detected in 2.6% of hospitalized children and 14.1% (P<.001) of ambulatory-treated patients. Thus, the influenza burden in asthma may be underestimated.

Procalcitonin is useful in identifying bacteraemia among children with pneumonia.

Empirical antibiotic use is prescribed in managing children with pneumonia worldwide. We assessed the usefulness of procalcitonin (PCT) and interferon-alpha (IFN-alpha) in differentiating viral from bacterial pneumonia. Among 159 hospitalized children, pneumonia was diagnosed based on clinical complaints plus pulmonary infiltrate. Aetiology was investigated for 9 viruses and 4 atypical and 3 typical bacteria. PCT and IFN-alpha were measured in the serum sample collected on admission. Eight patients had bacteraemic infections, 38 had non-bacteraemic typical infections, and 19 patients had atypical bacterial infections. Viral and unknown aetiology was established in 57 (36%) and 34 (21%) cases, respectively. Three patients with bacterial infection without collected blood culture were excluded. IFN-alpha (IU/ml) was detectable in 20 (13%) cases. The difference among median PCT values of the bacteraemic (4.22; 1.56-7.56), non-bacteraemic typical bacterial (1.47; 0.24-4.07), atypical bacterial (0.18; 0.06-1.03) and only viral (0.65; 0.11-2.22) subgroups was significant (p = 0.02). PCT was > or =2 ng/ml in 52 (33%) cases. The presence of IFN-alpha was associated with PCT <2 ng/ml (90% vs. 64%, p = 0.02). The negative predictive value (95% confidence interval) of PCT > or =2 ng/ml was 95% (89-100%), 89% (78-100%), 93% (85-100%) for differentiation of bacteraemic from viral, atypical bacterial and non-bacteraemic typical bacterial infection, respectively, and 58% (49-68%) for differentiation between bacterial and viral infection. PCT may be useful in identifying bacteraemia among children hospitalized with community-acquired pneumonia. IFN-alpha was uncommonly detected.

Impressive renal damage after acute pyelonephritis in a child.

Urinary tract infection (UTI) is one of the most common bacterial infections in children, and its role in the pathogenesis of scarred kidney is debated. We report on a 7-year-old child who presented with severe UTI. The early (day 4) renal computed tomography (CT) scan showed normal-sized kidneys (110 mm on the left, 105 mm on the right), whereas the control CT scan and dimercaptosuccinic acid (DMSA) scan, performed 1 and 2 months later, respectively, showed a small scarred right kidney (60 mm) with a 12% residual function. An intermittent right vesicoureteral reflux (VUR) was diagnosed by direct isotopic cystography and then treated by Cohen vesicoureteral reimplantation. The patient remained free of infectious recurrence, hypertension, or renal function decrease. This report demonstrates that one episode of acute pyelonephritis can lead to severe renal scarring. Whereas antenatal lesions are thought to have a stronger role in the causal pathway for reflux nephropathy than is UTI in addition to VUR, this observation reminds us that UTI can truly play an important role in damaging kidneys.

Hospitalization for severe bacterial infections in children after exposure to NSAIDs: a prospective adverse drug reaction reporting study.

BACKGROUND: NSAIDs are widely used to treat fever and pain in children, but their possible role in the progression of some bacterial infections is controversial. OBJECTIVE: This study was performed to analyse reported cases of severe bacterial infection associated with NSAID exposure in children admitted for this reason to a general paediatric department. METHODS: This study was based on the reporting system of hospital admissions for severe bacterial infections in children after NSAID exposure, and followed the recommendations of the European Guidelines of Pharmacovigilance for medicines used in a paediatric population. Data were prospectively collected and reported by active daily surveillance in the department from November 2002 to November 2005. RESULTS: Thirty-two cases of severe bacterial infections (cellulitis, soft tissue abscesses, parapneumonic empyema, necrotizing pneumonia, adenophlegmon [fever and a tender, warm and easily compressible neck mass] and lateral or retropharyngeal abscesses) were identified in children who had received NSAIDs, principally ibuprofen, in an exposure window of 15 days before the beginning of the signs of infection. Staphylococcus aureus, group A streptococci and Streptococcus pneumoniae were identified. Seven (22%) children required surgical treatment, and four (13%) were hospitalized in an intensive care unit. CONCLUSIONS: The frequency of hospitalization for severe bacterial infection as a possible adverse effect of NSAID use was 0.6% (95% CI 0.4, 0.9) of all admissions during the study period. The frequency of severe bacterial infections after exposure to NSAIDs was elevated (one case per month) in the department studied. Further work is necessary to confirm these findings, given the potential for recruitment and protopathic biases in our study.

[Epidemiology of parasitic diseases, hypereosinophilia, IgE from tropical and European parasitological origins]. / Epidémiologie des parasitoses, hyperéosinophilies sanguines et IgE d'origines parasitaires en milieux tempérés et tropicaux.

Etiologic investigations of hypereosinophilia, often accompanied by IgE elevation, depends on the patient's geographic origin and travel history. In France, helminth diseases are the only parasitoses associated with hypereosinophilia. Some, such as oxyurosis in children, are frequent but generally mild. More severe but less frequent infections include distomatoses, trichinellosis, taeniasis, echinococcosis and visceral larva migrans. Among subjects originating from or having travelled to tropical areas with poor hygiene, eosinophilia may be due to early intense polyparasitism and has little etiologic value. In Gabon, a warm, humid country in equatorial Africa, schoolchildren harbor an average of three different parasites capable of inducing hypereosinophilia or serum IgE elevation. These children's eosinophil counts start to rise at very young age, after weaning and contact with soil, and continue to increase rapidly until adulthood. Average values across all age groups are 1580 eosinophils/mm3 and 3300 kU IgE/L. Direct diagnosis of chronic parasitic infections is often possible in this setting, and specific treatments can be prescribed. In contrast, hypereosinophilia has less etiologic significance in patients originating from or having travelled to the tropics and who present to European parasitology units. Direct examination is rarely positive, and the etiologic diagnosis will thus be guided by epidemiologic, clinical and serologic findings. These findings are sometimes sufficient to initiate probabilistic treatment with albendazole, ivermectin and praziquentel.

Clinical decision rules for evaluating meningitis in children.

PURPOSE OF REVIEW: Distinguishing between bacterial and aseptic meningitis in children is sometimes difficult. Guidelines recommend that patients with acute meningitis be systematically hospitalized and treated with antibiotics until the cerebrospinal fluid culture results are available. This strategy ensures rapid treatment for bacterial meningitis, but also involves unnecessary admissions and antibiotics for aseptic meningitis. Some authors have, therefore, proposed different combinations of predictors in clinical decision rules to distinguish as early as possible between bacterial and aseptic meningitis. To be useful, these rules must have near-100% sensitivity for bacterial meningitis, good specificity (to reduce unnecessary antibiotics and admissions), and easy bedside application. RECENT FINDINGS: The present review examines the performance and level of validation of decision rules proposed after the Haemophilus influenzae vaccination entered widespread use. Most of these rules have been validated incompletely, if at all. Only one rule incorporates the best single validated predictive marker for distinguishing between bacterial and aseptic meningitis in children: serum procalcitonin level. SUMMARY: Two rules are highly promising, meeting the three major conditions after a retrospective validation process in large samples. These rules can be applied cautiously to patients with the same inclusion and exclusion criteria as those in the derivation sets, while awaiting prospective multicenter validation studies.

Human bocavirus: a cause of severe asthma exacerbation in children.

Real-time polymerase chain reaction for human bocavirus (HBoV) was performed in nasopharyngeal aspirate specimens from 166 children over 2 years of age hospitalized for severe asthma exacerbation. Whereas HBoV was detected in 21 of these children (13%), it was found in only 1 of 50 ambulatory children with stable asthma (2%), suggesting a major role of HBoV in acute exacerbations in asthmatic children.

Recovery from childhood community-acquired pneumonia in a developing country: Prognostic value of serum procalcitonin.

BACKGROUND: Childhood community-acquired pneumonia is a common and potentially life-threatening illness in developing countries. We assessed the prognostic value of serum procalcitonin level upon admission on clinical response to antibiotic treatment. METHODS: Out of 89 patients, the median (IQR) age was 19(12-29) months and 60% were boys. Viral (49.5%), typical bacterial (38%) and atypical bacterial (12.5%) infections as well as probable pneumococcal infections (26%) were diagnosed. RESULTS: Seventy-five (84%) children became afebrile ≤48h after treatment. In 14 children who remained febrile after 48h of treatment, median[IQR] serum procalcitonin (ng/ml) level on admission was higher than in those with rapid recovery (2.1[0.8-3.7] vs 0.6[0.1-2.2]; P=0.025). In the slow-responding children, pneumococcal infections were more common (71% vs 17%; P<0.001). Procalcitonin concentrations on admission were higher in children with pneumococcal pneumonia compared to children with non-pneumococcal pneumonia (2[0.7-4.2] vs 0.5[0.08-2.1]; P=0.002). The ROC curve found that <0.25ng/ml of serum procalcitonin had a high negative predictive value (93%[95%CI:80%-99%]) for pneumococcal infection. All children that remained febrile after 48h of treatment had procalcitonin >0.25ng/ml on admission. The majority of children with pneumonia in a developing country become afebrile within 48h after onset of antibiotic treatment. CONCLUSIONS: Serum procalcitonin <0.25ng/ml predicted rapid clinical response and non-pneumococcal etiology.

Sensitivity of the bacterial meningitis score in 889 children with bacterial meningitis.

OBJECTIVE: To validate sensitivity of the bacterial meningitis score (BMS) in a large population of children with bacterial meningitis (BM). STUDY DESIGN: Secondary analysis of prospective data for children presenting with BM to a hospital emergency department between January 2001 and February 2005. The BMS was applied to all children with acute BM using the same inclusion criteria proposed by the authors of the rule. The sensitivity of the rule was calculated. RESULTS: Of the 900 children aged 29 days to 18 years with acute BM who met all inclusion criteria, 889 had enough data for assigning the BMS. Use of the BMS correctly identified 884 children with BM, for 99.6% sensitivity (95% confidence interval: 98.9% to 99.8%). CONCLUSIONS: The sensitivity of the BMS to detect disease was very high, but a few cases of BM were missed. Further refinements of the BMS may be warranted to lower the false-negative rate.

Pertussis and respiratory syncytial virus infections.

During the winter 2005-2006, all infants <4 months of age admitted for bronchiolitis or acute respiratory tract infection in a tertiary care pediatric hospital in Paris were tested for respiratory syncytial virus (RSV) and pertussis with real-time polymerase-chain reaction (RT-PCR). A positive pertussis-PCR was found in 14/90 (16%) infants infected with RSV and in 5/30 negative for RSV. Similar clinical symptoms were found in all RSV-positive infants with or without pertussis co-infection. Most infants (73%) were not vaccinated against pertussis, and the other children had received one or two injections. In conclusion, pertussis-RSV co-infection is common in young infants, and pertussis-PCR should be used, whenever available.

[Respiratory syncytial virus in hospitalized children. A 3-year study]. / La fréquence du virus respiratoire syncytial et des autres virus respiratoires dans les hospitalisations de l'enfant. Une enquête de 3 ans.

OBJECTIVE: To assess the prevalence of respiratory syncytial virus (RSV) and other important respiratory viruses in children hospitalized in a pediatric hospital in Paris (France) during a 3-year period (2001 to 2004). PATIENTS AND METHODS: The study included all patients aged 8 days to 16 years admitted from the community through emergency department with bronchiolitis, pneumonia, upper respiratory tract infection, asthma or acute isolated fever and who had nasopharyngeal samples taken for viral identification by immunofluorescence (RSV, influenza, para-influenza, and adenoviruses). RESULTS: A virus was found in 464 of 1208 patients with samples taken. RSV was identified in 375 patients, 74% of them younger than 6 months and diagnosed with bronchiolitis. RSV was isolated more often than any other virus, overall and for all diagnoses except "isolated fever," for which influenza was more frequent. In patients aged 24 months or older, influenza and RSV were identified at the same frequency. Overall, influenza virus was found in 53 patients, adenoviruses in 24 and para-influenza viruses in 11. CONCLUSION: RSV was the respiratory virus isolated most often, even in older children, during this 3-year study. The relative rarity of hospitalizations due to para-influenza viruses is characteristic of this area, compared with some other countries.

Procalcitonin to reduce the number of unnecessary cystographies in children with a urinary tract infection: a European validation study.

OBJECTIVE: To validate high serum procalcitonin (PCT) as a predictor of vesicoureteral reflux (VUR) in children with a first febrile urinary tract infection (UTI). STUDY DESIGN: This secondary analysis of prospective hospital-based cohort studies included children ages 1 month to 4 years with a first febrile UTI. RESULTS: Of the 398 patients included in 8 centers in 7 European countries, 25% had VUR. The median PCT concentration was significantly higher in children with VUR than in those without: 1.6 versus 0.7 ng/mL (P = 10(-4)). High PCT (> or =0.5 ng/mL) was associated with VUR (OR: 2.3; 95% CI, 1.3 to 3.9; P = 10(-3)). After adjustment for all cofactors, the association remained significant (OR: 2.5; 95% CI, 1.4 to 4.4; P = 10(-3)). The strength of the relation increased with the grade of reflux (P = 10(-5)). The sensitivity of procalcitonin was 75% (95% CI, 66 to 83) for all-grade VUR and 100% (95% CI, 81 to 100) for grade > or =4 VUR, both with 43% specificity (95% CI, 37 to 48). CONCLUSIONS: High PCT is a strong, independent and now validated predictor of VUR that can be used to identify low-risk patients and thus avoid one third of the unnecessary cystourethrographies in children with a first febrile UTI.

Lack of value of procalcitonin for prediction of coronary aneurysms in Kawasaki disease.

We studied the clinical, biologic (white blood cells, C-reactive protein and procalcitonin) and echocardiographic findings in 18 children hospitalized for Kawasaki disease from January 1999 until February 2006 to determine if procalcitonin is a useful marker to predict coronary aneurysms. In our study, contrary to earlier reports, elevated procalcitonin was not correlated with development of coronary aneurysms.

Late-onset neonatal infections caused by group B Streptococcus associated with viral infection.

An association between viral infection and late-onset disease caused by group B Streptococcus (GBS), was systematically looked for in neonates hospitalized for fever during a 3 1/2 year period. Five neonates between 5 to 12.5 months of age presented with meningitis (2 cases) or with septicemia (3 cases) caused by GBS. Viral culture, immunofluorescence, and assay of IFNalpha in blood and cerebrospinal fluid were performed. A viral infection was proved in 4 cases and suspected in 1 case (rash and pharyngitis). We speculate that viral infection may provoke late-onset disease in colonized infants with GBS.