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Graphical abstract Schematic distribution of the clinical signs in multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2., The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been characterized by high transmission rates and high mortality in adults with predisposing factors, including age > 70 years, obesity, diabetes, systemic hypertension and other underlying diseases. During the second week of viral pneumonia, acute respiratory distress syndrome can occur and carries high mortality. Unlike most common respiratory viruses, children seem to be less susceptible to SARS-CoV-2 infection, and generally develop mild disease with low mortality. However, clusters of severe shock associated with high levels of cardiac biomarkers and unusual vasoplegia requiring inotropes, vasopressors and volume loading have recently been described. Both the clinical symptoms (i.e. high and persistent fever, gastrointestinal disorders, skin rash, conjunctival injection and dry cracked lips) and the biological signs (e.g. elevated C-reactive protein/procalcitonin and high levels of ferritinaemia) mimicked Kawasaki disease. In most cases, intravenous immunoglobin therapy improved cardiac function and led to full recovery within a few days. Adjunctive steroid therapy and sometimes biotherapy (e.g. anti-interleukin 1Ra and anti-interleukin 6 monoclonal antibodies) were often necessary. Although almost all children fully recovered within a week, some of them later developed coronary artery dilation or aneurysm. Thus, a new “multisystem inflammatory syndrome in children” related to SARS-CoV-2 has recently been described. Similarities with Kawasaki disease and the physiopathology of this syndrome still need further exploration.

Multisystemic inflammatory syndrome in children (mis-c) Asociated with covid Although children are less susceptible to sars-cov-2 and less symptomatic than adults with low mortality, clusters of Septic shock associated with elevated cardiac biomarkers and unusual vasoplegia have been recently described and Treated by inotropes, vasopressors, and fluid loading. Both clinical symptoms (i.e., high and persistent fever, gastrointestinal Disorders, skin rash, conjunctivitis and dry cracked lips) and biological signs (e.g., elevated crp/procalcitonin, high Levels of ferritinemia) resembled kawasaki disease. In most instances, intravenous immunoglobin therapy with glucosteroids Improved the cardiac function and led to full recovery within a few days. However, adjunctive biotherapy (e.g., Anti-il-1ra, anti-il-6 monoclonal antibodies) was sometimes necessary. Although almost all children fully recovered Within a few days, some of them developed late coronary artery dilation or aneurysm. Thus, a new "multisystem inflammatory Syndrome in children" (mis-c) associated with sars-cov-2 has been identified, and its pathophysiology better Understood.Syndrome inflammatoire multisystémique associé au covid Chez l’enfant Si les enfants apparaissent moins susceptibles au sars-cov-2 et sont moins symptomatiques que les adultes, avec Une faible mortalité, des états de choc associés à une élévation des biomarqueurs cardiaques et à une vasoplégie Inhabituelle, nécessitant un traitement par inotropes, vasopresseurs et un remplissage vasculaire ont été décrits. Les Symptômes cliniques observés (fièvre élevée et durable, troubles digestifs, rash cutané, injection conjonctivale, chéilite) Et le profil biologique (crp/procalcitonine élevées, hyperferritinémie) peuvent parfois mimer un syndrome de kawasaki Atypique. Cette nouvelle entité répond le plus souvent à la perfusion intraveineuse d’immunoglobulines associée à Une corticothérapie, et nécessite parfois une biothérapie anti-il-1ra ou anti-il-6. La majorité des enfants guérit en Quelques jours, avec cependant une possible dilatation des artères coronaires. Ainsi, un nouveau syndrome inflammatoire Multisystémique associé au sars-cov-2 mimant un syndrome de kawasaki a récemment été identifié chez L’enfant et sa physiopathologie est mieux comprise.

International audience

Resume La pandemie due a SARS-CoV-2 est caracterisee par une haute contagiosite et une mortalite elevee chez les adultes a risque (âge superieur a 65 ans, obesite, diabete, hypertension). Au decours d’une pneumonie virale, survient parfois une phase hyper-inflammatoire compliquee d’une defaillance multi-viscerale dont un Syndrome de Detresse Respiratoire Aigue (SDRA). Contrairement a la majorite des virus respiratoires, les enfants apparaissent moins susceptibles a SARS-CoV-2 et developpent generalement une forme peu severe, avec une faible mortalite. Cependant, des cas groupes d’etats de choc associes a des biomarqueurs cardiaques eleves et a une vasoplegie inhabituelle necessitant un traitement par inotropes, vasopresseurs et un remplissage vasculaire ont ete recemment decrits. Les symptomes cliniques observes (fievre elevee et durable, troubles digestifs, rash cutane, injection conjonctivale, cheleite) et le profil biologique (CRP/PCT elevees, hyperferritinemie) evoquent un syndrome de Kawasaki atypique qui repond a un traitement par perfusion intraveineuse d’immunoglobulines complete si besoin par une corticotherapie et/ou une biotherapie anti-IL-1Ra ou anti-IL-6. La majorite des enfants guerit en quelques jours avec cependant une possible dilatation des arteres coronaires. Ainsi, un nouveau syndrome inflammatoire multi-systemique associe a SARS-CoV-2 mimant un syndrome de Kawasaki a ete recemment identifie chez l’enfant et aide a mieux comprendre la physiopathologie de ce syndrome d’etiologie restee jusqu’ici inconnue.

International audience; Intravenous fluids are frequently used in hospitalized children. Hypotonic fluids have been the standard of care in pediatrics for many years. This might be explained by the empiricism of early recommendations favoring fluids with dextrose, but an insufficient amount of sodium. The risk of hyponatremia (

Most studies of inhaled nitric oxide (iNO) for prevention of bronchopulmonary dysplasia (BPD) in premature infants have focused on short-term mortality and morbidity. Our aim was to determine the long-term effects of iNO. A 7-year follow-up was undertaken of infants entered into a multicenter, double-blind, randomized, placebo-controlled trial of iNO for prevention of BPD in premature infants born between 24 and 28 weeks plus six days of gestation. At 7 years, survival and hospital admissions since the 2-year follow-up, home oxygen therapy in the past year, therapies used in the previous month and growth assessments were determined. Questionnaires were used to compare general health, well-being, and quality of life. A total of 305 children were assessed. No deaths were reported. Rates of hospitalization for respiratory problems (6.6 vs. 10.5%, iNO and placebo group, respectively) and use of respiratory medications (6.6 vs. 9.2%) were similar. Two patients who received iNO and one who received placebo had received home oxygen therapy. There were no significant differences in any questionnaire-documented health outcomes. iNO for prevention of BPD in very premature infants with respiratory distress did not result in long-term benefits or adverse long-term sequelae. In the light of current evidence, routine use of iNO cannot be recommended for prevention of BPD in preterm infants., SCOPUS: ar.j, DecretOANoAutActif, info:eu-repo/semantics/published

Summary Background Enteroviruses are the most frequent cause of acute meningitis and are seen increasingly in sepsis-like disease and fever without source in the paediatric population. Detection of enterovirus in cerebrospinal fluid (CSF) specimens by PCR is the gold standard diagnostic test. Our aim was to assess a method of detecting enterovirus in blood specimens by PCR. Methods We did a prospective, multicentre, observational study at 35 French paediatric and emergency departments in 16 hospitals. We recruited newborn babies (aged ≤28 days) and infants (aged >28 days to ≤2 years) with fever without source, sepsis-like disease, or suspected meningitis, and children (aged >2 years to ≤16 years) with suspected meningitis, who were admitted to a participating hospital. We used a standardised form to obtain demographic, clinical, and laboratory data, which were anonymised. Enterovirus PCR testing was done in blood and CSF specimens. Findings Between June 1, 2015, and Oct 31, 2015, and between June 1, 2016, and Oct 31, 2016, we enrolled 822 patients, of whom 672 had enterovirus PCR testing done in blood and CSF specimens. Enterovirus was detected in 317 (47%) patients in either blood or CSF, or both (71 newborn babies, 83 infants, and 163 children). Detection of enterovirus was more frequent in blood samples than in CSF specimens of newborn babies (70 [99%] of 71 vs 62 [87%] of 71; p=0·011) and infants (76 [92%] of 83 vs 62 [75%] of 83; p=0·008), and was less frequent in blood samples than in CSF specimens of children (90 [55%] of 163 vs 148 [91%] of 163; p

The vast majority of medicines have been developed for adults. Consequently, the prescribing of medicines for children must take into account their pharmacodynamic characteristics and must be calculated individually according to the degree of prematurity, the age, the weight or body area and the clinical condition. Medication errors are the most common type of medical errors, notably in children, due to dosage errors or prescribtion of inappropriate medicines. The best way to avoid them lies in the use of prescribing software, the involvement of pharmacists in care units, and proper communication between prescribing doctors, caregivers, pharmacists and families.

Vitamin D is synthesized in human skin upon sun exposure and is also a nutrient. It regulates calcium and phosphate metabolism and is essential for the maintenance of bone health. Vitamin D supplementation during infancy, in order to prevent rickets, is universally accepted. Many human cell types carry vitamin D receptor, this being a drive for conducting studies on the possible association between vitamin D status and other diseases. Studies have affirmed that a considerable number of healthy European children may be vitamin D deficient, especially in high-risk groups (darker pigmented skin, living in areas with reduced sun exposure and other disorders). However, the definition of deficiency is unclear due to inter assay differences and due to a lack of consensus as to what is an "adequate" 25(OH)D level. Therefore, there is no justification for routine screening for vitamin D deficiency in healthy children. An evaluation of vitamin D status is justified in children belonging to high-risk groups. All infants up to 1 year of age should receive an oral supplementation of 400 IU/day of vitamin D. Beyond this age, seasonal variation of sunlight should be taken into account when considering a national policy of supplementation or fortification.

The European Academy of Paediatrics (EAP) is the paediatric section of the European Union of Medical Specialists (UEMS). The UEMS is responsible for the supervision and approval of training programmes in paediatrics and in its subspecialties. This implies also that EAP has the responsibility to address the training of all professionals working with children, to ensure that their paediatric competences and skills are adequate when dealing with children. The EAP has developed syllabi for paediatricians that provide standards of practice, and criteria for the assessment of competencies in trainees and training centres across Europe. The EAP recommends that all health care professionals working with children should have an officially approved training in child health in addition to formal qualifications in their own field. Moreover, the existing paediatric workforce must maintain their knowledge and skills with relevant continuous professional development and medical education in child health. Conclusion: There is a need to reassess the training of all health care professionals caring for children, ensuring that it supports new models of integrated and multidisciplinary care and focuses on the needs of the child and the family. A standardised, competency-based minimum paediatric training programme/curriculum should be part in the specialty curriculums.

Background Henoch-Schonlein purpura, more recently renamed immunoglobulin A vasculitis (IgAV), is a systemic vasculitis characterized by IgA deposits. The current markers used to assess IgAV inaccurately evaluate the risk of nephritis occurrence and its long-term outcomes. The current study assessed biomarkers of nephritis outcomes. Methods This French multicentre prospective study enrolled 85 adult patients at the time of disease onset. Patients were assessed for clinical and biological parameters and re-examined after 1 year. Immunoglobulins, cytokines, IgA glycosylation, IgA complexes and neutrophil gelatinase-associated lipocalin (NGAL) concentrations were assessed in blood and urine. Results We identified 60 patients with IgAV-related nephritis (IgAV-N) and 25 patients without nephritis (IgAV-woN). At the time of inclusion (Day 1), the serum levels of galactose-deficient IgA1 (Gd-IgA1) and urinary concentrations of IgA, IgG, IgM, NGAL, interleukin (IL)-1β, IL-6, IL-8, IL-10, IgA-IgG and IgA-sCD89 complexes were higher in the IgAV-N patients than in the IgAV-woN patients (P

Post-malaria neurologic syndrome (PMNS) is a rare complication following a Plasmodium falciparum infection and its pathophysiology remains unclear. This is the first report of a pediatric PMNS following an infection acquired in Africa and the fourth description of pediatric PMNS overall. Neither intrathecal synthesis of Immunoglobin G nor specific P. falciparum antibodies were found in the cerebrospinal fluid.

White matter damage (WMD) and bronchopulmonary dysplasia (BPD) are the two main complications occurring in very preterm infants. Inhaled nitric oxide (iNO) has been proposed to promote alveolarization in the developing lung, and we have reported that iNO promotes myelination and induces neuroprotection in neonatal rats with excitotoxic brain damage. Our hypothesis is that, in addition to its pulmonary effects, iNO may be neuroprotective in rat pups exposed to hyperoxia. To test this hypothesis, we exposed rat pups to hyperoxia, and we assessed the impact of iNO on WMD and BPD. Rat pups were exposed to either hyperoxia (80% FiO2) or to normoxia for 8 days. Both groups received iNO (5 ppm) or air. We assessed the neurological and pulmonary effects of iNO in hyperoxia-injured rat pups using histological, molecular and behavioral approaches. iNO significantly attenuated the severity of hyperoxia-induced WMD induced in neonatal rats. Specifically, iNO decreased white matter inflammation, cell death, and enhanced the density of proliferating oligodendrocytes and oligodendroglial maturation. Furthermore, iNO triggered an early upregulation of P27kip1 and brain-derived growth factor (BDNF). Whereas hyperoxia disrupted early associative abilities, iNO treatment maintained learning scores to a level similar to that of control pups. In contrast to its marked neuroprotective effects, iNO induced only small and transient improvements of BPD. These findings suggest that iNO exposure at low doses is specifically neuroprotective in an animal model combining injuries of the developing lung and brain that mimicked BPD and WMD in preterm infants.

The vast majority of medicines have been developed for adults. Consequently, the prescribing of medicines for children must take into account their pharmacodynamic characteristics and must be calculated individually according to the degree of prematurity, the age, the weight or body area and the clinical condition. Medication errors are the most common type of medical errors, notably in children, due to dosage errors or prescribtion of inappropriate medicines. The best way to avoid them lies in the use of prescribing software, the involvement of pharmacists in care units, and proper communication between prescribing doctors, caregivers, pharmacists and families.

Inhaled nitric oxide (iNO) is commonly used in the treatment of very ill pre-term newborns. Previous studies showed that exogenous NO could affect endothelial NO synthase (eNOS) activity and expression in vascular endothelial cell cultures or adult rat models, but this has never been fully described in newborn rat lungs. We therefore aimed to assess the effects of iNO on eNOS expression and activity in newborn rats. Rat pups, post-natal day (P) 0 to P7, and their dams were placed in a chamber containing NO at 5 ppm (iNO-5 ppm group) or 20 ppm (iNO-20 ppm group), or in room air (control group). Rat pups were sacrificed at P7 and P14 for evaluation of lung eNOS expression and activity. At P7, eNOS protein expression in total lung lysates, in bronchial and arterial sections, was significantly decreased in the iNO-20 ppm versus control group. At P14, eNOS expression was comparable among all three groups. The amounts of eNOS mRNA significantly differed at P7 between the iNO-20 ppm and control groups. NOS activity decreased in the iNO-20 ppm group at P7 and returned to normal levels at P14. There was an imbalance between superoxide dismutase and NOS activities in the iNO-20 ppm group at P7. Inhalation of NO at 20 ppm early after birth decreases eNOS gene transcription, protein expression and enzyme activity. This decrease might account for the rebound phenomenon observed in patients treated with iNO., Inhaled NO decreases endogenous NO synthesis and favours rebound pulmonary hypertension after inhaled NO withdrawal http://ow.ly/WNDq2

We performed a cohort study of children who survived bacterial meningitis after the neonatal period at a single pediatric center in France over a 10-year period (1995-2004) to identify predictors of death and long-term neurological deficits in children with bacterial meningitis. We performed multivariate regression to determine independent predictors of death and neurologic deficits. We identified 101 children with bacterial meningitis of which 19 died during initial hospitalization. Need for mechanical ventilation [hazard ratio (HR) 11.5, 95 % confidence interval (CI) 2.4-55.5)] and thrombocytopenia defined as a platelet count150 × 10(9) per liter (HR 0.6, 95 % CI 0.4-0.9) at presentation were associated with death during initial hospitalization. At final assessment, 42 of the 70 survivors had no neurologic deficits identified; 20 had a single deficit, and eight had multiple deficits. A delay in initiation of antibiotics (HR 1.3, 95 % CI 1.1-1.7) and hydrocephalus on computed tomographic scan (HR 2.6, 95 % CI 1.1-6.0) were associated with having one or more long-term neurologic deficits. Identification of children at risk of death or long-term neurologic sequelae may allow therapeutic interventions to be directed to children at the highest risk.

La specialite de pediatrie doit se structurer autour d’un « tronc commun » de pediatrie generale suivi d’une surspecialite pediatrique, comme la pediatrie d’urgence, dont l’enseignement recommande est respectivement de trois et de deux ans au niveau europeen. La specialite de medecine d’urgence a ete recemment reconnue par l’Union europeenne des medecins specialistes (UEMS) comme une specialite medicale dont l’enseignement recommande est de cinq ans. Ces recommandations europeennes doivent tenir compte de la diversite des systemes de sante au sein des 27 pays de l’Union europeenne. Ainsi, en France, le futur DES de medecine d’urgence comportera six mois obligatoires de pediatrie d’urgence et six mois de stage libre qui peut etre en pediatrie. Le referentiel metier-competences pour la specialite de pediatrie d’urgence a ete recemment soumis a la Commission nationale de l’internat et du postinternat (CNIPI) dans le but d’obtenir la creation d’un DESC de type I de pediatrie d’urgence qui viendrait completer les deux formations specifiques de pediatrie et de medecine d’urgence, afin d’ameliorer grandement les connaissances, les competences et les gestes techniques des medecins et des internes qui travaillent dans les structures d’urgences pediatriques et generalistes.

Objective As few data are available on the causes of fever in children returning from international travel, the authors studied children presenting to a French tertiary care centre with fever. Methods Children presenting to the emergency department of the Robert Debre Paediatric Hospital, Paris, France between July and December 2007 with fever that occurred within 3 months of a stay abroad were included in this retrospective study. Results The children (n=538) had most commonly visited North Africa (NA) (n=214), sub-Saharan Africa (SSA) (n=185) and Europe (n=67). Their median age was 2.8 years (IQR 1.4–5.8). The median time between their return to France and the onset of fever was 5 days (IQR 0–18). Cosmopolitan infections represented 85% of the established diagnoses (97.8% and 63.9% in the children returning from NA and SSA, respectively). Fever of unknown origin accounted for 19.3% of cases. Malaria was the leading tropical infection. Excluding malaria, diarrhoeal diseases were more frequent in the children returning from NA (38.5%) than in those returning from SSA (24.5%). Malaria was associated with stays in endemic countries that exceeded 30 days (OR 3.13, 95% CI 1.02 to 9.59). Conclusion Cosmopolitan infections are the leading cause of fever in French children returning from tropical and subtropical areas. However, all febrile children who have returned from an endemic area should be tested for malaria.

The eradication of smallpox and the elimination of several other infectious diseases from much of the world has provided convincing evidence that vaccines are among the most effective interventions for promoting health. The current scepticism about immunisation among members of the new US administration carries a risk of decreasing immunisation rates also in Europe. While only a small minority of the population are strongly anti-vaccine, their public activities have significantly influenced an uncertainty among the general population about both the safety of and the necessity for vaccination. Therefore, the EAP calls for greater publically available, scientifically supported information on vaccination, particularly targeted at health care providers, for the further development of electronically based immunisation information systems (IIS). We further call on all European countries to work together both in legislative and public health arenas in order to increase vaccination coverage among the paediatric population. In the interest of children and their parents, the EAP expresses its strong support for childhood immunisation and recommended vaccination schedules. We are prepared to work with governments and media and share the extensive evidence demonstrating the effectiveness and safety of vaccines.

Resume Objectifs Evaluer la frequence et les modalites des conseils de prevention vis-a-vis des risques infectieux transmissibles avant un sejour en zone tropicale ou subtropicale. Methodes Description de la proportion des enfants ayant eu une consultation avant le voyage et des modalites de la prevention des risques infectieux transmissibles, en dehors de la vaccination, chez des enfants ayant consulte dans un centre hospitalier pediatrique parisien pour une fievre survenue dans les 3 mois suivant un retour d’Afrique. Etude retrospective a partir des observations medicales et d’entretiens telephoniques aupres des parents. Resultats Cent soixante-treize enfants ont ete inclus dont 98 et 75 revenaient respectivement d’Afrique sub-saharienne (ASS) et d’Afrique du Nord (AN). Soixante et onze enfants avaient moins de 2 ans (41 %). Cent quarante enfants (81 %) avaient eu une consultation preventive avant le depart. Les enfants ayant voyage en Afrique du Nord avaient moins consulte en amont du voyage que les enfants ayant voyage en Afrique sub-saharienne (respectivement 72,1 % versus 94,7 %, p Conclusion D’apres cette etude, bien que la majorite des enfants voyageurs en Afrique consultent avant le depart, la prevention pourrait etre amelioree en termes de frequence de consultation avant le voyage mais aussi de qualite des conseils prodigues, en particulier chez les enfants voyageant en Afrique du Nord.

Background Congenital diaphragmatic hernia (CDH) is associated with pulmonary hypertension and death. Administration of nitric oxide (NO) alone remains ineffective in CDH cases. We investigated in near full-term lambs with and without CDH the role of guanylate cyclase (GC), the enzyme activated by NO in increasing cyclic 3′-5′-guanylosine monophosphate, and the role of phosphodiesterase (PDE) 5, the enzyme-degrading cyclic 3′-5′-guanylosine monophosphate. Methods Congenital diaphragmatic hernia was surgically created in fetal lambs at 85 days of gestation. Pulmonary hemodynamics were assessed by means of pressure and blood flow catheters (135 days). In vitro, we tested drugs on rings of isolated pulmonary vessels. Results In vivo, sodium nitroprusside, a direct NO donor, and methyl-2(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5trimethoxyphenyl)-3-isoquinoline carboxylate sulfate (T-1032) and Zaprinast, both PDE 5 blockers, reduced pulmonary vascular resistance in CDH and non-CDH animals. The activation of GC by sodium nitroprusside and the inhibition of PDE 5 by T-1032 were less effective in CDH animals. In vitro, the stimulation of GC by 3(5′hydroxymethyl-2′furyl)-1-benzyl indazole (YC-1) (a benzyl indazole derivative) and the inhibition of PDE 5 by T-1032 were less effective in pulmonary vascular rings from CDH animals. The YC-1–induced vasodilation in rings from CDH animals was higher when associated with the PDE 5 inhibitor T-1032. Conclusions Guanylate cyclase and PDE 5 play a role in controlling pulmonary vascular tone in fetal lambs with or without CDH. Both enzymes seem to be impaired in fetal lambs with CDH.

Inhaled nitric oxide (iNO) is one of the most promising therapies used in neonates, but there is little information available about its effect on the developing brain. We explored the effects of both iNO and endogenous NO on developing white matter in rodents. Rat or mouse pups and their mothers were placed in a chamber containing 5 to 20 ppm of NO for 7 days after birth. Neonatal exposure to iNO was associated with a transient increase in central nervous system myelination in rats and C57BL/6 mice without any deleterious effects at low doses (5 ppm) or behavioral consequences in adulthood. Exposure to iNO was associated with a proliferative effect on immature oligodendrocytes and a subsequent promaturational effect. The role of endogenous NO in myelination was investigated in animals treated with the nitric oxides synthase inhibitor N (G) -nitro-L-arginine methyl ester ( L -NAME) in the neonatal period; this led to protracted myelination defects and subsequent behavioral deficits in adulthood. These effects were reversed by rescuing L-NAME-treated animals with iNO. Thus, we demonstrate considerable effect of both exogenous and endogenous NO on myelination in rodents. These data point to potential new avenues for neuroprotection in human perinatal brain damage.

Summary Background In animal models, inhaled nitric oxide improved gas exchange and lung structural development, but its use in premature infants at risk of developing bronchopulmonary dysplasia remains controversial. We therefore tested the hypothesis that inhaled nitric oxide at a low concentration, started early and maintained for an extended period in babies with mild respiratory failure, might reduce the incidence of bronchopulmonary dysplasia. Methods 800 preterm infants with a gestational age at birth of between 24 weeks and 28 weeks plus 6 days (inclusive), weighing at least 500 g, requiring surfactant or continuous positive airway pressure for respiratory distress syndrome within 24 h of birth were randomly assigned in a one-to-one ratio to inhaled nitric oxide (5 parts per million) or placebo gas (nitrogen gas) for a minimum of 7 days and a maximum of 21 days in a double-blind study done at 36 centres in nine countries in the European Union. Care providers and investigators were masked to the computer-generated treatment assignment. The primary outcome was survival without development of bronchopulmonary dysplasia at postmenstrual age 36 weeks. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00551642. Findings 399 infants were assigned to inhaled nitric oxide, and 401 to placebo. 395 and 400, respectively, were analysed. Treatment with inhaled nitric oxide and placebo did not result in significant differences in survival of infants without development of bronchopulmonary dysplasia (258 [65%] of 395 vs 262 [66%] of 400, respectively; relative risk 1·05, 95% CI 0·78–1·43); in survival at 36 weeks' postmenstrual age (343 [86%) of 399 vs 359 [90%] of 401, respectively; 0·74, 0·48–1·15); and in development of bronchopulmonary dysplasia (81 [24%] of 339 vs 96 [27%] of 358, respectively; 0·83, 0·58–1·17). Interpretation Early use of low-dose inhaled nitric oxide in very premature babies did not improve survival without bronchopulmonary dysplasia or brain injury, suggesting that such a preventive treatment strategy is unsuccessful. Funding INO Therapeutics.

With the advent of prenatal steroids, postnatal exogenous surfactant and less aggressive respiratory support, premature infants can develop chronic lung disease without even acute respiratory distress. This "new bronchopulmonary dysplasia" could be the result of impaired postnatal growth. Several experimental studies have suggested a possible role of the vascular endothelial growth factor/nitric oxide (VEGF/NO) pathway in restoring pulmonary angiogenesis and enhancing distal lung growth. The results of the clinical studies are, however, inconclusive, and it is currently unclear which subsets of premature infants might benefit from inhaled nitric oxide. Besides, severe intracranial haemorrhage and/or cystic periventricular leukomalacia may affect the most immature babies, many of whom are spared from severe initial respiratory disease. Recently, inhaled nitric oxide was shown to significantly decrease the incidence of these neurological events, and to improve the long-term outcome in a few clinical trials. At times neuroprotective, at times neurotoxic, nitric oxide is capable of divergent effects depending upon the extent of cerebral damage, the redox state of the cell, and the experimental model used. Recently, inhaled nitric oxide had recognized to have dramatic remote effects including angiogenesis and maturation on the developing brain in rodent pups. Therefore, the developmental consequences of inhaled NO should be further investigated to ensure its safety on the developing brain and to test its potential neurprotective effect.

Summary Bronchopulmonary dysplasia is a chronic lung disease that affects premature infants and contributes to their morbidity and mortality. With the advent of prenatal steroids and postnatal exogenous surfactant and less aggressive respiratory support, premature infants can develop chronic oxygen dependency without even acute respiratory distress. This ‘new bronchopulmonary dysplasia’ could be the result of impaired postnatal growth. Several experimental studies have suggested a possible role of the vascular endothelial growth factor/nitric oxide (VEGF/NO) pathway in restoring pulmonary angiogenesis and enhancing distal lung growth. The results of the clinical studies are, however, inconclusive, and it is currently unclear which subsets of premature infants might benefit from inhaled nitric oxide. Besides, severe intracranial haemorrhage and/or cystic periventricular leucomalacia may affect the most immature babies, many of whom are spared from severe initial respiratory disease. Recently, inhaled nitric oxide was shown to significantly decrease the incidence of these neurological events, and to improve the long-term outcome in a few clinical trials. At times neuroprotective, at times neurotoxic, nitric oxide is capable of divergent effects depending upon the extent of cerebral damage, the redox state of the cell, and the experimental model used. Recently, our group found that inhaled nitric oxide had remote effects including angiogenesis and maturation on the developing brain in rodent pups. Thus, we await the results of the recently completed randomised clinical trial of inhaled nitric oxide to prevent bronchopulmonary dysplasia (the European Nitric Oxide or ‘EUNO’ trial) where, besides the primary endpoint of chronic oxygen dependency reduction at 36 weeks' postconceptional age, long-term lung and brain will be followed-up until 7 years of age.

Aim The aim of this study was to determine the presence of the neuronal nitric oxide synthase (nNOS) in near full-term lambs with congenital diaphragmatic hernia (CDH) and its role in the modulation of pulmonary vascular basal tone. Methods We surgically created diaphragmatic hernia on the 85th day of gestation. On the 135th, catheters were used to measure pulmonary pressure and blood flow. We tested the effects of 7-nitroindazole (7-NINA), a specific nNOS antagonist and of N-nitro-l-arginine (l-NNA), a nonspecific nitric oxide synthase antagonist. In vitro, we tested the effects of the same drugs on isolated pulmonary vessels. The presence of nNOS protein in the lungs was detected by Western blot analysis. Results Neither 7-NINA nor l-NNA modified pulmonary vascular basal tone in vivo. After l-NNA injection, acetylcholine (ACh) did not decrease significantly pulmonary vascular resistance (PVR). In vitro, l-NNA increased the cholinergic contractile-response elicited by electric field stimulation (EFS) of vascular rings from lambs with diaphragmatic hernia. Conclusion We conclude that nNOS protein is present in the lungs and pulmonary artery of near full-term lamb fetuses with diaphragmatic hernia, but that it does not contribute to the reduction of pulmonary vascular tone at birth. Pediatr Pulmonol. 2008; 43:313–321. © 2008 Wiley-Liss, Inc.

The European Academy of Paediatrics (EAP) is gravely concerned about the human papillomavirus (HPV) vaccination crisis in Japan and particularly about the negative position taken by governmental authorities. Given that the HPV vaccine is both safe and effective, there is no recognizable reason to date to withhold this lifesaving and cost effective public health measure from a population. Therefore, the EAP strongly encourages the Japanese health authorities to actively support HPV vaccination for the future health of their children and adolescents.

The European Academy of Paediatrics (EAP) is gravely concerned about the human papillomavirus (HPV) vaccination crisis in Japan and particularly about the negative position taken by governmental authorities. Given that the HPV vaccine is both safe and effective, there is no recognizable reason to date to withhold this lifesaving and cost effective public health measure from a population. Therefore, the EAP strongly encourages the Japanese health authorities to actively support HPV vaccination for the future health of their children and adolescents.

In the vascular system, synthesis of the potent vasodilator nitric oxide (NO) is tightly regulated by the constitutively expressed endothelial NO synthase (eNOS). Activity of eNOS is controlled by Ca 2+ /calmodulin and various seryl/threonyl protein kinases. Less is known about the importance of phosphorylation and dephosphorylation of tyrosyl residues. Therefore the role of tyrosine phosphatase on the modulation of isolated rat pulmonary artery tone has been assessed. Inhibition of tyrosine phosphatase by sodium orthovanadate (SOV, 1×10 −6 M) significantly: 1) increased phenylephrine-induced vasoconstriction and 2) decreased endothelium-dependent relaxation to acetylcholine, but had no effect on endothelium-independent relaxation to the NO donor, sodium nitroprusside. In phenylephrine-precontracted pulmonary arterial rings, SOV (1×10 −7 –1×10 −5 M) had no effect on vascular tone but significantly relaxed rings which were pretreated with the NO-synthase inhibitor, N ω ‐nitro‐l‐arginine-methyl ester (l‐NAME). SOV-induced relaxation in the presence of l‐NAME was, however, abolished by glibenclamide. In conclusion, inhibition of tyrosine phosphatase altered pulmonary vascular tone by increasing vasoconstrictor response to phenylephrine and decreasing endothelium-dependent relaxation to acetylcholine. Furthermore, the tyrosine phosphatase inhibitor, sodium orthovanadate, exhibited original vasodilator properties which were only observed when nitric oxide synthesis was inhibited. Thus a new pathway involving the inhibitory effect of nitric oxide on a glibenclamide-sensitive diffusible relaxing factor, that might play an important role in the control of pulmonary vascular tone is described.

Inhaled nitric oxide (NO) is frequently administered to full term and preterm newborns in various clinical settings in order to alleviate pulmonary hypertension whilst improving oxygenation. However, the physiological effect of NO on early postnatal lung development has not yet been clearly described. We therefore investigated whether NO administered by inhalation affects lung development at early postnatal life.Pregnant rats were placed in a chamber containing 5 ppm (iNO-5 ppm group) and 20 ppm NO (iNO-20 ppm group), started from the last day of their pregnancy in order to keep rat pups under ambient NO from birth to 7 days postnatal. Control animals were kept at room air and all rat pups were sacrificed at postnatal day 7 and day 14.Lung-to-body weight and wet-to-dry lung weight ratios did not significantly differ among 3 groups at postnatal day 7 and day 14. Vascular volume densities (Vv) in both NO groups (5 and 20 ppm) were higher than controls (P0.05; P0.001). Pulmonary vessel number was significantly increased in iNO-20 ppm group. Radial alveolar counts (RAC) and mean linear intercepts (MLI) markedly increased (consistent with increased alveolarization) in iNO-20 ppm group. This was associated with upregulation of VEGF/VEGFR-2, MT1-MMP/MMP2 and HO-1 protein expression in iNO-20 ppm group.We concluded that inhaled NO at 20 ppm enhanced lung development possibly through increased expression of HO-1, VEGF/VEGFR-2, and MMP2 at early stage of postnatal rat life.

Resume Malgre les progres realises en reanimation ces dernieres annees, la mortalite du choc septique demeure inchangee. La reconnaissance des signes suspects d’infection meningococcique, l’institution d’une antibiotherapie urgente et d’un support hemodynamique intensif constituent toujours le traitement incontournable du purpura fulminans chez l’enfant. Des travaux recents soulignent l’importance des polymorphismes genetiques au niveau de plusieurs systemes pour rendre compte des formes les plus severes : profil cytokinique anti-inflammatoire IL-10/TNF- α, taux eleves d’inhibiteur-1 de l’activateur du plasminogene, deficit d’activation complementaire via la mannose binding lectin. Ces donnees permettent de mieux comprendre l’echec general de l’immunotherapie du choc septique, et d’expliquer les desillusions des reanimateurs pediatres. Aussi, un espoir raisonnable d’eradiquer cette maladie reside-t-il toujours dans la mise au point de nouveaux vaccins anti-meningocoques, malgre la complexite de leur diversite genetique et les recombinaisons intra-especes au sein du reservoir rhinopharynge. © 2001 Editions scientifiques et medicales Elsevier SAS purpura fulminans / choc septique / cytokine / coagulation intravasculaire disseminee / polymorphisme genetique

Resume Le developpement et l’intensification des soins en reanimation pediatrique ont fait emerger de nouveaux profils evolutifs, notamment des sejours prolonges de plusieurs mois. Le but de ce travail etait de determiner les causes de ces sejours prolonges et de reperer les facteurs de comorbidite. Materiel et methodes. – Quatre-vingt-quinze patients totalisant 100 sejours de plus de 30 jours ont ete admis dans le service de pediatrie reanimation de l’hopital Robert-Debre sur une periode de trois ans (1993–1995). Ils representent 9,1 % du total des admissions correspondant a 62,1 % des journees d’hospitalisation. Ces 100 dossiers ont ete analyses de facon retrospective. Resultats. – La majorite de ces enfants etaient des nouveau-nes (65 % des cas). Les maladies a l’origine de sejours prolonges etaient dominees par les anomalies congenitales graves (44 enfants) et la grande prematurite (26 enfants). La duree moyenne de ventilation par enfant etait de 110 jours (extremes : 17 a 789 jours). Deux facteurs de comorbidite ont ete degages : d’une part le reflux gastro-œsophagien (41 % des cas) ; d’autre part les infections nosocomiales (89 % des cas). Conclusion. – Une prise en charge optimale de ces maladies est necessaire pour permettre un raccourcissement des sejours.

Resume Les acquisitions recentes sur la pathogenie et la physiopathologie de la hernie diaphragmatique congenitale, le diagnostic antenatal et les progres de la reanimation neonatale et chirurgicale n'ont pas change fondamentalement le pronostic de cette malformation. Les obstetricians, pediatres et chirurgiens-pediatres se retrouvent donc devant plusieurs dilemmes : dilemme avant la naissance lorsqu'il s'agit de prevoir le pronostic et de proposer 5 bon escientla poursuite de la grossesse ou au contraire son interruption medicale ; dilemme apres la naissance lorsque, devant on nouveau-ne avec une hemie diaphragmatique congenitale en detresse respiratoire severe, il s'agit de decider jusqu'ou aller dans l'escalade therapeutique. A travers la revue de la litterature et de notre propre experience, cet article tente de faire le point sur la prise en charge perinatale et le devenir a moyen et long terme de cette malformation severe.

Inhaled nitric oxide (iNO) has been shown to improve oxygenation in severe persistent pulmonary hypertension of the newborn (PPHN). However, PPHN is often associated with various lung diseases. Thus, response to iNO may depend upon the aetiology of neonatal acute respiratory failure. A total of 150 (29 preterm and 121 term) newborns with PPHN were prospectively enrolled on the basis of oxygenation index (OI) higher than 30 and 40, respectively. NO dosage was stepwise increased (10-80 ppm) during conventional mechanical or high-frequency oscillatory ventilation while monitoring the oxygenation. Effective dosages ranged from 5 to 20 ppm in the responders, whereas iNO levels were unsuccessfully increased up to 80 ppm in the nonresponders. Within 30 min of iNO therapy, OI was significantly reduced in either preterm neonates (51+/-21 vs 23+/-17, P or =34 weeks, and associated diagnosis other than congenital diaphragmatic hernia. Conclusion, iNO improves the oxygenation in most newborns with severe hypoxaemic respiratory failure including preterm neonates. However, response to iNO is disease-specific. Furthermore, iNO when combined with adequate alveolar recruitment and limited barotrauma using exogenous surfactant and HFOV may obviate the need for extracorporeal membrane oxygenation in many term infants.

Congenital diaphragmatic hernia (CDH) is still an unsolved problem. A disease which was, for a long time, thought to be merely a hole in the diaphragm appears today to be an intriguing malformation with a poorly understood pathogenesis and a complex pathophysiology. CDH results in various degrees of pulmonary hypoplasia and severe persistent pulmonary hypertension of the newborn. Despite antenatal ultrasound diagnosis and continuous improvement in neonatal intensive care, these features could not be overcome, and the overall mortality rate in CDH is still reaching 50%. Experimental works during the past 20 years suggest that CDH is a disease of impaired lung development associated with, but not caused by, a structural defect of the diaphragm. Furthermore, there is increasing evidence that the lung in CDH is not only small but that there are numerous disorders (e.g. surfactant deficiency, decreased anti-oxidant activity, increased vascular reactivity with decreased nitric oxide and increased endothelin 1 activity, and left heart hypoplasia) which may be associated with impaired lung development. Although antenatal diagnosis of CDH is feasible by ultrasound, there is no reliable predictor of pulmonary hypoplasia, the main prognostic factor in CDH. Whilst modern therapeutic strategies such as high-frequency oscillatory ventilation, exogenous surfactant or inhaled nitric oxide may be beneficial in selected subjects, most newborns with hypoplastic lungs will not survive despite these postnatal therapies. Perhaps these newborns would benefit from antenatal treatment directed at altering lung growth early in utero to minimize pulmonary hypoplasia. Therefore, research is needed to elucidate the aetiology and pathogenesis of CDH. Knowledge about the cellular control of proliferation, differentiation and programmed cell death (apoptosis) in the organogenesis should clarify our understanding of these processes and allow us to develop drugs that stimulate lung growth or even correct the anatomical defect. Furthermore, early and reliable assessment of prognosis for fetuses with CDH at risk of death will become increasingly important in the identification of fetuses most likely to benefit from antenatal therapies and may eventually lead to decreased mortality.

The adult (acute) respiratory distress syndrome is a significant cause of morbidity in children. The mortality rates remain elevated, greater than 50%, and even greater than 80% in patients with underlying malignancies. The therapeutic interventions remain mainly supportive. Strategies of conventional mechanical ventilation are directed toward the use of high positive end-expiratory pressures, low positive inspiratory pressure, and permissive hypercapnia. High-frequency oscillatory ventilation and tracheal insufflation are not yet used extensively, although they should contribute to less aggressive ventilation. Surfactant replacement, nitric oxide inhalation, and partial liquid ventilation seem to be promising technologies, but controlled clinical studies are necessary before their wide-spread use. Extracorporeal membrane oxygenation remains the alternative technology in case of failure of conventional support.