Association of viral load with TRAIL, IP-10, CRP biomarker signature and disease severity in children with respiratory tract infection or fever without source: A prospective, multicentre cohort study.

BACKGROUND: To investigate the association of viral load (VL) with (i) tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), interferon gamma-induced protein-10, C-reactive protein, and a combinatorial score (BV score), and (ii) clinical severity. STUDY DESIGN: In this prospective, multicentre cohort substudy, children with respiratory tract infection or fever without source were enrolled. VL for influenza virus, rhinovirus, respiratory syncytial virus, and adenovirus was measured from nasopharyngeal swabs. The reference standard diagnosis was established based on expert panel adjudication. RESULTS: Of 1140 recruited patients, 333 had a virus monodetection. VL for the aggregated data set correlated with TRAIL and IP-10 levels, with the length of oxygen therapy, and inversely with the BV score. At a single viral level, only the influenza VL yielded a correlation with TRAIL, IP-10 levels, and the BV score. Children with a viral reference standard diagnosis had significantly higher VL than those with bacterial infection (p = 0.0005). Low TRAIL (incidence rate ratio [IRR] 0.6, 95% confidence interval [CI] 0.39-0.91) and young age (IRR 0.62, 95% CI 0.49-0.79) were associated with a longer hospital stay, while young age (IRR 0.33, 95% CI 0.18-0.61), low TRAIL (IRR 0.25, 95% CI 0.08-0.76), and high VL (IRR 1.16, 95% CI 1.00-1.33) were predictive of longer oxygen therapy. CONCLUSION: These findings indicate that VL correlates with biomarkers and may serve as a complementary tool pertaining to disease severity.

Eosinophilic esophagitis in children: doubts and future perspectives.

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic immune-mediated inflammatory disorder and represents the leading cause of food impaction. The pathogenesis of EoE is the result of an interplay between genetic, environmental and host immune system factors. New therapeutic approaches for EoE have been proposed. In this manuscript we review the current evidence regarding EoE management in pediatric age, with a particular focus on new findings related to the efficacy and safety of monoclonal antibodies. MAIN BODY: Conventional therapies have failed in treating some patients with EoE, which then requires aggressive procedures such as esophageal dilatation. The most effective available medical therapy for EoE is swallowed topic corticosteroids (fluticasone propionate and budesonide), which have two main drawbacks: they are related to well-known adverse effects (especially in the paediatric population), and there are not enough long-term data to confirm that they are able to reverse the remodelling process of the esophageal mucosa, which is the major cause of EoE symptoms (including dysphagia, abdominal pain, nausea, obstruction, perforation and vomiting). The monoclonal antibodies appear to be an interesting therapeutic approach. However, the studies conducted until now have shown substantial histological improvement not coupled with significant clinical improvements and no significant relationship between a decreasing number of eosinophils and clinical symptoms, highlighting the importance in the pathogenesis of EoE of cells such as T-helper cells, mast cells, B cells, epithelial cells and natural killer cells. CONCLUSIONS: Monoclonal antibodies targeting a signal involved in the pathogenesis of EoE may not break the complex self-propagating inflammatory activation responsible for perpetuation of the inflammatory response and the development of symptoms and complications. We speculate that combined biological therapies targeting more than one molecule or cell may provide better results, with conventional therapies potentially enhancing the effects of antibodies. However, further studies should aim to find the best therapeutic approach to target the cells involved in the remodelling process and to reverse the histological changes in this complex clinical condition.

First detection of a reassortant G3P[8] rotavirus A strain in Italy: a case report in an 8-year-old child.

BACKGROUND: Acute gastroenteritis (AGE) due to group A rotavirus (RVA) agent is one of the major causes of hospitalization in paediatric age. The G3P[8] RVA genotype has been usually considered as one of the major human genotypes, largely circulating in Asia, but showing low detection rates in the European countries. In recent years, the G3P[8] RVAs emerged also in Europe as a predominant genotype and the viral strains detected revealed high similarities with equine-like G3P[8] RVA strains, resulting in a new variant circulating in humans and able to cause AGE in the paediatric population. CASE PRESENTATION: An 8-year-old boy was admitted to the Emergency Room because he had suffered from severe diarrhoea, vomiting, and high fever over the previous two days. Severe dehydration was evident based on low serum concentrations of potassium and sodium, low glycaemia, and pre-renal failure (creatinine 2.48 mg/dL, urea 133 mg/dL). Immunological tests were within normal range. Enzyme immunoassay for the detection of RV was positive, and a sample of faeces was collected in order to perform the molecular characterization of the viral strain. The phylogenetic trees revealed relatedness between the VP7 and VP4 genes of the G3P[8] RVA Italian strain (namely PG2) and those belonging to recent G3P[8] RVAs detected worldwide. The G3 VP7 belonged to the G3-I lineage and shared the highest nucleotide sequence identity (99.8%) with the equine-like G3 previously identified in other countries. The P [8] VP4 revealed a similar clustering pattern to that observed for the VP7. In addition, the molecular characterization of the 11 gene segments of strain PG2 revealed a G3-P[8]-I2-R2-C2-M2-A2-N2-T2-E2-H2 genomic constellation. CONCLUSIONS: This case shows the first detection in Italy of a reassortant G3P[8] RVA associated with a severe AGE, which is unusual in a school-age child without any known severe underlying problems. The findings reported in this paper highlight the importance of continuously monitoring the RVA strains circulating in paediatric age in order to detect novel viral variants able to spread in the general population.

Approach to Neonates and Young Infants with Fever without a Source Who Are at Risk for Severe Bacterial Infection.

INTRODUCTION: Among neonates and infants <3 months of age with fever without a source (FWS), 5% to 15% of cases are patients with fever caused by a serious bacterial infection (SBI). To favour the differentiation between low- and high-risk infants, several algorithms based on analytical and clinical parameters have been developed. The aim of this review is to describe the management of young infants with FWS and to discuss the impact of recent knowledge regarding FWS management on clinical practice. MATERIALS AND METHODS: PubMed was used to search for all of the studies published over the last 35 years using the keywords: "fever without source" or "fever of unknown origin" or "meningitis" or "sepsis" or "urinary tract infection" and "neonate" or "newborn" or "infant <90 days of life" or "infant <3 months". RESULTS AND DISCUSSION: The selection of neonates and young infants who are <3 months old with FWS who are at risk for SBI remains a problem without a definitive solution. The old Rochester criteria remain effective for identifying young infants between 29 and 60 days old who do not have severe bacterial infections (SBIs). However, the addition of laboratory tests such as C-reactive protein (CRP) and procalcitonin (PCT) can significantly improve the identification of children with SBI. The approach in evaluating neonates is significantly more complicated, as their risk of SBIs, including bacteremia and meningitis, remains relevant and none of the suggested approaches can reduce the risk of dramatic mistakes. In both groups, the best antibiotic must be carefully selected considering the clinical findings, the laboratory data, the changing epidemiology, and increasing antibiotic resistance of the most common infectious bacteria.

A host signature based on TRAIL, IP-10, and CRP for reducing antibiotic overuse in children by differentiating bacterial from viral infections: a prospective, multicentre cohort study.

OBJECTIVES: Identifying infection aetiology is essential for appropriate antibiotic use. Previous studies have shown that a host-protein signature consisting of TNF-related apoptosis-induced ligand (TRAIL), interferon-γ-induced protein-10 (IP-10), and C-reactive protein (CRP) can accurately differentiate bacterial from viral infections. METHODS: This prospective, multicentre cohort study, entitled AutoPilot-Dx, aimed to validate signature performance and to estimate its potential impact on antibiotic use across a broad paediatric population (>90 days to 18 years) with respiratory tract infections, or fever without source, at emergency departments and wards in Italy and Germany. Infection aetiology was adjudicated by experts based on clinical and laboratory investigations, including multiplex PCR and follow-up data. RESULTS: In total, 1140 patients were recruited (February 2017-December 2018), of which 1008 met the eligibility criteria (mean age 3.5 years, 41.9% female). Viral and bacterial infections were adjudicated for 628 (85.8%) and 104 (14.2%) children, respectively; 276 patients were assigned an indeterminate reference standard outcome. For the 732 children with reference standard aetiology, the signature discriminated bacterial from viral infections with a sensitivity of 93.7% (95%CI 88.7-98.7), a specificity of 94.2% (92.2-96.1), positive predictive value of 73.0% (65.0-81.0), and negative predictive value of 98.9% (98.0-99.8); in 9.8% the test results were equivocal. The signature performed consistently across different patient subgroups and detected bacterial immune responses in viral PCR-positive patients. CONCLUSIONS: The findings validate the high diagnostic performance of the TRAIL/IP-10/CRP signature in a broad paediatric cohort, and support its potential to reduce antibiotic overuse in children with viral infections.

Gut dysbiosis and paediatric Crohn's disease.

OBJECTIVES: The main objective of this manuscript is to discuss our present knowledge of the relationships between dysbiosis and paediatric Crohn's disease (CD). The therapeutic role of the methods currently used to re-establish normal gut microbiota composition is also analysed. METHODS: PubMed was used to search for all of the studies published from January 2008 to June 2018 using the key words: "Crohn's disease" and "gut dysbiosis" or "microbiota" or "microbioma" or "probiotic" and "children" or "paediatric". More than 100 articles were found, but only those published in English or providing evidence-based data were included in the evaluation. RESULTS: Gut microbiota are primary actors in CD's pathogenesis. The new techniques developed in metagenomics allow us to reveal new details of microbiota composition in healthy subjects and CD patients, and to elucidate the link between microbiota and numerous pathologies, such as obesity, allergies and type 1 diabetes mellitus. CONCLUSION: Discoveries on the role of gut microbiota could potentially disclose new therapeutic options for CD treatment and improve the existing therapies. Further studies are needed to facilitate the diagnosis and tailor the therapy of a pathology that is an increasing burden on public health.

The Management of Paediatric Functional Abdominal Pain Disorders: Latest Evidence.

Recurrent abdominal pain (RAP) is one of the most common health complaints in both children and adults. Although RAP is considered a functional disorder rather than an organic disease, affected children and their families can still experience anxiety and concerns that can interfere with school, sports, and regular daily activities and lead to frequent attendances at pediatric emergency departments or pediatric gastroenterology clinics. Our review shows experts do not agree on a universally proven management that will work on every child presenting with functional abdominal pain (FAP). Treatment strategies include both non-pharmacological and pharmacological options. Non-pharmacological treatments are usually very well accepted by both children and their parents and are free from medication side effects. Nevertheless, they may be as effective as the pharmacological interventions; therefore, according to many experts and based on the majority of current evidence, a non-pharmacological approach should be the first intervention attempt in children with RAP. In particular, the importance of the bio-psychosocial approach is highlighted, as a majority of children will improve with counselling and reassurance that no serious organic pathologies are suspected, especially when the physician establishes a trustful relationship with both the child and their family. Placebo and pharmacological interventions could be attempted when the bio-psychosocial approach is not applicable or not efficacious. In some difficult cases, finding an effective treatment for FAP can be a challenge, and a number of strategies may need to be tried before symptoms are controlled. In these cases, a multidisciplinary team, comprising a pediatric gastroenterologist, dietician, psychologist, and psychotherapist, is likely to be successful.

Gut dysbiosis and irritable bowel syndrome: The potential role of probiotics.

OBJECTIVE: To discuss the role of gut dysbiosis in the development of irritable bowel syndrome (IBS) and the impact of probiotics as a potential therapeutic measure. METHODS: PubMed was used to search for all of the studies published over the last 15 years using the key words: "irritable bowel syndrome" and "gut dysbiosis" or "probiotic". More than 800 articles were found, but only those published in English or providing evidence-based data were included in the evaluation. RESULTS: IBS is a common disease for which no resolutive therapy is presently available. In recent years, strong evidence of a possible relationship between modifications of the gut microbiota composition and development of IBS has been collected. Moreover, the evidence showed that attempts to treat acute infectious and post-antibiotic gastroenteritis with some probiotics were significantly effective in a great number of patients, leading many experts to suggest the use of probiotics to address all of the clinical problems associated with IBS. CONCLUSION: The available data are promising, but presently, a precise definition of which probiotic or which mixture of probiotics is effective cannot be made. Moreover, the dose and duration of treatment has not been established. Finally, we do not know whether probiotic treatment should be different according to the type of IBS. Further studies are needed before probiotics can be considered a reliable treatment for IBS.

Is It Time to Use Probiotics to Prevent or Treat Obesity?

In recent years, attention has been given to the role potentially played by gut microbiota in the development of obesity. Several studies have shown that in individuals with obesity, the gut microbiota composition can be significantly different from that of lean individuals, that faecal bacteria can exert a fundamental role in modulating energy metabolism, and that modifications of gut microbiota composition can be associated with increases or reductions of body weight and body mass index. Based on this evidence, manipulation of the gut microbiota with probiotics has been considered a possible method to prevent and treat obesity. However, despite a great amount of data, the use of probiotics to prevent and treat obesity and related problems remains debated. Studies have found that the probiotic effect on body weight and metabolism is strain specific and that only some of the species included in the Lactobacillus and Bifidobacterium genera are effective, whereas the use of other strains can be deleterious. However, the dosage, duration of administration, and long-term effects of probiotics administration to prevent overweight and obesity are not known. Further studies are needed before probiotics can be rationally prescribed for the prevention or treatment of obesity. Control of the diet and environmental and life-style factors that favour obesity development remain the best solution to problems related to weight gain.

Celiac Disease Presenting with Peripheral Neuropathy in Children: A Case Report.

Background: Clinically relevant neurological manifestations in children with celiac disease (CD) are unusual, especially when they are considered as signs of the onset of the disease. In this paper, a case of Guillain-Barrè syndrome (GBS) as the first manifestation of CD in a 23-month-old child is reported. Case presentation: We describe a case of CD onset with peripheral neuropathy in a 23-month-old Bulgarian boy presenting with a sudden refusal to walk and absence of deep tendon reflexes in both lower limbs. Neurological symptoms were preceded by two months of gastrointestinal symptoms such as vomiting, abdominal distention, and clear signs of malnutrition and weight loss. When we evaluated the child six months after the onset of the symptoms, clinical and laboratory findings showed clear signs of peripheral neuropathy associated with malnutrition. Serum deamidated gliadin and tissue transglutaminase antibodies were therefore measured. The anti-gliadin levels were more than sixteen times higher than normal and the IgA anti-transglutaminase levels were four times higher than normal. Anti-endomysium antibodies were positive, and human leukocyte antigens (HLA) II typing confirmed a genetic predisposition to CD (DQ2 positive and DQ8 negative). Given the association between the clinical evidence of the disease and the results of the celiac screening tests, a diagnosis of CD was made without biopsy confirmation of the enteropathy. The child began a restricted gluten-free diet that led to complete recovery of the peripheral neuropathy, walking, reflexes, and overall improvement after three months on the diet. Conclusion: Our case underlines the rare but possible associations between CD and peripheral neuropathy in children as an onset symptom, even in the absence of gastrointestinal manifestations, thus suggesting that CD should always be considered in the differential diagnosis of peripheral neuropathy in children. A good knowledge of the extra-intestinal manifestations of CD is essential for the rapid introduction of a gluten-free diet that could be useful for the resolution of the neurological symptoms.

Valproic acid and nonalcoholic fatty liver disease: A possible association?

Valproic acid (VPA) is one of the most prescribed drugs in children with newly diagnosed epilepsy. Weight gain and obesity have been observed as side effects of VPA. These are often linked with other metabolic disturbances such as development of insulin resistance, dyslipidemia, metabolic syndrome (MetS) and non-alcoholic fatty liver disease or nonalcoholic fatty liver disease (NAFLD). NAFLD refers to a group of liver disorders with marked hepatic steatosis. It is associated with an increased incidence of cardiovascular diseases and overall reduced life expectancy. NAFLD occurs in 20%-25% of the general population and it is known to be the most common cause of chronic liver disease. NAFLD therefore represents a major public health issue worldwide. This study reviews and summarizes relevant literature that supports the existence of an association between VPA therapy and the development of NAFLD in children. Long-term VPA-therapy appears to be associated with an increased risk of developing NAFLD. Further studies are needed to clarify the pathogenic mechanisms that lie behind this association and to standardize the options for the use of this drug in overweight patients and in those with risks for developing MetS and NAFLD.

Neonatal identification of pituitary aplasia: a life-saving diagnosis. Review of five cases.

BACKGROUND: Neonatal onset hypopituitarism is a life-threatening, potentially treatable endocrine disease. A possible cause is congenital absence of the anterior pituitary gland, a condition very rarely reported in the literature. METHODS: A series of 5 cases of children with pituitary aplasia referred to the Centre of Paediatric Endocrinology 'Rina Balducci', Tor Vergata University, Rome, is presented. RESULTS: Major clinical features in our patients were respiratory distress on the first day of life, in spite of uneventful pregnancy, labour and delivery, metabolic acidosis, non-cholestatic jaundice, hypotonia, severe hypoglycaemia, hypogenitalism, and midline defects. Diagnosis was established by endocrine tests during hypoglycaemia and hypothalamic-pituitary MRI scan. Symptoms disappeared soon after replacement therapy was started. CONCLUSION: We stress the importance of performing baseline endocrine tests as soon as possible during hypoglycaemia and MRI of the brain aimed at visualizing the hypothalamic-pituitary area in neonates with hypogenitalism and severe unexplained hypoglycaemia, so that the irreversible neurological and developmental consequences of panhypopituitarism can be prevented by adequate replacement therapy.