A number of biomarkers have been studied for the diagnosis of sepsis in paediatrics, but no gold standard has been identified. Procalcitonin (PCT) was demonstrated to be an accurate biomarker for the diagnosis of sepsis in adults and showed to be promising in paediatrics. Our study reviewed the diagnostic accuracy of PCT as an early biomarker of sepsis in neonates and children with suspected sepsis. A comprehensive literature search was carried out in Medline/Pubmed, Embase, ISI Web of Science, CINAHL and Cochrane Library, for studies assessing PCT accuracy in the diagnosis of sepsis in children and neonates with suspected sepsis. Studies in which the presence of infection had been confirmed microbiologically or classified as “probable” by chart review were included. Studies comparing patients to healthy subjects were excluded. We analysed data on neonates and children separately. Our primary outcome was the diagnostic accuracy of PCT at the cut-off of 2-2.5 ng/ml, while as secondary outcomes we analysed PCT cut-offs 2.5 ng/ml. Pooled sensitivities and specificities were calculated by a bivariate meta-analysis and heterogeneity was graphically evaluated. We included 17 studies, with a total of 1408 patients (1086 neonates and 322 children). Studies on neonates with early onset sepsis (EOS) and late onset sepsis (LOS) were grouped together. In the neonatal group, we calculated a sensitivity of 0.85, confidence interval (CI) (0.76; 0.90) and specificity of 0.54, CI (0.38; 0.70) at the PCT cut-off of 2.0-2.5 ng/ml. In the paediatric group it was not possible to undertake a pooled analysis at the PCT cut-off of 2.0-2.5 ng/ml, due to the paucity of the studies. PCT shows a moderate accuracy for the diagnosis of sepsis in neonates with suspected sepsis at the cut-off of 2.0-2.5 ng/ml. More studies with high methodological quality are warranted, particularly in neonates, studies considering EOS and LOS separately are needed to improve specificity. PROSPERO Identifier: CRD42016033809 . Registered 30 Jan 2016.

A clinical heterogeneity was reported in patients with Cystic Fibrosis (CF) with the same CFTR genotype and between siblings with CF. We investigated all clinical aspects in a cohort of 101 pairs of siblings with CF (including 6 triplets) followed since diagnosis. Severe lung disease had a 22.2% concordance in sib-pairs, occurred early and the FEV1% at 12 years was predictive of the severity of lung disease in the adulthood. Similarly, CF liver disease occurred early (median: 15 years) and showed a concordance of 27.8% in sib-pairs suggesting a scarce contribution of genetic factors; in fact, only 2/15 patients with liver disease in discordant sib-pairs had a deficiency of alpha-1-antitrypsin (a known modifier gene of CF liver phenotype). CF related diabetes was found in 22 pairs (in 6 in both the siblings). It occurred later (median: 32.5 years) and is strongly associated with liver disease. Colonization by P. aeruginosa and nasal polyposis that required surgery had a concordance > 50% in sib-pairs and were poorly correlated to other clinical parameters. The pancreatic status was highly concordant in pairs of siblings (i.e., 95.1%) but a different pancreatic status was observed in patients with the same CFTR mutations. This suggests a close relationship of the pancreatic status with the “whole” CFTR genotype, including mutations in regulatory regions that may modulate the levels of CFTR expression. Finally, a severe course of CF was evident in a number of patients with pancreatic sufficiency. Physicians involved in care of patients with CF and in genetic counseling must be aware of the clinical heterogeneity of CF even in sib-pairs that, at the state of the art, is difficult to explain.

Differential diagnosis between sepsis and non-infectious inflammatory disorders demands improved biomarkers. Soluble Triggering Receptor Expression on Myeloid cells (sTREM-1) is an activating receptor whose role has been studied throughout the last decade. We performed a systematic review to evaluate the accuracy of plasma sTREM-1 levels in the diagnosis of sepsis in children with Systemic Inflammatory Response Syndrome (SIRS). A literature search of PubMed, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and ISI Web of Knowledge databases was performed using specific search terms. Studies were included if they assessed the diagnostic accuracy of plasma sTREM-1 for sepsis in paediatric patients with SIRS. Data on sensitivity, specificity, positive predictive value, negative predictive value, area under receiver operating characteristic curve were extracted. The methodological quality of each study was assessed using a checklist based on the Quality Assessment Tool for Diagnostic Accuracy Studies. Nine studies comprising 961 patients were included, four of which were in newborns, three in children and two in children with febrile neutropenia. Some data from single studies support a role of sTREM-1 as a diagnostic tool in pediatric sepsis, but cannot be considered conclusive, because a quantitative synthesis was not possible, due to heterogeneity in studies design. This systematic review suggests that available data are insufficient to support a role for sTREM in the diagnosis and follow-up of paediatric sepsis.

Elexacaftor/tezacaftor/ivacaftor (ETI) is a cystic fibrosis (CF) transmembrane conductance regulator modulator, which has shown efficacy in people with CF (pwCF) carrying the F508del (F) variant, both in homozygosity and heterozygosity with a minimal function (MF) variant. Limited data exist on the effects of ETI in pwCF with advanced lung disease. Our aim was to investigate ETI safety and effectiveness in this patient group in a real-life setting over 2 years. A multicenter observational cohort study was designed to gather real-world information on the effect of ETI treatment on CF patients (aged >12 years, genotype: F/MF mutation) with advanced lung disease as defined by a FEV1 < 40% predicted. Retrospective demographic and clinical data were recorded for the two years preceding and the two years following ETI initiation. The following outcomes were investigated: treatment-associated adverse events (AEs), drug interruptions (temporary or permanent), variations in percent predicted FEV1 (ppFEV1), sweat chloride concentration (SwCl), antibiotic use, body mass index (BMI), and quality of life. A total of 124 (51.6% males) pwCF were treated with ETI over 2 years. The median (IQR) age and ppFEV₁ were 34 (26, 43) years and 34 (29, 41) percentage points, respectively. ETI was discontinued in two pwCF due to lung transplantation, and temporarily interrupted in two because of skin rash, and in three following elevated levels of aminotransferase. Most AEs were mild and short-lasting. In 12.1% pwCF, we registered an increase greater than twice the upper limit of the normal range in alanine aminotransferase, and in 16% we registered an increase in conjugated bilirubin with no increase in aminotransferase. Both increases were recurrent in about half of the subjects. The mean differences (95% CI) for ppFEV₁ and SwCl, assessed as mean values in the pre-ETI and ETI treatment periods, were +11.8 (11.1 to 12.6) and −43.7 (−47.6 to −39.9) mmol/L. A modest increase in ppFEV₁ persisted during the second year of treatment. Number of oral and IV antibiotic cycles/year, as well as hospitalizations/year, decreased significantly from 3.6 to 1.2, from 2.4 to 0.6, and from 2.1 to 0.5 during ETI treatment. A total of 8 of 16 (50%) pwCF were taken off the waiting list for lung transplantation, and significant reductions in the percentages of pwCF using long-term oxygen therapy and non-invasive ventilation were observed. A poor concordance between ppFEV1 and SwCl was found. In only 3/82 (3.7%), subjects with chronic airway infection by Pseudomonas aeruginosa cultures were always negative during ETI treatment. In CF patients with advanced lung disease on ETI treatment, we observed an improvement in a number of clinically significant outcomes over a 2-year study period. However, several additional observations, such as liver dysfunction, variable degrees of lung function improvement, and limited impact on chronic airway infection, underscore the fact that the benefit–risk profile of ETI treatment in cystic fibrosis patients with advanced lung disease has not been fully elucidated and warrants prolonged-term monitoring.