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Background: Community-acquired pneumonia (CAP) represents one of the most common infectious diseases among children. Diagnosis of CAP is mainly clinical. Chest X-ray (CXR) remains the gold standard for the diagnosis in severe or controversial conditions. Recently, some authors have focused on the application of ultrasound in lung diseases but the role of lung ultrasound (LUS) in the diagnosis of CAP is still debated. We aimed to study the concordance between LUS and CXR in evaluating specific signs of CAP. As a secondary aim, we sought to determine the sensitivity and specificity of LUS in CAP diagnosis compared with CXR. Finally, we evaluated the role of LUS during the follow up., Methods: We enrolled 68 children (<16 years old) hospitalized from October 2018 to September 2019 with a clinical and radiological diagnosis of CAP (cases: N = 41), or with no respiratory diseases (controls: N = 27), in whom a CXR was performed for clinical indications. All the children underwent LUS during hospitalization. The average time needed to perform LUS was 5-10 min for each child, and 19/41 cases were re-evaluated by LUS and CXR 30 days after discharge., Results: Lung ultrasound confirmed CAP diagnosis in 40/41 patients. Concordance between the two techniques was K = 0.88 for the right lung and K = 0.70 for the left lung. Lung ultrasound showed a sensitivity of 97% and a specificity of 96% compared with CXR. At the follow up, sensitivity increased to 100% while specificity was 94%., Conclusions: Our study showed a potential benefit of LUS compared with CXR in the diagnosis and the follow up of CAP., (© 2020 Japan Pediatric Society.)

In vitro interferon (IFN)α treatment of primary human upper airway basal cells has been shown to drive ACE2 expression, the receptor of SARS-CoV-2. The protease furin is also involved in mediating SARS-CoV-2 and other viral infections, although its association with early IFN response has not been evaluated yet. In order to assess the in vivo relationship between ACE2 and furin expression and the IFN response in nasopharyngeal cells, we first examined ACE2 and furin levels and their correlation with the well-known marker of IFNs' activation, ISG15, in children (n = 59) and adults (n = 48), during respiratory diseases not caused by SARS-CoV-2. A strong positive correlation was found between ACE2 expression, but not of furin, and ISG15 in all patients analyzed. In addition, type I and III IFN stimulation experiments were performed to examine the IFN-mediated activation of ACE2 isoforms (full-length and truncated) and furin in epithelial cell lines. Following all the IFNs treatments, only the truncated ACE2 levels, were upregulated significantly in the A549 and Calu3 cells, in particular by type I IFNs. If confirmed in vivo following IFNs' activation, the induction of the truncated ACE2 isoform only would not enhance the risk of SARS-CoV-2 infection in the respiratory tract., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

To the editor: [...].

The expression rate of SARS-CoV-2 entry genes, angiotensin-converting enzyme 2 (ACE2), the main viral receptor and the proteases, furin and transmembrane serine protease 2 (TMPRSS2) in cystic fibrosis (CF) individuals is poorly known. Hence, we examined their levels in upper respiratory samples of CF patients ( n = 46) and healthy controls ( n = 45). Moreover, we sought to understand the interplay of type I interferon (IFN-I) with ACE2, furin and TMPRSS2 by evaluating their gene expression with respect to ISG15, a well-known marker of IFN activation, in upper respiratory samples and after ex vivo IFNβ exposure. Lower ACE2 levels and trends toward the reduction of furin and TMPRSS2 were found in CF patients compared with the healthy controls; decreased ACE2 amounts were also detected in CF individuals with pancreatic insufficiency and in those receiving inhaled antibiotics. Moreover, there was a strong positive correlation between ISG15 and ACE2 levels. However, after ex vivo IFNβ stimulation of nasopharyngeal cells, the truncated isoform (dACE2), recently demonstrated as the IFN stimulated one with respect to the full-length isoform (flACE2), slightly augmented in cells from CF patients whereas in those from healthy donors, dACE2 levels showed variable levels of upregulation. An altered expression of SARS-COV-2 entry genes and a poor responsiveness of dACE2 to IFN-I stimulation might be crucial in the diffusion of SARS-CoV-2 infection in CF.

Although there is increasing evidence showing that infants with viral bronchiolitis exhibit a high degree of heterogeneity, a core uncertainty shared by many clinicians is with regard to understanding which patients are most likely to benefit from bronchodilators such as albuterol. Based on our review, we concluded that older infants with rhinovirus (RV) bronchiolitis, especially those with a nasopharyngeal microbiome dominated by Haemophilus influenzae; those affected during nonpeak months or during non-respiratory syncytial virus (RSV) predominant months; those with wheezing at presentation; those with clinical characteristics such as atopic dermatitis or a family history of asthma in a first-degree relative; and those infants infected with RSV genotypes ON1 and BA, have the greatest likelihood of benefiting from albuterol. Presently, this patient profile could serve as the basis for rational albuterol administration in patients with viral bronchiolitis, at least on a therapeutic trial basis, and it could also be the starting point for future targeted randomized clinical trials (RCTs) on the use of albuterol among a subset of infants with bronchiolitis.

Background: Bronchiolitis is the most common acute viral infection of the lower respiratory tract in infants. Clinical severity is associated with different risk factors; however, no clinical, laboratory, or radiological findings are able to predict the course of the disease in full-term infants. Lung ultrasound (LUS) is a valid technique for the diagnosis and evaluation of pediatric respiratory diseases., Aims: The aim of our study was to correlate an LUS score with a clinical score, to describe lung ultrasound findings in cases and controls, and to compare LUS findings with chest X-ray (CXR) in infants hospitalized with bronchiolitis., Methods: We conducted a single-center, longitudinal, prospective study on 92 infants. Sixty-three out of 92 infants were hospitalized for acute bronchiolitis (cases) and twenty-nine out of 92 for diseases not involving the respiratory system (controls). All patients with bronchiolitis underwent a clinical evaluation with the assignment of a clinical severity score and performed lung ultrasound with the assignment of an LUS score. Twenty-three out of 63 infants with bronchiolitis underwent also a CXR for clinical indications. Control infants performed only LUS., Results: In infants with bronchiolitis LUS score showed a positive correlation with the clinical score (r = .62, p < .001) and the length of hospitalization (r = .42; p < .001). The need of oxygen therapy was more frequent in the patients with higher LUS score (p < .001). LUS findings observed in the cases were the presence of B-lines, subpleural consolidations, and abnormalities of the pleural line. No LUS alterations were observed in the controls. In patients who performed LUS and CXR, we found a correlation between the presence of abnormalities of the pleural line with LUS and the presence of air trapping with CXR (r = .55; p = .007)., (© 2020 Wiley Periodicals LLC.)

From 9 March to 3 May 2020, lockdown was declared in Italy due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Our aim was to evaluate how the SARS-CoV-2 pandemic and related preventive strategies affected pediatric emergency rooms (ERs) during this period. We performed a retrospective cohort multicenter study, comparing the lockdown period to the corresponding period in 2019. We examined 15 Italian pediatric ERs in terms of visit rates, specific diagnoses (grouped as air communicable diseases and non-air communicable diseases), and triage categories. During the lockdown period, ER admissions decreased by 81% compared to 2019 (52,364 vs. 10,112). All ER specific diagnoses decreased in 2020 and this reduction was significantly higher for air communicable diseases (25,462 vs. 2934, p < 0.001). Considering the triage category, red codes remained similar (1% vs. 1%), yellow codes increased (11.2% vs. 22.3%), and green codes decreased (80.3% vs. 69.5%). We can speculate that social distancing and simple hygiene measures drastically reduced the spread of air communicable diseases. The increase in yellow codes may have been related to a delay in primary care and, consequently, in ER admissions.

New biologics are being continually developed for paediatric asthma, but it is unclear whether there are sufficient numbers of children in Europe with severe asthma and poor control to recruit to trials needed for registration. To address these questions, the European Respiratory Society funded the Severe Paediatric Asthma Collaborative in Europe (SPACE), a severe asthma registry. We report the first analysis of the SPACE registry, which includes data from 10 paediatric respiratory centres across Europe. Data from 80 children with a clinical diagnosis of severe asthma who were receiving both high-dose inhaled corticosteroid and long-acting β2-agonist were entered into the registry between January 2019 and January 2020. Suboptimal control was defined by either asthma control test, or Global Initiative for Asthma criteria, or ≥2 severe exacerbations in the previous 12 months, or a combination. Overall, 62 out of 80 (77%) children had suboptimal asthma control, of whom 29 were not prescribed a biologic. However, in 24 there was an option for starting a licensed biologic. 33 children with suboptimal control were prescribed a biologic (omalizumab (n=24), or mepolizumab (n=7), or dupilumab (n=2)), and for 29 there was an option to switch to a different biologic. We conclude that the SPACE registry provides data that will support the planning of studies of asthma biologics. Not all children on biologics achieve good asthma control, and there is need for new trial designs addressing biologic switching., Competing Interests: Conflict of interest: N.M. Liu has nothing to disclose. Conflict of interest: K.C.L. Carlsen has nothing to disclose. Conflict of interest: S. Cunningham has nothing to disclose. Conflict of interest: G. Fenu reports advisory board fees from GSK, clinical trial sponsorship from Sanofi, expenses for congresses and meetings from Novartis, personal fees for teaching a course from Chiesi, and expenses for congresses and meetings from Lusofarmaco, outside the submitted work. Conflict of interest: L.J. Fleming reports grants from Asthma UK, and fees for expert consultation and speakers fees from AstraZeneca, GSK, Novartis, Teva, Bohringer Ingelheim, Respiri and Sanofi paid direct to her institution and outside of the submitted work Conflict of interest: M. Gappa reports that she has received honoraria for lectures and/or consultancy from Boehringer Ingelheim, GSK, Novartis and Sanofi. She believes that this has not influenced any of the submitted work. Conflict of interest: B. Karadag reports for the multicentre, phase III dupilumab study EFC14153 from Sanofi, outside the submitted work. Conflict of interest: F. Midulla has nothing to disclose. Conflict of interest: L. Petrarca has nothing to disclose. Conflict of interest: M.W.H. Pijnenburg reports a consultancy fee paid to her department by Sanofi Genzyme during the conduct of the study. Conflict of interest: T. Reier-Nilsen has nothing to disclose. Conflict of interest: N.W. Rutjes has nothing to disclose. Conflict of interest: F. Rusconi has nothing to disclose. Conflict of interest: J. Grigg reports personal fees for asthma advisory boards from AstraZeneca and GSK, personal fees for a continuing professional development lecture from Novartis, and personal fees for an asthma advisory board from Vifor Pharma, outside the submitted work., (Copyright ©ERS 2020.)

Background: Paediatricians rarely devote any time to screening and treatment for parental tobacco use. The present project is part of a Global Alliance against Chronic Respiratory Diseases (GARD)-Italy Demonstration Project, aimed to increase the skills of primary care physicians and paediatricians as "promoter of smoking cessation". The aims of this study were: (I) to identify latent classes of barriers and incentives for smoking cessation counseling among paediatricians using latent class analysis (LCA); (II) to investigate risk factors for inclusion into the identified classes., Methods: In 2018, 1,500 Italian paediatricians were invited to complete an online survey on passive smoke exposure in children. LCA was used to discover underlying response patterns, and to identify respondent groups with similar attitudes toward passive smoke exposure in children. Multinomial logistic regression helped investigate which explanatory variables influenced inclusion into a class. A P value <0.05 was considered significant., Results: The overall response rate was 71% (n=1,071/1,500). Three classes were identified: Class 1 "passive" (n=226, 21.10%); Class 2 "unmotivated" (n=124, 11.58%); and Class 3 "proactive" (n=721, 67.32%). Assuming Class 3 as reference, ever having been a smoker was borderline associated (P=0.052) with increased probability of inclusion into Class 1 (OR =1.43, 95% CI, 1.00-2.06). Having 6-15 or ≥15 years of work experience versus having less than five years was associated with decreased probability of being in the "passive" class (OR =0.46, 95% CI, 0.22-0.96 and OR =0.49, 95% CI, 0.27-0.87, respectively), as was discussing parents' addiction to alcohol/drugs (OR =0.50, 95% CI, 0.33-0.76)., Conclusions: We identified three profiles among Italian paediatricians related to barriers and incentives for smoking cessation promotion. Tailored educational interventions for paediatricians are required to promote smoking cessation programs., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (http://dx.doi.org/10.21037/jtd-gard-20-003). The authors have no conflicts of interest to declare., (2020 Journal of Thoracic Disease. All rights reserved.)

Objectives: Since an inappropriate and sustained activation of TLRs may contribute to a chronic inflammatory response resulting in detrimental effects in cystic fibrosis (CF) patients, we sought to examine whether HRV infection might alter the respiratory expression of TLRs according to the microbiological status of CF patients., Methods: Respiratory samples were collected from the respiratory tract of CF patients (n = 294) over a period of 12 months. In addition to the usual microbiological investigation, HRV-RNA detection and typing were performed by RT-PCR and sequencing. HRV viral load and TLRs levels were measured by RT-Real Time PCR., Results: HRV-RNA was detected in 80 out of 515 respiratory samples (15.5%) with a similar rate in all age groups (0-10 years, 11-24 years, ≥ 25 years). Patients infected with different HRV A, B and C species exhibited higher levels of TLR2, TLR4 and TLR8 as compared to HRV negative patients. Moreover, the expression level of TLR2, TLR4 and TLR8 correlated with high level of HRV viral load. HRV positive patients co-colonized by Staphylococcus aureus or Pseudomonas aeruginosa showed also enhanced amounts of TLR2 and TLR2/4-mRNAs expression respectively. In the case of presence of both bacteria, TLR2, TLR4, TLR8 and TLR9 levels are elevated in positive HRV patients., Conclusions: TLRs, especially TLR2 and TLR4, increased in HRV positive CF individuals and varies according to the presence of S. aureus, P. aeruginosa and both bacteria., Competing Interests: Conflicts of interests The authors declare that they have no conflicts of interests., (Copyright © 2020. Published by Elsevier Ltd.)

Novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) became pandemic by the end of March 2020. In contrast to the 2002-2003 SARS-CoV outbreak, which had a higher pathogenicity and lead to higher mortality rates, SARSCoV-2 infection appears to be much more contagious. Moreover, many SARS-CoV-2 infected patients are reported to develop low-titer neutralizing antibody and usually suffer prolonged illness, suggesting a more effective SARS-CoV-2 immune surveillance evasion than SARS-CoV. This paper summarizes the current state of art about the differences and similarities between the pathogenesis of the two coronaviruses, focusing on receptor binding domain, host cell entry and protease activation. Such differences may provide insight into possible intervention strategies to fight the pandemic.

Severe Acute Respiratory Syndrome - Coronavirus - 2 (SARS-CoV-2) and its related Coronavirus Disease - 19 (COVID-19) has become a health emergency worldwide. The medical community has been concerned since the beginning of the outbreak about the potential impact of COVID-19 in children, especially in those with underlying chronic diseases. Fortunately, COVID-19 has been reported to be less severe in children than in adults. However, epidemiologic and clinical data are scarce. Children show unique features of SARS-CoV-2 involvement that may account for the low rate of infection and death in this age group. The purpose of this review is to summarize the most relevant evidence of COVID-19 in children highlighting similarities and differences with adults., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Pneumonia is an important cause of morbidity and mortality in children. We described viral aetiologies, with particular interest in detecting SARS-CoV-2, in hospitalized pneumonia children. Human rhinovirus was the most frequently detected agent. No children tested positive for SARS-CoV-2. Our findings suggest that SARS-CoV-2 infection is rare in children and it was not circulating in Rome before COVID-19 outbreak., Competing Interests: Declaration of Competing Interest Authors have nothing to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: A study of respiratory syncytial virus-A (RSV A) genotype ON1 genetic variability and clinical severity in infants hospitalized with bronchiolitis over 6 epidemic seasons (2012-2013 to 2017-2018) was carried out., Methods: From prospectively enrolled term infants hospitalized for bronchiolitis, samples positive for RSV A ON1 (N = 139) were sequenced in the second half of the G gene. Patients' clinical data were obtained from medical files and each infant was assigned a clinical severity score. ANOVA comparison and adjusted multinomial logistic regression were used to evaluate clinical severity score and clinical parameters., Results: The phylogenetic analysis of 54 strains showed 3 distinct clades; sequences in the last 2 seasons differed from previous seasons. The most divergent and numerous cluster of 2017-2018 strains was characterized by a novel pattern of amino acid changes, some in antigenic sites. Several amino acid changes altered predicted glycosylation sites, with acquisition of around 10 new O-glycosylation sites. Clinical severity of bronchiolitis increased in 2016-2017 and 2017-2018 and changed according to the epidemic seasons only., Conclusions: Amino acid changes in the hypervariable part of G protein may have altered functions and/or changed its immunogenicity, leading to an impact on disease severity., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The role of human bocavirus (HBoV) as a respiratory pathogen has not been fulfilled yet. We aimed to describe clinical and serological characteristics of children with HBoV hospitalized for acute respiratory tract infection and to evaluate whether differences occur between HBoV alone and in co-infection., Methods: We retrospectively reviewed data from 60 children (median age of 6.2 months, range 0.6-70.9) hospitalized for acute respiratory symptoms, with HBoV detected from a respiratory sample, using a reverse transcriptase-PCR for 14 respiratory viruses (including respiratory syncytial virus (RSV), influenza virus A and B, human coronavirus OC43, 229E, NL-63 and HUK1, adenovirus, rhinovirus, parainfluenza virus1-3, and human metapneumovirus)., Results: HBoV was detected alone in 29 (48.3%) patients, while in co-infection with other viruses in 31 patients (51.7%), with a peak between December and January. Among the 60 patients, 34 were bronchiolitis, 19 wheezing, 3 pneumonia, 2 upper respiratory tract infection, and 2 whooping cough. Seven children (11.6%) required admission to the paediatric intensive care unit (PICU) for respiratory failure. No differences was observed in age, family history for atopy and/or asthma, clinical presentations, chest X-ray, or laboratory findings in children with HBoV alone vs. multiple viral detection. RSV was the most frequently co-detected virus (61.3%). When compared with HBoV detection alone, the co-detection of RSV and HBoV was associated with male sex (P = 0.013), younger age (P = 0.01), and lower blood neutrophil count (P = 0.032)., Conclusions: HBoV can be detected alone and in co-infection respiratory samples of children with an acute respiratory tract infection. A cause-effect relationship between HBoV and respiratory infection is not clear, so further studies are needed to clarify this point.

Respiratory Syncytial Virus (RSV) is the leading cause of bronchiolitis, and the severity may be influenced by the bacterial ecosystem. Our aim was to analyze the nasal microbiota from 48 infants affected by bronchiolitis from RSV virus and 28 infants with bronchiolitis but negative for the virus. Results showed a significantly lower biodiversity in the RSV-positive group with respect to the RSV-negative group, a specific microbial profile associated with the RSV-positive group different from that observed in the negative group, and significant modifications in the relative abundance of taxa in the RSV-positive group, as well as in the RSV-A group, with respect to the negative group. Furthermore, microbial network analyses evidenced, in all studied groups, the presence of two predominant sub-networks characterized by peculiar inter- and intra-group correlation patterns as well as a general loss of connectivity among microbes in the RSV-positive group, particularly in the RSV-A group. Our results indicated that infants with more severe bronchiolitis disease, caused by RSV-A infection, present significant perturbations of both the nasal microbiota structure and the microbial relationships. Patients with a milder bronchiolitis course (RSV-B-infected and patients who have cleared the virus) presented less severe alterations.

Aim: The most frequent cause of lower respiratory tract infection in infants is bronchiolitis. Up to now there is no agreement on the upper limit age of bronchiolitis. Our aim was to identify if there are clinical differences in infants hospitalized for bronchiolitis between 0-6 months and 6-12 months of age. A secondary aim was to establish whether there was differences in terms of recurrent wheezing at 12, 24, and 36 months of follow-up. Methods: We retrospectively analyzed clinical and virological records of 824 infants hospitalized for bronchiolitis during 11 consecutive epidemic seasons. From each infant at admission to the hospital nasopharyngeal washing was collected, clinical severity was assessed and clinical data were extracted from a structured questionnaire. At 12-24-36 months after discharge, parents were interviewed seeking information on recurrent wheezing. Results: A total of 773 infants (Group1) were ≤6 months of age, while 51 were >6 months (Group 2). No differences between family history for atopy and passive smoking exposure were observed between the two groups. Respiratory syncyzial virus was detected more frequently in Group 1 and human bocavirus in Group 2. The clinical severity score ( p = 0.011) and the use of intravenous fluids ( p = 0.0001) were higher in Group 1 with respect to Group 2 infants. At 36 months follow-up 163/106 (39.4%) Group 1 and 9/9 Group 2 infants experienced recurrent wheezing ( p = 0.149). Conclusion: We demonstrated that 0-6 months old infants bronchiolitis differs from > 6 months bronchiolitis., (Copyright © 2020 Nenna, Frassanito, Petrarca, Di Mattia and Midulla.)

Although recent guidelines recommend a minimalist approach to bronchiolitis, there are several issues with this posture. First, there are concerns about the definition of the disease, the quality of the guidelines, the method of administration of bronchodilators, and the availability of tools to evaluate the response to therapies. Second, for decades it has been assumed that all cases of viral bronchiolitis are the same, but recent evidence has shown that this is not the case. Distinct bronchiolitis phenotypes have been described, with heterogeneity in clinical presentation, molecular immune signatures and clinically relevant outcomes such as respiratory failure and recurrent wheezing. New research is critically needed to refine viral bronchiolitis phenotyping at the molecular and clinical levels as well as to define phenotype-specific responses to different therapeutic options., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Bronchiolitis severity is determined by a complex interaction among viral replication and antiviral immunity. The current respiratory syncytial virus (RSV)-A, genotype ON1 demonstrated a high replicative capacity but seemed to be clinically less severe than the previously circulating RSV-A, NA1. To learn insights about ON1 innate immune response, we analyzed expression levels of type I/III interferon (IFN)-related genes in the respiratory mucosa of infants with RSV bronchiolitis. We enrolled RSV-positive bronchiolitis patients over 12 epidemic seasons at a university hospital in Rome. From nasopharyngeal washings' cells (46 positive to NA1, 47 to ON1 and 28 to RSV-B, genotype BA), the mRNA copy number of the type III IFN receptor (IFNLR1 and IL10RB subunits), and of the type I/III IFN-stimulated genes, MxA and ISG56, was calculated using the threshold cycle relative quantification method with respect to an invariant gene. Expression levels of type III IFN receptor subunits genes positively correlated to each other and did not differ in infants infected with different RSV genotypes. The ISGs levels also positively correlated between them but differed among groups. MxA levels were significantly higher in NA1-infected infants than in those with ON1 and BA; ISG56 expression was slightly higher in NA1 than in the other strains. Interestingly, a moderate negative correlation existed between viral load and both ISGs values in ON1-infected infants only. The reduced ISG levels elicited during infections with ON1 (and BA) may cause a weaker control of RSV replication and/or an inadequate host immune response which may impact the risk of respiratory sequelae.

Aim: To test the hypothesis that the balance of type-1/type-2 immune response differs between infants hospitalized with respiratory syncytial virus (RSV) bronchiolitis during the peak months and those during the nonpeak months., Methods: We prospectively enrolled 90 unrelated full-term previously healthy infants hospitalized during the first year of life for RSV sole bronchiolitis over 2 epidemics (November 2016 to April 2017 and October 2017 to April 2018). We stratified infants as follows: hospitalized during the peak months (n: 71) and during the nonpeak months (n: 19). The frequencies of CD4+ producing interferon (IFN)-γ and interleukin (IL)-4 and of CD8+ producing IFN-γ T cells were measured by flow cytometry from infant peripheral whole blood. The T-helper cell (Th2) polarization index was calculated as the ratio between CD4+ T cells producing IL-4 and CD4+ T cells producing IFN-γ., Results: Infants hospitalized during nonpeak months were significantly less frequently breast-fed, had a higher eosinophils count, a significantly higher percentage of CD4+ T cells producing IL-4 and higher Th2 polarization index than infants hospitalized during the peak months., Conclusions: We elucidated the presence of different endotypes in infants with RSV sole bronchiolitis. Previously healthy full-term infants hospitalized during the nonpeak months seem to be more likely those with a possible predisposition to atopy.

Background: The only pharmacologic prophylaxis against respiratory syncytial virus (RSV) infection in preterm infants is the humanized monoclonal antibody palivizumab. After the 2014 modification of the American Academy of Pediatrics (AAP) recommendations, the Italian Medicines Agency (AIFA) limited the financial coverage for palivizumab prescriptions to otherwise healthy preterm infants with < 29 weeks of gestational age (wGA) aged < 12 months at the beginning of the 2016-2017 RSV season. However, due to the effect on disease severity and hospitalizations following this limitation, shown by several Italian clinical studies, in November 2017 AIFA reinstated the financial coverage for these infants. In this systematic review, we critically summarize the data that show the importance of palivizumab prophylaxis., Methods: Data from six Italian pediatric institutes and the Italian Network of Pediatric Intensive Care Units (TIPNet) were retrieved from the literature and considered. The epidemiologic information for infants 29-36 wGA, aged < 12 months and admitted for viral-induced acute lower respiratory tract infection were retrospectively reviewed. RSV-associated hospitalizations were compared between the season with running limitation, i.e. 2016-2017, versus 2 seasons before (2014-2015 and 2015-2016) and one season after (2017-2018) the AIFA limitation., Results: During the 2016-2017 RSV epidemic season, when the AIFA limited the financial coverage of palivizumab prophylaxis based on the 2014 AAP recommendation, the study reports on a higher incidences of RSV bronchiolitis and greater respiratory function impairment. During this season, we also found an increase in hospitalizations and admissions to the Pediatric Intensive Care Units and longer hospital stays, incurring higher healthcare costs. During the 2016-2017 epidemic season, an overall increase in the number of RSV bronchiolitis cases was also observed in infants born full term, suggesting that the decreased prophylaxis in preterm infants may have caused a wider infection diffusion in groups of infants not considered to be at risk., Conclusions: The Italian results support the use of palivizumab prophylaxis for otherwise healthy preterm (29-36 wGA) infants aged < 6 months at the beginning of the RSV season.

Tracheomalacia and tracheobronchomalacia may be primary abnormalities of the large airways or associated with a wide variety of congenital and acquired conditions. The evidence on diagnosis, classification and management is scant. There is no universally accepted classification of severity. Clinical presentation includes early-onset stridor or fixed wheeze, recurrent infections, brassy cough and even near-death attacks, depending on the site and severity of the lesion. Diagnosis is usually made by flexible bronchoscopy in a free-breathing child but may also be shown by other dynamic imaging techniques such as low-contrast volume bronchography, computed tomography or magnetic resonance imaging. Lung function testing can provide supportive evidence but is not diagnostic. Management may be medical or surgical, depending on the nature and severity of the lesions, but the evidence base for any therapy is limited. While medical options that include bronchodilators, anti-muscarinic agents, mucolytics and antibiotics (as well as treatment of comorbidities and associated conditions) are used, there is currently little evidence for benefit. Chest physiotherapy is commonly prescribed, but the evidence base is poor. When symptoms are severe, surgical options include aortopexy or posterior tracheopexy, tracheal resection of short affected segments, internal stents and external airway splinting. If respiratory support is needed, continuous positive airway pressure is the most commonly used modality either via a face mask or tracheostomy. Parents of children with tracheobronchomalacia report diagnostic delays and anxieties about how to manage their child's condition, and want more information. There is a need for more research to establish an evidence base for malacia. This European Respiratory Society statement provides a review of the current literature to inform future study., Competing Interests: Conflict of interest: C. Wallis has nothing to disclose. Conflict of interest: E. Alexopoulou has nothing to disclose. Conflict of interest: J.L. Antón-Pacheco has nothing to disclose. Conflict of interest: J.M. Bhatt reports personal fees from Vertex, outside the submitted work. Conflict of interest: A. Bush has nothing to disclose. Conflict of interest: A.B. Chang reports grants from National Health and Medical Research Council, Australia, and other funding from GSK, Up to Date and BMJ Evidence Centre, outside the submitted work. Conflict of interest: A-M. Charatsi has nothing to disclose. Conflict of interest: C. Coleman is an employee of European Lung Foundation. Conflict of interest: J. Depiazzi has nothing to disclose. Conflict of interest: K. Douros has nothing to disclose. Conflict of interest: E. Eber has nothing to disclose. Conflict of interest: M. Everard has nothing to disclose. Conflict of interest: A. Kantar has nothing to disclose. Conflict of interest: I.B. Masters has nothing to disclose. Conflict of interest: F. Midulla has nothing to disclose. Conflict of interest: R. Nenna has nothing to disclose. Conflict of interest: D. Roebuck has nothing to disclose. Conflict of interest: D. Snijders has nothing to disclose. Conflict of interest: K. Priftis has nothing to disclose., (Copyright ©ERS 2019.)

The 10-year-old European syllabus for paediatric respiratory medicine (PRM; also known as paediatric pulmonology) was updated by a consensus-based method using an expert task force for redrafting, and a subsequent Delphi process to achieve consensus. There was a high degree of consensus for the final syllabus, which has been streamlined and made more relevant to current practice. All modules are now mandatory apart from the undertaking of research projects, which is optional. Although there are still a number of countries in Europe which do not recognise PRM as a separate subspecialty, there are paediatric respiratory physicians practising in every country in Europe, and a current and harmonised European syllabus in the subspecialty remains important for defining the training and areas of practice of PRM practitioners., Competing Interests: Conflict of interest: R. Primhak has nothing to disclose. Conflict of interest: N. Tabin is an employee of the European Respiratory Society. Conflict of interest: N. Beydon has nothing to disclose. Conflict of interest: J. Bhatt has nothing to disclose. Conflict of interest: E. Eber has nothing to disclose. Conflict of interest: J. Hammer has nothing to disclose. Conflict of interest: A. Martinez-Gimeno has nothing to disclose. Conflict of interest: F. Midulla has nothing to disclose. Conflict of interest: R. Nenna has nothing to disclose. Conflict of interest: J. Paton has nothing to disclose. Conflict of interest: R. Ross Russell has nothing to disclose.

Objectives: To evaluate the causes and management of acute ataxia (AA) in the paediatric emergency setting and to identify clinical features predictive of an underlying clinically urgent neurological pathology (CUNP)., Study Design: This is a retrospective medical chart analysis of children (1-18 years) attending to 11 paediatric emergency departments (EDs) for AA in an 8-year period. A logistic regression model was applied to identify clinical risk factors for CUNP., Results: 509 patients (mean age 5.8 years) were included (0.021% of all ED attendances). The most common cause of AA was acute postinfectious cerebellar ataxia (APCA, 33.6%). Brain tumours were the second most common cause (11.2%), followed by migraine-related disorders (9%). Nine out of the 14 variables tested showed an OR >1. Among them, meningeal and focal neurological signs, hyporeflexia and ophthalmoplegia were significantly associated with a higher risk of CUNP (OR=3-7.7, p<0.05). Similarly, the odds of an underlying CUNP were increased by 51% by each day from onset of ataxia (OR=1.5, CI 1.1 to 1.2). Conversely, a history of varicella-zoster virus infection and vertigo resulted in a significantly lower risk of CUNP (OR=0.1 and OR=0.5, respectively; p<0.05)., Conclusions: The most frequent cause of AA is APCA, but CUNPs account for over a third of cases. Focal and meningeal signs, hyporeflexia and ophthalmoplegia, as well as longer duration of symptoms, are the most consistent 'red flags' of a severe underlying pathology. Other features with less robust association with CUNP, such as seizures or consciousness impairment, should be seriously taken into account during AA evaluation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

In the last twenty years, despite high vaccination coverage, epidemics of pertussis are occurring in both developing and developed countries. Many reasons could explain the pertussis resurgence: the increasing awareness of the disease, the availability of new diagnostic tests with higher sensitivity, the emergence of new Bordetella pertussis (B. pertussis) strains different from those contained in the current vaccines, the asymptomatic transmission of B. pertussis in adolescents and adults and the shorter duration of protection given by the acellular pertussis (aP) vaccine. New preventive strategies have already been implemented, such as booster doses of aP vaccine in adolescents and adults, maternal immunisation during pregnancy and the "cocooning" strategy, but more are still needed. Knowing what is new about this old disease is necessary to reduce its incidence and to protect infants too young to be vaccinated, which have the highest risk of complications and death., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: We aimed to study respiratory syncytial virus (RSV) genotype distribution, clinical presentation, and disease severity in infants with bronchiolitis from RSV subtypes and new RSV genotypes., Methods: We prospectively enrolled previously healthy term infants less than 1 year old hospitalized for bronchiolitis in an Italian university hospital over 12 epidemic seasons. In 312 nasopharyngeal washings positive for RSV, we sequenced the viral genotype and analyzed this according to patient data. Strain-specific RSV loads were quantified for 273 specimens., Results: From 2005-2006 to 2011-2012, the RSV-A genotype NA1 predominated, and was replaced in 2012 by the novel ON1. All infants infected with RSV subtype B were genotype BA. Stratifying data according to genotypes NA1, ON1, and BA showed that NA1-infected infants were the youngest and had the most severe clinical course. Conversely, BA-infected infants had less severe symptoms and more frequently had eosinophilia and a family history of asthma. Infants with the ON1 genotype had a milder clinical course than those with NA1 and more risk factors for asthma, despite having the highest viral loads., Conclusion: The disease course in infants hospitalized for acute RSV bronchiolitis may depend on the RSV genotype.

Bronchiolitis is the most common acute lower respiratory tract infection in infants and the first cause of hospitalization in this age group. Despite it has been studied for over 70 years, its management remains controversial and nowadays the treatment is only supportive. Pediatricians should be well acquainted with the clinical course of the disease. In particular, they should know that the severity of respiratory symptoms peaks between days 3-7 of the disease and dehydration is a key sign to consider for the management. In this review, we will discuss the most controversial points in the management of bronchiolitis according to six evidence-based guidelines, six clinical practice guidelines and five consensus-based reviews.

The development of new asthma biologics and receptor blockers for the treatment of paediatric severe asthma raises challenges. It is unclear whether there are sufficient children in Europe to recruit into randomised placebo-controlled trials to establish efficacy and safety in this age group. In February 2016, the European Respiratory Society funded a clinical research collaboration entitled "Severe Paediatric Asthma Collaborative in Europe" (SPACE). We now report the SPACE protocol for a prospective pan-European observational study of paediatric severe asthma. Inclusion criteria are: 1) age 6-17 years, 2) severe asthma managed at a specialised centre for ≥6 months, 3)clinical and spirometry evidence of asthma, and 4) reaching a pre-defined treatment threshold. The exclusion criterion is the presence of conditions which mimic asthma symptoms. Eligible children will be prospectively recruited into a registry, recording demographics, comorbidities, quality of life, family history, neonatal history, smoking history, asthma background, investigations, and treatment. Follow-up will provide longitudinal data on asthma control and treatment changes. The SPACE registry, by identifying well-phenotyped children eligible for clinical trials, and the amount of overlap in eligibility criteria, will inform the design of European trials in paediatric severe asthma, and facilitate observational research where data from single centres are limited., Competing Interests: Conflict of interest: N.M. Liu has nothing to disclose. Conflict of interest: W. van Aalderen has nothing to disclose. Conflict of interest: K.C.L. Carlsen has received financial support from governmental and other bodies for studies not related to the present project, andhas no conflict of interest to declare. Conflict of interest: C. Coleman is an employee of the European Lung Foundation. Conflict of interest: J.D. Chalmers reports grants and personal fees from Glaxosmithkline (research grants for COPD), Boehringer-Ingelheim (research grants for COPD studies), Pfizer (research grants for COPD), Bayer Healthcare (research into bronchiectasis) and Grifols (research into bronchiectasis); grants from AstraZeneca (research grants for COPD); personal fees from Napp (for consulting), outside the submitted work. Conflict of interest: S. Cunningham has nothing to disclose. Conflict of interest: R.M. Fernandes has nothing to disclose. Conflict of interest: L.J. Fleming reports other from Novartis (lecture fees and advisory board fees paid to her institution), Vectura (consultancy fees, paid to her institution), Boehringer Ingelheim (advisory board fees, paid to her institution) and AstraZeneca (lecture fees paid to her institution), outside the submitted work. Conflict of interest: M. Gappa reports personal fees from GSK (advisory board), Boehringer (advisory board and speaker honorarium) and Novartis (advisory board and speaker honorarium), outside the submitted work. Conflict of interest: B. Karadag has nothing to disclose. Conflict of interest: F. Midulla has nothing to disclose. Conflict of interest: M.W.H. Pijnenburg has nothing to disclose. Conflict of interest: N.W. Rutjes has nothing to disclose. Conflict of interest: F.Rusconi has nothing to disclose. Conflict of interest: J. Grigg reports personal fees (honorarium for advisory board) from GSK and Vifor Pharmaceuticals, outside the submitted work.

In this article, the group chairs of the Paediatric Assembly of the European Respiratory Society (ERS) highlight some of the most interesting findings presented at the 2017 ERS International Congress, which was held in Milan, Italy., Competing Interests: Conflict of interest: J. Grigg reports personal fees from GSK and Vifor Pharmaceuticals (honoraria for advisory boards), outside the submitted work. Conflict of interest: G. Hall reports serving on Vertex MBW and LCI Advisory Boards, outside the submitted work.

The International Standards for Tuberculosis Care define the essential level of care for managing patients who have or are presumed to have tuberculosis, or are at increased risk of developing the disease. The resources and capacity in the European Union (EU) and the European Economic Area permit higher standards of care to secure quality and timely TB diagnosis, prevention and treatment. On this basis, the European Union Standards for Tuberculosis Care (ESTC) were published in 2012 as standards specifically tailored to the EU setting. Since the publication of the ESTC, new scientific evidence has become available and, therefore, the standards were reviewed and updated.A panel of international experts, led by a writing group from the European Respiratory Society (ERS) and the European Centre for Disease Prevention and Control (ECDC), updated the ESTC on the basis of new published evidence. The underlying principles of these patient-centred standards remain unchanged. The second edition of the ESTC includes 21 standards in the areas of diagnosis, treatment, HIV and comorbidities, and public health and prevention.The ESTC target clinicians and public health workers, provide an easy-to-use resource and act as a guide through all the required activities to ensure optimal diagnosis, treatment and prevention of TB., Competing Interests: Conflict of interest: S. Aliberti reports grants and personal fees from Bayer Healthcare, Aradigm Corporation, Grifols, Chiesi and INSMED, and personal fees from AstraZeneca, Basilea, Zambon, Novartis, Raptor, Actavis UK Ltd and Horizon, outside the submitted work., (The content of this work is copyright of the authors or their employers. Design and branding are copyright ©ERS 2018.)

Background: As the expression of type III IFN receptor is restricted to the mucosal surfaces, its evaluation could be crucial to characterize the role of IFNλs during bronchiolitis., Objectives: This study was designed to investigate airway type III IFN receptor (IFNLR1/IL10RB) expression during respiratory syncytial virus (RSV) or human rhinovirus (HRV) bronchiolitis., Study Design: Seventy-one 1-6 month old infants hospitalized with their first episode of acute RSV or HRV bronchiolitis were selected for this study. Expression of IFNLR1, IL10RB and IFN-stimulated genes (ISGs) MxA and ISG56 in cells of nasopharyngeal washings taken within the first 48 h of admission were determined by a real-time hydrolysis probe RT-PCR assay. The ability of types I and III IFNs to induce the expression of both IFNLR1 and IL10RB in vitro was also evaluated., Results: Airway IFNLR1 transcript levels were significantly higher in HRV bronchiolitis infants compared to those with RSV bronchiolitis. No differences were recorded for IL10RB-mRNA between RSV or HRV infection. IFNLR1 mRNA levels increased significantly in infants infected with the C species of HRV and in those with a higher clinical score index and with an eosinophil count >3%. There were no correlations in vivo between type III IFN receptors and those of ISGs and neither IFNLR1 nor IL10RB were induced in vitro by IFNs., Conclusions: These results suggest that IFNLR1 are increased in HRV-infected infants with more severe bronchiolitis and blood eosinophilia and in those infected with the HRVC species., (Copyright © 2018. Published by Elsevier B.V.)

Measuring work of breathing (WOB) is an intricate task during high-flow nasal cannula (HFNC) therapy because the continuous unidirectional flow toward the patient makes pneumotachography technically difficult to use. We implemented a new method for measuring WOB based on a differential pneumotachography (DP) system, equipped with one pneumotachograph inserted in the HFNC circuit and another connected to a monitoring facemask, combined with a leak correction algorithm (LCA) that corrects flow measurement errors arising from leakage around the monitoring facemask. To test this system, we used a mechanical lung model that provided data to compare LCA-corrected respiratory flow, volume and time values with effective values obtained with a third pneumotachograph used instead of the LCA to measure mask flow leaks directly. Effective and corrected volume and time data showed high agreement (Bland-Altman plots) even at the highest leak. Studies on two healthy adult volunteers confirmed that corrected respiratory flow combined with esophageal pressure measurements can accurately determine WOB (relative error < 1%). We conclude that during HFNC therapy, a DP system combined with a facemask and an algorithm that corrects errors due to flow leakages allows pneumotachography to measure reliably the respiratory flow and volume data needed for calculating WOB., (Copyright © 2018. Published by Elsevier Ltd.)

Bronchiolitis is the first lower respiratory tract viral infection manifesting in infants younger than 12 months of age. Our aim was to evaluate clinical and serological differences in infants with bronchiolitis from a single or from multiple viruses. Our secondary aim was to investigate differences in recurrent wheezing episodes after 12-24-36 months of follow-up. We reviewed the clinical records for 486 full-term infants hospitalized for bronchiolitis with at least one virus detected in the nasopharyngeal aspirate. In 431 (88.7%) patients one virus was detected and in 55 (11.3%) infants more than one virus was found. No differences were observed in the length of hospitalization, clinical severity score, O 2 supplementation or admission to the intensive care unit. Single virus was associated with higher serum C-reactive protein (C-RP) than infants with multiple viruses and higher blood neutrophil counts. Respiratory syncytial virus (RSV) was the most frequently detected virus. RSV alone was associated with higher C-RP (P = 0.007), compared to RSV coinfection. Infants with human rhinovirus (hRV) alone had higher white blood cell counts, higher blood neutrophils, and higher serum C-RP levels than hRV co-infection (P = 0.029, P = 0.008, P = 0.008). RSV + hRV, the most frequent co-infection, was associated with lower neutrophil count and lower C-RP levels (P = 0.008, P = 0.016) and less fever (P = 0.012), when comparing RSV versus hRV versus RSV + hRV. No differences were found in the frequency of recurrent wheezing between single versus multiple viruses after bronchiolitis. Our findings suggest that in infants with bronchiolitis multiple viral co-infections can occur, without influence in the clinical severity of the disease. Infants with co-infection seems to mount a lower inflammatory response., (© 2017 Wiley Periodicals, Inc.)

Objectives: We describe the way we treated 7 children with critical long-term complications after metallic balloon-expandable stenting in the left mainstem bronchus., Methods: Endoscopic follow-up included a first bronchoscopy 3 weeks after stenting, then monthly for 3 months, every 4-6 months up to 1 year and at scheduled times to calibrate stent diameter up to final calibration. When major complications occurred, patients underwent chest computed tomographic angiography., Results: In 1 of the 7 children (median age 2.8 years), metallic left bronchial stenting served as a bridge to surgery. After a median 4-year follow-up, all 7 children experienced recurrent stent ovalizations with stent breakage in 3 and erosion in 1. In 4 children, computed tomographic angiography showed abundant peribronchial fibrous tissue, in 2 left mediastinal rotation and in 1 displacement along the left bronchus after pulmonary re-expansion as the cause of stent-related complication. Of the 7 children, 6 underwent surgery (5 posterior aortopexy and 1 section of the ligamentum arteriosus) and 3 required nitinol stents placement within the metallic ones. One patient completed the follow-up, and 1 patient was lost to follow-up. All 5 remaining children still have permanent bronchial stents in place, patent and re-epithelialized after a median 10.5-year follow-up. There were no deaths., Conclusions: Satisfactory anatomical relationships when children have stents placed in the left mainstem bronchus alone do not guarantee the final success. Several mechanisms intervene to cause critical stent-related complications in children during growth. Permanent metallic stents should be used carefully, and only in selected patients., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

The sustained imbalance between oxidant and antioxidant species contributes to lung damage in patients with cystic fibrosis (CF). Glutathione (GSH) is an important component of the antioxidant defense in the airways epithelial lining fluid and its transportation out of the cells may be altered in CF. The aim of this study was to assess the oxidants/antioxidants balance in the airways of patients with CF. We measured the concentrations of GSH, the total antioxidant capacity and the concentration of 8-iso-prostaglandin F 2α (8-isoprostane), a marker of oxidative stress, in the exhaled breath condensate of 17 non-smoking patients with CF, in stable phase, and in 17 age-matched healthy subjects. The levels of GSH and total antioxidant capacity in patients with CF were significantly lower than in healthy subjects (0.66 ± 0.07 μM versus 1.30 ± 0.08 μM, p < 0.001, respectively for GSH; 0.157 ± 0.02 mM and 0.32 ± 0.01 mM, p < 0.05, respectively for antioxidant capacity). The concentration of 8-isoprostane was higher in CF than in healthy controls (26.5 ± 0.1 pg ml -1 versus 10.8 ± 0.1 pg ml -1 ; p < 0.05). A low concentration of antioxidant agents, particularly glutathione, and increased levels of 8-isoprostane in the exhaled breath suggest an altered oxidizing environment in the airways of patients with CF. This altered redox environment in the epithelial liquid surface may contribute to progressive lung disease.

Paediatric airway endoscopy is accepted as a diagnostic and therapeutic procedure, with an expanding number of indications and applications in children. The aim of this European Respiratory Society task force was to produce a statement on interventional bronchoscopy in children, describing the evidence available at present and current clinical practice, and identifying areas deserving further investigation. The multidisciplinary task force panel performed a systematic review of the literature, focusing on whole lung lavage, transbronchial and endobronchial biopsy, transbronchial needle aspiration with endobronchial ultrasound, foreign body extraction, balloon dilation and occlusion, laser-assisted procedures, usage of airway stents, microdebriders, cryotherapy, endoscopic intubation, application of drugs and other liquids, and caregiver perspectives. There is a scarcity of published evidence in this field, and in many cases the task force had to resort to the collective clinical experience of the committee to develop this statement. The highlighted gaps in knowledge underline the need for further research and serve as a call to paediatric bronchoscopists to work together in multicentre collaborations, for the benefit of children with airway disorders., Competing Interests: Conflict of interest: C. Coleman and S. Masefield are employees of the European Lung Foundation. T. Tonia acts as a methodologist for the European Respiratory Society., (Copyright ©ERS 2017.)

Background: We sought to clarify possibly modifiable risk factors related to pollution responsible for acute bronchiolitis in hospitalized infants., Methods: For this observational study, we recruited 213 consecutive infants with bronchiolitis (cases: median age: 2 months; age range: 0.5-12 months; boys: 55.4%) and 213 children aged <3 years (controls: median age: 12 months; age range: 0.5-36 months; boys: 54.5%) with a negative medical history for lower respiratory tract diseases hospitalized at 'Sapienza' University Rome and IRCCS Bambino Gesù Hospital. Infants' parents completed a standardized 53-item questionnaire seeking information on social-demographic and clinical characteristics, indoor pollution, eating habits and outdoor air pollution. Multivariate logistic regression analyses were run to assess the independent effect of risk factors, accounting for confounders and effect modifiers., Results: In the 213 hospitalized infants the questionnaire identified the following risk factors for acute bronchiolitis: breastfeeding ⩾3 months (OR: 2.1, 95% confidence interval [CI]: 1.2-3.6), presence of older siblings (OR: 2.8, 95% CI: 1.7-4.7), ⩾4 cohabitants (OR: 1.5, 95% CI: 1.1-2.1), and using seed oil for cooking (OR: 1.7, 95% CI: 1.2-2.6). Having renovated their home in the past 12 months and concurrently being exposed daily to smoking, involving more than 11 cigarettes and two or more smoking cohabitants, were more frequent factors in cases than in controls ( p = 0.021 and 0.05), whereas self-estimated proximity to road and traffic was similar in the two groups., Conclusions: We identified several risk factors for acute bronchiolitis related to indoor and outdoor pollution, including inhaling cooking oil fumes. Having this information would help public health authorities draw up effective preventive measures - for example, teach mothers to avoid handling their child when they have a cold and eliminate exposure to second-hand tobacco smoke.