key: cord-023239-06a03o14
authors: nan
title: II. Topic Sessions
date: 2016-06-10
journal: Pediatr Pulmonol
DOI: 10.1002/ppul.23455
sha: 
doc_id: 23239
cord_uid: 06a03o14

nan

Although the majority of children with asthma achieve symptom control on low or moderate doses of maintenance inhaled steroids, there is a small proportion that remain uncontrolled despite high doses of prescribed maintenance therapy. These children are prescribed treatments equivalent to stage 4/5 of the British Thoracic Society (BTS) guidelines for asthma management, and either need at least this amount of therapy to achieve control, or have persistent symptoms and frequent exacerbations despite maximal treatment. Children with poor control despite maximal prescribed therapy have Problematic Severe Asthma 1 . However, the reasons for poor control may be very varied and can broadly be divided into two sub-categories. The first, "Difficult Asthma" is the term used to describe patients whose asthma is difficult to control because of a failure to address the basics of asthma management, an incorrect diagnosis has been made, or there has been a failure to address associated comorbidities. Underlying reversible and modifiable factors that can result in poor control include poor adherence, unfavourable environmental exposures such as tobacco smoke and aero-allergens to which the patient is sensitised, poor inhaler technique and psychosocial issues 2 . If modifiable factors are successfully identified and addressed, then control can be achieved in children with Difficult Asthma without the need for escalating therapy or additional invasive investigations. A multidisciplinary team (MDT) is critical to enable modifiable factors to be identified and addressed in children with Difficult Asthma. The team must include specialist respiratory nurses, a psychologist, pharmacist, physiotherapist and medical staff. Significant resources are therefore required to manage paediatric Difficult Asthma optimally and only specialist centres should be tasked with the assessment of these patients. Although this may have an impact on healthcare resources, long term benefits for lung health are significant. The second sub-category of children that have poor asthma control despite maximal therapy are those with true Severe Asthma. These patients remain with persistent symptoms, or can only be controlled on maximal doses of maintenance therapy, often including oral steroids, AFTER underlying reversible or modifiable factors have been identified and addressed 3 . Importantly, more than half of all children with Problematic Severe Asthma have Difficult Asthma because of underlying modifiable or reversible factors preventing asthma control 4 . Therefore, the overall approach to managing a child with Problematic Severe Asthma includes an initial step to identify and treat Difficult Asthma, and if symptoms persist after this, true Severe Asthma can be confirmed, which requires additional investigation and management 5 . Very clear criteria and definitions that allow distinctions between Difficult and Severe Asthma have been specified for both adults and children aged six years and above by the European Respiratory Society and American Thoracic Society 3 . An important point to consider when faced with a child that has poor asthma control despite maximal doses of prescribed maintenance therapy is that once above a threshold of treatment (>800mcg/day or equivalent of budesonide), the child should be referred to a specialist for further management. The National Review of Asthma Deaths in the UK identified 20% of asthma deaths occurred in patients who should have been referred to a specialist for management of problematic asthma 6 .

The modifiable factors that result in a child having Difficult Asthma may be identified extremely efficiently if the MDT approach described is adopted. However, what remains equally important is the continuing assessment and follow-up of patients with difficult asthma in order to ensure:

1. Maintenance therapy is reduced to the minimal amount needed to achieve control 2. Symptoms do improve after all modifiable factors have been addressed, and there is no progression to true severe asthma À either after short term follow-up or in the longer term 3. The basics of inhaler technique / device / adherence / allergen exposure are all being maintained A retrospective analysis of follow-up of children with difficult asthma for up to six years revealed that those in whom underlying modifiable factors were identified and addressed had an improvement in lung function and reduction in exacerbations over time, while being able to reduce maintenance dose of inhaled steroids such that the majority fell below the threshold for problematic severe asthma 4 . However, there was a large drop out in the number of patients that could be traced for the full six years, highlighting the need for better prospective longitudinal data of outcomes for children with difficult asthma. These missing data are essential in light of recent cohort studies that have followed children with severe asthma to adulthood and shown the irreversible reduction in lung function and prevalence of COPD 7 .

Asthma is one of the most common chronic diseases in children, with a high prevalence in many developed and developing countries. Worldwide prevalence of asthma in children varies from 1.6-36.8% according to the International Study of Asthma and Allergies in Childhood (ISSAC) study.

(1) Despite its high prevalence, information about the prevalence of severe asthma in children is unknown, particularly in countries in transition. Some estimates come from different studies that have shown that the prevalence of severe asthma in a general population is approximately 0.5-5% among children with asthma, however its true prevalence in a low-income country is unknown. (2) (3) (4) According to ISSAC phase III, the centers with the highest prevalence of severe asthma symptoms were mostly from English language countries, Latin America, Africa, the Indian subcontinent and the Eastern Mediterranean. (5) Lack of control of the disease has been attributed to various factors such as low accessibility to basic medications, weak healthcare services, poor compliance with prescribed therapy, lack of asthma education, and social and cultural factors.

In general, asthma in both children and adults represents a significant problem in public health given the reduced quality of life, school or work absenteeism and increased healthcare costs, especially in countries in transition. In addition, asthma severity and control in childhood are of particular importance as they have been shown to translate into asthma morbidity in adulthood. (6) Practical guidelines addressing the management of severe asthma in children have pointed out various aspects important in the development of this condition: medication issues, the environment, asthma education, comorbidity, and psychological problems. Worldwide, but particularly in countries in transition, both intrinsic (race, ethnicity, weight) and extrinsic (exposure to allergens, indoor or outdoor pollutants) factors may overlap in a single child to enhance or diminish asthma control and severity. Different to many developing countries from other continents, asthma is highly prevalent in Latin America. Moreover, ISSAC phase III showed that asthma prevalence in this region is still on the rise. Furthermore, evidence suggests that poorly controlled asthma in some areas of Latin America leads to significant economic costs attributed to emergency and unscheduled visits, and high mortality rates from asthma. (7) Similar to other regions, asthma control is not obtained in most patients, despite available management guidelines and evidence of ICS as controllers. Several surveys have shown that close to 2.4% of all patients met all the GINA criteria for total asthma control, proposing under-recognition of uncontrolled asthma, underuse of appropriate controller treatment, inadequate patient education, and patient denial as possible explanations. (8) Also, several risk factors such as poverty, environmental factors, diet, genetics, vitamin D deficiency and tobacco smoking have detrimental effects on asthma control. Cross-sectional data from 616 children with asthma in Costa Rica suggested that low serum vitamin D detected in children with mild to moderate asthma is associated with asthma severity. (9) Since the development of worldwide guidelines on the diagnosis and management of asthma, special attention on achieving and maintaining asthma control as the key goal in asthma treatment has been a priority. In clinical studies of children with asthma, satisfactory asthma control can be achieved and maintained in most patients by regular treatment with ICS. Nevertheless, large population-based surveys consistently show that poor asthma control is common in many children with asthma, despite ICS treatment. (10) Other several studies have shown a reduction in the number of hospitalizations caused by asthma in various countries in transition when effective preventive and controller measures are implemented, (11) mainly avoidance of risk factors, importance on the use of basic medications and patient education. Patients should be educated about the cause of asthma, what triggers the condition, how it should be monitored and managed and, importantly, the outcomes that can be expected and when to recognize lack of asthma control. Moreover, health professionals should also be educated regarding under-recognition and under-treatment of asthma, as patients or parents tend to deny the severity of symptoms. In a recent study performed in Costa Rica (12) , we aimed to examine trends in hospitalization and mortality due to asthma over a 15-year period (1997-2011) , in particular following a National Asthma Plan (NAP). This NAP consisted of education meetings at all major public health care centers, emphasizing early diagnosis, early treatment using ICS as first-line therapy for asthma control, early use of reliever medication to treat exacerbations, appropriate referral to specialists for asthma care, and avoidance of common allergen sources (e.g. dust-mite and cockroaches) or tobacco smoke. Concurrent with this program, general practitioners, pediatricians and internists were first allowed to prescribe ICS for asthma (only pulmonologists or allergists could prescribe ICS before 2003). As a result of the implementation of the NAP, the total number of asthma hospitalizations in Costa Rica in both children and adults decreased by approximately 53% over this period. In children younger than 10 years, hospitalizations for asthma were reduced by 57% in boys and 54% in girls between 1997 and 2011. In addition, the number of deaths due to asthma decreased by 80% over the 12-year period, with a more marked reduction occurring after implementation of the NAP. In parallel with the decrement in asthma hospitalization and mortality, the number of prescriptions for ICS (beclomethasone) increased by 129%.

In summary, asthma prevalence in deprived regions is high and shows increased severity. Reasons for inadequate asthma control in poor populations include low accessibility to effective controller medications, weak infrastructure of health services for the management of chronic disease, poor adherence to therapy, lack of educational approaches, and social, cultural and language barriers. However, recent studies have shown several alternatives to control its burden and improve outcomes. There is urgent need for more research into severe asthma, in particular in children in countries in transition.

It has now become a much used adage that asthma is not a single disease but rather multiple diseases which present with common symptoms [1, 2] . This paradigm has been fundamental in shaping the way we think about asthma and possible approaches to treatment and management strategies. If one is not treating a single disease when we talk about what is commonly known as the syndrome of asthma, then we need a more personalised medication strategy to treat these different syndromes. Alongside this acknowledgment of moving medicine towards more personalised treatment and management strategies, statistics and machine learning have been instrumental in helping us to shape the face of medicine by fostering engagement between clinicians, basic scientists, statisticians and mathematical modellers in order to attain a more unbiased approach to classifying different subgroups of patients using probabilistic models. The proliferation of genetic, molecular, clinical and biological data has made it necessary to use a cross-disciplinary approach to understanding the underlying mechanisms which precipitate distinct profiles of asthma and allergic disease during childhood.

Statistical analysis to understand subtypes of childhood wheezing The seminal paper by Martinez et al. [3] was the first to propose the existence of different subgroups of childhood wheezing. Based on visual assessment of patterns of wheeze during childhood using data from the Tuscan Children's Respiratory Study, they identified four groups of wheezers: "No Wheeze", "Transient Early Wheeze", "Late-onset Wheeze" and "Persistent Wheeze". This classification has been used as a classical basis for subsequent definitions of distinct subgroups of wheeze and has provided the building block for statistical pattern recognition-based methods to identify heterogeneous groups of children based on probabilistic modelling of the longitudinal profiles of asthma and wheeze over time. One such statistical technique is latent class analysis. Latent class analysis assumes that the longitudinal fluctuation observed in data is measured with uncertainty. Some of this uncertainty is due to random error, but another element of this uncertainty may be due to the existence of a subgroup or latent class which explains some of the heterogeneity in clinical measures which is not directly observed. Henderson et al. were the first to apply such models using a data-driven approach based on wheeze observations from the Avon Longitudinal Study of Parents and Children [4] . Using latent class analysis based on parental reporting of wheeze, this group identified two additional phenotypes to those identified by Martinez et al.: "Prolonged Early" and "Intermediateonset" wheeze. This classification has been replicated in other studies. [5] One of the caveats of basing these modelling strategies on parental reporting of wheeze is that parents may not be able to correctly ascertain a clinical diagnosis of wheeze [6] . In light of this, Belgrave et al. extended these methods by jointly modelling data from both parental questionnaires and general practitioner records which provided complementary data to give a more accurate measure of wheeze [7] . This model identified two classes of persistent wheeze: a "Persistent Controlled Wheeze" group and a "Persistent Troublesome Wheeze" group who had poorer lung function and more reactive airways compared to the other wheeze groups, including the "Persistent Controlled Wheeze" group.

Where Machine Learning begins and statistical modelling ends Identifying consistently defined and optimal numbers of subgroups of wheeze across different cohorts is challenging. Within the era of "big data" rather than focusing on traditional statistical methodology, the medical field is looking towards data science as a means to extract knowledge and meaning from the vast quantity of information provided by clinical data. To achieve this, both traditional statistical inference methods based on robust assumptions and machine learning models which are more amenable to data complexity, breadth and depth. Although there is overlap between the functionality of machine learning and statistics, the flexibility of machine learning is driven towards learning from data and integrating new information in order to update models and create more accurate models with better model performance. The programmatic focus of machine learning which incorporates vast amounts of computational power provides an excellent framework where tools traditionally used for statistical modelling would be unable to accommodate large, multi-scale datasets.

In the near future, the capability of machine learning to be able to learn from data interactively may facilitate computer-assisted reasoning in identifying subgroups of patients. Identifying such subgroups may be crucial in proposing effective personalised treatment strategies. Such an approach will also allow us to capitalise on the existent data. As data-transparency and data-sharing become more widespread in the global community, we will have a better understanding of the evolution of asthma and allergic diseases.

Research into identifying heterogeneous subgroups of asthma and allergic disease has reached crucial milestones. We have moved from a subjective approach to classifying subgroups of wheezers, whereby the clinician gives a clinical assessment or diagnosis of the most likely subgroup based on observed clinical history, and we are moving towards computer-assisted reasoning, whereby we can use new information to predict the most likely class assignment based on models derived from prospective data. Such reasoning would also allow us to model the evolution of asthma and allergic diseases in the future.

Populations of microbes (such as bacteria and yeasts) inhabit the skin and all mucosal surfaces. Healthy individuals host thousands of different types of bacteria and different body sites have their own distinctive communities, with estimates suggesting that 50%-90% of all the cells in the human body are microbes. The highest density and greatest diversity of bacteria is found within the gastrointestinal tract. Research suggests that the relationship between the microbiome and humans is not only commensal (a non-harmful coexistence), but is a mutualistic, symbiotic relationship with benefits for both (1) . Even though we live in such a "dirty" bacterial world, infections due to bacteria are relatively very rare in individuals with a competent immune system. The microorganisms that make up a microbiome perform a wide range of useful functions, such as fermenting unused energy substrates, educating the immune system, preventing growth of pathogens, regulating the development of organs such as the gut, producing vitamins for the host and producing hormones to influence host metabolism such as directing the host to store fats. In particular, specific microbe-host interactions are thought to be critical for inducing mucosal tolerance and immune regulatory cells such as Tregs. Why do we develop "tolerance" to the microbes living in us and on us? Perhaps we should consider tolerance as an alternative defense strategy. The continuous effort involved in destroying the microbes that surround us would impair organ function and require vast amounts of energy, which is not compatible with life. For this reason, it makes much more sense to have robust tolerance mechanisms that work in tune with potent effector responses, to ensure optimal host fitness. An intriguing question is that posed by the concept of the hygiene hypothesis in that altered exposure to microbes may influence the induction of tolerogenic immune responses, thereby making individuals more susceptible to react aggressively to nondangerous encounters with antigens such as allergens.

The balance between immune tolerance and inflammation is regulated through the crosstalk between epithelial and immune cells with the microbiome involving many signaling pathways and molecules. Direct contact with bacterial-associated structures can activate receptors (e.g. TLRs) on host cells, which induce signaling cascades resulting in both innate and adaptive polarized immune responses. The microbiome is also metabolically active and microbial metabolites have been shown to exert significant effects on host immune signaling networks (e.g. SCFAs and biogenic amines). The biogenic amine histamine can promote either pro-or anti-inflammatory effects depending on which of its four receptors are activated (2) . Some, but not all, commensal bacteria express histidine decarboxylase (the enzyme needed to convert histidine to histamine). Lactobacillus saerimneri 30a produces high levels of biologically active histamine and feeding this strain to mice resulted in a deterioration in health, particularly in histamine receptor 2 knock-out mice (3). Significant efforts are underway to determine the positive and negative health effects associated with production of histamine by the microbiota (4). Abnormalities in microbiome composition and/or metabolic activity have been shown in a wide range of disease states including type-2 diabetes, obesity, inflammatory bowel disease, colorectal cancer and allergies. Efforts to use microbiome-associated therapeutics (e.g. probiotics) have clearly shown beneficial effects in animal models, with inconsistent findings in humans probably due to differences in the bacterial strains used. One probiotic bacterium that has shown consistent immunoregulatory effects in murine models and humans is B. longum subsp. longum 35624. Murine models have demonstrated that oral consumption of this strain results in the induction of Treg cells and these Treg cells dampen NFkB activation, preventing excessive inflammation induced by Salmonella infection (5, 6) . Similarly, in humans, oral consumption induces Treg cells, which is associated with increased secretion of IL-10 by peripheral blood cells (7) . Interestingly, this strain reduces systemic pro-inflammatory biomarkers in patients with psoriasis, IBS patients with chronic fatigue syndrome and patients with ulcerative colitis (8) . The mechanism involved includes the recognition of this bacterium via TLR-2/6 and DC-SIGN by myeloid dendritic cells and TLR-9 by plasmacytoid dendritic cells, resulting in changes in dendritic cell cytokine secretion and the production of metabolites such as retinoic acid (9) . However, these effects and mechanisms are not seen even with closely related bacterial strains, suggesting that the careful selection of microbes is essential for the future clinical development of immunotherapeutic microbes for allergy and asthma. Overall, it can be concluded that the vast majority of microbes, which interact continuously with the host, are not bad. Certain specific microbes can positively influence the host, while there is a minority that can have negative effects on the host. GWAS findings are based upon association p-values below 5 Ã 10 À8 , socalled "genome-wide significance", as well as replication in independent populations. This generally requires very large sample sizes and in order to obtain these, a 'Team Science' approach has been used where several studies have combined their data in meta-GWAS. The largest GWAS on asthma to date combined data from 23 different studies involving more than 26,000 individuals from the GABRIEL consortium and identified 6 genome-wide significant asthma loci.(1) Similar meta-GWAS have been conducted, for example by the EAGLE consortium, revealing a number of susceptibility loci for asthma-related traits, including FeNO,(2) eczema,(3) and allergic sensitization.(4) It could be expected that the large heterogeneity in disease phenotypes introduced by combining many different studies in meta-GWAS would preclude valid discoveries. Nevertheless, GWAS on asthma and the related traits have resulted in identification of relatively few, but robust, loci with more consistency between studies compared to previous candidate gene studies. One example of this is the first large-scale GWAS on allergic sensitization.(4) By meta-analysis of data from 16 different studies, it included a discovery phase of approximately 5,800 cases and 10,000 controls and a similar-sized replication phase. Allergic sensitization was assessed objectively and defined by elevated levels of allergen-specific IgE and/or a positive skin prick test. This study identified 10 loci associated with allergic sensitization at the genome-wide significant level and with robust replication. Simultaneously, another large GWAS was performed on allergic symptoms including approximately 54,000 individuals. (5) In spite of the large phenotype differences between the two studies, there was a high agreement in results with all of the 10 genome-wide significant loci from the sensitization study also showing strong association in the study on allergic symptoms, and previous GWAS findings were confirmed. There has been some disappointment with the results from GWAS. The identified loci only explain a minor part of the heritability, and the susceptibility variants identified in GWAS are mainly common variants with relatively small effect sizes (often with odds ratios around 1.1 per risk allele) with no clinical relevance on the individual level. (1, 4) On the other hand, GWAS have identified novel and robust susceptibility loci, with the potential to provide important understanding of disease mechanisms. Also, comparison of results from GWAS on different diseases and traits have increased the understanding of the mechanistic relationship between these, for example the relationship between allergic sensitization and asthma,(4) between allergen-specific IgE and total IgE levels, (4) and between atopy and autoimmunity. (3) (4) (5) Larger, consortium-based studies on asthma and the related phenotypes are ongoing and are expected to identify many novel susceptibility loci. Novel loci discovered from these larger studies are likely to have even smaller effect sizes than the ones previously found but, from the perspective of understanding disease pathology, each novel locus may potentially pinpoint a novel mechanism and a potential treatment target. Furthermore, the era of genome-wide nucleotide sequencing applied on gene expression-and epigenome-profiling has brought new possibilities of combining GWAS data with data from large public 'omics repositories. These data will increase the usefulness of GWAS data by providing understanding of functional effects related to susceptibility loci, and future GWAS on asthma and related diseases will be a part of integrated approaches to discover how different molecular layers modulate the genetic effect on disease, and will thereby be a central component in the attempt to tailor and improve medical treatment. Asthma is a highly heterogeneous disease probably consisting of several subtypes of disease associated with different functional mechanisms. Genetic loci may be involved in specific disease mechanisms and thereby help understanding this heterogeneity. For example, the strongest asthma locus identified in GWAS, the 17q12-21 locus, seems strongly associated with an asthma phenotype characterized by onset in early childhood (1) and recurrent, severe exacerbations (6) and was stronger associated with asthma than allergic rhinitis. (5) In contrast, another locus at chromosome 11q13 has been associated with multiple allergy-related phenotypes, including allergic sensitization,(4) allergic symptoms,(5) eczema,(3) and asthma, suggesting a different, allergy-related, disease mechanism. The heterogeneous nature of asthma suggests that an alternative to increasing sample size in genetic studies is to focus on more specific phenotypes. Such phenotypes are likely closer associated to specific mechanisms and the genetic substrate and might therefore increase study power. This was demonstrated by a GWAS focusing on a specific asthma phenotype characterized by onset in early childhood and recurrent, severe exacerbations. (6) In spite of the relatively small sample size, this study resulted in association results of the same magnitude as previous much larger GWAS (1) and with much larger effect sizes, particularly for the children with the highest number of exacerbations. One novel asthma gene, CDHR3, was identified, and it was confirmed, in a collaborative effort involving several birth cohort studies, that the CDHR3 locus was strongly associated with asthma exacerbations in the first years of life, both in individuals of European and non-European ancestry. These results highlight the potential of future genetic studies focusing on more homogenous phenotypes. One important future step is the translation of genetic associations to disease mechanisms. A major limitation of GWAS is that they often merely identify a susceptibility locus without any clear relationship to a specific gene or biological function. Two examples of this are the 17q12-21 and 11q13 loci mentioned above, where the underlying mechanisms are still poorly understood several years after their discovery, even though these loci are strong and probably central to the pathogenesis of asthma and allergy. One example of a GWAS discovery where the functional mechanism might have been identified is CDHR3. In the discovery study (6) , it was suggested that the association to asthma was caused by a specific functional variant affecting surface expression of CDHR3. A later study reported that CDHR3 functions as a rhinovirus C receptor and showed that the functional variant associated with asthma exacerbations increases rhinovirus C binding and replication. (7) This potentially explains the underlying mechanism of this locus and identifies a target for future asthma and virology research. Another major future challenge is to understand how genetic susceptibility interacts with environmental factors. Gene-environment interactions are not accounted for in normal GWAS and that might be one reason for the large heritability not explained by GWAS findings. One important environmental risk factor for childhood asthma and other wheezing disorders is viral infections, and focusing on this environmental factor might be a tool to understanding mechanisms of asthma genes. (8) As an example, children with 17q12-21 risk variants seem more susceptible to rhinovirus infections, (9) and the finding that CDHR3 seems to be a rhinovirus C receptor (7) indicates that children carrying CDHR3 risk variants will have a specific susceptibility to rhinovirus C infections, a hypothesis that is currently being tested. Only a few genome-wide gene-environment interaction studies have been performed, and the results of these have generally been disappointing without convincing findings. There are many inherent challenges in such studies. First, they might require even larger sample sizes than normal GWAS, and exact information on environmental exposures is difficult to obtain in such large-scale studies. Furthermore, the effect of a specific environmental exposure can be difficult to disentangle from that of other related environmental factors. An alternative approach is to perform cell or animal models where specific exposures can be controlled.(8) A recent study investigated the potentially protective effect of endotoxin and farm dust exposure in a mouse model of house dust mite-sensitized asthma.(10) It was found that A20 was an important mediator of the protective effects of endotoxin exposure, and this was validated in human bronchial epithelial cells. Furthermore, a potential modifying effect of A20 was supported by 'look up' of SNPs located near the human TNFAIP3 gene using data from an earlier genome-wide interaction study. This potential gene-environment interaction needs to be replicated, but this study exemplifies how mechanistic studies targeting specific environmental exposures and the use of experimental models can facilitate identification of genes involved in gene-environment interactions.

In conclusion, improved understanding of the genetic architecture of asthma and other childhood wheezing disorders will require a combination of GWAS focusing on more homogeneous subtypes of disease, geneenvironment interaction studies in birth cohorts and in cell models, and integration with other types of omics data. This challenge can only be overcome by a 'Team Science' approach bringing together many studies to provide sufficient statistical power and bringing together researchers from many disciplines to translate clinical associations to mechanistic understanding. Such studies present great challenges but also the opportunity to understand asthma pathogenesis and heterogeneity, and ultimately to improve prevention and treatment of disease. Recently, WHO definitions have changed to classify children with lower chest indrawing as having pneumonia rather than severe pneumonia and recommending treatment with oral antibiotics as ambulatory cases. [1] However, a recent meta-analysis reported that no single clinical feature is sufficient to accurately diagnose radiological pneumonia and that the WHO recommended diagnostic signs alone lack sufficient sensitivity or specificity, particularly for identifying children who need antibiotics. [2] Radiological diagnosis of pneumonia has relied largely on changes on chest X-ray, principally consolidation or interstitial infiltrates. [3] However, chest X-rays are subject to variable interpretation, expose a child to ionizing radiation and require infrastructure and skill to do. Recently, chest ultrasound has been suggested as a feasible imaging modality for diagnosis of childhood pneumonia. Ultrasound has several advantages including that it can be used as a point-of-care test, can be taught to non-radiologists, is quick to perform and does not involve exposure to radiation. Initial studies suggest that it has high sensitivity and specificity for pneumonia compared to chest X-rays. [4, 5] Diagnosis of the etiology of pneumonia remains challenging as bacteremia is rare, distinguishing colonizing from pathogenic organisms may not be possible on respiratory specimens and co-infections are common. Improvements in specimen collection and improved molecular techniques for detection of organisms have enabled more accurate detection of organisms, however ascribing etiology may be difficult unless the organism is invariably pathogenic. Advances in specimen collection include the use of induced sputum in infants and young children, which provides a better specimen for detection of specific pathogens such as B. pertussis or M. tuberculosis. [6] Urine antigen detection has not proven to be useful for pneumococcal pneumonia or for pulmonary tuberculosis in children. [7, 8] For induced sputum, testing of sequential, repeat specimens provides a higher yield for pathogens such as M. tuberculosis. [9] Careful attention to specimen collection methods and use of different specimens may maximize the yield especially in the context of new sensitive molecular detection techniques. [10] With the availability of improved tools for etiological diagnosis, and with better vaccine coverage for conjugate vaccines, including pneumococcal conjugate vaccine, viral pathogens especially RSV and other bacteria, such as S. aureus or pertussis, are emerging as prominent causes of childhood pneumonia. [11] [12] [13] In areas of high TB prevalence, M. tuberculosis has been reported to be associated with acute pneumonia in children, with culture confirmed disease occurring in approximately 8% of cases. [14] However, better tools for detection of potential pathogens have also provided data on the complexity of etiology, with several potentially pathogenic organisms frequently identified in a single pneumonia episode. Further delineation of the interactions between different organisms and pneumonia pathogenesis is needed. Asthma affects as many as 334 million people of all ages in all parts of the world and is the commonest long-term respiratory condition affecting children in developed countries, the prevalence and morbidity varying by ethnic group 1 . Accurate diagnosis and effective management of respiratory diseases such as asthma requires objective measures of lung function, but reliable use of such measures is only possible if appropriate normative ranges are available to distinguish the effects of disease and treatment from those of growth and development.

Evidence for ethnic differences in lung function Ethnic differences in lung function have been well documented 2 . In the past, attempts to interpret observed ethnic differences in lung function were often confounded by selection bias related to use of small population samples that were not necessarily representative or generalizable, use of different methods, equipment and quality control (QC) criteria, failure to adjust for other important determinants of lung function, including socio-economic circumstances and/or inappropriate statistical analyses. In recent years, many of these problems have been addressed by applying standard methodology, inclusion criteria and QC to large, ethnically homogenous groups. Current research shows that after adjusting for age, sex and standing height, forced expired volume in 1 sec (FEV 1 : a measure of airway calibre) and forced vital capacity (FVC: a measure of lung size) are both reduced by approximately 14% in individuals of African ancestry (Black) across the entire life span when compared with those of European ancestry (White) [3] [4] [5] [6] . Similar though smaller reductions have been observed among South Asian (from Indian subcontinent) [7] [8] [9] and South-East Asian (e.g. China, Thailand, Malaysia, etc) 6 subjects. Since these "ethnic" reductions in FEV 1 and FVC are generally proportional, the FEV 1 /FVC ratio, which is the most commonly used outcome to assess airways obstruction, is usually independent of ethnic background [5] [6] [7] , suggesting that there are no structural or functional ethnic differences in lung design. Thus the observed ethnic differences in lung function appear to be primarily limited to lung size rather than airway or dynamic respiratory characteristics. However, the same adjustment factor cannot be used for all lung volume outcomes. For example, there is evidence that the lower FVC found among Black children can be attributed at least in part to a relatively high residual volume, suggesting that factors such as anatomic differences in diaphragmatic position or respiratory muscle strength might contribute to some of the observed differences 5 . Furthermore, lung function indices that are internally adjusted for the size of the individual's resting lung volume, such as the Lung Clearance Index (LCI: a measure of gas mixing efficiency) 10, 11 or specific airways resistance (sRaw: a measure of airway calibre adjusted for lung volume) 11 , do not appear to be influenced by ethnic background. Nevertheless, since larger sample sizes will be required to confirm these findings, data interpretation of LCI and sRaw from non-White subjects should currently be undertaken with caution.

Recently, the Global Lung function Initiative (GLI) collated results from >74,000 healthy non-smokers aged 3-95 years to create the first allage, multi-ethnic reference equations for spirometry with appropriate age dependent lower limits of normal 6 . Prediction equations were derived using the LMS method, which allows simultaneous modelling of the mean (mu), the coefficient of variation (sigma) and skewness (lambda) of the distribution, and reference equations were derived for Caucasians (White); African-Americans (Black), North-and South-East Asians. These equations enable assessments to be evaluated over the entire age range using a single reference data set, thereby avoiding the errors that can occur when switching between equations, particularly during the transition between paediatric and adult care 12 .

Defining ethnicity Ethnicity is extremely difficult to define. Self-assigned ethnicity may differ from observer-assigned ethnicity and in certain countries it is against the law to record ethnic origin for any purpose. Furthermore, in recent censuses in both the UK (2011) and US (2010), mixed-race populations have been shown to be the fastest-growing ethnic group. Thus, classifying ethnicity may become an increasingly complex task! Could differences in body proportions explain the ethnic differences in lung function? Standing height is a major determinant of lung volumes, reflecting the fact that lung size is adapted to our metabolic needs. However this is not ideal since the size of the lungs is more closely related to thoracic size than leg length and differences in body proportions may underpin much of the observed ethnic variation in lung function. The Size and Lung function In Children (SLIC) study was designed to improve normative reference ranges for lung function by taking differences in body physique into account to facilitate early diagnosis and treatment of lung disease in all children, irrespective of ethnic background 7 . However, of the numerous additional anthropometric measurements undertaken to quantify body physique, only sitting height and chest width significantly contributed to the prediction of spirometric lung function. Chest dimensions and lean mass also significantly predicted FEV 1 and FVC within each ethnic group, but did not affect differences between groups. The persistence of ethnic differences after adjustment for sitting height, chest dimensions, body composition and socio-economic factors may reflect the fact that some factors affecting chest size such as diaphragmatic position or muscle strength cannot be assessed by anthropometry, and emphasises the importance of taking ethnicity into account when interpreting spirometry data 7 .

While some studies have shown an association between socio-economic conditions (SEC) 13, 14 and lung function and suggested that this is a key factor in explaining ethnic differences in lung function 15 , there is increasing evidence that the contribution of SEC to variability of lung function is very small except under the most adverse of conditions 7, 14, 16 . A recent study in India 8 , using identical equipment and techniques as those used in the SLIC study found that while average FEV 1 and FVC in urban Indian children were similar to those in Indian children residing in the UK, they were significantly higher than in semiurban and rural Indian children (by $6% and 11% respectively). These results probably reflect the marked differences in the degree of social deprivation between the UK and India 7,8 and suggest that there may be a threshold effect of poverty on lung function. Adjusting for sitting height has been shown to reduce the contribution of SEC to ethnic variability 7, 14 .

The use of inappropriate reference equations and misinterpretation can lead to serious errors with respect to both under-and over-diagnosis. In the past, attempts to correct for ethnic differences, if made at all, tended to apply the same fixed adjustment factor across all ages 2 , all ethnic groups, both sexes and all spirometric outcome measures, an approach now shown to be oversimplistic 14, 17 .

In addition to errors relating to ethnic differences in lung function, misdiagnosis may also occur when fixed cut-offs, such as 80% predicted FEV 1 or 0.7 FEV 1 /FVC are used; particularly in young children and elderly adults. While %predicted has historically been used to interpret lung function results, z-scores are more appropriate as they take into account the between-subject variability of measurements for any given outcome at any given age, as well as the predicted value 17 . Similarly, use of <0.7 as a fixed threshold for abnormal FEV 1 /FVC can lead to gross under-diagnosis of airway obstruction in the young and over-estimation in the elderly 17 .

With exception of extreme deprivation, ethnic differences in lung function cannot be explained by socio-economic factors. After adjusting for confounders, genetic factors do contribute to ethnic differences in body physique and lung function. Given the marked ethnic differences in lung function, the magnitude of which are similar across the entire life span, it is essential that lung function results in children are interpreted using ethnic specific equations whether in clinical practice or epidemiological research. Although GLI-2012 do not and never will cover all ethnic groups, appropriate use of age, height and sex adjusted values of FEV 1 /FVC ratio derived from these equations (which is consistent across all ethnic groups) will facilitate better identification of airway obstruction in children irrespective of ethnic background. Failure to adjust lung function for ethnic differences will result in overestimation of both the severity of airway obstruction and the severity and prevalence of restrictive lung disease.

It is now recognised that asthma is a complex, heterogeneous disease. Therefore, we need to move away from offering a single approach to management for all children and consider the identification of individual phenotypes for each child to enable optimal treatment and control. The specific facets of the disease that need to be considered and defined in each child include: i. An accurate description of symptom pattern (exacerbations alone, or persistent symptoms with and without exacerbations), ii. The nature of airway inflammation (eosinophilic, neutrophilic or non-inflamed), iii. The type and degree of structural airway changes (remodelling). Although asthma control can be achieved in most children with low-moderate doses of inhaled steroids, we remain unclear about the choice of optimal maintenance therapy for each child. How should a decision between regular inhaled steroids, or leukotriene receptor antagonists be made? When additional therapies are required to achieve control, a scientific rationale for add-on therapies also is unavailable. The majority of decisions about therapies are made using a "trial of treatment" approach 1 . If one approach is not successful, then another is adopted without a clear thought process dictating choice of treatments. It is apparent that we need to change our current one size fits all approach to the management of asthma in children. Although perhaps less important for children with mild or moderate disease, this becomes extremely important when we consider those with more severe disease.

Personalised medicine for severe asthma Although atopy, airway hyperresponsiveness, eosinophilic inflammation and remodelling are the cardinal pathophysiological features of paediatric asthma, we now know that each of these features can be present to very different degrees in the individual child 2-4 . Pathology has been most studied in children with severe disease, and although features such as eosinophilic inflammation and increased airway smooth muscle represent the patients as a group, there is huge overlap between children with and without asthma, and a huge spread of severity of these features within the group of children with severe asthma 2 . This within-group variability means assessments need to be made in the individual before deciding on the most appropriate add-on therapy. A proposed approach to identifying the "individual phenotype" in children with severe asthma is to split response to steroids into different domains (Bossley C et al. J Allergy Clin Immunol 2016, In Press). Not all children with asthma have abnormal lung function, not all have inflammation or remodelling, the response to a trial of systemic steroids can therefore be split into the following: i. Lung function response, ii. Inflammation response (exhaled nitric oxide and sputum eosinophils) and iii. Symptom response. We have analysed this approach in 54 patients with severe therapy resistant asthma and shown a similar proportion of children (approx. 40%) responded to systemic corticosteroids in each domain, but there were no reliable predictors of a response pattern. Furthermore, only 13% were complete responders (response in all domains), 15% were nonresponders (no response in any domain) and the majority (72%) were partial responders (response in >1 domain). These data highlight that childhood severe asthma is heterogeneous and a complete response in symptoms, inflammatory and physiological parameters is rare (Bossley C et al. J Allergy Clin Immunol 2016, In press). Individual response patterns to systemic steroids need to be applied in the future to guide the choice of addon therapies in each child as a step towards achieving personalised medicine. Subsequently, this multi-domain approach was applied clinically to identify characteristics of responders to the add-on therapy Omalizumab. It became apparent that only those with a positive response in the inflammation domain (a significant reduction in exhaled nitric oxide after a trail of systemic steroids) had a beneficial response from Omalizumab 5 .

As increasing numbers of add-on therapies become available for use, specifically in the context of severe asthma, we need to better define pathophysiological phenotypes in individual patients and we need to understand the mechanisms mediating disease in children. In addition, we now need to incorporate individual genotypes into our definition of phentoypes to more accurately define treatment responses 6 , as has been successfully done for response to montelukast in preschool wheeze 7 . Not only will this individualised approach allow us to discover novel molecular targets that will be effective specifically in the paediatric population, but it will also enable us to objectively choose the best therapy tailored to the individual child.

Europe consistently report that 20-40% of children with a recognized asthma diagnosis require acute medical care yearly. This is a reflection of the inadequacy of the available treatment options for prevention and treatment of exacerbations, suggesting that asthma with severe exacerbations may represent a distinct subtype of disease and demonstrating a need for improved understanding of its pathogenesis. Asthma heritability is estimated at 50-80%. A number of genes have been verified in genome-wide association studies (GWAS), but still the genetic background of asthma remains poorly understood. Larger GWAS may reveal new susceptibility loci with smaller effects, but due to the large heterogeneity of asthma (1), an alternative strategy may be to increase phenotype specificity. A specific phenotype is likely to be closer related to a specific pathogenetic mechanism and may therefore markedly increase the power of genetic studies. This was the background for a GWAS focusing on a particular asthma phenotype defined by repeated, severe exacerbations in early childhood. (2) A sufficient number of cases were obtained by identification of children with recurrent acute hospitalizations for asthma between 2 and 6 years of age in the Danish National Patient Register, and extraction of DNA from dried blood spots from the Danish Newborn Screening Biobank. The case phenotype was rare with only 1/1000 of children born in Denmark between 1982 and 1995 fulfilling the inclusion criteria. The final study comprised 1,173 children with repeated hospitalization and 2,511 healthy controls.

Five loci were identified with genome-wide significant association (Pvalue < 5 Ã 10-8): GSDMB, IL33, RAD50, IL1RL1 and CDHR3. Even though the sample size of this GWAS was less than one fifth of the largest published GWAS on asthma from the GABRIEL consortium,(3), it identified a similar number of genome-wide significant loci with similar statistical significance. The effect estimates were remarkably high with odds ratios between 1.4 and 2.3 per risk allele, compared to the odds ratios around 1.1-1.2 usually found in GWAS on complex traits. Further increasing phenotype specificity by stratified analysis in the 358 children with the highest number of exacerbations resulted in a further increase in effect estimates, with odds ratios between 1.6 and 2.7 per risk allele, and strong statistical significance. These strong results demonstrate the value of focusing on a more specific phenotype in asthma genetics. Furthermore, it indicates that studies on this severe and early-onset phenotype is a "cost effective" approach whereby methodologies requiring large resources and/or strong statistical power can be applied in a limited number of individuals and still provide powerful results. The top-locus in this study, at chromosome 17q12-21 near GSDMB/ ORMDL3, has consistently been associated with childhood onset asthma. (3) (4) (5) The effect size in the present study was remarkable with an OR of 2.3 (P-value ¼ 1.3 Ã 10 À48 ) and increasing to 2.7 for the children with highest number of exacerbations. This suggests an important role for this locus in severe exacerbations in early childhood in line with a previous report from the COPSAC 2000 birth cohort study.(5) CDHR3 had not previously been associated with asthma or any other disease. The association with asthma was replicated in the publically available GABRIEL results (3) Protein structure modeling showed that the risk-associated variant is located at the interface between two domains where it could be involved in disulfide rearrangement and interfere with inter-domain stabilization, overall protein stability or conformation, in agreement with the observation in experimental studies of altered cell surface expression. (2) The biological function of CDHR3 is unknown but it seems to be a highly plausible asthma gene. It belongs to the cadherin gene family of transmembrane proteins involved in several cellular processes including epithelial polarity, cell-cell interaction, and differentiation (6) and is highly expressed in the lungs. Also, other members of the cadherin family have been associated with asthma and related traits, including E-cadherin. (7) Recently, it was reported that CDHR3 functions as a receptor for rhinovirus C. (8) CDHR3 was differentially expressed in epithelial cells susceptible to rhinovirus C infection compared to unsusceptible cells, and its expression on epithelial cells enabled rhinovirus C binding and replication. Importantly, introduction of the risk variant at rs6967330 by transfection resulted in 10-fold increased RV-C binding and progeny yield compared to the non-risk variant. These data provide strong evidence that CDHR3 is a rhinovirus C receptor and that the association signal in the CDHR3 gene might result from increased susceptibility to RV-C infections. This finding is in line with the exacerbationrelated phenotype from the discovery GWAS, since rhinovirus C has been reported to be the most common viral trigger of severe asthma exacerbations in children and associated with more severe disease and higher rates of hospital readmissions compared to other respiratory viral infections.(9,10) If correct, this would indicate that children with the CDHR3 risk variants are specifically susceptible to rhinovirus C infections compared to illnesses triggered by other viruses, a hypothesis that is currently being tested.

In conclusion, the strong results found in this GWAS on childhood asthma with severe exacerbations demonstrate the value of specific phenotyping in the search for asthma genes. Focusing on this extreme subtype of disease might reveal mechanisms that would not be revealed in studies of milder disease, but might also increase the understanding of general asthma mechanisms. Identification of CDHR3 as a risk gene might be one of the first examples where the underlying mechanism of an asthma GWAS finding is understood. Future studies of this gene may improve understanding and treatment of asthma exacerbations in childhood. The timing of bacterial colonization early in life is thought to be important for appropriate immune education and the transmission from mother to the fetus during pregnancy and birth is being better described. Cultures of meconium have shown diverse groups of Gram-positive and Gram-negative bacteria, possibly not all derived post-delivery. The development of the gut microbiome is a dynamic process and early colonization with Bacteroides and Bifidobacterium species might play a crucial role in the development of immune regulation (1) . Factors that can influence early life colonization include antibiotic treatment, method of delivery, maternal and infant diet and biodiversity in the home, surrounding environment and in family members. The gut microbiome increases in diversity during the first years of life. Germ-free mice, which are not exposed to live bacteria, display exaggerated TH2 and IgE responses, associated with diminished polarization of Treg cells. Monocolonization of the mice with specific microbes, but not all microbes, suppresses the IgE response and promotes Treg differentiation (2) . However, certain immunological changes, such as increased iNKT numbers in the mucosa, cannot be reversed following colonization of mice later in life (3). Interestingly, more severe allergic responses and anaphylaxis were observed in mice who received a microbiome transplant from allergic animals, suggesting that certain microbial species can actually promote allergic responses (4).

The immune system at birth is dominated by TH2 cells. However, the human fetus has a functional immune system at a relative early status of development comprising CD4þ and CD8þ T cells but also FOXP3þ Treg cells. One concept gaining support is that the developing fetus may become educated by whole bacteria or their genetic material that is provided via maternal serum. DNA from Bifidobacteria and Lactobacilli, two genera typically used as probiotics, are found in human placenta. In contrast, in utero exposure to potentially pathogenic bacteria such as Ureaplasma species leads to immune dysregulation commonly ending in fatal complications. Maternal consumption of probiotic-containing food components may reduce the risk for childhood allergic diseases and mouse models demonstrate a reduced risk of inflammatory bowel diseases. Epigenetic mechanisms may be critical since application of Acinetobacter lwoffii to pregnant mice reduced the airway hypersensitivity response of the offspring. The promoter region of IFN-g in CD4þ T cells of the offspring had high levels of histone-4 acetylation, associated with enhanced transcription, while the IL-4 promoter region had lower levels of histone-4 acetylation (5). Moreover, exposure of pregnant mothers to the farm environment, which have high levels of Acinetobacter lwoffii, was associated with DNA demethylation of the Foxp3 locus and methylation of the TH2-associated genes RAD50 and IL-13. Since gut microbiota composition during the first months of life seems to be important for development of appropriate immune regulatory networks and thereby influence later life disease risk, intervention with probiotics, prebiotics or synbiotics might be most effective at this age or even during pregnancy. Probiotics can be defined as live micro-organisms which, when administered in adequate amounts, confer a health benefit on the host. Notably, the definition of a probiotic does not differentiate between the wide range of potential health benefits and it is clear that not all probiotics will influence the immune system in the same way. Findings observed with one probiotic strain cannot be extrapolated to other probiotic strains. Current evidence does not indicate that the probiotics clinically tested to date reduce the risk of children developing allergy but there are significant differences between studies such as the use of different probiotic strains, different age groups and different endpoints (6) . Despite very poor quality of evidence, it has been suggested that there may be benefits in specific high risk groups, such as pregnant women at high risk of having an allergic child, in women who breastfeed infants at high risk of allergy and in infants at high risk of developing allergy. In general, probiotic-supplemented formula was found to be well tolerated and safe for infants. In conclusion, a better description of the bacterial strains and metabolites, which influence immune function, is required in order to allow for the improved design and selection of future probiotic strains for prevention and treatment of allergic disorders (7). People with cystic fibrosis (CF) are living longer lives than ever in the past. The median predicted survival in developed countries is now above 40 years of age and adults with CF are outnumbering pediatric patients in several regions. Various reasons may explain such improvement in life expectancy, including the establishment of CF-dedicated and multidisciplinary centers; greater attention to nutritional issues and use of pancreatic enzymes replacement therapy; airway clearance techniques tailored to individual needs and attitudes; infection control measures; use of antibiotics both chronically by inhalation and aggressively to treat pulmonary exacerbations; mucolytic and airway hydration therapies; and liver and lung transplantation (1, 2). On account of the overwhelming evidence that organ impairment begins very early, even in asymptomatic CF infants, there is now general consensus that at least some of these strategies of care should be implemented as soon as possible in order to prevent or delay irreversible structural lung damage. Indeed, this has possibly been the main argument in favor of CF NBS (3).

The strength of such argument has been tested by several studies and considering different approaches. Randomized studies À Only two randomized trials on newborn screening for CF have been completed (5, 6, 7). These evaluations need many years of follow-up and, given the high degree of evidence in favor of CF newborn screening presently available, further implementation of similar studies seems improbable and possibly non ethical.

Observational studies À Although most of these studies confirm clinical benefits from early diagnosis of CF, their results are hampered by several biases inherent to the methodological approach. The constant improvement in treatment and the consequent longer survival has an influence on the comparison of screened individuals and unscreened historical controls. On the other hand, examining the clinical evolution of screened infants and unscreened controls from different geographical areas but born in the same years may be affected by different care practices. Finally, ascertainment biases may also have an impact on the assessment of outcomes, as patients presenting clinically are likely to have more severe CF than those identified through screening or unscreened patients with very critical disease may have died before being diagnosed. Health economics studies À These studies use surrogate end-points, such as the quantity of treatment needed to remain healthy, and are based on the assumption that the optimal management offered to CF patients makes it harder to detect evidence of better clinical outcome in those diagnosed by screening. Late-diagnosed patients may show clinical pictures similar to those diagnosed early, but at the expense of a considerably heavier burden of care (8) .

Most of these studies have focused on respiratory and nutritional outcomes and on HTA assessments. Their overall results clearly point in the direction of a positive effect on height and weight, of longer survival and of health service savings in populations screened at birth for CF. Positive effects may also be obtained in several other domains, namely:

-The prevention of salt loss syndrome thanks to early beginning of salt supplementation -

The opportunity of surveying from birth the natural history of CF -A better understanding of the early stages of CF. -

The possibility of testing presymptomatic therapeutic strategies, both conventional and patient targeted. Cystic Fibrosis (CF) is associated with the presence of two CF-causing mutations, one in each parental CFTR gene, resulting in the absence or abnormality of the CFTR protein and defect in electrolyte transport across epithelial membranes, the most well known being sweat chloride >60 mmol/L. Even in 2016, CF remains by essence a clinical diagnosis. The wide range and severity of symptoms/ organs involved between and within individuals makes it a clinical decision as to whether or not a person should be managed as a CF patient. This is especially the case in a small number of ambiguous or atypical cases.

In 1998, a first diagnosis consensus listed criteria for CF diagnosis: (i) one or more of the phenotypic features of the disease or (ii) CF in a sibling or (iii) a positive immunoreactive trypsin (IRT), in association with at least one other feature, including a positive sweat test result on two occasions, a CF-causing mutation in each CFTR gene or an abnormal nasal potential difference (NPD) (1). This consensus statement of the US Cystic Fibrosis Foundation was later modified in Europe based on the concept of CFTR dysfunction included in the diagnosis algorithm (2) . Most atypical CF patients are diagnosed based on sweat tests and/or genetic analysis. These "mild CF" individuals usually present later in their lives with pancreatic sufficiency and milder respiratory disease. They frequently carry wide clinical spectrum mutations. The difficulty occurs when patients present with clinical symptoms suggestive of CF and a sweat chloride value in the intermediate range (30-59 mmol/l). Among these subjects, those with abnormalities in NPD measurement or 2 identified CFTR mutations have, on average, more severe lung disease than the remaining subjects, although their disease symptoms are milder than those in subjects with a sweat chloride concentration above 60 mmol/L. Therefore, from a physician's and also from a patient's perspective, these individuals must be differentiated from subjects with the classical life-shortening form of CF. The remaining cases, termed "possible" or "borderline", are difficult to classify because there is poor agreement between sweat test results and prognosis on the one hand and the frequent presence of at least one CFTR mutation of uncertain clinical relevance on the other. The term "CFTR-related disorders" (CFTR-RDs) designates these varied conditions, which include multi-system disease and monosymptomatic disorders associated with CFTR dysfunction but which do not fulfill the diagnostic criteria for CF (3). This encompasses 3 main clinical entities with CFTR dysfunction: CBAVD (congenital bilateral absence of the vas deferens), acute recurrent or chronic pancreatitis and disseminated bronchiectasis.

Diagnosis of CBAVD is based on impalpable vas deferens on scrotal examination. Even if in a proportion of men scrotal palpable vas deferens are present, surgical exploration reveals a fibrous cord or a non-permeable duct. CBAVD males have either a severe and a mild/variable (88%) or two mild/ variable (12%) CFTR mutations (4) . Approximately 34% of men with CBAVD have a CFTR mutation in one gene and the splicing variant IVS8-5T on the other allele, often in association with a longer polymorphic dinucleotide repeat, a combination that does not result in CF, but reduces levels of functional CFTR protein in Wolffian tissues, which constitutively produce less full-length CFTR mRNAs than other tissues (5) . About 30% of patients with idiopathic chronic pancreatitis or recurrent acute pancreatitis are found to carry CFTR mutations. No specific CFTR mutations have been reported, but rare class 4 or class 5 mutations are often found (6) . An increased incidence of CFTR gene mutations has been found in bronchiectasis. According to the studies, at least 1 CFTR mutation is found in 10-50%, and 2 mutations in 5-20% of cases. Mutations found are mostly uncommon and likely to result in residual CFTR function (7) . No specific CFTR mutation is associated directly with bronchiectasis. (2) . These patients must be monitored carefully for development of any complications and appropriate therapy implementation.

It should be pointed out, however, that labeling patients with mild or unclear manifestations with a CF diagnosis may have negative implications such as psychological, reproductive, social, employment, and insurance issues. Therefore the explanation of the diagnostic challenge, including also prognosis, must be fully and honestly explained to the patient and or his family.

Department of Pediatrics, CF and PCD Center, Hadassah Hebrew-University Medical Center, Mount Scopus, Jerusalem, <EitanK@hadassah.org.il>

Effective mucociliary clearance (MCC) in the respiratory system requires proper mucus production and functioning airway surface fluid layer as well as competent and coordinated ciliary beating. The vital role of these systems is best demonstrated in patients with genetic defects such as primary ciliary dyskinesia (PCD) and cystic fibrosis (CF), both of which are characterized by impaired MCC leading to acute and chronic sino-pulmonary infections. PCD is caused by defects in genes that encode the structure or regulate the movement or function of the respiratory cilia. CF is caused by mutations in the CFTR gene causing abnormality in the airway surface fluid layer, with production of thickened and viscous mucus leading to impaired MCC. In both diseases, recurrent and chronic respiratory infections and persistent inflammation cause progressive lung damage. Most patients with CF suffer from pancreatic insufficiency (CF-PI); however, approximately 15% have sufficient pancreatic enzyme production to maintain normal fat absorption (CF-PS). Patients with PCD are similar to patients with CF-PS in that they have normal pancreatic function, and are usually without the nutritional deficiencies that are typically associated with more severe pulmonary disease in CF. In addition, PCD and CF-PS are often diagnosed at a later age and have better survival compared to CF-PI (1,2). Therefore when comparing CF and PCD, one should differentiate between patients with CF-PI and CF-PS. Santamaria et al. compared chest HRCT scan scores for patients with PCD and a group of age-and gender-matched CF patients and showed that patients with PCD had significantly less structural damage than CF patients (3) . A recent study comparing between PCD and CF-PS and CF-PI revealed that patients with PCD had disease severity in terms of pulmonary function and structural abnormality similar to patients with CF-PS, which was significantly less severe when compared to patients with CF-PI (4). Furthermore, when comparing structural abnormalities by HRCT, there was a significant disparity in the distribution of the structural changes in the lungs between the three groups of patients: in PCD, the upper lung zones were relatively preserved and most changes were localized to the middle and lower lobes, whereas in CF-PI, the upper lobes were remarkably involved. In CF-PS, there was no characteristic distribution of the structural damage (4) . Other studies showed that In PCD, contrary to CF groups, there was no correlation between FEV 1 and CT Score and between FEV 1 and age (3) (4) (5) (6) (7) (8) , which provides further support to the understanding that, in PCD, lung function is not a strong indicator of severity of lung disease and therefore, follow-up by low radiation chest HRCT scans should be considered. It is important to note that, in general, patients with PCD receive less intensive therapy (9) . They are not always followed regularly in specialized centers, and many are not adherent to routine treatments. The most common bacterial infection in PCD patients is H. influenzae, which is significantly less common in older CF patients (4, 10) . In CF, chronic infection with P. aeruginosa is associated with a more severe lung disease (11) . However, among patients with PCD, there was no correlation between P. aeruginosa infection and pulmonary function or HRCT severity score, suggesting a different role for this microorganism in the pathogenesis of pulmonary disease in PCD (4). Bush et al. compared the mucous properties in both diseases and demonstrated that inflammation, measured by IL-8 concentration, was greater in PCD sputa, and that there were no significant differences in biophysical or transport properties of sputum between the two groups; however, survival in patients with PCD was generally better (12). Ratjen et al. (13) assessed the inflammatory response in the airways of CF and PCD patients during pulmonary exacerbation. In stable PCD patients, no significant differences were found in sputum inflammatory markers between individuals colonized with different bacterial pathogens. However, higher bacterial density for S. aureus and H. influenzae was found in patients with CF versus PCD, and the absolute neutrophil counts were higher in PCD patients. While sputum elastase activity was similar in PCD and CF at the time of exacerbation, it decreased with antibiotic therapy in PCD but not CF patients. Thus, PCD patients differ from those with CF in their responses to treatment of pulmonary exacerbations, with higher neutrophil elastase activity persisting in the CF airways at the end of treatment. Joenesen et al. (14) measured the difference in breath profiles of patients with PCD and CF, with and without distinct chronic lung infections, using an electronic nose. No significant difference was found between the breath profiles of PCD patients with a chronic PA infection and PCD patients without a chronic infection. However, there was a significant difference between the breath profiles of CF patients with a chronic PA infection and CF patients without a chronic PA infection, suggesting a different response to infection between PCD and CF.

In conclusion, although PCD and CF are both characterized by impaired MCC and respiratory infections, patients with PCD have a different lung disease expression compared to patients with CF-PS and with CF-PI, as assessed by FEV 1 , HRCT, nutritional status and bacterial infection on sputum cultures. In PCD, normal FEV 1 can be maintained over time in spite of severe structural damage. This suggests a greater involvement of the large airways in PCD and the small airways in CF. Furthermore, P. aeruginosa infection is less common in PCD than in CF. Bronchopulmonary dysplasia (BPD) is the most important complication following mechanical ventilation in preterm infants and no definite therapy can eliminate this complication. Although the mechanism is not completely clear, pulmonary inflammation is believed to play a central role in the pathogenesis. Glucocorticoid is one of the most effective therapies to treat or prevent BPD. However, systemic glucocorticoid therapy is not generally recommended because of long-term adverse events (1,2). Our previous pilot study in neonates and studies in animals indicated that surfactant can be used as a vehicle to deliver a topical glucocorticoid, budesonide, to the lung periphery and effectively suppress lung inflammation and lung injury (3.4.5). The mechanism for the effective delivery of budesonide using surfactant as vehicle is based on a physical phenomenon, the "Marangoni effect": in the interface between high and low surface tension, a convection force is generated and this force can be used as a vehicle to facilitate the delivery of medication (6) . This is an important delivery method because inhaled glucocorticoid is technically difficult and the effect has been shown to be limited (7, 8 There was no significant difference between the groups during the study in serum electrolytes, glucose, BUN and in blood pressure, and in physical growth. There was no significant difference between the groups in neuromotor function, and in MDI, PDI and in neurodevelopmental impairment (NDI) score when examined at 2-3 years of corrected age. We concluded that in very low birth weight infants with severe respiratory distress syndrome, intra-tracheal administration of surfactant/budesonide compared with surfactant alone significantly decreased the incidence of BPD or death without apparent short term or long term adverse effect. Further large-sample, double-blind trials are warranted.

Measuring lung function in "non-collaborating" children has always been one of most difficult tasks for pediatric pulmonologists. This is because young children are not able to perform the voluntary forced expiratory maneuvers generally used in adults and schoolchildren. In infants and children up to 2 years, this problem has been generally overcome by the use of sedation, although this contributes to make lung function measurements less suitable for routine clinical use in this age group. Preschool children (2-5 years) are too old to be sedated and yet too young to properly perform the forced expiratory maneuvers required for spirometry. For this age group, several techniques that just require tidal breathing have been implemented during the past decades. The American Thoracic Society/European Respiratory Society (ATS/ERS) Working Group on Lung Function in Young Children has published technical recommendations for most infant (1,2) and preschool techniques (3) and their clinical applications have also been recently summarized (4) . This lecture will focus on the most used pulmonary function tests (PFTs) in infants and preschool children.

Chloral hydrate (80-100 mg/kg, maximum 1 g) is commonly used to sedate infants and young children up to 2 years for performing lung function testing. However, chloral hydrate is no longer available in the U.S.A. and the use of other sedatives might lead to different results (4). The most commonly used PFTs in infants are the raised volume rapid thoracoabdominal compression and infant plethysmography. Other PFTs that are performed during tidal breathing (e.g.: tidal breathing measurements, multiple breath washout, forced oscillation technique) are more suitable to be used without sedation, especially in younger infants. The raised volume rapid thoracoabdominal compression (RVRTC) allows for the measurement of forced expiratory flow and volume in sedated infants (2) . Repeated inflations using a pressure of 30 cmH 2 O are applied through a facemask and an inflatable jacket is then activated to rapidly compress the infant's chest and abdomen to obtain forced vital capacity (FVC), forced expiratory volume in 0.5 seconds (FEV 0.5 ) and forced expiratory flow (FEF) at defined proportions of FVC. To ensure that flow limitation has been reached, the inflation pressure of the jacket is increased at each maneuver until no further increase in flow is noticed. Recently published reference equations using a current commercially available device (5) will improve the interpretation of the results. RVRTC has been successfully used in children with all kinds of respiratory diseases, including children with cystic fibrosis (CF), children born prematurely, and those with recurrent wheezing (4), showing its capability to distinguish disease populations from healthy control subjects and to detect lung function changes in clinical intervention trials. However, its long-term clinical utility still remains to be established. Moreover, the need for sedation along with the time and resource intensity required are other important limitations for its use in routine clinical practice (4) . Infant plethysmography is used to measure functional residual capacity (FRCpleth) in sedated infants (1) . Specific airway resistance (sRaw) can also be measured, provided that a proper electronic thermal compensation is applied to the system to account for thermal artifacts. This technique is based on the same principle (Boyle's law) as plethysmography for older subjects and uses an infant whole body plethysmograph where the infant lies supine breathing through a facemask sealed with silicon putty (1). Infant plethysmography has been successfully applied to children with lung disease, especially CF and bronchopulmonary dysplasia (BPD) (4). However, as for RVRTC, its long-term clinical utility remains to be ascertained and its role in routine clinical practice is hence very limited.

Preschool children (2-5 years) are too old to be sedated, but also too young to properly perform the forced expiratory maneuvers required for spirometry. For this age group, several techniques that just require tidal breathing have been implemented during the past decades, allowing for lung function to be measured in awake children (3) . Also, modified acceptability criteria for spirometry have been proposed for the use in preschool children (3) . It is important to highlight that the feasibility of any lung function technique in preschool children strongly depends on the capability of the operator of keeping the child quiet and focused (3). Spirometry has been proposed for preschool children using modified acceptability criteria (3). Since the forced expiratory volume in 1 second (FEV 1 ) often cannot be obtained in preschoolers due to their different lung physiology, the use of FEV in 0.5 (FEV 0.5 ) or 0.75 seconds (FEV 0.75 ) is recommended in this age group. Also, FVC should not be reported if flow stops at more than 10% of peak flow (early termination), but FEV may still be reported. Less stringent repeatability criteria have also been proposed in preschool children: at least two acceptable maneuvers should be obtained with the two FVC and FEV within 100 mL or 10%, but in case of a single acceptable maneuver, this should be recorded nevertheless (3) . Spirometry is reported to be feasible in 55-85% of 4-5 year old children, but its feasibility tends to be much lower in younger children (4) . Global multiethnic reference equations including preschool children have recently be published (6) . Spirometry has been reported to discriminate healthy controls from preschool children with CF and with recurrent wheezing, although substantial overlap between groups may occur and bronchodilator response appears to be more sensitive than baseline values (4). However, a careful and rigorous approach to the use of spirometry must be taken in preschool children and several gaps in our knowledge still limit the application of this technique to clinical practice in this age group (4).

The interrupter technique is based on the principle that a sudden flow interruption at the mouth during tidal breathing would make alveolar pressure rapidly equilibrate with mouth pressure, thus allowing an estimation of alveolar pressure by measuring mouth pressure. The interrupter resistance (R int ) is then calculated dividing the change in mouth pressure by the flow measured immediately before the interruption ("classical" technique) or immediately after the interruption ("opening" technique). Measuring R int has been proved to be particularly suitable for preschool children, its feasibility being generally higher than 80% in this age group (4). Proper reference values have been published (7) and cut-off values for the bronchodilator response have also been reported. R int is able to detect changes in the airway caliber and has been successfully used in preschool children with recurrent wheezing (4). However, its utility in clinical care remains to be established, especially by longitudinal studies (4) . The forced oscillation technique (FOT) is used to measure the impedance of the respiratory system (Z rs ) during tidal breathing by applying, through a mouthpiece and a filter, low-frequency pressure oscillations generated by a loudspeaker (usually 4-48 Hz) (3) . Changes in flow and pressure measured at the mouth are used to calculate Z rs and its two components, resistance (R rs , reflecting frictional losses) and reactance (X rs , reflecting elastic properties at low frequencies and inertial forces at higher frequencies). Forcing signals based on sinusoidal waves or impulses have been used, both as single-frequency or composite signals. Frequencies between 5 and 10 Hz are considered to reflect the mechanical properties of the total airways. FOT has a good feasibility in preschool children (>80%) and several reference equations have been published (8) . FOT has been used in many studies on children with recurrent wheezing, showing a good capability in discriminating health from disease, especially when bronchodilator response is used (4). However, for this technique as well, longitudinal studies on its clinical utility in young children are still needed (4). The multiple breath washout (MBW) is based on the washout of an inert gas (typically N 2 washout using 100% O 2 ) to measure ventilation inhomogeneity and FRC during tidal breathing (3). Non-resident inert gases have also been used. The lung clearance index (LCI, the number of lung volumes expressed as FRCs required to washout the inert gas) is the most commonly used MBW index. The general standard operating procedure for this technique has been recently reported (9) . LCI has a good feasibility in preschool children (nearly 80%). LCI has been successfully used in preschool children with CF (4), proving to be more sensitive than spirometry and plethysmography in detecting abnormal lung function. However, longitudinal studies on the clinical utility of MBW in preschool children are lacking (4) and more data are needed before LCI or other MBW indices can be recommended in the routine clinical management of patients with CF (10). Specific airway resistance (sRaw) can be measured at tidal breathing in preschool children using a whole body plethysmograph. Since sRaw is the product of airway resistance by the thoracic gas volume, it can be calculated without the need to breathe against a closed valve (11), provided that a proper electronic thermal compensation is applied to obviate the need for the panting maneuver. The measurement of sRaw has a good feasibility in young children and reference values are also available (11) . However, the lack of consensus on measurement methods and outcome measures makes it difficult to compare results among centers and methodological techniques are urgently needed for this technique.

An accurate assessment of pulmonary function is now possible in infants and preschool children using a number of techniques. Although these techniques have proven to be powerful research tools, further studies are needed to ascertain their utility in the clinical care of infants and young children with lung disease. . Past studies have shown that persistent echocardiographic evidence of PH beyond the first few months of life is associated with up to 40% mortality in infants with BPD. The association of PH with poor survival in BPD has continued into the recent era of the "new BPD," especially in infants with severe disease who require prolonged support with mechanical ventilation. Thus, developing insights into the pathogenesis and pathobiology of PH and related pulmonary vascular disease (PVD) in BPD continue as an important challenge and may help to improve early and late cardiopulmonary outcomes after preterm birth. Mechanisms that coordinate normal vascular growth and alveolarization during development or cause abnormal lung growth in BPD are poorly understood. Disruption of key signals between airway epithelium and endothelial cells can alter vascular and alveolar growth, resulting in decreased arterial and airspace structure. For example, hyperoxic lung injury in newborn animals decreases expression of the critical proangiogenic and endothelial cell survival factor, vascular endothelial growth factor (VEGF). Early impairment of VEGF production inhibits vascular growth and impairs endothelial function, which leads to PH. In addition, disruption of angiogenesis due to adverse antenatal factors, such as chorioamnionitis, preeclampsia or maternal smoking, and postnatal events after premature birth, can cause vascular injury that not only lead to PH but can also impair distal lung growth. Ongoing laboratory studies suggest that the developing endothelial cell plays a key role in the regulation and coordination of epithelial growth and distal airspace structure through the production of critical "angiocrines," such as nitric oxide (NO), hepatocyte growth factor, vitamin A, insulin growth factor-1 and others. Thus, since angiogenesis is necessary for normal alveolarization, it has been suggested that protecting the developing pulmonary vasculature from early injury may not only lower PVR and improve gas exchange, but may enhance distal lung growth and improve long term outcomes. Abnormalities of the pulmonary circulation in severe BPD include altered tone and reactivity, structure and growth, which can cause right heart failure, impaired gas exchange, pulmonary edema, decreased exercise capacity and other clinical problems. Physiologic abnormalities of the pulmonary circulation in BPD include elevated pulmonary vascular resistance (PVR) and abnormal vasoreactivity, as evidenced by the marked vasoconstrictor response to acute hypoxia and by impaired gas exchange due to abnormal distribution of lung blood flow. Abnormal pulmonary vascular structure also contributes to high PVR due to increased smooth muscle cell hyperplasia and altered vascular compliance caused by increased production of an abnormal extracellular matrix. Growth of the distal lung circulation is abnormal in infants with severe BPD, and decreased arterial growth (angiogenesis) reduces vascular surface area that further impairs gas exchange and increases the risk for the development of PH and impaired exercise capacity in older children.

Prominent bronchial or other systemic-to-pulmonary collateral vessels were noted in early morphometric studies of infants with BPD, and can be readily identified in many infants during cardiac catheterization. Although these collateral vessels are generally small, large collaterals may contribute to significant shunting of blood flow to the lung, causing edema and need for higher FiO 2 . In addition, recent autopsy studies suggest the presence of striking intrapulmonary anastomotic, or "shunt," vessels that link the distal pulmonary and bronchial vessels, and may contribute to poor oxygenation. Past clinical studies have further shown that metabolic function of the pulmonary vasculature is impaired in BPD, as reflected by the lack of pulmonary clearance of circulating norepinephrine during passage through the lung, which may contribute to left ventricular dysfunction and systemic hypertension. Clinical studies have recently shown that early echocardiographic findings of PVD after preterm birth are strongly associated with the development and severity of BPD and PH at 36 weeks corrected age. Interestingly, these findings were not only associated with a worse respiratory course during the initial hospitalization, but also late respiratory outcomes, including respiratory exacerbations, hospitalizations and the need for asthma medications. Ongoing studies are exploring the impact of PH-specific drug therapies, such as sildenafil and other agents, on PH and related complications. Thus, PVD in preterm infants with BPD is characterized by altered lung vascular development, growth, structure, and function, which precede the onset of measureable PH. PVD due to disruption of normal pulmonary vascular development in association with preterm birth is an important determinant of the pathobiology of BPD and contributes significantly to morbidity and mortality. Exposure to adverse stimuli during the antenatal and/ or early postnatal periods impairs normal pulmonary vascular development and creates an imbalance between risk and resiliency factors. Recent studies have revealed the magnitude of PH in preterm infants, but many aspects of PVD remain understudied, and ongoing investigations continue to explore risk factors, mechanisms of disease, and long-term outcomes. Prospective studies are needed to definitively establish standardized clinical criteria for PVD and PH in BPD, and to determine the best methods for early diagnosis, risk stratification and disease monitoring. Larger collaborative studies and improved clinical infrastructure to conduct these important investigations will provide answers to these critical questions. Recent evidence suggests that CFTR does not act as a pure ion channel but as a platform for multiple cellular signaling pathways. Importantly, the protein interactomes of WT-and F508del-CFTR are rather different, and there is growing consensus that indirect measures that avoid the enhanced degradation of F508del-CFTR may restore its function. Recently, we discovered that CFTR orchestrates a proteostatic network that influences multiple cellular functions by acting as a hub protein. This hub-dysfunction model proposes that the proteostasis network is widely deranged, both in transgenic CF mice and in primary nasal epithelial cells freshly collected from CF patients bearing F508del-CFTR either in homozygous or compound heterozygous form, at two levels. Firstly, autophagy, the major mechanism determining cytoplasmic protein turnover, is blocked due to tissue transglutaminase (TG2)-mediated depletion of the essential autophagy-related protein Beclin 1 (BECN1), leading to secondary accumulation of the autophagic substrate SQSTM1/p62. Secondly, peptide fragments released from proteolytically-cleaved F508del-CFTR provoke an over-activation of a pleiotropic protein kinase (protein kinase CK2), which in turn contributes to F508del-CFTR degradation. Combined inhibition of TG2 by cysteamine, which is FDA-approved for the treatment of cystinosis, and over-active CK2 by the over-the-counter greentea flavonoid epigallocatechin-gallate (EGCG) respectively rescue and stabilize a functional F508del-CFTR protein at the PM, both in mice and in primary nasal cells from CF patients bearing F508del-CFTR or other class II-CFTR mutations. Pre-clinical evidence on transgenic mice has provided the mechanistic proof-of-concept for using this combination of proteostasis regulators as an alternative CFTR-repairing therapy. Moreover the combination treatment reduces lung inflammation and this beneficial effect persists up to 2 weeks following cysteamine withdrawal provided that EGCG was administered during washout.

This prompted an open-label phase-2 trial to assess the individual response to the synergistic combination of cysteamine and EGCG in CF patients bearing different CFTR mutations. The combination treatment was well tolerated and decreased sweat chloride from baseline while increasing the abundance and function of CFTR protein and restored autophagy in nasal cells. Notably, the treatment decreased CXCL8 and TNF-a in the sputum and improved respiratory function. These positive effects were particularly strong in patients carrying F508del-CFTR (or other class II) mutations in homozygosity or heterozygosity, whereas patients with class I CFTR mutation failed to respond to therapy. Altogether, these results suggest that the combination treatment acts "on target", according to the hypothesis underpinning our drug design. Discordance in therapeutic response rate complicates mutation-specific approaches, thus entailing the need of patient-centered (personalized) approaches to assess drug efficacy. Testing the putative individual responsiveness to treatment by appropriate biomarkers before in vivo therapy should support the decision to treat. We show that restoring CFTR function in vitro in nasal cells in response to cysteamine plus EGCG, is highly predictive of whether the combination treatment will restore CFTR function in vivo. Hence, this in-vitro assay may constitute a tool to guide the clinical development of CF treatments, allowing to select patients for new therapeutic options. General frame for care Infants with CF must receive care in an accredited CF care center. They must be reviewed in clinic frequently after diagnosis, for example once a month during the first 6 months of age, every 2 months until 1 year of age, and every 3 months thereafter (3). After initial diagnosis, the CF center should contact the primary care professionals for regular ambulatory follow-up to implement therapeutic strategy. Parents of infants with CF should be offered access to genetic advice and counseling. The standard childhood immunization schedule must be applied in accordance with national guidelines. Anti-influenza vaccination is recommended for the infant from the 6 th month of life and for all household members and healthcare providers. According to French guidelines, vaccination against chicken pox could be recommended.

Growth targets should reflect genetic potential, sibling height and local population demographics (1) . French guidelines recommend to catch-up birth weight percentile at 6 months (3). At 2 years, weight-for-height should be at the 50 th percentile and height at the target height percentile (target height: average of the height of the 2 parents plus 6.5 cm for boys and minus 6.5 cm for girls) (3). Energy intake evaluation should be performed by a dietician on a regular basis and adapted to achieve the objectives of weight-for-height growth. Energy intake could be as much as 150% of the daily recommended calorie intake for the same age in the general population (4). Breast feeding is encouraged, all the more that recent data acknowledge its protective effect against Pseudomonas aeruginosa infection (4, 5). Formula with hydrolyzed cow's milk protein is recommended in infants with risks of malabsorption, or severe undernourishment. Sodium chloride supplementation is systematic, particularly in the case of breast feeding and should be adapted to natriuresis (6) . It should be increased during periods of hot weather and all other causes of high salt loss (diarrhea, fever, ileostomy, etc.). At initial diagnosis, infants must have pancreatic function assessed by stool fecal elastase. If elastase is normal, repeat assessment is recommended. Pancreatic enzyme replacement therapy should be started at diagnosis in case of clinical symptoms of exocrine pancreatic insufficiency even before obtaining the results of the elastase assay. The starting dose could be 2.000 IU lipase per 100 ml of milk. In case of persistence of symptoms of pancreatic insufficiency despite a maximum dose of 10.000 UI/kg/day of lipase, it may be necessary to evaluate the patient's compliance and the methods of conservation and administration of the pancreatic extracts. In case of poor weight-for-height growth despite an adapted substitutive pancreatic opotherapy, an evaluation is necessary including a dietetic review, a search for sodium insufficiency and other etiologies of malabsorption. In case of persistence of symptoms of exocrine pancreatic insufficiency despite a maximum dose of 10.000 UI/kg/day of lipase and in the absence of other etiologies, the administration of gastric secretion inhibitors may be envisaged.

Bacterial cultures of bronchial flora should be performed at each session of physiotherapy or, in case of abnormal clinical status, ideally on bronchial secretions expectorated or obtained by sputum induction (7).

A chest X-ray should be performed at baseline and annual assessment, and, in case of clinical abnormality. High Resolution Computed Tomography should complete the assessment in case of clinical or radiological abnormality and/or at initial assessment according to local practice to detect early bronchiectasis (8) . Systematic respiratory physiotherapy is recommended from the time of diagnosis. The frequency of sessions of physiotherapy depends on the clinical status of the infant. Regular therapy might be recommended even in the asymptomatic infant (3). Any evidence of respiratory infection justifies performing a respiratory culture and adapted antibiotic treatment of the isolated pathogens. Infection by Staphylococcus aureus sensitive to Meticillin should be treated by adapted antibiotherapy. In case of isolation of S. aureus resistant to Meticillin, a treatment aiming eradication is recommended. Evidence of P. aeruginosa justifies systematic antibiotic treatment, even in the asymptomatic infant. Although there is still no consensus, treatment might begin with an inhaled antibiotic, eventually associated with oral Ciprofloxacin. In case of persistence of P. aeruginosa after initial therapy, or if the infant presents with severe clinical signs, intravenous antibiotics should be considered (1, 2, 3) . For other pathogens, there is less clear agreement and treatment should be guided by local policies. In the absence of clinical improvement despite an adapted antibiotherapy, bronchial sampling by bronchoalveolar lavage should be considered and non-infectious causes should be searched for, including gastroesophageal reflux, asthma and an ENT cause.

Respiratory syncytial virus (RSV) may have adverse effects on respiratory status in patients with CF (9) . There is insufficient evidence to support systematic recommendation of Palivizumab in the CF infant even if some small studies suggest that there could be benefit from the use of RSV prophylaxis in infants with CF (10). US and French guidelines state that Palivizumab could be discussed, namely for the infant of less than 6 months of age during an epidemic period (2,3). Finally, dornase alfa, 7% hypertonic saline might be used in symptomatic infants (2) .

With increasing numbers of infants with CF being diagnosed by newborn screening across most of Europe and in North America, we will have the opportunity for large cohort follow-up and randomized controlled trials. This will help to establish still lacking best available evidence to harmonize therapeutic strategy in infants newly diagnosed with the final aim of improving clinical status at later ages.

Department of Pediatrics, CF and PCD Center, Hadassah Hebrew-University Medical Center, Mount Scopus, Jerusalem, Israel <EitanK@hadassah.org.il>

Bronchiectasis is the distraction of the normal anatomy of conducting airways that results in impaired mucociliary clearance leading to chronic cough, sputum production, and recurrent infections and inflammation that cause further damage to the bronchial and bronchiolar walls leading to a vicious cycle of airway injury. The prevalence of non-CF bronchiectasis (NCFB) in children differs between developed and poor countries. In the developed world, the most common cause of bronchiectasis in children is cystic fibrosis (CF), followed by primary ciliary dyskinesia and immune deficiencies. However, up to half of cases remain without a known etiology. In developing countries, a systematic review of 989 children (1) demonstrated that an etiology was identified in 63% of children, with a previous severe pneumonia of bacterial or viral etiology and B-cell defects as the most common identified disorders. Bronchiectasis should be suspected in patients who present with chronic productive cough of mucopurulent sputum. Physical findings in bronchiectasis patients are nonspecific but may include crackles and wheezes on lung examination and clubbing of the digits. Pulmonary function testing results generally show airflow obstruction. The diagnosis of bronchiectasis is confirmed by HRCT scan which is now the gold standard for diagnosis. These include bronchial dilatation (an internal bronchial diameter greater than the diameter of the accompanying bronchial artery [i.e., the "signet ring" formation]) and a lack of bronchial tapering on sequential slices (2) . Patients in whom bronchiectasis has been diagnosed should be evaluated for potential underlying causes. They need to undergo chest CT scan to define the extent of their disease. Patients with focal disease require bronchoscopy to evaluate for a localized airway obstruction as the cause of the bronchiectasis. Patients with diffuse bronchiectasis should be assessed for underlying systemic abnormalities including congenital disorders, chronic aspiration, impaired mucociliary clearance and systemic or local innate immune dysfunction. All patients with bronchiectasis should have a regular routine microbiological examination of their sputum for routine bacterial and NTM organisms. Pulmonary exacerbations of NCFB are known to be associated with poor outcomes, and infections are common causes. Gram-negative bacteria are isolated more frequently in patients with NCFB, with H. influenzae and P. aeruginosa representing the majority of identified species. However, up to 40% of sputum samples fail to grow any pathogenic bacteria (3). Patients with sputum samples dominated by P. aeruginosa (PA) had a higher frequency of exacerbation and poorer lung function compared to patients whose samples were dominated by other organisms (4). Nontuberculous mycobacteria (NTM) are opportunistic pathogens that afflict patients with preexisting lung disease; in particular those with NCFB, shown in a meta-analysis by Chu et al. to be prevalent in nearly 10% of the patients (5). Respiratory viruses were found in nearly 50% of exacerbations. The goals of bronchiectasis treatment are to reduce the number of exacerbations and to improve quality of life. If an underlying systemic etiology such as immune deficiency is identified, it should be addressed. Pharmacologic agents and the mechanical mobilization of secretions have been evaluated to a limited degree in patients with non-CF bronchiectasis. Short-acting or long-acting bronchodilator adrenergic and anticholinergic agents are commonly prescribed, but there have been no randomized controlled trials to support their use. Pulmozyme had adverse effects when studied in patients with non-CF bronchiectasis. Inhaled mannitol showed improved time to first exacerbation and quality of life. Nebulized hypertonic saline solution (7%) have shown promise in the treatment of patients with both CF and non-CF bronchiectasis, but long-term prospective trials are needed. The role of the use of maintenance antibiotic therapy is uncertain in patients with non-CF bronchiectasis. Rotating oral antibiotic strategies have been commonly used. For exacerbations, antibiotic therapy should be tailored to their sputum microbiology results. Severe exacerbations, particularly in patients who are infected with organisms that are resistant to therapy with oral quinolones, require IV antibiotic therapy. Azithromycin has been shown to attenuate MUC5AC and MUC2 gene expression, thereby suppressing the synthesis of mucin on human airway epithelial cells. Clinically, this was demonstrated in a study that found that mean 24-hour sputum volume and QOL were significantly lower in patients with bronchiectasis after 12 weeks of azithromycin compared with control subjects (6) . A recent randomized, double-blind, placebo-controlled trial in adults assigning patients to receive 500 mg azithromycin or placebo three times a week for 6 months, showed that azithromycin significantly reduced the exacerbation rate with no significant effect on FEV1 (7) . Based on the above and other studies, it is recommended that all patients with NCFB be treated with azithromycin. Long-term inhaled antibiotics are used for patients with uncontrolled NCFB, but until more recently, data on their efficacy have been lacking.

The use of mechanical aids, including chest physical therapy with postural drainage, active cycle of breathing, oscillatory positive expiratory pressure devices, and high frequency assisted airway clearance, also constitute potential adjunct therapies for patients with bronchiectasis. Though these modalities are considered to be standard therapy for patients with CF bronchiectasis, their utility is less well proven in patients with non-CF bronchiectasis. It was shown that comprehensive medical care in children with NCFB was associated with a decrease in exacerbation rates (8) . These findings further exemplify the importance not only of identifying NCFB in pediatric patients, but also of ensuring that they receive close surveillance. Treatment burden with lack of immediate apparent outcomes cause patients to avoid daily therapy and seek therapy only for exacerbations. Resectional surgery and lung transplantation are rarely required. Surgical treatment has classically been an option for patients who have localized bronchiectasis with persistent symptoms despite maximal therapy, or recurrent infections with resistant pathogens (9). The prognosis for patients with bronchiectasis is variable given the heterogeneous nature of the disease. Because there are so few randomized controlled trials of therapies for non-CF bronchiectasis, patients must be evaluated and treated on an individual basis in a tailored, patient-focused approach in a specialized center to optimally evaluate and treat individuals with bronchiectasis.

In humans, the dominant innervation to the airways is provided by the parasympathetic vagus nerve, whose activation induces the release of acetylcholine [1] . Acetylcholine, the primary parasympathetic neurotransmitter in the airways, interacts predominantly with nicotinic receptors and the five muscarinic receptor subtypes. In addition to its well-known functions, i.e. bronchoconstriction and mucus secretion regulation, there is evidence that acetylcholine might also modulate inflammatory cell chemotaxis and activation and participate in signaling events that lead to airway wall remodeling [2] . These findings can have significant implications for anticholinergic therapy of diseases characterized by airway inflammation, bronchial obstruction and mucus hypersecretion, since a variety of data indicate that the function of muscarinic receptors is altered in these patients.

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels, formed by five homologous or identical subunits, arranged to form a central ion channel [3, 4] . Depending on the subunit composition, nAChRs show different kinetics and pharmacological properties. In lung tissues, the "muscle" nAChRs are localized at the neuromuscular junctions of the smooth muscle cells, whilst the "neuronal" nAChRs are expressed by autonomic ganglia, but also by almost every cell type, including bronchial and alveolar epithelial cells, endothelial cells, pulmonary neuroendocrine cells, submucosal glands, airway and vascular smooth muscles, fibroblasts and alveolar macrophages [4] . Although nAChRs are classically linked to the depolarization of the plasma membrane required for neurotransmission, non-neuronal nAChRs in the lung act most frequently as calcium channels and have been linked to regulatory proteins controlling cell proliferation [2] [3] [4] . The functional role of nAChRs is particularly complex and depends on subunit composition, dose response, and duration of ligand stimulation. Although nAChR activation often leads to a positive feedback loop that induces receptor expression, chronic stimulation of nAChRs can produce channel desensitization and decreased activity. The majority of studies of nAChR function in the lung are related to the effects of nicotine, i.e. to tobacco-induced mutagenesis and lung carcinogenesis, whilst little is known on the physiological functions in regulating lung growth and repair, airway epithelial cell proliferation and differentiation and electrolyte transport [3] .

Muscarinic receptors belong to the large family of G protein-coupled receptors, characterized by seven transmembrane domains. Out of the five subtypes identified, only M1, M2 and M3 receptors have been detected in the airway and lung tissues of most mammals, including humans. Almost all airway and lung cell types express muscarinic receptors. M1 receptors are present mainly in the peripheral lung tissue and in the alveolar walls: they are expressed by airway epithelial cells, where they modulate electrolyte and water secretion, by goblet cells, where they regulate mucus production, and by the ganglia, where they facilitate parasympathetic neurotransmission. M2 and M3 receptors represent the major populations in the large airways. M2 receptors are expressed by neurons, where they function as autoreceptors inhibiting the release of acetylcholine from both preganglionic nerves and from parasympathetic nerve terminals. In airway smooth muscles, they modulate different ion channels involved in cell contraction, effects that require concomitant M3 receptor-mediated release of calcium from intracellular stores. In fibroblasts and smooth muscles, M2 receptors stimulate cell proliferation and modulate cellular responses associated with airway remodeling [2, 4] . M3 receptors are the dominant receptor subtype in the regulation of airway smooth muscle contraction and of mucus secretion from submucosal glands and goblet cells [3] . M3 receptors can also favor airway smooth muscle proliferation, increasing the responses to epidermal growth factor and platelet-derived growth factor [3] .

Acetylcholine, in addition to the parasympathetic nerve, is also synthesized and released by a large number of non-neuronal cells, including neuroendocrine, ciliated, basal and secretory epithelial cells where it can act as an autocrine or paracrine signaling molecule. Secretory and ciliated cells release acetylcholine into the luminal periciliary fluid, whereas endocrine and basal cells secrete acetylcholine basally [3] . Current knowledge suggests that the local auto/paracrine production of acetylcholine by epithelial cells may play a role in regulating various aspects on the innate mucosal defense mechanisms, including mucociliary clearance. Acetylcholine is known to increase ciliary beat frequency in the airways and to modulate the release of inflammatory mediators by these cells through M3 receptors and to affect inflammatory cells involved in the pathogenesis of obstructive airway diseases [3] . Expression of muscarinic receptors has also been shown by most inflammatory cells, including macrophages (M1-M3) , T-and B-lymphocytes (M1-M5), mast cells (M1), neutrophils (M1-M3) and eosinophils (M1). In these cells, muscarinic receptors appear to be involved in cell proliferation and release of pro-inflammatory mediators [2, 3] . Arteries, veins and bronchopulmonary anastomoses also express muscarinic receptors (M3) and dilate in response to acetylcholine released by vagal nerve stimulation.

The postganglionic nerve fibers do not form defined synapses to their target cells but a terminal meshwork called 'autonomic plexus' with numerous varicosities, called sites of transmitter release, in variable and only rarely close contact to cells, such as airway smooth muscle [4] . Release of acetylcholine from the parasympathetic nerve terminals in the airways appears to be under complex prejunctional regulatory mechanisms. The available data indicate that acetylcholine release can be enhanced by a variety of pro-inflammatory mediators (histamine, bradykinin, neuropeptides) and by b 2 -adrenergic agents, whist it is under the inhibitory control of muscarinic autoreceptors and downregulated by eicosanoids, such as PGE 2 , opioids, nitric oxide and a 2 -adrenergic agents [5] .

The activity of M3 receptors in smooth muscle appears to be spared or even increased in asthmatics, possibly because of a greater affinity of the acetylcholine binding site. There is also no evidence that muscarinic receptors are overexpressed or upregulated in airway smooth muscle in disorders characterized by bronchial obstruction or hyperresponsiveness although an acquired loss or impairment of neuronal M2 receptor function may be involved in their pathogenesis [15] . These functional changes occur after exposure to allergens, infectious agents (viruses) or pollutants (ozone) and result in increased acetylcholine release from parasympathetic nerves [6] . M2 autoreceptors dysfunction in allergic asthma is caused by the eosinophil basic protein released by activated eosinophils that, upon binding to M2 autoreceptor sialic acids, acts as an allosteric antagonist [3] . With the same mechanism, an early recruitment and activation of eosinophils is thought to cause the airway hyperreactivity that follows environmental ozone exposure [3] . In contrast, viral respiratory infections are purported to induce bronchial hyperresponsiveness through different mechanisms, including: a) the inhibition of M2 receptor synthesis, mediated by the release of interferon-g by activated CD8þ T-lymphocytes; b) the production of neuraminidase, that determines functional impairment of M2 receptor activity by cleaving their sialic acid; c) M2 receptor dysfunction, caused by the activation of the substance P (NK1) receptor overexpressed by influenza, parainfluenza and respiratory syncytial virus [3] . Interestingly, increased substance P production has been reported in patients with asthma and gastroesophageal reflux, a disorder that recognizes vagus-mediated oesophageal-tracheobronchial reflexes in its pathogenesis. Experiments performed in humans have corroborated the relevance of pathogenesis of M2 autoreceptors in generating airflow limitation showing that M2 receptor selective agonists inhibit cholinergic-induced bronchoconstriction in normal individuals but not in asthmatic patients [3] . Defects in M2 autoreceptor activity may also explain bronchoconstriction induced by b-blockers in asthma. These drugs can increase cholinergic tone downregulating the action of endogenous catecholamines on b 2 -adrenoceptors present on cholinergic nerves [3] .

Thus, in extreme synthesis, the three muscarinic receptor subtypes expressed in the airways have different, somehow conflicting functions: M1 and M3 receptors facilitate cholinergic-induced events, including bronchoconstriction and mucus glands secretory activities, whilst M2 receptors have a feedback inhibitory function, regulating the release of acetylcholine from cholinergic nerve endings. This information is of great importance to understand the activity of the three anti-cholinergic agents that can be used to treat patients with reversible airway obstruction. Two of these, ipratropium and oxitropium bromide, are short-acting and non-selective muscarinic antagonists. Because of the lack in selectivity, they also block M2 receptors, increasing acetylcholine release, and therefore reducing the degree of their "useful" action on M1 and M3 receptors [3] . In contrast, the more recent longacting anticholinergic drug tiotropium bromide is characterized by a kinetic selectivity for M1 and M3 receptors over M2 receptors: it dissociates rapidly from M2 receptors and very slowly from M1 and M3 receptors [3, 7] . To date, the anti-cholinergic agents most commonly used to treat respiratory disorder in childhood is the "non-selective" ipratropium bromide which, alone or associated with inhaled b 2 -adrenoceptors agonists, has been demonstrated to significantly improve pulmonary function and clinical outcomes in acute asthma, in preschool wheezing, although no long-term assessments have been included [3, 8] . Interestingly, preliminary data show that inhaled tiotropium bromide, once daily, is well tolerated and also improves lung function in pediatric patients with cystic fibrosis [9] and in asthmatic adolescents, symptomatic despite inhaled corticosteroids [10] . Evidence from experimental models also suggest that tiotropium bromide may also modulate the acetylcholine-induced inflammatory and remodeling changes induced in the airways by a variety of stimuli, leading to hopes of having favorable clinical responses in other respiratory disorders.

A relevant role in the pathogenesis of obstructive airway disorders is thought to be played by an increased acetylcholine release, at least in part due to M2 receptor dysfunction. The most commonly prescribed short-acting anticholinergic drug, ipratropium bromide, is not selective for muscarinic receptor subtypes. Despite some efficacy in the most common pediatric airway diseases such as asthma and pre-school wheeze and cystic fibrosis, ipratropium bromide is not commonly prescribed as a standalone medication. The more recently introduced anticholinergic drug, tiotropium bromide, has advanced pharmacologic properties such as long duration of action and a functional selectivity for M1 and M3 receptors over M2 receptors, and has shown a good efficacy and safety profile in adult respiratory disorders, such as asthma, cystic fibrosis and chronic obstructive pulmonary disease. Ongoing studies are now under way to define its therapeutic role for pediatric airway diseases.

Inhalation of smoke from Datura strammonium, a member of the deadly nightshade family, was recommended for the treatment of asthma in 17th century Ayuverdic literature. General Gent, himself an asthmatic, on return from India in the early 19th century, was reported to have brought this therapy to England. Strammonium and belladonna cigarettes were widely used to treat respiratory disease until the middle of the 20 th century. However there were frequent side effects, including tachycardia, hallucinations, and even addiction. With the introduction of synthetic atropine derivatives with fewer side effects, there has been a renewed interest in anticholinergic therapy for asthma. Bronchial smooth muscle tone is predominantly set by cholinergic activation. Patients with asthma have increased bronchial smooth muscle tone and mucus hypersecretion, likely as a result of cholinergic activity. Anticholinergic medications can relax smooth muscle in children with acute asthma, These drugs also appear to have anti-inflammatory properties, and may reduce goblet cell hyperplasia driven by neutrophil elastase À a feature of severe asthma known to be resistant to steroid therapy. The short-acting anticholinergic agents, ipratropium bromide and oxitropium bromide, have been used in asthma for many years, primarily for acute asthma in the emergency department. Paradoxically, although the addition of an anticholinergic medication to a beta agonist can decrease acute asthma severity and hospital admission, studies suggest that continuing the anticholinergic while the patient is in hospital does not hasten recovery or decrease length of hospital stay. However these studies have been small and potentially underpowered. Until the past decade, these results have dampened enthusiasm for studying anticholinergic medications as maintenance asthma therapy. This has changed with long-acting anticholinergic (LAMA) bronchodilators under investigation or are available for treating lung disease: These include tiotropium, aclidinium, glycopyrronium, glycopyrrolate and umeclidinium. The once-daily LAMA, tiotropium bromide, is demonstrated to improve lung function and decrease the risk of exacerbation in adolescents and adults with moderate to severe asthma, despite the use of inhaled corticosteroids (ICS) and long-acting b 2 -agonists (LABAs). In September 2015, the FDA in the United States approved tiotropium for the long-term, maintenance treatment of asthma in patients 12 years of age and older. Tiotropium by Respimat soft-mist inhaler is now included in the Global Initiative for Asthma report (GINA) 2015 Global Strategy for Asthma Management and Prevention. In Phase 3 studies, tiotropium improved asthma symptoms in 68% of enrolled subjects and decreased exacerbations by 21% whilst having a safety profile similar to that of placebo. Studies also show that tiotropium was effective in improving pulmonary function (FEV1) and decreasing asthma attacks in children age 6-11 with poor asthma control despite use of a medium dose of ICS with or without a leukotriene modifier. There was no difference in effectiveness when comparing the FDA-approved dose or 2.5 mcg (2 Â 1.25 mcg) once daily tiotropium to a higher dose of 5 mcg. Initial studies in children younger than 6 years do not appear to show benefit.

With increasing knowledge about the diverse actions of the cholinergic system in asthma and the role of muscarinic receptors in the airway, we are gaining an increased appreciation of how anticholinergic medication can play an important role in treating children and adults with chronic and poorly-controlled asthma. 

The 2008 ERS Task Force opted to not use the term asthma to describe preschool wheezing illness since there was insufficient evidence showing that the pathophysiology of preschool wheezing illness is similar to that of asthma in older ages. The Task Force referred to Pre School Wheezing and described episodic (viral wheeze) for children who wheeze intermittently and are well between episodes versus multiple-trigger wheeze for children who wheeze both during and outside discrete episodes.(2) We will therefore in our current discussion refer to this young age morbidity as an entity that should be discussed separately from asthma, acknowledging that much has yet to be learned on the nature of this entity. Amongst the many mechanism of virus-induced airway hyperreactivity; a common phenomenon in pediatric practice related to this young age group, studies have shown that cholinergic overactivity such as through the modulation of Substance P may mediate virus-induced airway hyperreactivity. Virus-specific CD8þ T lymphocytes may induce cholinergic activation through M2 receptor dysfunction.(3) Hence anticholinergic medications may have a role in viral-induced wheeze with compounds that display selectivity for M1 and M3 muscarinic receptors over M2 receptors having advantages over nonselective compounds.

A number of small studies addressed the role of anticholinergics in acute bronchiolitis but failed to show a role for this acute intervention. A study on 69 infants who were randomly assigned to receive nebulized salbutamol, ipratropium bromide or placebo resulted in faster improved clinical scores and oxygen saturation levels in the bronchodilator groups than in the placebo, but no effect to change the natural course of the disease. (4) In studies on this topic from 1981, inhaled ipratropium bromide administered to wheezy children (3 -32 months of age) improved lung function when measured by total body plethysmography and forced oscillation technique. (5) The authors were unable to differentiate between responders and nonresponders by clinical or by physiological parameters, but submitted that the differential distribution of obstruction between small and large airways may underlie response or lack thereof; and that subjects with a predominance of large airways obstruction were the responders to inhaled ipratropium. A logical if unproven additional speculation was that anticholinergics decrease airway secretions and with it reduce large airway resistance. A Cochrane review examining the effect of adding ipratropium bromide to B 2 -agonists in wheezy infants (6) suggested that the combined therapy improved symptom scores after 24 hours compared to the use of jB 2 -agonist alone. The ERS Task Force cited above(2) offered evidence-based recommendations on the definition, assessment and treatment of wheezing disorders in preschool children. Addition of ipratropium bromide to short acting B 2 -agonists was suggested for patients with severe wheeze. In the 2014 review of the Task Force recommendations no reference was made to the use of anticholinergic medications. (7) Tracheobronchomalacia It is widely believed amongst pediatric pulmonologists that administration of B 2 -agonists in infants with airway structural instability, predominantly tracheobronchomalacia is detrimental, while the use of anticholinergics for bronchodilatation is safe. This notion derives from a study of only 3 infants with intrathoracic tracheomalacia, using infant pulmonary function testing and demonstrating that flows improved significantly after administration of metacholine but worsened after administration of albuterol.(8) These results suggest that in patients with abnormally collapsible tracheas or large bronchi, stimulation of the smooth muscle can improve airway stability, thereby increasing forced expiratory flows, while relaxation of airway smooth muscle by bronchodilators can exacerbate obstruction. The sole support for this observation comes from a review of a series of patients with tracheobronchomalacia from Chile, in whom beta-agonist medications were discontinued while the anticholinergics were not. (9) The effect of anticholinergic medication has not been assessed directly in any study, and thus whether this class of medications may have a different effect compared to beta 2 -agonists in such pathology has not been established. Further studies on the effect of the various bronchodilators for such pathologies using newer technologies to assess airway resistance (e.g., forced oscillation) should be undertaken. While more invasive and challenging, a technique of direct quantitative assessment of tracheal collapsibility in infants with tracheomalacia has been described, and may be the most adequate technique to answer this important clinical question. (10) Tiotropium bromide in pediatric use -asthma and the Asthma-COPD Overlap Syndrome Ipratropium bromide has a limited role in childhood asthma, largely due to lack of selectivity. The more recently introduced long-acting muscarinic antagonists/anticholinergic (LAMA), tiotropium bromide, presents advanced pharmacologic properties such as selectivity for M3 muscarinic receptors over M2 receptors and long duration of action. A high safety profile and increasing evidence of efficacy have rendered it a mainstay medication for COPD with an emerging role in adult asthma. Few studies have emerged on its role in the treatment of childhood asthma and defining its therapeutic niche for pediatric airway diseases. In a recent 1-year randomized controlled trial, tiotropium add-on therapy in adolescents with moderate asthma, (11) significantly improved lung function and was safe and well tolerated when added to at least ICS maintenance therapy. A study of 71 pediatric patients with asthma and chronic cough from an asthma center (12) concluded that tiotropium can be beneficial in 3 distinct patient populations: add-on therapy to asthmatics on maximal maintenance medication, an alternative to highdose inhaled steroids in patients who are experiencing significant side effects, and patients with bronchorrhea as their predominant symptom manifested by a chronic productive cough, the latter population is most likely explained by its drying effect on airway secretions. A recent editorial (13) states "Approximately 1 in 12 people worldwide are affected by asthma or chronic obstructive pulmonary disease (COPD); once regarded as two distinct disease entities, these two conditions are now recognized as heterogeneous and often overlapping conditions. The term "asthma-COPD overlap syndrome" (ACOS) has been applied to the condition in which a person has clinical features of both asthma and COPD". In recent years multiple reports describing this interface between asthma and COPD have been published recognizing that the demarcation line between these two entities is difficult to define. While the precise definition in various populations is still being worked out, and it is obvious that the majority of such patients are adults, there is early recognition that some pediatric populations, who are viewed as asthmatic, yet have no airway reversibility, may constitute an early presentation of the Overlap Syndrome. The mainstay therapies for COPD are long-acting inhaled bronchodilators, including longacting B2-agonists (LABAs) and LAMAs, with its characteristic member being tiotropium bromide. In patients with COPD they are recognized as being equally effective because they reduce air trapping by relaxing airway smooth muscle as a result of reducing the effects of intrinsic cholinergic tone. It is therefore intriguing to speculate that once a better definition of the Overlap Syndrome emerges in pediatrics, an important role for tiotropium is likely to emerge particularly as a potential steroid sparing medication.

Peter D Sly, AO MBBS, MD, DSc, FRACP, FERS, F Thor Soc, FAPSR, FAHMS p.sly@uq.edu.au

The measurement of lung function is of major importance in clinical practice or respiratory medicine and in respiratory research. Much has been learned about the risk factors underlying respiratory disease by measuring lung function in patients and comparing it with that in healthy controls. However, for managing an individual patient or assessing risk of disease onset or progression, it is necessary to know whether an individual's lung function is "normal" or "abnormal". Over the years, a number of sets of normative equations have been produced by individual research groups in different parts of the world. These have been incorporated into commercially-available spirometers and used in populations other than those in which the data were collected. This situation was far from ideal, especially as some of the normative equations were many decades old.

What is the GLI? Data were obtained from 73 centers in 33 countries (n ¼ 160,330) ; however not all could be used due to lack of data on ethnicity (which is illegal in France!), small numbers, missing data, lack of quality control and other factors. Data were also pooled by region with data from Europe, Israel, While FEV 1 and FVC varied between ethnic groups, they did so proportionally, meaning that FEV 1 /FVC was independent of ethnicity. The lower limit of normality for FEV 1 and FVC showed age dependence that differed between males and females, reaching 80% by mid-childhood and falling progressively below 80% from approximately 40 years of age. The rate of fall in the lower limit of normal for FEV 1 and FVC was identical for women but FVC declined more slowly in males. A ratio of FEV 1 / FVC >0.7 is taken to indicate pathological airflow limitation; however, the proportion of the healthy non-smoking population with FEV 1 /FVC >0.7 rises steadily to 20-25% at 80 years of age.

How well do the GLI reference equations predict lung function in people in individual countries? Given that the GLI reference equations were compiled by pooling data from a variety of sources, one might expect that the equations would provide good estimates of lung function for populations that were well represented in the pooled data whereas they may not for populations either not included or underrepresented in the pooled data. Indeed this appears to be the case, with the GLI equations adequately representing lung function in Australasian caucasians 2 , but not performing as well for adults in Brazil 3 , North Africa 4 , Madagasca 5 , and children in Poland 6 and peri-urban and rural India 7 . Further study is required to ascertain how widely the GLI reference equations can and should be applied.

What constitutes "normal" data? An important consideration when creating reference equations is what characterizes a "normal" population and who should be excluded? The dataset used to construct the GLI reference equations excluded ever smokers, but is this reasonable? If 20-30% of an adult population smoke, should they be excluded from equations designed to the lung function of that population? Maternal smoking during pregnancy results in long-term reduction in lung function 8 but is not generally taken into consideration when defining a healthy population. "Healthy" children are often defined as those with no prior asthma or hospitalization for respiratory problems, born full term with birth weight ! 2.5 kg and asymptomatic at the time of testing 9 . However, Lum et al. 9 recently demonstrated that with the exception of clear-cut factors such as current and chronic respiratory disease, including children born prematurely or with low birth weight, prior asthma and mildly symptomatic made little difference to the reference equations but increased the generalizability to the target population. This debate continues!

The implications of switching to the GLI equations will depend on how well the GLI equations represent lung function of the local population. In Poland, a switch from the 1998 Polish reference values to the 2012 GLI would see an increase in diagnosis of obstructive lung disease from 17.5% to 20.3% and an increase in diagnosis of restrictive lung disease from 3.8% to 7.6%. Whether this represents an over-diagnosis with GLI or an under-diagnosis with the old equations is a matter of clinical judgment. The impact on parents and children with cystic fibrosis is likely to be substantial as families tend to focus on lung function, especially FEV 1 expressed as a percent of predicted as evidence of the state of the child's lung disease. A change in number for a technical reason must be balanced against the likelihood of creating anxiety in the clinic population.

Respiratory symptoms are very frequent in infants and young children. Special emphasis has been put on symptoms signaling bronchial obstruction and bronchial hyperresponsiveness as these may be associated with early onset of asthma. Since the early 1980 0 s, several research groups have been focusing on early events in the development of asthma, especially seeking potential risk factors for predicting persistent symptoms. Structural changes in the bronchial mucosa and lung function impairment in children with early obstructive symptoms have also been studied. It was documented that eosinophilic inflammation and remodeling (particularly epithelial basement membrane thickening and increased airway smooth muscle mass) are consistently present in patients with persistent asthma. Interestingly, some markers of inflammation and even those of initial remodeling have already been described in children before the clinical diagnosis of asthma could be confirmed 1 . This finding supports the hypothesis of remodeling not being a late consequence of a long lasting eosinophilic inflammation but that it may run in parallel with the development of asthma, if not even precede or initiate inflammation in the bronchial mucosa. This hypothesis was later supported by further research based on bronchial biopsies in infants. Eosinophilic inflammation and some markers of remodeling have been documented in the bronchial mucosa of symptomatic children as early as in the second year of life 2 . In a recent study, we were able to show that basement membrane thickening could be found even in young children at risk of developing asthma even without a history of recurrent wheeze 3 . However, the significance of these findings in terms of long term prognosis still remains less documented. It is known that airway hyperresponsiveness in infancy is associated with persistent symptoms later in childhood 4 . Also, reduced airway patency at birth was shown to be linked to an increased risk of developing asthma and severe bronchial hyperresponsiveness by the age of 10 years 5 . Long-term follow up of children investigated in infancy and reassessed in later childhood have so far showed that reduced baseline lung function in symptomatic infants was significantly associated with subsequent respiratory morbidity as well as with the need of anti-asthma medication at the age of 3 years. In addition, the usage of inhaled corticosteroids at the age of 3 years also seems to be in positive correlation with basement membrane thickening and increased number of mast cells in bronchial mucosa in bioptic samples taken earlier in infancy 6 . This study has thus suggested that early morphological changes in the airway wall might indeed play a role in determining subsequent respiratory morbidity. On the other hand, at the next follow-up of these children at the age of eight years, the positive correlation between current respiratory symptoms and markers of inflammation and remodeling described in infancy was no longer found 7 . This finding is consistent with the results of the follow-up of our group of children where we did not find a significant correlation between lung function (both FEV 1 and FVC) measured in preschool age and basement membrane thickness measured earlier in infancy and toddler's age both in the risk group and control group of children (unpublished data). More recently, airway smooth muscle mass has come into the center of interest of many researchers in respiratory medicine. Smooth muscle hyperplasia and hypertrophy in the bronchial wall of patients with asthma are considered to be a consistent feature of bronchial remodeling. It is notably a possible dysfunction of newly formed smooth muscle bundles that deserves attention and more studies in this area are urgently required. The first works in children have shown that the increase in the airway smooth muscle mass in the bronchial wall might be associated with school age asthma 8 . Lately, another study has described a negative correlation between the airway responsiveness at the age of 8 years and airway smooth muscle mass in infancy 7 . However, this area of airway remodeling still remains poorly understood, especially with regard to its role in childhood asthma. Based on currently available data, reduced lung function at birth or in early childhood is apparently associated with the persistence of symptoms and the decrease in lung function in later life. However, it still has not been reliably confirmed whether this low lung function has any correlation with early signs of airway remodeling. More long-term follow-up studies are needed in pediatric patients comprising both tissue biopsies taken in early age followed by longitudinal long-term lung function monitoring.

Nasal and sinus disease is universal in cystic fibrosis (CF). Because nasal and sinus disease usually coexist, we will refer to this as "sinonasal disease". Since the mucosa of the sinuses and upper respiratory tract and the mucosa of the lower respiratory tract are similar, disease may be similar in both locations and sinonasal disease could influence the severity of pulmonary disease. This view of the "universal airway" has been demonstrated in patients with pulmonary conditions, such as asthma and COPD. In these diseases, an improvement in sinus health is reflected by an improvement in the lower airway disease. This has not been well studied in CF but the implications of this relationship combined with increasing life span makes an understanding of sinonasal disease important to the care of these patients. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in CF carriers appear to be independently associated with a higher prevalence of sinonasal disease; 36% of carriers reported chronic rhinosinusitis compared to the 13-14% in the general population. The bacterial flora of the sinuses changes with patient age, can include anaerobes and fungi, and often mirrors the organisms present in the lower respiratory tract. A link between sinus infection and lower respiratory tract infection may contribute to morbidity following lung transplantation and immunosuppression. Somewhat surprisingly, the prevalence of otitis media in CF appears to be no greater than in an age-matched general population. Endoscopy and computerized tomography have broadened our understanding of how CF affects the sinuses. Endoscopic sinus exams are almost always abnormal and give a better indication of the presence of nasal polyposis than physical examination of the nose alone. Nasal polyps become more common with age and may represent a proliferative airway repair mechanism. Sinus CT has demonstrated several anomalies characteristic of sinonasal disease in CF such as bulging or displacement of the lateral nasal wall, demineralization of the uncinate process, and hypoplasia or aplasia of the paranasal sinuses. Serious complications of sinonasal disease in CF are rare and include mucoceles and periorbital abscesses. These usually require surgery.

There are few randomized, controlled trials evaluating medical or surgical treatments of CF sinus disease. Sinus surgery may provide some benefit, though there are no established selection criteria for appropriate candidates. The trend today in Neonatal Intensive Care Units (NICUs) is to be as gentle and less invasive as possible in the care of neonates. This attitude takes place in every field of Neonatology, and will discuss its implementation specifically in the respiratory care administered to premature infants with respiratory distress syndrome (RDS). 1, 2 Prenatal corticosteroid therapy is recommended in all pregnancies with threatened preterm labor below 34 weeks' gestation. Recently, it was shown that such therapy could also be beneficial in late preterm infants as it significantly reduced the rate of a neonatal composite of respiratory treatments in the first 72 hours or stillbirth or neonatal death within 72 hours after delivery. 3 At delivery, the term stabilization and not resuscitation is preferred for the vast majority of very preterm infants. Only a minority of babies should require delivery room intubation. Neopuff can be helpful in the delivery room and the transport to the NICU, and enables the administration of continuous positive airway pressure (CPAP) and intermittent positive pressure ventilation under controlled conditions. Recent large trials that reflect current practice (including greater utilization of maternal steroids and routine post delivery stabilization on NCPAP) demonstrated less risk of bronchopulmonary dysplasia (BPD) or death when using early stabilization on NCPAP with selective surfactant administration to infants requiring intubation. The comprehensive strategy to prevent BPD in the NICU is based on ventilatory and non-ventilatory measures. 4 The ventilatory route allows an individualized endotracheal intubation approach. Recent studies concluded that early nasal CPAP (NCPAP) is a safe alternative to immediate intubation even in extremely low birth weight (ELBW) infants. 1, 2, 4 Endotracheal intubation and ventilation can result in significant damage to premature lungs and are independently associated with cerebral palsy. Furthermore, despite new modes of ventilation and surfactant, BPD remains a significant morbidity and its incidence was correlated with the use and length of endotracheal mechanical ventilation. BPD in itself is associated with adverse neurodevelopmental outcome. Thus, we need to avoid endotracheal ventilation, if possible. When the infant requires nasal respiratory support (NRS), we should aim for adequate oxygenation (SpO 2 of 90-95%), 1 permissive hypercapnia (PaCO 2 of 45-55 mm Hg, pH >7.22) and gentle ventilation, similarly as in endotracheal ventilation. 1, 4 NCPAP is recommended as the early primary treatment of active respiratory distress syndrome (RDS) (to avoid intubation or as part of the INSURE [INtubation SURfactant Extubation] approach), or later, post extubation at RDS resolution, in order to allow shortening of the duration of endotracheal ventilation and to treat apnea of prematurity. 1, 2 Recent studies 1, 4 report comparable rates of BPD in ELBW infants treated initially with NCPAP as compared to endotracheal ventilation with surfactant administration. Can we enhance NCPAP and get better outcome for NRS by using nasal intermittent positive pressure ventilation (NIPPV)? NIPPV was defined as a method of augmenting NCPAP by delivering ventilator breaths via nasal prongs. The rationale behind the use of NIPPV is the administration of "sigh" to the infant, thus opening microatelectasis and recruiting more ventilation units. It was shown that synchronized NIPPV (SNIPPV) compared with NCPAP may improve the patency of the upper airway, could activate the respiratory drive, improves thoraco-abdominal synchrony, stabilizes the chest wall, improves lung mechanics and decreases the work of breathing in premature infants. When NIPPV was compared to NCPAP for the different indications of NRS, it was shown to enhance the potential of NRS. 4 A recent meta-analysis demonstrated a relative risk reduction for intubation in the first 72 hours in the NIPPV group compared with NCPAP (RR 0.60, 95% CI 0.43, 0.83). 5 The NIPPV trial 6 was a large international multicenter randomized trial powered to study the important outcome of BPD, recruiting 1,009 extremely low birth weight babies, and it showed no difference between babies randomized to NIPPV compared with CPAP. SNIPPV vs. NCPAP for later use, post extubation at RDS resolution, as a "bridge" to spontaneous unsupported breathing, was shown to be more effective than NCPAP. A pooled meta-analysis showed that SNIPPV was more effective than NCPAP in preventing failure of extubation [RR 0.21 (0.10, 0.45)] and the number needed to treat was only 3 infants to prevent one extubation failure. 7 SNIPPV vs. NCPAP, post extubation, also tended to decrease the rate of BPD. SNIPPV may also be more effective than NCPAP for apnea of prematurity. 4 A meta-analysis regarding apnea of prematurity suggests that SNIPPV is more efficacious with apnea that is frequent or severe. However, the studies performed addressed short-term outcomes and as such could not properly address the incidence of requirement for reintubation. Thus, more studies are needed before recommending SNIPPV as standard of care for apnea of prematurity.

While non-invasive ventilation is probably safe, its success depends on gestational age. The data indicate that surfactant may still have a significant role in the treatment of RDS, especially in ELBW infants. Recent studies reported on an intubation rate of $50% in their NCPAP group in ELBW infants. 1, 2, 4 This leads us to the INSURE approach. This approach may allow the infant to benefit from both surfactant and NRS. A Cochrane review 8 concluded that the INSURE approach with NCPAP compared with later selective surfactant administration, continued mechanical ventilation, and extubation from low respiratory support was associated with less need for mechanical ventilation, lower incidence of BPD and fewer air leak syndromes. Another option for surfactant application to the trachea without endotracheal intubation was described by using a thin catheter in spontaneously breathing preterm infants receiving NCPAP. This technique was reported to reduce the need for mechanical ventilation. 9 There are ongoing trials with inhaled surfactant. To summarize, NCPAP is still the most common mode of non invasive respiratory support worldwide. 1, 2 The available evidence supports the preference of early or later use of NIPPV/SNIPPV compared to NCPAP because of minimizing the use and the length of endotracheal ventilation. 4 There are data to suggest that this approach may also reduce the rate of BPD, however this has yet to be shown. 4 The results of a large international RCT comparing both primary and post-extubation use of NIPPV with NCPAP, with a composite primary outcome of death or BPD at 36 weeks' corrected age, indicate no additional benefit, or risk, conferred by NIPPV in comparison to NCPAP. 6 Whether NIPPV/SNIPPV is more beneficial than NCPAP within the INSURE approach needs to be shown. Recently, heated, humidified high-flow nasal cannula (HHHFNC) is frequently used as a mode of NRS. High flows result in washout of anatomical and physiological dead space and contribute to improved fractions of alveolar gases with respect to carbon dioxide as well as oxygen and decrease the work of breathing and the energy cost of gas conditioning. HHHFNC probably creates positive end expiratory pressure (PEEP) that may contribute to its beneficial effect. However, the PEEP that is not monitored had raised concerns regarding the safety of HHHFNC in terms of air leak. Recent prospective studies support the notion that HHHFNC is as effective as NCPAP for early stages of RDS, post extubation 10 and for apnea of prematurity. Yet, more studies, especially in the initial treatment of RDS and in ELBW infants, are needed before adopting HHHFNC as an alternative mode of NRS in these conditions. New modes of NRS such as neurally adjusted ventilator assist (NAVA), and nasal high frequency ventilation, need to be further studied before concluding on benefits for the short and long term outcomes in premature infants. Non-ventilatory measures in the treatment of RDS, such as caffeine, nutrition, fluid and PDA management and postnatal steroids in certain conditions should be included in the care of premature infants with RDS in order to minimize the rate of BPD. 1, 4 The noninvasive ventilator strategy needs to be confirmed by large prospective randomized controlled trials (with long-term follow up) in order to assure it is applicable to most ELBW infants. Furthermore, the strategy needs to be tailored to individualized infants according to the infant's maturation; antenatal steroid treatment and severity of RDS; general condition; and to certain practical NICU conditions such as experience, personnel and timing during the day.

For many years, it has been generally accepted that the pathophysiology of RSV bronchiolitis is driven by the inflammatory response evoked by horizontal (i.e., interpersonal) transmission of the virus in the first few months after birth (1). However, a recently published study has brought to the forefront a striking new idea: RSV may be transmitted vertically from the respiratory tract of the mother to the lungs of the fetus (2) . Until now, we believed that when a pregnant woman got a cold, the developing fetus was protected by the placenta from RSV and other respiratory viruses. In this study, pregnant rats were inoculated with a recombinant RSV strain that could be tracked through expression of a red fluorescent protein (rrRSV). The same virus was subsequently found in 30 percent of fetuses exposed in utero, as well as in the lungs of 40 percent of newborn rats and 25 percent of rats born to inoculated mothers when tested in adulthood. These data provide proof of concept for the transplacental transmission of RSV from mother to offspring and the persistence of vertically transmitted virus in lungs after birth. Notably, the intrauterine RSV infection changed expression and function of critical neurotrophic pathways that control the development of cholinergic nerves in the budding airways and lung tissues (3). These changes in cholinergic innervation of the fetal respiratory tract resulted in the development of postnatal airway hyperreactivity upon reinfection with the same virus (2) . The airway smooth muscle tone was normal in the absence of stimulation and its contraction was normal in the absence of either maternal or neonatal infection. But in pups reinfected with RSV after prenatal exposure to the virus, markedly potentiated contractile responses were measured after either electrical nerve stimulation or methacholine inhalation, suggesting the involvement of both pre-and postjunctional mechanisms. These findings are consistent and provide a plausible mechanism to the epidemiologic evidence that early-life RSV infection -or possibly reinfection -predisposes a subpopulation of children to recurrent wheezing and asthma that typically spans through the first decade of life even in the absence of atopic phenotype (4). To our knowledge this is the first report of vertical transmission of RSV, or for that matter any common respiratory virus. A number of infectious agents, including herpesviruses and retroviruses, have been shown to cross the placenta and establish persistent infection in offspring. The new evidence extends this possibility to other infections, such as RSV, once regarded as temporary and localized and that instead may be longer lasting and more pervasive than we thought. Also, as shown for other viral pathogens, if RSV seeds the fetus before full T-cell maturation, this could lead to induction of prenatal tolerance and justify the limited synthesis of interferon and other inflammatory cytokines that have been noted when newborns develop severe infections (5) .

Vertical RSV and asthma -The general concept that we have been working under for decades is that nothing bad happens in the lungs until the baby is born -even with serious conditions such as cystic fibrosis -and that the lungs are "clean" of pathogens at birth. But if human studies replicate the findings from animal models outlined above, our understanding of the pathogenesis of RSV infections would be completely changed. It would turn back the clock of respiratory developmental diseases by months and mean that we would need to start thinking about lung development and pathology during pregnancy rather than at birth. This could create a paradigm shift by extending our focus on prevention from the first few years after birth to also include the last few months before birth. This new paradigm is in line with the emerging evidence that many (or most) chronic inflammatory, degenerative, and even neoplastic diseases plaguing adults have their origins from often-subtle events occurring during fetal life. The "foetal programing hypothesis" was originally formulated by Dr. David Barker more than two decades ago to explain the extensively reproduced and confirmed epidemiologic evidence that low birth weight predisposes to cardiovascular disease in late adulthood (6) . Dr. Barker died aged 75 in September 2013, leaving the legacy of this initially controversial, but now widely accepted, idea that common chronic illnesses such as cancer, cardiovascular disease and diabetes result not always from bad genes and an unhealthy adult lifestyle, but from poor intrauterine and early postnatal health. In one of his last public speeches, he argued: "The next generation does not have to suffer from heart disease or osteoporosis. These diseases are not mandated by the human genome. They barely existed 100 years ago. They are unnecessary diseases. We could prevent them had we the will to do so." We believe the same concepts can be extended to chronic obstructive airway diseases like asthma and COPD. Asthma is the final product of complex interactions between genetic and environmental variables. Prenatal events like the intrauterine exposure to viruses with specific tropism for the developing respiratory epithelium (7) or imbalanced maternal diet (8) will cause a shift in the trajectory of structural and functional airway development towards a hyperreactive phenotype. The same intrauterine exposures can affect gene expression via epigenetic modifications like DNA methylation, histone acetylation, and by altering the relative expression of regulatory micro-RNAs (9) . The resulting neonatal phenotype will predispose the child to aberrant responses to common respiratory infections and airborne irritants, thereby increasing the risk of obstructive lung disease later in life. Postnatal events, such as exposure to indoor and outdoor pollutants and allergens, can further shift the equilibrium of the adult phenotype by exacerbating airway inflammation and hyperreactivity (10) . The continuous range of possible developmental trajectories and multiple sequential events acting during development will define the severity and duration of disease.

The incidence, severity and mortality from childhood pneumonia has declined substantially in the last decade due to improved socioeconomic conditions, better access to care, wider implementation of effective management and preventative strategies and development and availability of improved vaccines, particularly the pneumococcal (PCV) and H influenzae type b (Hib) conjugate vaccines. [1] However, pneumonia remains the leading cause of childhood mortality globally outside the neonatal period and a major cause of morbidity and hospitalization despite good immunization coverage. [2, 3] Further, early childhood pneumonia has increasingly been associated with the development of chronic noncommunicable respiratory diseases into childhood and adulthood, such as asthma or chronic obstructive airways disease (COPD). [4, 5] With improved global coverage of the newer conjugate vaccines, it is likely that viral causes of pneumonia may be responsible for an increasing proportion of pneumonia cases. [6] However, defining the etiology of pneumonia may be challenging as it can be difficult to distinguish colonizing from pathogenic organisms in respiratory specimens, blood culture rarely is positive and pneumonia, especially severe disease, may frequently be due to multiple co-pathogens. The development of better methods for specimen collection and of molecular diagnostics have provided more sensitive techniques to define potential etiologic agents but further compound the difficulty of ascribing pathogenicity. [7, 8] Despite these limitations, studies in the post-PCV era have reported an increasing predominance of viruses in childhood pneumonia cases, with a virus identified in 70-90% of cases. [9, 10] In children vaccinated with 13valent PCV (PCV13), RSV has been reported to be the predominant pathogen in case control analyses from both high income countries and lowmiddle country settings. However, there is frequent co-occurrence of other potential pathogens with RSV, including bacteria and other viruses. [9] Children under 6 months of age are at highest risk of RSV disease. [11] To adequately interpret data on viruses in the context of childhood pneumonia, the prevalence of these in healthy control children must be considered. Using case control designs, viruses identified in association with pneumonia have been RSV, influenza virus and human metapneumovirus (hMPV); adenovirus, parainfluenza virus and coronavirus have been variably associated with pneumonia while the prevalence of rhinovirus has consistently been similar in cases and controls. [9, 10, 12, 13] The use of quantitative measurements of viral load has not shown to be useful in distinguishing cases from controls except for RSV and for hMPV, but the presence of these alone is sufficient to ascribe etiology.

These studies indicate that RSV is a major cause of pneumonia in the era of conjugate vaccines for bacterial pathogens, particularly in young infants. However they also highlight the limitations of current diagnostic strategies, particularly the poor sensitivity of current tests for bacterial etiology and the potential for incorrectly assigning etiology based on molecular diagnostics. They also provide further data on the complexity of ascribing pneumonia etiology, showing interactions between multiple potential pathogens. Despite these limitations, the emerging data indicate that a key strategy for reducing the burden of childhood pneumonia lies in prevention of RSV disease in young children.

Identifying the etiology of pneumonia is key for initiating appropriate management strategies particularly use of antibiotics and to guide development of new vaccines. The reduction in bacterial pneumonia through conjugate vaccines underscores the need to reconsider the empiric treatment of pneumonia in settings where there are strong immunization programs. Case management with antibiotics for pneumonia or severe pneumonia in the World Health Organization Integrated Management of Childhood Illness (IMCI) program has been a highly effective strategy for reducing mortality prior to widespread conjugate vaccine availability [14] , but defining the residual burden and identifying clinical or laboratory features that distinguish bacterial from viral pathogens will be important before any change in pneumonia strategy can be recommended globally.

Late preterm (LP) newborns (born at 34-0/7 to 36-6/7 weeks gestational age) comprise the fastest growing subset of neonates, accounting for approximately 74% of all preterm births and about 8-9% of total births in the US [1] . "Late preterm" infants are born near term, but are "immature". The late premature birth interrupts normal in utero fetal development during the last 6 weeks of gestation that are probably a "critical period" of growth and development of the fetal lungs [2] . Three factors play a role in the respiratory vulnerability of LP infants [2] : 1. Prematurity with its developmental and consequently physiologic components; 2. Heightened rate of respiratory morbidity in the neonatal period; 3.

Short-term pulmonary outcome Respiratory complications are the prime morbidities of LP infants [2] . A large retrospective study [3] found that the odds of respiratory morbidity (respiratory distress syndrome [RDS] , transient tachypnea of the newborn [TTN], pneumonia, respiratory failure, surfactant administration, and mechanical ventilation) decreased significantly with each advancing week of gestation up to 38 weeks compared with 39 to 40 weeks. Despite a relatively low absolute risk for RDS or TTN at 34 weeks compared with more premature infants, this rate poses an increased risk for LP infants when compared with term infants [2] . Acknowledgement of these morbidities led to studies aiming to decrease this burden. A recent large randomized controlled study [4] showed that administration of betamethasone to women at risk for late preterm delivery significantly reduced the rate of a neonatal composite of respiratory treatments in the first 72 hours (the use of continuous positive airway pressure or high-flow nasal cannula for at least 2 hoursr, supplemental oxygen with a fraction of inspired oxygen of at least 0.30 for at least 4 hours, extracorporeal membrane oxygenation, or mechanical ventilation) or stillbirth or neonatal death within 72 hours after delivery. Of note, neonatal hypoglycemia was more common in the betamethasone group than in the placebo group.

Late prematurity may affect the respiratory system in the long term [2] . Several studies reported an association of preterm birth (30-36 weeks' GA) without clinical lung disease with altered lung development and function [2] . Friedrich et al. [5] in a longitudinal study found that despite normal lung volume, healthy preterm infants had persistently reduced airflow through the age of 16 months and concluded that preterm birth in itself was associated with altered lung development. A single study [6] showed a potential improvement, especially for large airway function, with advancing age.

A recent large prospective cohort study showed that the number of hospitalizations caused by respiratory problems during the first year of life was doubled in moderately/late preterm (32-36 weeks' GA) compared with term infants [7] . At preschool age, moderately preterm infants revealed more nocturnal cough or wheeze during or without a cold and increased use of inhaled steroids. At the age of 5 years, rates of respiratory symptoms between moderate and early preterm born (<32 weeks' GA) children were similar; both were higher than in term born children. Whether LP birth is associated with airway disease such as asthma in early childhood remains controversial [2] . Different findings in published studies could result from the different methods of asthma diagnosis, age groups at diagnosis, and from the difficulties in diagnosing asthma in early childhood. A recent study [8] found that late preterm birth history is not independently associated with childhood asthma until 7 years of age. LP infants are more vulnerable to viral respiratory infections, particularly RSV, which are more severe in these infants vs. term infants. The pernicious combination of RSV bronchiolitis affecting an a priori compromised lung/ airways of LP infants may have a lasting effect on respiratory function and consequent long-term morbidity [2] . Long-term persistence of an early decrease in pulmonary function tests (PFT) was demonstrated by a longitudinal follow-up into early adulthood for an unselected random population in the Tucson Children's Respiratory Study [9] . These observations suggest that the notion of a "critical developmental period" for the respiratory system does exist. Deficits in lung function during early life, especially if associated with lower respiratory illnesses (especially RSV), increase the risk for chronic obstructive pulmonary disease later in adult life [10] .

Summary LP infants are born during a "critical developmental time period" for the lungs. This may result in short and long-term pulmonary consequences. In addition, to screen the population at high-risk for disease. Therefore, the effectiveness of early case finding should be a priority, but it depends on several factors such as health care system, contact tracing, and laboratory diagnosis.

The diagnosis of TB in children is a common clinical challenge, and relies on a careful assessment of history of exposure, clinical examination, and relevant investigations. The most recommended approach to the diagnosis of TB in both children and adults is based on the WHO guidelines recommendations from 2010 and 2014 (table 1) . (2, 3) Important factors to consider in all children with suspected TB is the endemic setting as well as the age and immune status of the child. In countries with a low incidence of TB, a positive contact with a case in combination with suggestive symptoms makes diagnosis more straightforward. In high TB endemic areas, a history of TB contact remains important, but is much less sensitive, given that transmission often occurs through unknown source cases. (5) Laboratory tests for the diagnosis of infections can be grouped into two groups: detection of microbes (or components) and detection of components of the immune response to the microbe. The sensitivity of the first group will depend on the quality of the specimen and the concentration of microorganisms. This group includes microscopy, culture, ELISA, and nucleic acid detection (PCR). The second group measures the activity of the immune system against microbe-specific antigens in the possibly infected host. This category includes antibody detection and activated T cells. The gold standard for the diagnosis of TB is bacillary detection by smear or culture. In adults, microscopy can detect up to 60% À 70% of culture-positive samples. In children, this does not work as well due to limited access to appropriate body specimens, and also because children usually have paucibacillary disease, since cavitating disease is rare in children. Studies have shown that under best circumstances, acid-fast bacilli sputum smear is positive in only about 10-15% of children with TB while culture gives a better yield of 30-40%. Until recently, the diagnosis of LTBI has been based exclusively on the TST, which has relatively poor sensitivity and specificity. Despite these limitations, it remains the standard of care for diagnosis of LTBI worldwide, particularly in low-income countries. Interferon Gamma Release Assays (IGRAs) measure the in vitro response to specific M. tuberculosis antigens.

Although they offer several advantages over TST such as better specificity, single visit, little inter-observer variability, and no booting effect; they have not been found better than TST, and are not able to predict the risk of infected individuals developing active TB disease. Given their increased cost, replacing TST by IGRAs as a public health intervention in resourceconstrained setting is not recommended. Novel approaches to confirmation of TB have been developed. These include methods based on rapid culture techniques and genotypic techniques that improve detection of M. tuberculosis. An example is the Xpert MTB/RIF assay, which is a fully automated realtime DNA based test that can detect both TB and rifampicin resistance in less than two hours. (3, 6, 7) As expected, it should be used rather than conventional microscopy and culture in children suspected of having MDR-TB. The clinical diagnosis of primary TB in children remains challenging because of non-specific signs and symptoms and difficulty with acquiring diagnostic specimens. Because of this, the diagnosis of primary TB in practice, relies on a combination of clinical features and chest X-ray (CXR) findings. The detection of lymphadenopathy in the hilar and para-tracheal regions on the frontal CXR, supported by identification of subcarinal lymphadenopathy on the lateral CXR, represent a useful surrogate marker of TB at relatively low cost. However, sensitivity and specificity for identifying lymphadenopathy on CXR in children is relatively poor with significant inter-observer variation in the interpretation of radiographs, complicated further by poor quality of radiographs. Affecting both accuracy and observer agreement is the lack of standardized imaging criteria and lymph nodes sizecriteria for a positive diagnosis of primary TB. Attempts are therefore being made to establish 'objective' chest radiograph signs backed up by a standard set of images as a guide. Ultrasound is an especially attractive imaging alternative to CXR as it does not involve radiation or require sedation and because it is relatively cheap and mobile. Ultrasound of the mediastinum has been used to detect mediastinal lymphadenopathy and can also be used to detect extrapulmonary TB through abdominal imaging, at the same sitting. It is particularly useful in rural settings where no other imaging is available. The ability to store digital ultrasound images and cine-loops also enables teleradiology support by expert interpretation and opinion, from a distance. Computed tomography (CT) and magnetic resonance imaging (MRI) are obvious diagnostic imaging considerations that will improve diagnostic accuracy of primary TB, but the radiation dose in CT, the need for anesthesia in MRI, the limited availability and high cost are real barriers to their clinical utility. MRI is preferred to CT because it does not involve ionizing radiation. However, the disadvantages of MRI for lung imaging (poor signal generated from the air in the lungs and movement artefacts from breathing), the cost and the requirement for the child to keep still for a prolonged period (requiring anesthesia) have slowed its use in thoracic infections. Yet, whole body MRI, including thoracic imaging is mainstream for detecting lymphadenopathy in childhood lymphoma. The preferred imaging technique varies with the suspected pathology and available equipment. Dynamic imaging techniques such as inspiratory/ expiratory CXR, fluoroscopy, and inspiratory/expiratory or cine CT permit the lungs and airways to be imaged at different phases of the respiratory cycle. Inspiratory/expiratory CXR and inspiratory/expiratory chest CT have long been the preferred initial imaging methods for detecting foreign body aspiration or bronchiolitis obliterans, respectively, on the basis of air trapping rather than direct visualization of the airway obstruction. Fluoroscopy has historically been the preferred noninvasive method for diagnosing tracheobronchomalacia due to its ease of performance, even in uncooperative patients, and its high specificity, but it is limited by its subjective interpretation, low sensitivity, poor depiction of the paratracheal structures, and inability to simultaneously display the anteroposterior and lateral walls of the airway and quantify luminal cross-sectional area 1 .

In infants and children too young to comply with breath-hold instructions, inspiratory/expiratory phases can be simulated by imaging during right/left lateral decubitus or prone/supine positioning. Controlled-ventilation CT under sedation or anesthesia also permits inspiratory/expiratory imaging of the lungs and airways in uncooperative patients. Dynamic cine CT technique allows the airways to be imaged sequentially during successive phases of the respiratory cycle, but coverage was initially limited to short (4 cm or less) segments of the airway, resulting in sampling misregistration and preventing synchronous evaluation of the true extent and severity of airway collapse during the same phase of the respiratory cycle 1 . Made possible by recent technologic advances including more rapid gantry rotation and wider detector arrays (up to 16 cm craniocaudal coverage), dynamic volumetric cine CT now allows all or nearly all of the lungs and central airways to be imaged rapidly and sequentially throughout the respiratory cycle without the need for sedation or intubation. This technique is capable of providing multiplanar, 3D and 4D information about the airways during normal tidal breathing or forced expiratory maneuvers, as well as depicting the relationship of the airways to the adjacent vasculature if intravenous contrast is administered 2 .

With dynamic volumetric cine CT, intrinsic and extrinsic causes of airway narrowing can be distinguished and fixed airway stenosis can be differentiated from expiratory central airway collapse due to tracheobronchomalacia (softening of tracheobronchial cartilage) or excessive dynamic airway collapse (inward bulging of the posterior membrane) 3 . Tracheobronchomalacia is primary (congenital) in approximately 1/2100 children and often resolves in isolated mild to moderate cases by 2 years of age as the cartilage geometry and composition matures and posterior membrane tone develops. Tracheobronchomalacia is often accompanied by gastroesophageal reflux disease and is associated with other foregut anomalies, especially esophageal atresia and tracheoesophageal fistula. Tracheobronchomalacia can be secondary to extrinsic compression, chronic airway inflammation, intubation, or positive pressure ventilation and is identified in about onefourth of children with chronic respiratory symptoms or signs such as wheezing, barking cough, recurrent respiratory tract infection, apnea, cyanotic spells, or difficulty weaning from respiratory support 4 . Tracheobronchomalacia was originally defined as >50% reduction in airway cross-sectional diameter during coughing, but false positives are very common with this definition, especially for the bronchi in which physiologic expiratory airway narrowing is more pronounced than for the trachea. The shape and cross-sectional area of the airway lumen can be precisely determined by CT, but there is no current consensus on the optimal threshold degree of expiratory airway collapse for a diagnosis of tracheobronchomalacia among children of varying ages with or without coexisting lung disease during either tidal breathing or forced expiration. Expiratory collapse of normal airways can occur in the setting of obstructive lung disease such as asthma or bronchopulmonary dysplasia due to increased pleural pressure and increased peripheral airways resistance that reduces airway transmural pressure 4 . Dynamic volumetric cine CT provides objective information to classify expiratory central airway collapse according to the FEMOS (functional status, extent, morphology, origin, severity) system 5 , but it should be noted that the degree of luminal narrowing is only one factor in airflow limitation. Evidence of airway compression or expiratory collapse on imaging does not necessarily indicate a condition requiring therapeutic intervention, and correlation with the clinical symptoms, signs, risk factors, and pulmonary function tests is necessary to determine the functional significance 1, 4 . In addition to the noninvasive nature, the advantages of dynamic volumetric cine CT over bronchoscopy include the ability to directly evaluate for vascular structures or soft tissue masses that impinge on the airway, depict the airways distal to a narrowing impassable by bronchoscope, and assess the lung parenchyma for conditions such as air trapping that may be associated with dynamic central airway collapse 2 . A disadvantage of CT is the exposure to ionizing radiation. For perspective, dynamic airway CT incurs a radiation dose similar or less to than that from a year of natural background radiation exposure 6 . Dynamic cine magnetic resonance imaging (MRI) avoids exposure to ionizing radiation and is capable of imaging the central airways and vasculature 7 , but is limited by a longer scan time, more frequent need for sedation/anesthesia and less detailed depiction of the lung parenchyma compared to CT. Additional studies in children are needed to determine how the anatomic and functional information provided by dynamic CT is best applied to the diagnosis, treatment planning, and post-therapeutic monitoring of pediatric airway disorders.

The main driving force to develop sophisticated MRI sequences for pediatric chest imaging is that MRI is a radiation-free technique. This is especially important for children who are more sensitive to ionizing radiation than adults [8] . This justifies the use of chest MRI for short-and long-term follow-up of chronic lung diseases such as cystic fibrosis (CF), so as to reduce the lifelong cumulative radiation dose [1] . Chest MRI is challenging because of the magnetic heterogeneous environment in the chest region [2] . Lung parenchyma is a low proton density structure and hence has a reduced signal-to-noise ratio [3] . In addition, the numerous airtissue interfaces within a voxel induce strong localized microscopic magnetic field gradients, which produce extensive MRI signal dephasing leading to extremely short T2 star (T2 Ã ) and geometric distortions. These effects become stronger at higher magnetic field strengths (i.e. 3 T), which are increasingly used in clinical settings for enhanced signal-to-noise ratio [1] . However, signalto-noise ratio in cases of lung pathology, such as pneumonia, edema, tumors and atelectasis, is increased by higher fluid content and amount of tissue. These conditions result in higher proton density and improved visualization [4] . Moreover, MRI has the advantage of integrating anatomical and functional information in a single examination, a possibility not as readily available with other imaging modalities. MRI can provide functional information regarding lung perfusion using gadolinium contrast [5] , lung mechanics using dynamic acquisitions [6] , and ventilation using inhaled hyperpolarized gases [7] , oxygen enhancement or dynamic motion-based methods [8] . Moreover, DWI is able to give new insight in the management of pneumonia, especially in CF Patients [9] . Chest MRI has reached the point where it can be used in routine clinical practice. Although MRI cannot yet be compared to CT for anatomical detail, new sequences allow acquisition of lung images with high diagnostic quality in less than 15 s, which makes MRI feasible in a clinical setting. MRI can be considered an alternative to CT for the diagnosis of lung diseases and for monitoring response to treatment in pediatric lung disease. Moreover, in some diseases that require long-term follow-up, such as cystic fibrosis, MRI can play an important role in reducing lifelong radiation exposure related to repeated CT scans. Furthermore, MRI has the ability to offer functional information: information regarding lung mechanics, perfusion and ventilation can provide new insight in different pediatric lung diseases. This functional information can not only improve our understanding with regard to the pathophysiology of pediatric lung diseases, it can also open new diagnostic and therapeutic options. Obstructive sleep apnea syndrome (OSAS) is characterized by prolonged partial airway obstruction and/or intermittent complete obstruction (obstructive apnea) during sleep, affecting about 2% to 3% of children [1] . OSAS is a complex syndrome with multiple etiologic factors: the main causative factor is adenotonsillar hypertrophy while other conditions, such as craniofacial dysmorphism, obesity, hypotonic neuromuscular diseases, despite inducing reduction of the caliber of the upper airways, are commonly mistreated [2] . Adenotonsillectomy has been considered for many years the only treatment in children with OSAS although its efficacy remains uncertain, depending on the severity and on the presence of other co-morbidities, [3] . Since a residual OSA is reported in a large proportion of children after adenotonsillectomy [3] , and children with OSA display a complex phenotype (mild or major craniofacial anomalies, and/or comorbid obesity, and/or adenotonsillar enlargement), a multi-therapeutic approach to pediatric OSAS and a defined timing of therapy are required [3, 4] . A narrow upper airway accompanied by maxillary constriction and mandibular retrusion is commonly reported in children with OSAS [5] . The skeletal conformation showing hyperdivergent skeletal growth pattern associated with posterior displacement of the tongue base, increases the upper airway narrowing and craniomandibular, intermaxillary, goniac and mandibular angles leading to a high-arched (ogival) palate [6] . Rapid maxillary expansion (RME) is the most common dento-facial orthopedic procedure used in young patients to treat maxillary transverse deficiencies, starting up to 4 years of age. Recently, it has been demonstrated to be efficacious to treat OSAS in children with a narrow palate and malocclusion: a significant reduction in the apnea-hypopnea index and in diurnal symptoms after six months of therapy with RME [7] , and positive long-term effects in children with OSA and malocclusions treated with RME have been reported [8] . Similar results were obtained after one year of treatment with RME in 16 preschool and school-aged non obese children with OSAS and dental malocclusions with a significant drop in clinical symptoms as well as apnea-hypopnea index [8] . This study also demonstrated that starting treatment early when the bone is still extremely plastic and its growth rate is maximum increases the percentage of success of RME treatment. A two-year follow up after the end of the RME application was performed in the same population of children confirming a stable decrease in apnea-hypopnea index, an increase of mean overnight oxygen saturation and a persistent improvement in clinical symptoms [9] . Finally, a recent randomized study showed preliminary results regarding the effect of RME applied before adenotonsillectomy compared to the effect of RME applied after surgery, in children with OSA. No significant differences between the two different approaches were described [10] .

In conclusion, orthodontic treatment is a valid treatment for OSA, improving clinical symptoms, respiratory parameters measured during PSG with long lasting effect. The widening of the maxilla, the corrections of dental malocclusions and the correct relationships between maxillary and mandibular arches with respect to the anterior cranial base, are the main craniofacial changes induced by RME that may explain the efficacy of orthodontic therapy. Orthodontic therapy should be encouraged in pediatric OSAS, and an early approach may permanently modify nasal breathing and respiration, thereby preventing obstruction of the upper airway.

Towards the turn of the century, David Gozal's group published a series of papers that raised important questions. In a sample of 297 1 st grade pupils whose school performance was in the lowest decile of their class ranking, they found that 18% had sleep-associated intermittent hypoxia and/or hypercapnia; school performance improved in those whose parents had opted for adenotonsillectomy (1) . They then showed that 13% of 14-15 year olds with poor school performance had parent-reported snoring at age 4-5, compared to only 5% among those with good school performance (2). Finally, a group of first graders with snoring, but no obstructive sleep apnea, i.e. an obstructive apnea index <1, performed worse on measures related to attention, social problems and visuospatial function than non-snorers, suggesting that simple snoring may not be as benign as hitherto widely believed (3) . Against this background, we set out to perform the Hannover Study on Sleep Apnea in Childhood (HASSAC), a community-based cross-sectional study on several aspects of sleep-disordered breathing (SDB) in 1144 primary school children incorporating a two-phase sequential screening procedure: Participants were screened for symptoms and signs of SDB using an SDBquestionnaire and home pulse oximetry (HPO), those with outlying results on either screening method subsequently underwent an abbreviated home polysomnography (hPSG) for a final diagnosis of obstructive sleep apnea syndrome (OSAS). Overall, participants were representative of the underlying population of third-graders in the study region. We found that 10.1% of this cohort were habitual snorers, while the population prevalence for OSAS was 2.8% (4, 5) . We then wanted to know how these symptoms affected behavior and academic achievements. For this, we used parental questionnaires and collected teachers' ratings, and defined poor school performance as grade 4 or worse in the last school report form, or requirement for special assistance, with this classification roughly corresponding to the lowest quintile of a class. We found that children with habitual snoring, compared to those who never snored, had 3-10 times the odds for daytime symptoms such as hyperactivity, difficulty concentrating, falling asleep while watching TV or at school or having peer problems, and 2-3 times the odds for poor school performance in mathematics, science and spelling (4, 6) . There was a clear dose-effect gradient, i.e. the proportion of children with poor school performance increased with increasing frequency of parent-reported snoring. Considering its high prevalence, and assuming a causal link to disturbed behavior, habitual snoring appeared to be a substantial public health problem in primary school children.

Given this association, we wanted to know how this is mediated, i.e. whether this is mainly through detrimental effects of intermittent hypoxemia or more likely due to recurrent arousal. Contrary to our hypothesis, the increased odds for poor school performance or daytime symptoms associated with habitual snoring stayed the same once children exhibiting intermittent desaturation in their overnight pulse oximetry recording had been excluded, suggesting that even so-called benign snoring, i.e. snoring without hypoxemia, may in fact not be benign.

If not via intermittent desaturation, could the relationship with poor school performance be mediated via frequent arousals elicited by recurrent obstructive apnea? To address this question, we took advantage of the fact that children with an abnormal questionnaire score in our HASSAC study also underwent hPSG. Thus, we re-analyzed our data on the relationship of snoring with daytime symptoms and poor school performance after excluding all children with a mixed-obstructive apnea/hypopnea index (MAOHI) !0.5, but again, the risk for poor school performance was not reduced among snorers after excluding those with recurrent apneas. Given that simple snoring has such a strong association with daytime symptoms À are these reversible? In our HASSAC study, we could collect 1year follow-up data in 82 snorers and 80 controls. Among these, 42 snorers (51%) had stopped snoring. While their scores for emotional problems, hyperactivity and problems with peers improved, their school performance did not (6) . This is in line with other data suggesting that reduced scores in executive functioning and IQ seen in children prior to adenotonsillectomy may not improve following this operation (7) . Similarly, in the Avon longitudinal study on parents and children (ALSPAC), even those whose SDB symptoms peaked at age 30 months and abated thereafter still had almost twice the odds for hyperactivity and 60% higher odds for behavioral problems at age 7 years (8). Taken together, there is now a growing body of evidence that frequent snoring in children may not be as benign as previously thought, but may instead be associated with impaired behavior and poor academic achievements. These problems may even persist after snoring ceases, which À if these statistical associations were confirmed as causal À would argue for their early recognition and treatment. Here, it is encouraging to see that in another longitudinal study on snoring and daytime symptoms, the proportion of children who did not snore at age 2 and 3 years was 42% in those who were breastfed for less than 1 month, but 83% in those who were breastfed for 12 months or longer (9) , suggesting that breastfeeding may reduce the risk of snoring during early childhood. In addition, given the limited availability of sleep labs, we urgently need better and easier-toperform screening methods to identify those who may need treatment for their snoring, e.g. in whom poor school performance can be predicted from a screening test (10) . Also, interventions such as nasal steroids, montelukast or orthodontic treatment may deserve further study.

Diagnosis of OSAS using home respiratory polygraphy (HRP). Alonso-Alvarez et al. 3 prospectively assessed the diagnostic reliability of HRP in children aged 2 to 14 years with a clinical suspicion of OSAS. They found a sensitivity of 91% and a specificity of 94% and concluded that HRP emerges as a potentially useful and reliable approach for the diagnosis of moderate/ severe OSAS in children.

Drug-induced sedation endoscopy (DISE) aims to reproduce upper airway obstruction during sleep and is gaining increasing popularity, with the hope of guiding efficient surgery and cure OSDB children. In a meta-analysis, Galluzi et al. 4 concluded that DISE may benefit a minority of children with OSAS, and should only be used in children with unremarkable clinical evaluation or upon persistent OSAS after AT.

Obstructive sleep-disordered breathing and obesity Pathogenesis of OSAS in obese adolescents. Literature on the pathogenesis of OSAS in adolescents is very limited. Schwab et al. 5 prospectively compared upper airway magnetic resonance imaging in 137 adolescents aged 12 to 16 years. Results indicated that lymphoid tissue, rather than other soft tissue components (tongue, lateral pharyngeal walls, parapharyngeal fat pads), are the primary upper airway anatomical risk factors for OSAS. While the pathogenesis of OSAS is clearly multifactorial (e.g., decreased upper airway reflexes in OSAS obese adolescents) and often require additional treatment, the results are clinically important since they suggest that AT should still be considered as the first-line treatment in adolescents with OSAS. OSDB and metabolic syndrome. In a systematic assessment of the literature on the interactions between sleep, OSDB, obesity and disruptions of metabolic homeostasis in children and adolescents, Hakim et al. concluded that obesity and OSDB appear to contribute to the initiation and progression of each other, and that both are linked to the metabolic phenotype 6 . One intriguing mechanism postulates that OSDB/ disrupted sleep as well as other factors favoring obesity, such as high-fat/ fructose diet, disrupt the gut microbiome and lead to increased systemic levels of lipopolysaccharides, in turn promoting inflammation and metabolic dysfunction.

Treatment of sleep-disordered breathing in children Watchful waiting. Chervin et al. 7 followed 192 children aged 5 to 9 years with mild/moderate OSAS after seven months of watchful waiting only. They found resolution of OSAS in 42% of the children. Independent predictors of resolution were lower AHI and normal waist circumference. The authors concluded that, in practice, a baseline low AHI and normal waist circumference, or low Pediatric Sleep Questionnaire and snoring score, may help identify an opportunity to avoid AT. Myofunctional therapy (MT). Camacho et al. 8 performed a meta-analysis of the use of MT as a treatment for OSAS in adults and children. Although the total number of patients (especially children, n ¼ 25) was low, the effects were highly significant. Overall, MT decreased AHI by 50-60% in pediatric and adult patients. In children, a positive effect was reported when used as the only treatment in mild OSAS as well as to consolidate OSAS cure after AT þ rapid maxillary expansion. The authors concluded that MT could be an adjunct to other OSAS treatments in patients of all ages.

Evolution of obstructive sleep-disordered breathing in children Evolution in preschool children with OSDB. Walter et al. 9 investigated the long-term evolution of OSDB in preschool-aged children with normal weight. Half of the preschoolers with OSDB were treated, most often by adenoidectomy and/or tonsillectomy. Overall, OSDB resolved in half of the children, either spontaneously (35%) or with treatment (57%). However, 40% still had OSAS, similarly to observations in school-aged children. Intriguingly, complete resolution of OSDB at three years post-treatment was more likely in preschoolers with moderate/severe OSAS compared to those with mild OSAS or primary snoring. Long-term evolution of OSAS. Spilsbury et al. 10 reported results on both remission and incidence of OSAS in 490 participants who underwent PSG at 8-11 and 16-19 years of age. The authors first observed that OSAS in middle childhood usually remitted by adolescence. Secondly, while habitual snoring and obesity predicted OSAS at each time point, distinct additional risk factors for OSAS were found in middle childhood vs. adolescence. Hence, prematurity, a disadvantaged neighborhood or African-American origin also predicted OSAS in middle childhood, while risk factors in adolescents included male sex and previous AT. Finally, obesity, but not habitual snoring, in middle childhood predicted adolescent OSAS. These results confirm that prevention and treatment of obesity appears of utmost importance in the fight against pediatric OSAS. Evolution of OSAS after treatment. Lee et al. 11 performed a meta-analysis of PSG findings after AT for OSAS in 3413 obese and non-obese children.

The overall success rate was 51% for postoperative AHI < 1 event /h (34% for obese vs. 49% for non-obese). Postoperative AHI was positively correlated with AHI and body mass index before surgery. The authors concluded that residual OSAS after AT persists in about 50% of children, especially in children with severe OSAS and obesity.

A plea to abandon asthma as a disease concept

Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome

Interpretative strategies for lung function tests

Applicability of the global lung function spirometry equations in contemporary multiethnic children

Impact of ethnicity and extreme prematurity on infant pulmonary function

Interpretation of pediatric lung function: impact of ethnicity

Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations

Lung function in children in relation to ethnicity, physique and socioeconomic factors

Disparities in pulmonary function in healthy children across the Indian urban-rural continuum

Etiology of ethnic differences in childhood spirometry

Age and height dependence of lung clearance index and functional residual capacity

Ethnic differences in fraction of exhaled nitric oxide and lung function in healthy young children

Stitching and switching: the impact of discontinuous lung function reference equations

Influence of socioeconomic status on lung function and prediction equations in Indian children

Ethnic differences in adolescent lung function: anthropometric, socioeconomic, and psychosocial factors

The use of ethnically specific norms for ventilatory function in African-American and white populations

Lung function in the children of immigrant and UK-born south-Asian mothers

The Global Lung Function Initiative: dispelling some myths of lung function test interpretation

Addition to inhaled corticosteroids of longacting beta2-agonists versus anti-leukotrienes for chronic asthma. The Cochrane database of systematic reviews

Pediatric severe asthma is characterized by eosinophilia and remodeling without T(H)2 cytokines

Novel concepts in airway inflammation and remodelling in asthma

Long-term effectiveness of a staged assessment for paediatric problematic severe asthma

The utility of a multidomain assessment of steroid response for predicting clinical response to omalizumab

Asthma genetics and personalised medicine. The Lancet. Respiratory medicine

Intermittent montelukast in children aged 10 months to 5 years with wheeze (WAIT trial): a multicentre, randomised, placebo-controlled trial

Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease

A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations

A large-scale, consortium-based genomewide association study of asthma

Effect of 17q21 Variants and Smoking Exposure in Early-Onset Asthma

Chromosome 17q21 gene variants are associated with asthma and exacerbations but not atopy in early childhood

Molecular evolution of the cadherin superfamily

Altered expression of epithelial junctional proteins in atopic asthma: possible role in inflammation

Cadherin-related family member 3, a childhood asthma susceptibility gene product, mediates rhinovirus C binding and replication

Human rhinovirus species C infection in young children with acute wheeze is associated with increased acute respiratory hospital admissions

Bacterial strain-specific induction of Foxp3þ T regulatory cells is protective in murine allergy models

Microbial exposure during early life has persistent effects on natural killer T cell function

A microbiota signature associated with experimental food allergy promotes allergic sensitization and anaphylaxis

Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection induced by microbes

Sheikh A; EAACI Food Allergy and Anaphylaxis Guidelines Group. EAACI food allergy and anaphylaxis guidelines. Primary prevention of food allergy

European Cystic Fibrosis Society Standards of Care: Best Practice guidelines

European Cystic Fibrosis Society Standards of Care: Framework for the Cystic Fibrosis Centre

European best practice guidelines for cystic fibrosis neonatal screening

Evidence for newborn screening for cystic fibrosis

Neonatal screening for cystic fibrosis in Wales and the West Midlands: clinical assessment after five years of screening

Nutritional benefits of neonatal screening for cystic fibrosis. Wisconsin Cystic Fibrosis Neonatal Screening Study Group

Bronchopulmonary disease in children with cystic fibrosis after early or delayed diagnosis

Economic implications of newborn screening for cystic fibrosis: a cost of illness retrospective cohort study

The diagnosis of cystic fibrosis: a consensus statement

H Cuppens, and M Sinaasappel on behalf of the Diagnostic Working Group. Cystic fibrosis: terminology and diagnostic algorithms

Recommendations for the classification of diseases as CFTR-related disorders

Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France

Variation in a repeat sequence determines whether a common variant of the cystic fibrosis transmembrane conductance regulator gene is pathogenic or benign

Mutations of the cystic fibrosis gene in patients with chronic pancreatitis

CFTR gene mutations in adults with disseminated bronchiectasis

Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice

CFTR CFTR Biomarkers: time for promotion to surrogate endpoint?

Genotype-phenotype correlations in cystic fibrosis

Primary ciliary dyskinesia: A consensus statement on diagnostic and treatment approaches in children

Structural and functional lung disease in primary ciliary dyskinesia

Differences in disease expression between primary ciliary dyskinesia and cystic fibrosis with and without pancreatic insufficiency

Progression of lung disease in primary ciliary dyskinesia: Is spirometry less accurate than CT?

Longitudinal lung function and structural changes in children with primary ciliary dyskinesia

Evaluation of pulmonary disease using static lung volumes in primary ciliary dyskinesia

Lung function in patients with primary ciliary dyskinesia: A cross-sectional and 3-decade longitudinal study

Management of primary ciliary dyskinesia in european children: Recommendations and clinical practice

Primary ciliary dyskinesia: Diagnostic and phenotypic features

on behalf of the ECFS Patient Registry Steering Group. Factors associated with FEV1 decline in cystic fibrosis: analysis of the data of the ECFS Patient Registry

Mucus properties in children with primary ciliary dyskinesia: Comparison with cystic fibrosis

Changes in airway inflammation during pulmonary exacerbations in patients with cystic fibrosis and primary ciliary dyskinesia

Exhaled Breath Analysis Using Electronic Nose in Cystic Fibrosis and Primary Ciliary Dyskinesia Patients with Chronic Pulmonary Infections

Committee on Fetus and Newborn. Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants

Committee on Fetus and Newborn. Policy statement-postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia

Early intratracheal instillation of budesonide using surfactant as a vehicle to prevent chronic lung disease in preterm infants: a pilot study

Intratracheal budesonide supplementation in addition to surfactant improves pulmonary outcome in surfactant-depleted newborn piglets

Surfactant and corticosteroid effects on lung function in a rat model of acute lung injury

Introduction to Marangoni convection

Inhaled versus systemic corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates

Early inhaled glucocorticoid therapy to prevent bronchopulmonary dysplasia

Intratracheal administration of budesonide/surfactant to prevent bronchopulmonary dysplasia

Plethysmographic measurements of lung volume and airway resistance

ERS/ATS task force on standards for infant respiratory function testing

Raised volume forced expirations in infants: Guidelines for current practice

Statement: Pulmonary Function Testing in Preschool Children

An official American Thoracic Society workshop report: optimal lung function tests for monitoring cystic fibrosis, bronchopulmonary dysplasia, and recurrent wheezing in children less than 6 years of age

New reference ranges for interpreting forced expiratory manoeuvres in infants and implications for clinical interpretation: a multicentre collaboration

Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations

Reference ranges for interrupter resistance technique: the Asthma UK Initiative

Respiratory impedance and bronchodilator responsiveness in healthy children aged 2 to 13 years

Consensus statement for inert gas washout measurement using multiple-and single-breath tests

Multiple-Breath Washout as a Lung Function Test in Cystic Fibrosis. A Cystic Fibrosis Foundation Workshop Report

Plethysmographic measurements of specific airway resistance in young children

Chronic lung disease after premature birth

Value of echocardiography in assessing the outcome of BPD

Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era

Pulmonary vascular response to to oxygen in infants with severe BPD

Pulmonary vascular extraction of circulating norepinephrine in infants with BPD

Histologic Evidence of Intrapulmonary Arteriovenous Shunt Vessels in Premature Infants with Severe BPD

Pulmonary vascular disease in BPD: physiology, diagnosis and treatment

Bronchopulmonary dysplasia: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases

Guidelines on the early management of infants diagnosed with cystic fibrosis following newborn screening

Cystic Fibrosis Foundation evidence À based guidelines for management of infants with cystic fibrosis

Recommandations nationales pour la prise en charge du nourrisson d epist e atteint de mucoviscidose. Consensus de la f ed eration des Centres de Ressources et de Comp etences de la Mucoviscidose

Growth and pulmonary outcomes during the first 2 years of life of breastfed and formula-fed infants diagnosed with cystic fibrosis through the Wisconsin Routine Screening Program

Do infants with cystic fibrosis need a protein hydrolysate formula? A prospective, randomized, comparative study

Evaluation of salt supplementation in cystic fibrosis infants

Induced sputum compared to bronchoalveolar lavage in young, non-expectorating cystic fibrosis children

Risk factors for bronchiectasis in children with cystic fibrosis

Palivizumab for prophylaxis against respiratory syncytial virus infection in children with cystic fibrosis

Palivizumab immunoprophylaxis effectiveness in children with cystic fibrosis

The etiologies of non-CFbronchiectasis in childhood: a systematic review of 989 subjects

CT of airways disease and bronchiectasis

An investigation into causative factors in patients with bronchiectasis

Rapid identification of bacterial species associated with bronchiectasis via metagenomic approach

A novel microbiota stratification system predicts future exacerbations in bronchiectasis

Prevalence of nontuberculous mycobacteria in patients with bronchiectasis: a meta-analysis

Efficacy of azithromycin in the treatment of bronchiectasis

Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EM-BRACE): a randomised, double-blind, placebo-controlled trial

Respiratory exacerbations in indigenous children from two countries with noncystic fibrosis chronic suppurative lung disease/bronchiectasis

Localised pulmonary resection for bronchiectasis in hypogammaglobulinaemic patients

Autonomic regulation of the airways

Regulation of airway inflammation and remodeling by muscarinic receptors: perspectives on anticholinergic therapy in asthma and COPD

Treatment of disorders characterized by reversible airway obstruction in childhood: are anticholinergic agents the answer?

The airway cholinergic system: physiology and pharmacology

Tiotropium bromide (Ba 679 BR), a novel long-acting muscarinic antagonist for the treatment of obstructive airways disease

Pulmonary neuronal M2 muscarinic receptor function in asthma and animal models of hyperreactivity

Anticholinergics in the treatment of children and adults with acute asthma: a systematic review with metaanalysis

The development of anticholinergics in the management of COPD

Tiotropium in asthmatic adolescents symptomatic despite inhaled corticosteroids: a randomised dose-ranging study

Treatment of disorders characterized by reversible airway obstruction in childhood: are anti-cholinergic agents the answer?

Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach

Mechanisms of virus induced exacerbations of asthma

Efficacy of salbutamol and ipratropium bromide in the management of acute bronchiolitis--a clinical trial

Bronchodilator effect of inhaled ipratropium bromide in wheezy toddlers

Anticholinergic drugs for wheeze in children under the age of two years

Classification and pharmacological treatment of preschool wheezing: changes since 2008

Effect of altering smooth muscle tone on maximal expiratory flows in patients with tracheomalacia

Tracheobronchomalacia in pediatric patients: clinical experience

Quantitative assessment of tracheal collapsibility in infants with tracheomalacia

Tiotropium add-on therapy in adolescents with moderate asthma: A 1-year randomized controlled trial

Tiotropium use in pediatric patients with asthma or chronic cough: a case series

The Asthma-COPD Overlap Syndrome

Multi-ethnic reference values for spirometry for the 3-95 year age range: the global lung function 2012 equations

The Global Lung Initiative 2012 reference values reflect contemporary Australasian spirometry

Comparison between reference values for FVC, FEV 1 , and FEV 1 /FVC ratio in white adults in Brazil and those suggested by the Global Lung Function initiative 2012

The recent multi-ethnic global lung initiative 2012 (GLI 2012 ) reference values don't reflect contemporary adult's North African spirometry

Spirometry reference values for Malagasy adults aged 18-73 years

The influence of the reference values on the interpretation of lung function in children: comparison of the Global Lung Initiative 2012 and Polish 1998 reference values

Disparities in pulmonary function in healthy children across the Indian urban-rural continuum

Persistent effects of maternal smoking during pregnancy on lung function and asthma in adolescents

How "healthy" should children be when selecting reference samples for spirometry?

Markers of eosinophilic inflammation and tissue re-modelling in children before clinically diagnosed bronchial asthma

Airway remodeling and inflammation in symptomatic infants with reversible airflow obstruction

Structural changes in the bronchial mucosa of young children at risk of developing asthma

Childhood asthma and increased airway responsiveness: a relationship that begins in infancy

Reduced Lung Function at Birth and the Risk of Asthma at 10 Years of Age

Lung function, airway remodelling and inflammation in symptomatic infants: outcome at 3 years

Lung function, airway remodeling, and inflammation in infants: outcome at 8 years

Increased airway smooth muscle in preschool wheezers who have asthma at school age

European Association of Perinatal Medicine. European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants-2013 update

Surfactant and noninvasive ventilation

NICHD Maternal-Fetal Medicine Units Network. Antenatal betamethasone for women at risk for late preterm delivery

A Comprehensive approach to the prevention of bronchopulmonary dysplasia

Nasal intermittent positive-pressure ventilation vs. nasal continuous positive airway pressure for preterm infants with respiratory distress syndrome: a systematic review and meta-analysis

A trial comparing noninvasive ventilation strategies in preterm infants

Nasal continuous positive airway pressure versus nasal intermittent positive ventilation for preterm neonates: a systematic review and meta-analysis

Early surfactant administration with brief ventilation vs. selective surfactant and continued mechanical ventilation for preterm infants with or at risk for respiratory distress syndrome

Avoidance of mechanical ventilation by surfactant treatment of spontaneously breathing preterm infants (AMV): an open-label, randomised, controlled trial

High-flow nasal cannulae in very preterm infants after extubation

Respiratory syncytial virus infection and bronchiolitis

Vertical transmission of respiratory syncytial virus modulates pre-and postnatal innervation and reactivity of rat airways

The role of neurotrophins in inflammation and allergy

RSV and asthma: Speed-dating or long-term relationship?

Vertical transmission of respiratory syncytial virus to fetuses in utero conveys elevated nerve growth factor expression and airway hyperreactivity upon repetitive post-natal RSV re-challenge infections

Fetal nutrition and cardiovascular disease in adult life

Alternative mechanisms for respiratory syncytial virus (RSV) infection and persistence: could RSV be transmitted through the placenta and persist into developing fetal lungs?

Maternal high-fat diet in pregnancy results in metabolic and respiratory abnormalities in offspring

MicroRNA-221 modulates RSV replication in human bronchial epithelial cells by targeting NGF expression

Less air pollution leads to rapid reduction of airway inflammation and improved airway function in asthmatic children

Child pneumonia at a time of epidemiological transition

Incidence and severity of childhood pneumonia in the first year of life in a South African birth cohort: the Drakenstein Child Health Study

Global, regional, and national causes of child mortality in 2000-13, with projections to inform post-2015 priorities: an updated systematic analysis

Early life origins of chronic obstructive pulmonary disease

Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children

Childhood pneumonia: the role of viruses

Specimen collection for the diagnosis of pediatric pneumonia

Laboratory methods for determining pneumonia etiology in children

Community-acquired pneumonia among U. S. children

Respiratory viruses associated with communityacquired pneumonia in children: matched case-control study

Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis

Aetiological role of common respiratory viruses in acute lower respiratory infections in children under five years: A systematic review and meta-analysis

A preliminary study of pneumonia etiology among hospitalized children in Kenya

The effect of case management on childhood pneumonia mortality in developing countries

HIGHLY PREVALENT CLINICAL ISSUES

Infant mortality statistics from the 2006 period linked birth/infant death data set

Late Preterm Infants: Near term but still in a critical developmental time period

Consortium on safe labor. Respiratory morbidity in late preterm births

NICHD Maternal-Fetal Medicine Units Network. Antenatal betamethasone for women at risk for late preterm delivery

Growth rate of lung function in healthy preterm infants

Effect of late preterm birth on longitudinal lung spirometry in school age children and adolescents

Moderately preterm children have more respiratory problems during their first 5 years of life than children born full term

Risk of asthma in late preterm infants: A propensity score approach

Poor airway function in early infancy and lung function by age 22 years: a non-selective longitudinal cohort study

Overview of issues in the longitudinal analysis of respiratory data

Assistant Professor, Department of Pediatrics, School of Medicine, University of Costa Rica. <quiquesoto@gmail.com> Bibliography 1. Global Tuberculosis Report 2013. Geneva. World Health Organization. 2013. 2. World Health Organization WHO

World Health Organization WHO. Guidance for national tuberculosis programmes on the management of tuberculosis in children

A refined symptom-based approach to diagnose pulmonary tuberculosis in children

Proportion of tuberculosis transmission that takes place in households in a high-incidence area

Assessment of the Xpert MTB/RIF assay for diagnosis of tuberculosis with gastric lavage aspirates in children in sub-Saharan Africa: a prospective descriptive study

Evaluation of the Xpert MTB/RIF assay at a tertiary care referral hospital in a setting where tuberculosis and HIV infection are highly endemic

Treatment of paediatric TB: revised WHO guidelines

Immune-based diagnostics for TB in children: what is the evidence? Paediatric Respiratory Reviews

Interferon-gamma assays in the immunodiagnosis of tuberculosis: a systematic review

Systematic review: T-cell-based assays for the diagnosis of latent tuberculosis infection: an update

Tracheobronchomalacia in children: review of diagnosis and definition

Dynamic volume CTA of the airway and vasculature in children: technical report

Tracheobronchomalacia and excessive dynamic airway collapse

Paediatric tracheomalacia

Description of a multidimensional classification system for patients with expiratory central airway collapse

Comparison of standard-dose and reduced-dose expiratory MDCT techniques for assessment of tracheomalacia in children

Real-time, cine magnetic resonance imaging for evaluation of the pediatric airway

General Hospital Ca' Foncello, Treviso (Italy) À <gmorana61@gmail.com> 2 Department of Radiology, Sophia Children's Hospital

MRI of the lung (2/3). Why ... when ... how?

MR imaging of pulmonary parenchyma

Impact of lung volume on MR signal intensity changes of the lung parenchyma

/3): methods

Contrast-enhanced 3D MRI of lung perfusion in children with cystic fibrosis-initial results

Spirometer-controlled cine magnetic resonance imaging used to diagnose tracheobronchomalacia in paediatric patients

Imaging of lung function using hyperpolarized helium-3 magnetic resonance imag-ing: review of current and emerging translational methods and ap-plications

Epidemiology of pediatric obstructive sleep apnea

Upper airway collapsibility in children with obstructive sleep apnea syndrome

Adenotonsillectomy outcomes in treatment of obstructive sleep apnea in children: a multicenter retrospective study

Pediatric obstructive sleep apnea: complications, management, and long-term outcomes

Craniofacial morphology in preschool children with sleep-related breathing disorder and hypertrophy of tonsils

Craniofacial modifications in children with habitual snoring and obstructive sleep apnoea: a case-control study

Randomized controlled study of an oral jaw-positioning appliance for the treatment of obstructive sleep apnea in children with malocclusion

Rapid maxillary expansion in children with obstructive sleep apnea syndrome: 12 months follow-up

Efficacy of rapid maxillary expansion in children with obstructive sleep apnea syndrome: 36 months of follow-up

Adeno-tonsillectomy and rapid maxillary distraction in pre-pubertal children, a pilot study

Germany <christian-f.poets@med.uni-tuebingen.de> References 1. Gozal D. Sleep-disordered breathing and school performance in children

Snoring during early childhood and academic performance at ages thriteen to fourteen years

Neurobehavioral Implications of Habitual Snoring in Children

Snoring, intermittent hypoxia and academic performance in primary school children

Population prevalence of obstructive sleep apnoea in a community of German third graders. The European respiratory journal: official journal of the European Society for

Habitual snoring, intermittent hypoxia, and impaired behavior in primary school children

Adenotonsillectomy and neurocognitive deficits in children with Sleep Disordered Breathing

Sleep-disordered breathing in a population-based cohort: behavioral outcomes at 4 and 7 years

Persistent snoring in preschool children: predictors and behavioral and developmental correlates

Predicting poor school performance in children suspected for sleep-disordered breathing

Utility of symptoms to predict treatment outcomes in obstructive sleep apnea syndrome

Pediatric OSAS: Oximetry can provide answers when polysomnography is not available

Reliability of home respiratory polygraphy for the diagnosis of sleep apnea in children

Drug induced sleep endoscopy in the decision-making process of children with obstructive sleep apnea

Understanding the anatomic basis for obstructive sleep apnea syndrome in adolescents

Obesity and Altered Sleep: A Pathway to Metabolic Derangements in Children?

Childhood Adenotonsillectomy Trial. Prognosis for spontaneous resolution of OSA in children

Myofunctional therapy to treat obstructive sleep apnea: a systematic review and meta-analysis

Long-term improvements in sleep and respiratory parameters in preschool children following treatment of sleep disordered breathing

Remission and incidence of obstructive sleep apnea from middle childhood to late adolescence

Polysomnographic findings after adenotonsillectomy for obstructive sleep apnea in obese and non-obese children: A systemic review and meta-analysis

This last year has seen a number of significant advances in the field of pediatric sleep-disordered breathing. The following is a personal selection of a few publications.

Overnight polysomnography (PSG) is considered necessary to diagnose children suspected of sleep-disordered breathing (SDB). In practice, however, most children do not have access to overnight PSG, due to the lack of sleep laboratories worldwide. The quest for a simpler means to diagnose SDB, or at least to prioritize children for referral to a sleep laboratory, remains a high priority. Questionnaire. In a prospective study in children aged 5 to 9 years with obstructive sleep apnea syndrome (OSAS), Rosen et al. 1 found that, conversely to PSG, the Pediatric Sleep Questionnaire results reflect OSASrelated impairment in behavior, quality of life and sleepiness as well as predict their improvement post-adenotonsillectomy (AT). The authors concluded that while PSG is needed to diagnose OSAS, results from a careful clinical assessment provide important adjunctive information on comorbidities and their improvement after surgery. Overnight oximetry in OSDB children. Kaditis et al. 2 performed a systematic analysis of the literature on the use of nocturnal oximetry in children with obstructive SDB (OSDB ¼ from primary snoring to OSAS). Their conclusion confirmed that overnight oximetry (SpO 2 ) is useful for diagnosing OSDB and for predicting post-AT complications in a child with a history suggestive of OSDB. Overall, a desaturation index (!4%) higher than 2 episodes/hour can predict both mild and moderate-to-severe OSDB, while criteria based on clusters of desaturation such as the McGill oximetry score can predict moderate-to-severe OSDB.