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Journal: Expert review of respiratory medicine

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Human cilia were once thought merely to be important in respiratory mucociliary clearance, with primary ciliary dyskinesia (PCD) the sole manifestation of ciliary dysfunction. There are now known to be three types of cilia: primary, nodal and motile. Cilia are complex, likely involving more than 1000 gene products; in this review, recent advances in PCD genetics, and the potential relationships with genes causing other ciliopathies, are discussed. PCD is the most important respiratory disease, characterized by upper and lower airway infection and inflammation and disorders of laterality. Ciliary gene mutations are now known to cause single organ disease, as well as complex syndromes. The focus of the review is primarily PCD, in the context of the expanding ciliopathy spectrum. The authors consider the clinical situations in which ciliary disease should be considered, and the implications for specialist respiratory practice.

Concepts: DNA, Gene, Genetics, Cell, Genetic disorder, Biology, Cilium, Ciliopathy

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Wheezing and asthma are significant clinical problems for infants and young children, particularly following premature birth. Recurrent wheezing in infants can progress to persistent asthma. As in adults, altered airway structure (remodeling) and function (increased bronchoconstriction) are also important in neonatal and pediatric airway diseases. Accumulating evidence suggests that airway disease in children is influenced by perinatal factors including perturbations in normal fetal lung development, postnatal interventions in the intensive care unit (ICU) and environmental and other insults in the neonatal period. Here, in addition to genetics, maternal health, environmental processes, innate immunity and impaired lung development/function can all influence pathogenesis of airway disease in children. We summarize current understanding of how prenatal and postnatal factors can contribute to development of airway diseases in neonates and children. Understanding these mechanisms will help identify and develop novel therapies for childhood airway diseases.

Concepts: Immune system, Medicine, Pregnancy, Childbirth, Infant, Asthma, Fetus, Breastfeeding

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Introduction Cystic fibrosis (CF) is a genetic disease that primarily affects the respiratory system and often leads to respiratory failure and premature death. Although pulmonary complications contribute to 85% of deaths, non-pulmonary complications are responsible for significant morbidity and mortality in adults with CF. Areas covered This review summarizes acute and chronic non-pulmonary complications in CF patients, with emphasis on emerging complications and in the context of the current growth and ageing of the CF adult population. It also addresses the potential benefits of CF transmembrane conductance regulator (CFTR) modulator therapy. Complications that occur after solid organ (e.g. lung and/or liver) transplantation have been excluded. The review is based on an extensive search of the available literature, using Pubmed and international guidelines, and on the authors' clinical experience. Expert commentary Acute non-pulmonary complications have been well described but should be recognized and managed carefully. Managing chronic non-pulmonary complications is an important and changing aspect of CF patient care, particularly with the emergence of novel complications in adults. Early detection of non-pulmonary complications is essential to the development of prevention and treatment strategies that aim to further improve the survival and health status of adult CF patients.

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The complexity and heterogeneous nature of asthma and chronic obstructive pulmonary disease (COPD) results in difficulties in diagnosing and treating patients. Biomarkers that can identify underlying mechanisms, identify patient phenotypes and to predict treatment response could be of great value for adequate treatment. Areas covered: Biomarkers play an important role for the development of novel targeted therapies in airways disease. Blood biomarkers are relatively non-invasive, easy to obtain and easy to apply in routine care. Several blood biomarkers are being used to diagnose and monitor chronic airways diseases, as well as to predict response to treatment and long-term prognosis. Blood eosinophils are the best studied biomarker, the most applied in clinical practice, and until now the most promising of all blood biomarkers. Other blood biomarkers, including serum periostin, IgE and ECP and plasma fibrinogen are less studied and less relevant in clinical practice. Recent developments include the use of antibody assays of many different cytokines at the same time, and ‘omics’ techniques and systems medicine. Expert commentary: With the exception of blood eosinophils, the use of blood biomarkers in asthma and COPD has been rather disappointing. Future research using new technologies like big-data analysis of blood samples from real-life patient cohorts will probably gain better insight into underlying mechanisms of different disease phenotypes. Identification of specific molecular pathways and associated biomarkers will then allow the development of new targets for precision medicine.

Concepts: Immune system, Medicine, Asthma, Medical terms, Diagnosis, Chronic obstructive pulmonary disease, Pulmonary hypertension, Spirometry

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COPD is a heterogeneous disease responsible for a major burden on public and individual health. A wide variety of intrinsic and environmental risk factors are involved, and exert their influence at various time points during the life span of individuals. Knowledge of these factors is of utmost importance to develop appropriate screening and prevention programs, and may help improving the pathophysiological knowledge of the disease. Accordingly, there are multiple targets of information and education on risk factors for COPD, including the general population and patients, workers and employers, doctors and other healthcare professionals, researchers, policy-makers, payers, etc. Gender and socioeconomic factors need to be specifically considered. Importantly, it is likely that increasing the specific knowledge of COPD risk factors among the above-mentioned targets cannot not be obtained without increasing the general knowledge of COPD in the population, which at present is dramatically low.

Concepts: Time, Health care, Health care provider, Epidemiology, Patient, Individual, Specific properties, Socioeconomics

1

The advent of computed tomography permitted recognition of the coexistence of pulmonary fibrosis and emphysema (CPFE). Emphysema is usually encountered in the upper lobes preceding fibrosis of the lower lobes, and patients are smokers, predominantly male, with distinct physiologic profile characterized by preserved lung volumes and markedly reduced diffusion capacity. Actually, the term CPFE is reserved for the coexistence of any type and grade of radiological pulmonary emphysema and the idiopathic usual interstitial pneumonia computed tomography pattern as well as any pathologically confirmed case. CPFE is complicated by pulmonary hypertension, lung cancer and acute lung injury and may present different outcome than that of its components.

Concepts: Cancer, Pulmonology, Lung, Lung cancer, Pneumonia, Chronic obstructive pulmonary disease, Emphysema, Idiopathic pulmonary fibrosis

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Progress in allogeneic hematopoietic stem cell transplantation (HSCT) procedures have been associated with improved survival in HSCT recipients. However, they have also brought to light organ-specific complications, especially pulmonary complications. In this setting, pulmonary complications are consistently associated with poor outcomes, and improved management of these complications is required. Areas covered: We review the multiple infectious and noninfectious lung complications that occur both early and late after allogeneic HSCT. This includes the description of these complications, risk factors, diagnostic approach and outcome. A literature search was performed using PubMed-indexed journals. Expert commentary: Multiple lung complications after allogeneic HSCT can be diagnosed concomitantly and require a multidisciplinary approach. A specific clinical evaluation including a precise analysis of a lung CT scan is necessary. Management of these lung complications, especially the noninfectious ones, is impaired by the lack of prospective, randomized control trials, suggesting preventive strategies should be developed.

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Idiopathic pulmonary fibrosis (IPF) is a chronic, debilitating, fibrotic lung disease leading to respiratory failure and ultimately to death. It is characterized by marked heterogeneity regarding its clinical course. Despite significant progress in the understanding of its pathogenesis, the course of the disease and the response to treatment of an individual patient cannot be reliably predicted today. Areas covered: Non-invasive biomarkers, in particular serum biomarkers, for the (early) diagnosis, differential diagnosis, prognosis and prediction of therapeutic response are described. The molecules are classified according to their involvement into alveolar epithelial cell injury, fibroproliferation and matrix remodeling as well as immune regulation. Furthermore, genetic variants of TOLLIP, MUC-5B, and other genes associated with a differential response to treatment and with the development and/or the prognosis of IPF are reported. Expert commentary: The combination of multiple biomarkers may identify comprehensive biomarker signatures in IPF patients. This is a way to apply personalized medicine approach to patient affected by IPF in order to not only improve our ability to diagnose and treat disease, but also offer the potential to detect disease at an earlier stage, when it is potentially easier to treat effectively.

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Asthma and allergic rhinitis (AR) are chronic conditions in which management needs adherence to prescribed drugs. Despite the benefits of regular maintenance of asthma and AR therapy, low adherence is a frequent issue in clinical practice. Areas covered: The aim of this review is to provide a targeted analysis of the more recent literature on adherence in asthma and AR, focused on the following areas: adherence extent, barriers and consequences, effects of educational interventions and use of new technologies to improve the level of adherence. Expert commentary: Despite the extent, reasons and effects of this problem being well known, non-adherence in asthma and allergic AR remains worryingly high. Poor adherence leads to unsatisfactory health outcomes, with a negative impact on patients and society. Recent literature suggests that successful programs to improve adherence should include a combination of strategies. The new technologies represent a promising tool to improve adherence.

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Lower respiratory tract infections (LRTIs) are the leading infectious disease cause of death in the world and the fifth overall cause of death. From an epidemiological point of view, most consider pneumonia, influenza, bronchitis (including acute exacerbations in chronic obstructive pulmonary disease [AECOPD]), and bronchiolitis to be the most important LRTIs. Areas covered: This review will describe the epidemiology of LRTIs in adults focusing on community-acquired pneumonia, influenza, and AECOPD, utilizing data from the more recent literature. Expert commentary: LRTIs remain exceedingly common, although there have been significant changes in their epidemiology over recent years, both with regard to their frequency and the infecting pathogens. Part of the change in the epidemiology may relate to changing population demographics, the varying prevalence of smoking, and the introduction of the pneumococcal conjugate vaccine in children and patterns of vaccine usage. Furthermore, antigenic variations in the influenza viruses dictate the frequency and characteristics of the influenza epidemics and pandemics.