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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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Distinct pathologies can cause chronic obstructive pulmonary disease (COPD). Emphysema is a COPD-phenotype characterized by destruction of lung parenchyma. Alpha-1 antitrypsin deficiency (AATD) is a genetic cause of emphysema, whereas smoking is the most important risk factor of non-AATD emphysema. A general underappreciation of non-AATD emphysema has hampered progress in the field, and clinical guidelines have prohibited the use of emphysema as a diagnosis. Non-AATD emphysema, however, is far from irrelevant as it associates with dyspnea, reduced exercise capacity and relevant outcome measures. Areas covered: Mechanisms underlying enhanced tissue loss in emphysema are protease/antiprotease imbalance, increased oxidative stress, several fundamental cell biological processes such as programmed cell death and autophagy, and impaired repair mechanisms. Therapeutic options for emphysema vary from smoking cessation to lung volume reduction. Current pharmacological treatments have less favorable effects in emphysematous than in non-emphysematous COPD patients. Expert opinion: We advocate the acknowledgement of non-AATD emphysema as a clinical diagnosis and propose to end the era of bringing all pathologies that may lead to chronic airflow limitation together under the umbrella-term of COPD. Decelerating proteolysis and restoring damage should be main targets in emphysema. Vitamin A/K, hyaluronan, copper and roflumilast are promising candidates.

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Introduction The prevalence of chronic obstructive pulmonary disease (COPD) increases exponentially with aging. Its pathogenesis, however, is not well known and aside from smoking cessation, there are no disease-modifying treatments for this disease. Areas covered COPD is associated with accelerating aging and aging-related diseases. In this review, we will discuss the hallmarks of aging including genomic instability, telomere attrition, epigenetic alteration, loss of proteostasis, mitochondrial dysfunction, deregulated nutrient sensing, cellular senescence, stem cell exhaustion, and altered intercellular communication, which may be involved in COPD pathogenesis. Expert opinion COPD and the aging process share similar molecular and cellular changes. Aging-related molecular pathways may represent novel therapeutic targets and biomarkers for COPD.

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Activation of antigen-independent inflammation (a.k.a. the “innate” immune response (IIR)) plays a complex role in allergic asthma (AA). Although activation of the pulmonary IIR by aerosolized bacterial lipopolysaccharide early in life may be protective of AA, respiratory viral infections promote AA. The mechanisms how the mucosal IIR promotes allergic sensitization, remodeling, and altered epithelial signaling are not understood. Areas covered: This manuscript overviews: 1. Mechanistic studies identifying how allergens and viral patterns activate the mucosal IIR; 2. Research that reveals a major role played by specialized epithelial cells in the bronchiolar-alveolar junction in triggering inflammation and remodeling; 3. Reports linking the mucosal IIR with epithelial cell-state change and barrier disruption; and, 4. Observations relating mesenchymal transition with the expansion of the myofibroblast population. Expert commentary: Luminal allergens and viruses activate TLR signaling in key sentinel cells producing epithelial cell state transition, disrupting epithelial barrier function, and expanding the pulmonary myofibroblast population. These signals are transduced through a common NFkB/RelA -bromodomain containing 4 (BRD4) pathway, an epigenetic remodeling complex reprogramming the genome. Through this pathway, the mucosal IIR is a major modifier of adaptive immunity, AA and acute exacerbation-induced remodeling.

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The role of noninvasive positive pressure ventilation (NIPPV) in patients with stable chronic obstructive pulmonary disease (COPD) in the home-setting remains controversial. Despite studies suggesting potential benefits, there is an apparent under-utilization of such therapy in patients with stable COPD in a domiciliary setting. Areas covered: The reasons for under-utilization in the home-setting are multi-factorial, and we provide our perspective on the adequacy of scientific evidence and implementation barriers that may underlie the observed under-utilization. In this article, we will discuss continuous PAP, bilevel PAP, and non-invasive positive pressure ventilation using a home ventilator (NIPPV). Expert commentary: Many patients with stable COPD and chronic respiratory failure do not receive NIPPV therapy at home despite supportive scientific evidence. Such under-utilization suggests that there are barriers to implementation that include provider knowledge, health services and payor policies. For patients with stable COPD without chronic respiratory failure, there is inadequate scientific evidence to support domiciliary NIPPV or CPAP therapy. In patients with stable COPD without chronic respiratory failure, studies aimed at identifying patient characteristics that determine effectiveness of domiciliary NIPPV therapy needs further study. Future implementation and health-policy research with appropriate stakeholders are direly needed to help improve patient outcomes.