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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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Objectives: The current study aims to evaluate the correlation between pre-diagnostic body mass index (BMI) as well as BMI trajectory in relation to lung cancer development and mortality risks. Methods: This analysis is based on Prostate, Lung, Colorectal, and Ovary (PLCO) trial datasets. Based on 145544 participants with complete information about pre-diagnostic BMI/BMI trajectory, associations of BMI measurements during adult life (at 20 years, 50 years and at enrolment into the study) with lung cancer development and mortality risks were determined. Multivariate Cox regression models were used to determine hazard ratios (HRs) of lung cancer development and mortality risks. Results: Higher BMI at 20 years, 50 years as well as the time of enrolment was associated with lower probability of lung cancer development (P=0.004; P<0.001; P< 0.001; respectively). Among different BMI trajectories, lung cancer risk was decreased among patients who had normal BMI at age 20 then became overweight (P<0.001) or obese (P<0.001) at the age of 50 compared to patients who maintained normal BMI. Likewise, death from lung cancer was reduced among patients with higher BMI at 20 years, 50 years as well as at the time of enrolment (P=0.027; P<0.001; P<0.001). Additionally, death from lung cancer was reduced among patients who had normal BMI at age 20 then became overweight (P<0.001) or obese (P<0.001) at the age of 50 compared to patients who maintained normal BMI. Conclusions: Overall, higher pre-diagnostic BMI seems to be associated with lower probability of lung cancer development and death. Moreover, an escalating temporal trajectory of pre-diagnostic BMI seems to be associated with a lower risk of the development of and death from lung cancer.

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Introduction: Community-acquired pneumonia (CAP) has the highest rate of mortality of all infectious diseases, especially among the elderly. Severe CAP (sCAP) is defined as a CAP in which intensive care management is required and is associated with an unfavorable clinical course. Areas covered: This review aims to identify prevention strategies for reducing the incidence of CAP and optimized management of sCAP. We highlight the main prevention approaches for CAP, focusing on the latest vaccination plans and on the influence of health-risk behaviors. Lastly, we report the latest recommendations about the optimal approach for sCAP when CAP has already been diagnosed, including prompt admission to ICU, early empirical antibiotic therapy, and optimization of antibiotic use. Expert opinion: Despite improvements in the diagnosis and treatment of sCAP, more efforts are needed to combat preventable causes, including the implementation and improvement of vaccine coverage, anti-tobacco campaigns and correct oral hygiene. Moreover, future research should aim to assess the benefits of early antimicrobial therapy in primary care. Pharmacokinetic studies in the target population may help clinicians to adjust dosage regimens in critically ill patients with CAP and thus reduce rates of treatment failure.

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Introduction: Asthma is the most common chronic disease in children. Avoiding triggers, and pharmacologic treatment with short acting beta-agonist, inhaler corticosteroids and anti-leukotriene are often enough to obtain symptoms control. Nevertheless, there is a subset of children with severe asthma and poor symptom control despite maximal therapy. In these patients, anti-IgE and anti-IL5 monoclonal antibodies are suggested as the fifth step of Global Initiative for Asthma guidelines. Area covered: Immunotherapeutic treatments are now suggested for asthma management. This article will discuss the available evidence on allergen immunotherapy and biologic drugs in pediatric asthma treatment. Expert opinion: Previously published studies demonstrated a good efficacy and safety profile of Allergen Immunotherapy in patients with mild-moderate asthma and sensitization to one main allergen. New understanding of mechanisms underlying severe asthma inflammation has allowed the identifications of specific biomarkers guiding the clinician in the choice of patient specific drug. Among the suggested immunotherapeutic options, omalizumab (blocking IgE) remains the first choice for atopic “early onset” asthma in patients aged over 6 years. Instead, mepolizumab (blocking the IL5 ligand) should be considered for “eosinophilic” asthma. Other biologic drugs are under consideration but data on the pediatric population are still lacking.

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Introduction: The pathogenesis of sarcoidosis is not yet completely understood, although in recent years our knowledge has made considerable progress. Areas covered: This review aims to highlight the latest findings, identified from PubMed, EMBASE and Web of Science, on the pathogenetic mechanisms of sarcoidosis, considering the studies on potential environmental antigens, genetic background and host immune responses. Particular emphasis has been on recent studies on antigens, as it now seems clear that it is not a single, but various antigens of microbial and non-microbial origin that share the ability to induce the series of immune-inflammatory events that lead to granuloma formation, activating host genetically influenced immune responses that involve innate and even more adaptive immunity. The dysregulation of Th17, Th17.1 cells and Tregs, and their role in the resolution and maintenance of granulomatous inflammation has been reported. Expert opinion: The considerable amount of data that has been accumulated on sarcoidosis pathogenesis will have to be carefully interpreted, particularly to discover which pathways lead to severe forms with organ damage. There is an urgent need for a panel of biomarkers indicating the involvement of the various pathways, to be used for better characterizing patient phenotypes and developing targeted therapies.