Journal: Expert review of respiratory medicine
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.
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.
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.
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.
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.
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.
Trimodality therapy (including surgery, chemotherapy and radiation therapy) represents an important management approach of early-stage malignant pleural mesothelioma (MPM). The oncological value, as well as the proper sequence of the three modalities, is still under investigations. Areas Covered: The article covers the timing of chemotherapy in the management plan either “neoadjuvant approach” or in the adjuvant setting. It evaluates also how to select patients for induction chemotherapy and how to assess the response to treatment. Expert Opinion: Management of patients with early-stage MPM must be completed in a multidisciplinary team in tertiary centers. Availability of newer prognostic and response assessment tools should facilitate the use of induction chemotherapy as well as the selection of patients who might benefit from radical surgery.
Spirometry, the most common lung function test, is used to evaluate individuals with respiratory complaints or known respiratory disease. However, its underutilization and the misinterpretation of its parameters are causes for concern. Areas covered: This review describes new spirometry-derived metrics, new reference equations, recent recommendations for presentation of results, recent spirometry-based prevalence studies, and technological advances in spirometry equipment. Expert Opinion: The underutilization of spirometry can be overcome by increasing access to portable, hand-held, and user-friendly spirometers, together with strategies that increase awareness of the importance of spirometry. New metrics derived from spirometry, together with traditional spirometric criteria, can identify individuals with structural lung disease and respiratory morbidity. Some problems with the reference equations were solved by the Global Lung Function Initiative (GLI), which covers a wider age range and more ethnic groups and provides limits of normality using the z-score. Despite these advantages, the GLI equations lack data from large populations (especially those from Africa, South Asia, and Latin America) and greater representation of older people. Another disadvantage attributed to the GLI is the lack of predicted values for peak expiratory flow and other airflows, limiting the interpretation of the maximal expiratory flow-volume curve.
Spirometric reference values are crucial in screening, diagnosis and monitoring the therapeutic course of respiratory diseases. These values from a representative population are key to making a precise interpretation of respiratory diseases. The objective of this study is to determine the spirometric reference values of a healthy Jordanian population.
Cystic fibrosis (CF) is the most common autosomal recessive disorder affecting approximately 70,000 people worldwide. The lack of functional cystic fibrosis transmembrane conductance regulator (CFTR) causes dysregulation of epithelial fluid transport in the lungs, gastrointestinal tract, and sweat glands. Areas covered: The most common disease-causing CFTR mutation, F508del, is present in nearly 75% of those affected and results in a defective protein. Therapies to improve the function of this mutant protein have the promise to reduce morbidity and mortality in the majority of patients with CF. The combination of lumacaftor, which corrects the aberrant intracellular trafficking of F508del, and ivacaftor, which potentiates CFTR function, is known as OrkambiTM, and is the first drug approved for the treatment of cystic fibrosis (CF) in patients who are homozygous for F508del. OrkambiTM is currently approved for use in children aged 2 and older based on recent data from open-label Phase 3 clinical safety studies. In older patients, treatment with lumacaftor/ivacaftor is associated with a modest, statistically significant improvement in lung function and reduced pulmonary exacerbations in placebo-controlled trials; these findings are also observed in Phase IV observational studies. While severe side effects are rare, chest tightness, elevation of transaminases, and cataracts have been reported and recommendations for monitoring have been established. Expert opinion: OrkambiTM somewhat improves clinical outcomes for people with CF who are homozygous for the F508del mutation, and does so with a reasonable safety profile. This therapy represents a major advance in the therapy for CF, but further advances are needed, perhaps with addition of a third agent to this combination small molecule therapy, in order to expand both the targeted population and beneficial effects.