Progressive Loss Of Lung Function Research Articles

Controlling the Risk Domain in Pediatric Asthma through Personalized Care.

Strategies to control the risk domain of NHLBI EPR-3 (National Heart, Lung, and Blood Institute Expert Panel Report-3) asthma guidelines, which includes exacerbations requiring systemic corticosteroids, reduction in lung growth, and progressive loss of lung function, and treatment-related adverse effects, are evolving in children and adolescents. Increasing evidence demonstrates that children and adolescents with asthma are at risk of a reduction in lung growth, leading to lower lung function and potentially chronic obstructive pulmonary disease as adults. Readily available clinical biomarkers for atopy, including aeroallergen testing, total serum IgE, blood eosinophilia, and spirometry, are being utilized to phenotype difficult-to-treat pediatric patients, to assess risk for seasonal exacerbations, and to predict response to controller therapies. The Composite Asthma Severity Index is a novel, freely available scoring system to define asthma control, incorporating NHLBI EPR-3 risk and impairment domains. As new asthma controller therapies, such as tiotropium, are introduced for pediatric use, the safety of established controller therapies including inhaled corticosteroid and long-acting beta-agonist are being reexamined. Macrolide antibiotics may be an oral corticosteroid sparing alternative for the treatment of severe respiratory tract infection in preschool-aged children. Seasonally directed courses of omalizumab may provide an alternative approach to prevent fall asthma exacerbations in children. Combining these pharmaceuticals and biomarker-directed therapies provide potential new options and personalized approaches to gain asthma control in pediatric patients failing current management.

Persistent activation of interlinked type 2 airway epithelial gene networks in sputum-derived cells from aeroallergen-sensitized symptomatic asthmatics

Atopic asthma is a persistent disease characterized by intermittent wheeze and progressive loss of lung function. The disease is thought to be driven primarily by chronic aeroallergen-induced type 2-associated inflammation. However, the vast majority of atopics do not develop asthma despite ongoing aeroallergen exposure, suggesting additional mechanisms operate in conjunction with type 2 immunity to drive asthma pathogenesis. We employed RNA-Seq profiling of sputum-derived cells to identify gene networks operative at baseline in house dust mite-sensitized (HDMS) subjects with/without wheezing history that are characteristic of the ongoing asthmatic state. The expression of type 2 effectors (IL-5, IL-13) was equivalent in both cohorts of subjects. However, in HDMS-wheezers they were associated with upregulation of two coexpression modules comprising multiple type 2- and epithelial-associated genes. The first module was interlinked by the hubs EGFR, ERBB2, CDH1 and IL-13. The second module was associated with CDHR3 and mucociliary clearance genes. Our findings provide new insight into the molecular mechanisms operative at baseline in the airway mucosa in atopic asthmatics undergoing natural aeroallergen exposure, and suggest that susceptibility to asthma amongst these subjects involves complex interactions between type 2- and epithelial-associated gene networks, which are not operative in equivalently sensitized/exposed atopic non-asthmatics.

Asthma and Medicines - Long-Term Side-Effects, Monitoring and Dose Titration.

Asthma is a major pediatric respiratory morbidity requiring long-term management. A thorough knowledge of long-term medication side-effects in children is, thus, essential for every physician dealing with childhood asthma. Establishing diagnosis and initiating treatment is just a beginning of the journey. Ongoing monitoring is an essential component of comprehensive asthma management programme. Monitoring includes not only assessment of asthma control but also checking for adherence to treatment, technique of inhaler device use, associated co-morbities, if any, and potential environmental exposure. Various tools - both subjective and objective - are available for assessment of asthma control. However, evidence for their optimum use in different settings and patient groups is lacking and monitoring has to be customized depending on available resources and individual patient characteristics. Patient education is an important component of long-term asthma therapy. The ultimate aim is to achieve optimum asthma control i.e., achieve and maintain control of clinical symptoms, decrease future risk to patients (risk of exacerbations, progressive loss of lung function and development of fixed airflow obstruction, adverse effects of medications) and enabling the child to lead a life without restrictions, at lowest possible dose of drugs. This article reviews the side-effects of medications used for long-term management of asthma and discusses current literature on asthma monitoring and dose titration in pediatric population to help the asthma therapist not only prescribe the drugs rationally but also help the family make right choices for treatment.

Особенности лечения интерстициальной лимфоцитарной болезни легких у пациентов с синдромами иммунной дизрегуляции: клинический пример

Immune dysregulation syndromes (CTLA4 and LRBA deficiency) belong to the combined primary immunodeficiencies with defective tolerance due to lack of T regulatory lymphocytes function and resulting autoimmune complications. One of them is interstitial lymphocytic lung disease (ILLD), caused by pathologic bronchi-associated lymphoid tissue hyperplasia, progressive loss of lung function and decreased life expectancy. ILLD diagnosis is based on pathomorphological lung changes and radiologic symptoms. Targeted therapy with Abatacept in patients with immune dysregulation syndromes provides control of the autoimmune complications, including ILLD and is well tolerated. Here we demonstrate two cases of patients with immune dysregulation syndromes and ILLD treated with Abatacept.

COPD: time to improve its taxonomy?

Due to well-conducted epidemiological studies and advances in genetics, molecular biology, translational research, the advent of computed tomography of the lungs and bioinformatics, the diagnosis of chronic obstructive pulmonary disease (COPD) as a single entity caused by susceptibility to cigarette smoke is no longer tenable. Furthermore, the once-accepted concept that COPD results from a rapid and progressive loss of lung function over time is not true for a sizeable proportion of adults with the disease. Now we know that some genetic predisposition and/or different environmental interactions (nutritional, infectious, pollution and immunological) may negatively modulate post-natal lung development and lead to poorly reversible airflow limitation later in life, consistent with COPD. We believe it is time to rethink the taxonomy of this disease based on the evidence at hand. To do so, we have followed the principles outlined in the 1980s by J.D. Scadding who proposed that diseases can be defined by four key characteristics: 1) clinical description (syndrome), 2) disorder of structure (morbid anatomy), 3) disorder of function (pathophysiology) and 4) causation (aetiology). Here, we propose a pragmatic approach to the taxonomy of COPD based on different processes that result in a similar syndromic presentation. It can accommodate changes over time, as the pathobiology that may lead to COPD expands. We hope that stakeholders in the field may find it useful to better define the patients now boxed into one single entity, so that specific studies can be designed and conducted for each type of COPDs.

Lumacaftor (VX-809) restores the ability of CF macrophages to phagocytose and kill Pseudomonas aeruginosa.

Cystic fibrosis (CF), the most common lethal genetic disease in Caucasians, is characterized by chronic bacterial lung infection and excessive inflammation, which lead to progressive loss of lung function and premature death. Although ivacaftor (VX-770) alone and ivacaftor in combination with lumacaftor (VX-809) improve lung function in CF patients with the Gly551Asp and del508Phe mutations, respectively, the effects of these drugs on the function of human CF macrophages are unknown. Thus studies were conducted to examine the effects of lumacaftor alone and lumacaftor in combination with ivacaftor (i.e., ORKAMBI) on the ability of human CF ( del508Phe/ del508Phe) monocyte-derived macrophages (MDMs) to phagocytose and kill Pseudomonas aeruginosa. Lumacaftor alone restored the ability of CF MDMs to phagocytose and kill P. aeruginosa to levels observed in MDMs obtained from non-CF (WT-CFTR) donors. This effect contrasts with the partial (~15%) correction of del508Phe Cl- secretion of airway epithelial cells by lumacaftor. Ivacaftor reduced the ability of lumacaftor to stimulate phagocytosis and killing of P. aeruginosa. Lumacaftor had no effect on P. aeruginosa-stimulated cytokine secretion by CF MDMs. Ivacaftor (5 µM) alone and ivacaftor in combination with lumacaftor reduced secretion of several proinflammatory cytokines. The clinical efficacy of ORKAMBI may be related in part to the ability of lumacaftor to stimulate phagocytosis and killing of P. aeruginosa by macrophages.

P3.04-002 A Randomized Phase II Study of Carboplatin plus Nab-Paclitaxel with or Without Nintedanib for NSCLC with IPF (J-SONIC): Trial in Progress

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by worsening dyspnea and progressive loss of lung function. Acute exacerbation of IPF is associated with high morbidity and mortality. Several studies have provided evidence of an association between lung cancer and IPF, with a prevalence of lung cancer in IPF patients ranging from 9.8% to 38%. Although the efficacy of nintedanib for IPF has been demonstrated, it has remained unknown whether this agent also reduces the risk of chemotherapy-induced acute exacerbation of IPF.

P231 Assessing follow-up on restrictive pattern identified by outpatient clinic spirometry

Undiagnosed restrictive lung disease can lead to progressive loss of lung function therefore it is important for allergists to have a plan in place to ensure appropriate follow up.

Efficacy of Rhesus Theta-Defensin-1 in Experimental Models of Pseudomonas aeruginosa Lung Infection and Inflammation.

Chronic airway infection and inflammation contribute to the progressive loss of lung function and shortened survival of patients with cystic fibrosis (CF). Rhesus theta defensin-1 (RTD-1) is a macrocyclic host defense peptide with antimicrobial and immunomodulatory activities. Combined with favorable preclinical safety and peptide stability data, RTD-1 warrants investigation to determine its therapeutic potential for treatment of CF lung disease. We sought to evaluate the therapeutic potential of RTD-1 for CF airway infection and inflammation using in vitro, ex vivo, and in vivo models. We evaluated RTD-1's effects on basal and Pseudomonas aeruginosa-induced inflammation in CF sputum leukocytes and CF bronchial epithelial cells. Peptide stability was evaluated by incubation with CF sputum. Airway pharmacokinetics, safety, and tolerance studies were performed in naive mice. Aerosolized RTD-1 treatment effects were assessed by analyzing lung bacterial burdens and airway inflammation using an established model of chronic P. aeruginosa endobronchial infection in CF (ΔF508) mice. RTD-1 directly reduces metalloprotease activity, as well as inflammatory cytokine secretion from CF airway leukocyte and bronchial epithelial cells. Intrapulmonary safety, tolerability, and stability data support the aerosol administration route. RTD-1 reduced the bacterial lung burden, airway neutrophils, and inflammatory cytokines in CF mice with chronic P. aeruginosa lung infection. Collectively, these studies support further development of RTD-1 for treatment of CF airway disease.

Effect of acute predation with bacteriophage on intermicrobial aggression by Pseudomonas aeruginosa.

In persons with structural lung disease, particularly those with cystic fibrosis (CF), chronic airway infections cause progressive loss of lung function. CF airways can be colonized by a variety of microorganisms; the most frequently encountered bacterial and fungal pathogens are Pseudomonas aeruginosa and Aspergillus fumigatus, respectively. Co-infection with P. aeruginosa and A. fumigatus often results in a more rapid loss of lung function, indicating that interactions between these pathogens affect infection pathogenesis. There has been renewed interest in the use of viruses (bacteriophage, mycoviruses) as alternatives to antibiotics to treat these infections. In previous work, we found that filamentous Pf bacteriophage produced by P. aeruginosa directly inhibited the metabolic activity of A. fumigatus by binding to and sequestering iron. In the current study, we further examined how filamentous Pf bacteriophage affected interactions between P. aeruginosa and A. fumigatus. Here, we report that the antifungal properties of supernatants collected from P. aeruginosa cultures infected with Pf bacteriophage were substantially less inhibitory towards A. fumigatus biofilms. In particular, we found that acute infection of P. aeruginosa by Pf bacteriophage inhibited the production of the virulence factor pyoverdine. Our results raise the possibility that the reduced production of antimicrobials by P. aeruginosa infected by Pf bacteriophage may promote conditions in CF airways that allow co-infection with A. fumigatus to occur, exacerbating disease severity. Our results also highlight the importance of considering how the use of bacteriophage as therapeutic agents could affect the behavior and composition of polymicrobial communities colonizing sites of chronic infection.

Update in diagnosis and management of interstitial lung disease

The field of interstitial lung disease (ILD) has undergone significant evolution in recent years, with an increasing incidence and more complex, ever expanding disease classification. In their most severe forms, these diseases lead to progressive loss of lung function, respiratory failure and eventually death. Despite notable advances, progress has been challenged by a poor understanding of pathological mechanisms and patient heterogeneity, including variable progression. The diagnostic pathway is thus being continually refined, with the introduction of tools such as transbronchial cryo lung biopsy and a move towards genetically aided, precision medicine. In this review, we focus on how to approach a patient with ILD and the diagnostic process.

P53 and miR-34a Feedback Promotes Lung Epithelial Injury and Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease. The pathogenesis of interstitial lung diseases, including its most common form, IPF, remains poorly understood. Alveolar epithelial cell (AEC) apoptosis, proliferation, and accumulation of myofibroblasts and extracellular matrix deposition results in progressive loss of lung function in IPF. We found induction of tumor suppressor protein, p53, and apoptosis with suppression of urokinase-type plasminogen activator (uPA) and the uPA receptor in AECs from the lungs of IPF patients, and in mice with bleomycin, cigarette smoke, silica, or sepsis-induced lung injury. Treatment with the caveolin-1 scaffolding domain peptide (CSP) reversed these effects. Consistent with induction of p53, AECs from IPF lungs or mice with diverse types of lung injuries showed increased p53 acetylation and miR-34a expression with reduction in Sirt1. This was significantly reduced after treatment of wild-type mice with CSP, and uPA-deficient mice were unresponsive. Bleomycin failed to induce miR-34a in p53- or plasminogen activator inhibitor-1 (PAI-1)-deficient mice. CSP-mediated inhibition of miR-34a restored Sirt1, suppressed p53 acetylation and apoptosis in injured AECs, and prevented pulmonary fibrosis (PF). AEC-specific suppression of miR-34a inhibited bleomycin-induced p53, PAI-1, and apoptosis and prevented PF, whereas overexpression of precursor-miR-34a increased p53, PAI-1, and apoptosis in AECs of mice unexposed to bleomycin. Our study validates p53-miR-34a feedback as a potential therapeutic target in PF.

Heterologous Matrix Metalloproteinase Gene Promoter Activity Allows In Vivo Real-time Imaging of Bleomycin-Induced Lung Fibrosis in Transiently Transgenized Mice.

Idiopathic pulmonary fibrosis is a very common interstitial lung disease derived from chronic inflammatory insults, characterized by massive scar tissue deposition that causes the progressive loss of lung function and subsequent death for respiratory failure. Bleomycin is used as the standard agent to induce experimental pulmonary fibrosis in animal models for the study of its pathogenesis. However, to visualize the establishment of lung fibrosis after treatment, the animal sacrifice is necessary. Thus, the aim of this study was to avoid this limitation by using an innovative approach based on a double bleomycin treatment protocol, along with the in vivo images analysis of bleomycin-treated mice. A reporter gene construct, containing the luciferase open reading frame under the matrix metalloproteinase-1 promoter control region, was tested on double bleomycin-treated mice to investigate, in real time, the correlation between bleomycin treatment, inflammation, tissue remodeling and fibrosis. Bioluminescence emitted by the lungs of bleomycin-treated mice, corroborated by fluorescent molecular tomography, successfully allowed real time monitoring of fibrosis establishment. The reporter gene technology experienced in this work could represent an advanced functional approach for real time non-invasive assessment of disease evolution during therapy, in a reliable and translational living animal model.

Once daily aerosolised tobramycin in adult patients with cystic fibrosis in the management of Pseudomonas aeruginosa chronic infection

It is estimated that about 60–70% of Cystic Fibrosis patients develop Pseudomonas aeruginosa chronic infection,with progressive loss of lung function, as well as increased antibiotic resistance and mortality. The current strategy is to maintain lung function by chronic suppressive antipseudomonas antibiotic therapy. Tobramycin inhalation solution was the first approved aerosolised antibiotic to be used against P. aeruginosa; inhalatory tobramycin frequency of administration is twice daily and inhalation time is estimated to be 15 to 20 min. From the pharmacokinetic point of view, aminoglycosides are dose-dependent antibiotics and therefore once-daily dosing intravenous regimens have shown to be superior to the conventional multiple daily dosing. Therefore, there is no pharmacological reason to prefer the b.i.d administration as it is usually performed in current clinical practice. Should this be confirmed also for inhalatory route, the use of once-daily dosed aerosolized tobramycin could be an important step in making treatment burden easier in CF patients. The aim of this proof of concept study was to explore the effectiveness of treatment with once daily inhaled tobramycin in reducing P. aeruginos a density in sputum of chronically infected patients.

Clinical Tools to Assess Asthma Control in Children.

Asthma affects an estimated 7 million children and causes significant health care and disease burden. The most recent iteration of the National Heart, Lung and Blood Institute asthma guidelines, the Expert Panel Report 3, emphasizes the assessment and monitoring of asthma control in the management of asthma. Asthma control refers to the degree to which the manifestations of asthma are minimized by therapeutic interventions and the goals of therapy are met. Although assessment of asthma severity is used to guide initiation of therapy, monitoring of asthma control helps determine whether therapy should be maintained or adjusted. The nuances of estimation of asthma control include understanding concepts of current impairment and future risk and incorporating their measurement into clinical practice. Impairment is assessed on the basis of frequency and intensity of symptoms, variations in lung function, and limitations of daily activities. "Risk" refers to the likelihood of exacerbations, progressive loss of lung function, or adverse effects from medications. Currently available ambulatory tools to measure asthma control range are subjective measures, such as patient-reported composite asthma control score instruments or objective measures of lung function, airway hyperreactivity, and biomarkers. Because asthma control exhibits short- and long-term variability, health care providers need to be vigilant regarding the fluctuations in the factors that can create discordance between subjective and objective assessment of asthma control. Familiarity with the properties, application, and relative value of these measures will enable health care providers to choose the optimal set of measures that will adhere to national standards of care and ensure delivery of high-quality care customized to their patients.

Durability of Sirolimus for Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM), a rare, multisystem disorder primarily affecting women of reproductive age, is characterized by cystic-appearing lung lesions, progressive loss of lung function, chylous effusions and renal angiomyolipomas. Sirolimus, an mammalian target of rapamycin inhibitor, has been shown to stabilize lung function, reduce symptoms and resolve chylous effusions in the short term for patients with LAM. Herein, we report a premenopausal female with LAM who experienced complete and durable resolution of her chylothoraces with significant and sustained improvement in lung function on sirolimus.

Update in diagnosis and management of interstitial lung disease

The field of interstitial lung disease (ILD) has undergone significant evolution in recent years, with an increasing incidence and more complex, ever expanding disease classification. In their most severe forms, these diseases lead to progressive loss of lung function, respiratory failure and eventually death. Despite notable advances, progress has been challenged by a poor understanding of pathological mechanisms and patient heterogeneity, including variable progression. The diagnostic pathway is thus being continually refined, with the introduction of tools such as transbronchial cryo lung biopsy and a move towards genetically aided, precision medicine. In this review, we focus on how to approach a patient with ILD and the diagnostic process.

Alpha-1 Antitrypsin Deficiency: Phenotypes and Quality of Life.

Alpha-1 antitrypsin deficiency (AATD) is a recognized genetic cause of rapidly progressive loss of lung function conventionally assessed by the decline in FEV1. However, there is less information concerning other physiological measures and the impact on quality of life. Data derived predominantly from the UK national registry show that AATD presents with various physiological phenotypes with differing clinical impact and progression. In general, the decline in quality of life is surprisingly slow despite rapid loss of lung function, which may reflect the benefits of centralized services for patients with AATD. Use of the new GOLD classification identifies patient characteristics that relate to mortality and disparate symptomatology despite similar spirometric impairment.

OC36 - Diagnostic approach of primary cilia dyskinesia: Greek experience.

Theme: Complex health care and chronic disease management. Primary Cilia Dyskinesia (PCD) is a rare, genetically heterogeneous disease that causes chronic pulmonary inflammation and progressive loss of lung function due to the dysfunction of cilia. To present the Greek experience in development and implementation of standardized operational procedures (SOP) in diagnostic testing of PCD. After special training, SOP consisting of nasal NO (nNO) measurement, high speed videomicroscopy (HVM), transmission electron microscopy (TEM) and shipment of the sample for high resolution immunofluorescence (IF) microscopy in difficult cases, were applied. From September 2014 until December 2015 197 tests were performed to 147 suspected patients. 17 patients were finally diagnosed with PCD. PCD is a rare disease that can be diagnosed through SOP. Early diagnosis and appropriate treatment of PCD will reduce not only the morbidity and mortality to patients, but also the burden of healthcare costs.

An update on chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide. It is a chronic condition which affects the respiratory system and worsens over time. Cigarette smoking and advancing age are the two major risks associated with this disease. It is concerning that the global incidence of this chronic illness is on the rise. Current projections indicate that it will become the third leading cause of death by the year 2020. Inflammatory changes underlie the pathophysiology of COPD. Irreversible damage and progressive narrowing of the air passages follow. COPD is characterised by the progressive loss of lung function. In addition, the Global Initiative for Chronic Obstructive Lung Disease released the latest update on its global strategy for the diagnosis, management, and prevention of COPD in 2015. This article provides an overview of the causative risk factors, underlying disease process, pathophysiological changes, and the classification and management of COPD, including the latest perspectives on this highly prevalent condition.