Desmond M. Murphy

Recent Advances in the Pathophysiology of Asthma

There has been an increased understanding, over the past 2 decades, that asthma is a chronic, immunologically mediated condition with a disturbance of the normal airway repair mechanism, which results in inflammatory changes and airway remodeling. The airway inflammation and remodeling together likely explain the clinical manifestations of asthma. The mechanisms by which the external environmental cues, together with the complex genetic actions, propagate the inflammatory process that characterize asthma are beginning to be understood. There is also an evolving awareness of the active participation of structural elements, such as the airway epithelium, airway smooth muscle, and endothelium, in this process. In tandem with this has come the realization that inflammatory cells respond in a coordinated, albeit dysfunctional manner, via an array of complex signaling pathways that facilitate communication between these cells; these structural elements within the lung and the bone marrow serve as reservoirs for and the source of inflammatory cells and their precursors. Although often viewed as separate mechanistic entities, so-called innate and acquired immunity often overlap in the propagation of the asthmatic response. This review examines the newer information on the pathophysiologic characteristics of asthma and focuses on papers published over the past 3 years that have helped to improve current levels of understanding.

Simvastatin attenuates release of neutrophilic and remodeling factors from primary bronchial epithelial cells derived from stable lung transplant recipients

Obliterative bronchiolitis (OB), the major cause of chronic lung allograft dysfunction, is characterized by airway neutrophilia, inflammation, and remodeling, with progressive fibroproliferation and obliteration of small airways that ultimately leads to patient death. Statins have potential anti-inflammatory effects and have been demonstrated to confer a survival advantage in lung transplant patients. We postulated that the beneficial effects of simvastatin in lung transplantation are in part due to inhibition of the epithelial production of key mediators of neutrophil chemotaxis, inflammation, and airway remodeling. Our objective was to assess the effect of simvastatin on a unique population of primary bronchial epithelial cells (PBECs) derived from stable lung allografts, with specific reference to airway neutrophilia and remodeling. PBEC cultures were stimulated with IL-17 or transforming growth factor (TGF)-beta, with and without simvastatin. Supernatant levels of factors critical to driving airway neutrophilia and remodeling were measured. IL-17 upregulated IL-8, IL-6, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor (GM-CSF), and VEGF, whereas TGF-beta increased IL-6, GM-CSF, matrix metalloproteinase (MMP)-2, and MMP-9. Simvastatin attenuated effects of both IL-17 and TGF-beta. We have demonstrated the ability of simvastatin to attenuate release of airway neutrophilic and remodeling mediators and to inhibit their upregulation by TGF-beta and IL-17. These data illustrate the potential of simvastatin to alleviate neutrophilic airway inflammation and remodeling in the transplanted lung and may have additional relevance to other neutrophilic airway conditions, such as chronic obstructive pulmonary disease.

Inhaled versus nebulised tobramycin: A real world comparison in adult cystic fibrosis (CF)

BACKGROUND There are no published data on real-life clinical experience comparing inhaled antibiotic therapy via new rapid delivery systems with nebulised antibiotic therapy in CF. This real world study compares safety, effectiveness and tolerability using tobramycin inhaled powder (TIP) versus tobramycin inhaled solution (TIS). METHODS Adult patients with CF commencing TIP (n=78) completed a questionnaire assessing safety, efficacy, tolerability, patient-satisfaction and self-reported adherence to TIS at baseline and during 12 months of TIP therapy. FEV1% predicted and exacerbation rate were recorded at each visit. RESULTS There was a significant improvement in adherence scores, with a significant decrease in the number of intravenous antibiotic courses received during 12 months of TIP compared with the preceding 12 months using TIS. 94% of patients who had previously used TIS preferred TIP therapy over TIS. CONCLUSIONS Inhaled powder tobramycin in CF is associated with improved adherence, tolerability and decreased exacerbation rates compared to nebulised treatment in real-life practice.

Ivacaftor in a G551D homozygote with cystic fibrosis.

1. Major EO, Frohman E, Douek D. JC viremia in natalizumabtreated patients with multiple sclerosis. N Engl J Med 2013; 368:2240-1. 2. Gorelik L, Lerner M, Bixler S, et al. Anti-JC virus antibodies: implications for PML risk stratification. Ann Neurol 2010;68: 295-303. 3. Biogen Idec medical information home page (https://medinfo .biogenidec.com/medinfo). 4. Rudick RA, O’Connor PW, Polman CH, et al. Assessment of JC virus DNA in blood and urine from natalizumab-treated patients. Ann Neurol 2010;68:304-10.

Efficacy of leukotriene receptor antagonists and synthesis inhibitors in asthma

Cysteinyl leukotrienes are important mediators of asthmatic responses. They are the most potent bronchoconstrictors known; their release is triggered by exposure to inhaled allergens after exercise and after aspirin ingestion by subjects with aspirin-sensitive asthma. The cysteinyl leukotrienes promote inflammatory cell migration into the airways, as well as bone marrow eosinophilopoiesis after allergen inhalation. Leukotriene inhibitors are effective at attenuating asthmatic responses to all of these stimuli and are also effective at treating persistent asthma. These drugs are a viable alternative to low-dose inhaled corticosteroid (ICS) treatment but should be reserved for patients who cannot or will not use ICSs, often because of concerns about potential side effects of ICS treatment, which limits their use, particularly in children. Leukotriene receptor antagonists are also alternatives to long-acting inhaled beta(2)-agonists as add-on therapy to ICSs, but their efficacy together with ICSs is less than that of ICS/long-acting inhaled beta(2)-agonist combinations. Leukotriene receptor antagonists have an excellent safety profile.

A study to assess inhaler technique and its potential impact on asthma control in patients attending an asthma clinic

Abstract Objectives: The aim of this study was to evaluate inhaler technique and symptom control in patients with poorly controlled asthma at baseline and at follow-up in a dedicated asthma clinic in a tertiary hospital. We also investigated the impact of asthma on these patients’ quality of life. Methods: Patients referred to a newly established asthma clinic in Cork University Hospital were prospectively recruited over a 6-month period. Their inhaler technique was assessed by a pulmonary nurse specialist using a validated scoring system. They received instruction on inhaler usage when scores were suboptimal. Patients completed a validated asthma control questionnaire (ACQ) and asthma quality of life questionnaire (AQLQ). At follow-up 3–4 months later, the inhaler technique was reassessed and the ACQ questionnaire repeated. Results: Forty-six patients were recruited (female = 74%), and 40/46 were followed up. Mean [SD] FEV1 % predicted at baseline = 76.5% [21.5]. About 63% of the patients were classified as incorrectly using their inhaler at their initial assessment. This decreased to 20% at follow-up, indicating an overall significant improvement in inhaler usage post-training (p = 0.003). ACQ scores improved significantly from median [interquartile range] 2.70 [1.66] to 2.00 [1.90] (p = 0.002). Baseline measurement indicated that patients’ quality of life was moderately affected by asthma, with a median AQLQ score of 4.75 [1.97]. Conclusion: This study demonstrates the importance of educating and formally assessing inhaler technique in patients with asthma as a part of their ongoing clinical review.

Macrolide antibiotics and the airway: antibiotic or non-antibiotic effects?

Importance of the field: The macrolides are a class of antibiotics widely prescribed in infectious disease. More recently, there has been considerable interest in potential indications for these agents, in addition to their simple antibacterial indications, in a number of lung pathophysiologies. Areas covered in this review: Demonstrated clinical efficacy of macrolides in diseases such as diffuse panbronchiolitis was difficult to ascribe to a direct antimicrobial action. More recently, positive experiences in dealing with post-transplant bronchiolitis obliterans syndrome suggests that other chronic lung diseases may benefit from macrolide therapy. This is important, as the treatment options for such diseases are often very limited. In this review, potential antibiotic and non-antibiotic beneficial actions of macrolide therapy are discussed and conclusions drawn from a limited but growing literature. What the reader will gain: The reader will gain an overview of lung diseases that may benefit from macrolides, and a consideration of the possible mechanisms underlying such benefit. Take home message: The key message from our review is that this class of agents may prove to be a useful therapeutic option for a range of respiratory diseases, but that further trials and mechanistic studies are required to clarify their role.

T cell‐mediated induction of thymic stromal lymphopoietin in differentiated human primary bronchial epithelial cells

Inhaled peptide challenge has been shown to induce T cell‐mediated, isolated late asthmatic reaction (LAR), characterized by recruitment of CD4+ T cells and increased levels of thymus and activation‐regulated chemokine (TARC; CCL17). Epithelial‐derived thymic stromal lymphopoietin (TSLP) has been shown to modulate dendritic cell function to promote TH2 responses via CCL17 production.

A randomised clinical trial of feedback on inhaler adherence and technique in patients with severe uncontrolled asthma

In severe asthma, poor control could reflect issues of medication adherence or inhaler technique, or that the condition is refractory. This study aimed to determine if an intervention with (bio)feedback on the features of inhaler use would identify refractory asthma and enhance inhaler technique and adherence. Patients with severe uncontrolled asthma were subjected to a stratified-by-site random block design. The intensive education group received repeated training in inhaler use, adherence and disease management. The intervention group received the same intervention, enhanced by (bio)feedback-guided training. The primary outcome was rate of actual inhaler adherence. Secondary outcomes included a pre-defined assessment of clinical outcome. Outcome assessors were blinded to group allocation. Data were analysed on an intention-to-treat and per-protocol basis. The mean rate of adherence during the third month in the (bio)feedback group (n=111) was higher than that in the enhanced education group (intention-to-treat, n=107; 73% versus 63%; 95% CI 2.8%–17.6%; p=0.02). By the end of the study, asthma was either stable or improved in 54 patients (38%); uncontrolled, but poorly adherent in 52 (35%); and uncontrolled, but adherent in 40 (27%). Repeated feedback significantly improved inhaler adherence. After a programme of adherence and inhaler technique assessment, only 40 patients (27%) were refractory and adherent, and might therefore need add-on therapy. On a period of monitored adherence only 27% of patients were refractory and adherent and thus need add-on therapy http://ow.ly/ddQr30gTpmb

A protocol for a randomised clinical trial of the effect of providing feedback on inhaler technique and adherence from an electronic device in patients with poorly controlled severe asthma

Introduction In clinical practice, it is difficult to distinguish between patients with refractory asthma from those with poorly controlled asthma, where symptoms persist due to poor adherence, inadequate inhaler technique or comorbid diseases. We designed an audio recording device which, when attached to an inhaler, objectively identifies the time and technique of inhaler use, thereby assessing both aspects of adherence. This study will test the hypothesis that feedback on these two aspects of adherence when passed on to patients improves adherence and helps clinicians distinguish refractory from difficult-to-control asthma. Methods This is a single, blind, prospective, randomised, clinical trial performed at 5 research centres. Patients with partially controlled or uncontrolled severe asthma who have also had at least one severe asthma exacerbation in the prior year are eligible to participate. The effect of two types of nurse-delivered education interventions to promote adherence and inhaler technique will be assessed. The active group will receive feedback on their inhaler technique and adherence from the new device over a 3-month period. The control group will also receive training in inhaler technique and strategies to promote adherence, but no feedback from the device. The primary outcome is the difference in actual adherence, a measure that incorporates time and technique of inhaler use between groups at the end of the third month. Secondary outcomes include the number of patients who remain refractory despite good adherence, and differences in the components of adherence after the intervention. Data will be analysed on an intention-to-treat and a per-protocol basis. The sample size is 220 subjects (110 in each group), and loss to follow-up is estimated at 10% which will allow results to show a 10% difference (0.8 power) in adherence between group means with a type I error probability of 0.05. Trial registration number NCT01529697; Pre-results.