Long-term corticosteroid use, adrenal insufficiency and the need for steroid-sparing treatment in adult severe asthma.

Secondary adrenal insufficiency (AI) occurs as the result of any process that disrupts normal hypothalamic and/or anterior pituitary function and causes a decrease in the secretion of steroid hormones from the adrenal cortex. The most common cause of secondary AI is exogenous corticosteroid therapy administered at supraphysiologic dosages for ≥ 1 month. AI caused by oral corticosteroids (OCS) is not well-recognized or commonly diagnosed but is often associated with reduced well-being and can be life-threatening in the event of an adrenal crisis. Corticosteroid use is common in respiratory diseases, and asthma is a representative condition that illustrates the potential challenges and opportunities related to corticosteroid-sparing therapies. For individuals with severe asthma (approximately 5%-10% of all cases), reduction or elimination of maintenance OCS without loss of control can now be accomplished with biologic therapies targeting inflammatory mediators. However, the optimal strategy to ensure early identification and treatment of AI and safe OCS withdrawal in routine clinical practice remains to be defined. Many studies with biologics have involved short evaluation periods and small sample sizes; in addition, cautious approaches to OCS tapering in studies with a placebo arm, coupled with inconsistent monitoring for AI, have contributed to the lack of clarity. If the goal is to greatly reduce and, where possible, eliminate long-term OCS use in severe asthma through the increasing adoption of biologic treatments, there is an urgent need for clinical trials that address both the speed of OCS withdrawal and how to monitor for AI.

Mepolizumab for the treatment of eosinophilic granulomatosis with polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare but potentially life-threatening antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis which affects, to varying degrees, the lungs, paranasal sinuses, heart, kidneys, skin and peripheral nervous system. It is strongly associated with asthma. Peripheral eosinophilia is a defining feature of EGPA and eosinophilic inflammation is often observed in biopsies of affected tissues. Acute and chronic management focuses on the control of inflammation with systemic corticosteroids and other immunosuppressants, all of which carry a significant burden of adverse effects. The development of monoclonal antibody therapies against interleukin-5 (IL-5), the major driver of eosinophilic inflammation, has therefore garnered significant interest among clinicians treating EGPA, who are hopeful that the targeted antieosinophilic effects of such drugs observed in large-scale asthma studies may be replicated in EGPA cohorts. In this review we discuss the features of EGPA, including the current understanding of the eosinophil's role in its pathogenesis. We also review the evidence to date regarding the efficacy of mepolizumab (an anti-IL-5 monoclonal antibody) in severe eosinophilic asthma and the smaller evidence base regarding its efficacy in EGPA, an indication for which it recently received U.S. Food and Drug Administration approval. The possible limitations of mepolizumab in EGPA management are also considered and suggestions put forward regarding the issues that further studies should seek to explore.

The current and future role of biomarkers in type 2 cytokine-mediated asthma management.

Assessment and management of asthma is complicated by the heterogeneous pathophysiological mechanisms that underlie its clinical presentation, which are not necessarily reflected in standardized management paradigms and which necessitate an individualized approach to treatment. This is particularly important with the emerging availability of a variety of targeted forms of therapy that may only be appropriate for use in particular patient subgroups. The identification of biomarkers can potentially aid diagnosis and inform prognosis, help guide treatment decisions and allow clinicians to predict and monitor response to treatment. Biomarkers for asthma have been identified from a variety of sources, including airway, exhaled breath and blood. Biomarkers from exhaled breath include fractional exhaled nitric oxide, measurement of which can help identify patients most likely to benefit from inhaled corticosteroids and targeted anti-immunoglobulin E therapy. Biomarkers measured in blood are relatively non-invasive and technically more straightforward than those measured from exhaled breath or directly from the airway. The most well established of these are the blood eosinophil count and serum periostin, both of which have demonstrated utility in identifying patients most likely to benefit from targeted anti-interleukin and anti-immunoglobulin E therapies, and in monitoring subsequent treatment response. For example, serum periostin appears to be a biomarker for responsiveness to inhaled corticosteroid therapy and may help identify patients as suitable candidates for anti-IL-13 treatment. The use of biomarkers can therefore potentially help avoid unnecessary morbidity from high-dose corticosteroid therapy and allow the most appropriate and cost-effective use of targeted therapies. Ongoing clinical trials are helping to further elucidate the role of established biomarkers in routine clinical practice, and a range of other circulating novel potential biomarkers are currently being investigated in the research setting.

Dynamic laryngeal narrowing during exercise: a mechanism for generating intrinsic PEEP in COPD?

INTRODUCTION: Patients with COPD commonly exhibit pursed-lip breathing during exercise, a strategy that, by increasing intrinsic positive end-expiratory pressure, may optimise lung mechanics and exercise tolerance. A similar role for laryngeal narrowing in modulating exercise airways resistance and the respiratory cycle volume-time course is postulated, yet remains unstudied in COPD. The aim of this study was to assess the characteristics of laryngeal narrowing and its role in exercise intolerance and dynamic hyperinflation in COPD. METHODS: We studied 19 patients (n=8 mild-moderate; n=11 severe COPD) and healthy age and sex matched controls (n=11). Baseline physiological characteristics and clinical status were assessed prior to an incremental maximal cardiopulmonary exercise test with continuous laryngoscopy. Laryngeal narrowing measures were calculated at the glottic and supra-glottic aperture at rest and peak exercise. RESULTS: At rest, expiratory laryngeal narrowing was pronounced at the glottic level in patients and related to FEV1 in the whole cohort (r=-0.71, p<0.001) and patients alone (r=-0.53, p=0.018). During exercise, glottic narrowing was inversely related to peak ventilation in all subjects (r=-0.55, p=0.0015) and patients (r=-0.71, p<0.001) and peak exercise tidal volume (r=-0.58, p=0.0062 and r=-0.55, p=0.0076, respectively). Exercise glottic narrowing was also inversely related to peak oxygen uptake (% predicted) in all subjects (r=-0.65, p<0.001) and patients considered alone (r=-0.58, p=0.014). Exercise inspiratory duty cycle was related to exercise glottic narrowing for all subjects (r=-0.69, p<0.001) and patients (r=-0.62, p<0.001). CONCLUSIONS: Dynamic laryngeal narrowing during expiration is prevalent in patients with COPD and is related to disease severity, respiratory duty cycle and exercise capacity.

Lipid-laden bronchoalveolar macrophages in asthma and chronic cough.

BACKGROUND: The presence of lipids in alveolar macrophages (AMs) may impair their phagocytic response, and determine airway inflammation and obstruction. OBJECTIVE: To determine the factors such as severity of asthma, chronic cough, airway inflammation and obesity that may influence the presence of lipids in lung macrophages. METHODS: Bronchoalveolar lavage fluid (BALF) was obtained from 38 asthmatics (21 severe and 17 mild/moderate), 16 subjects with chronic cough and 11 healthy control subjects. The presence of lipids in macrophages was detected using an Oil-red-O stain and an index of lipid-laden macrophages (LLMI) was obtained. RESULTS: LLMI scores were higher in healthy subjects (median 48 [IQR 10-61]) and the severe asthma group (37 [11.5-61]) compared to mild/moderate asthmatics (7 [0.5-37]; p < 0.05 each). Subjects reporting a history of gastro-oesophageal reflux disease (GORD) had higher LLMI values (41.5 [11.3-138] versus 13 [0-39.3], p = 0.02). There was no significant correlation between LLMI and chronic cough, BAL cell differential counts, FEV1, FEV1/FVC or body mass index (BMI). CONCLUSIONS: The reduced LLMI in mild/moderate asthma may be related to lower incidence of GORD. However, this was not related to the degree of airflow obstruction, obesity or airway inflammation.

Airway dysfunction in elite athletes--an occupational lung disease?

Airway dysfunction is prevalent in elite endurance athletes and when left untreated may impact upon both health and performance. There is now concern that the intensity of hyperpnoea necessitated by exercise at an elite level may be detrimental for an athlete's respiratory health. This article addresses the evidence of causality in this context with the aim of specifically addressing whether airway dysfunction in elite athletes should be classified as an occupational lung disease. The approach used highlights a number of concerns and facilitates recommendations to ensure airway health is maintained and optimized in this population. We conclude that elite athletes should receive the same considerations for their airway health as others with potential and relevant occupational exposures.

Effect of inhaled interleukin-5 on eosinophil progenitors in the bronchi and bone marrow of asthmatic and non-asthmatic volunteers.

BACKGROUND: Asthma is characterized by increases in mature eosinophils and their progenitors within the bronchus and bone marrow. IL-5 plays a key role in eosinophil development in the bone marrow and at the site of allergic inflammation. We therefore studied the effects of nebulized IL-5 on eosinophils, their progenitors and in situ haemopoiesis within the airway and bone marrow. METHODS: Nine atopic asthmatics and 10 non-atopic non-asthmatic control volunteers inhaled 10 microg of IL-5 or placebo via a nebulizer in a double-blind, randomized, cross-over study. Bronchoscopy, bone marrow aspiration and peripheral blood sampling were performed 24 h after nebulization. Four weeks later, volunteers inhaled the alternative solution and underwent a repeat bronchoscopy and bone marrow aspiration. RESULTS: Inhalation of IL-5 significantly decreased CD34(+)/IL-5Ralpha mRNA(+) cells within the bronchial mucosa and the percentage of CD34(+) cells that were CCR3(+) within the bone marrow of atopic asthmatic, but not control, volunteers. Inhalation of IL-5 also induced a significant increase in bronchial mucosal eosinophils in the non-atopic non-asthmatic control volunteers, but not in the asthmatics. IL-5 had no effect on spirometry or airways hyper-reactivity in either group. CONCLUSIONS: Inhaled IL-5 modulated eosinophil progenitor numbers in both the airways and bone marrow of asthmatics and induced local eosinophilia in non-asthmatics.

Interactions between eotaxin, histamine and mast cells in early microvascular events associated with eosinophil recruitment to the site of allergic skin reactions in humans.

BACKGROUND: The mechanism whereby allergen induces eotaxin expression at the site of allergic inflammation is incompletely understood. Structural cells, including endothelial cells, are a major source of eotaxin. OBJECTIVE: We have investigated, in vivo and in vitro, the relationship between mast cell activation and the expression of eotaxin (eotaxin 1) by endothelial cells. METHODS: The effects of intradermal allergen challenge and histamine injection on eotaxin mRNA and protein generation were studied in atopic subjects using immunofluorescence, immunohistochemistry and in situ hybridization. Histamine-induced expression of eotaxin mRNA and protein by endothelial cells was also measured, as was histamine-induced eosinophil adhesion to cultured endothelial cells. RESULTS: A rapid increase in degranulating cutaneous mast cells, together with a concomitant increase in eosinophils, was observed 60 min after allergen challenge. This was accompanied by the appearance of immunoreactive eotaxin that peaked at 1 h around blood vessels and at 3 h within the tissue. Intradermal histamine injection produced an increase in the number of eotaxin+ cells in the tissues, which was maximal at the 3-h time-point. In vitro, endothelial cells produced eotaxin mRNA and protein product in a dose- and time-dependent fashion following incubation with histamine, an effect that was blocked by levocetirizine. Pre-incubation of endothelial cells with histamine also induced a significant increase in eosinophil adherence, an effect that was inhibited with an anti-eotaxin blocking monoclonal antibody. CONCLUSION: The antigen-induced expression of eotaxin by endothelial cells and the adherence and subsequent migration of eosinophils from the microvasculature to the tissues are rapid events partially under the control of histamine released from degranulating mast cells.

Resolution of late-onset asthma following high-dose chemotherapy.

We describe a patient with moderately severe (British Thorax Society Step IV/V) asthma requiring regular inhaled and oral corticosteroids to control symptoms who experienced resolution of her asthma following high-dose chemotherapy and autologous stem cell transplantation for breast cancer. As far as the authors are aware this is the first reported case.