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.

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.

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.