The Utility of Cardiopulmonary Exercise Testing in Difficult Asthma

Background: Unexplained persistent breathlessness in patients with difficult asthma despite multiple treatments is a common clinical problem. Cardiopulmonary exercise testing (CPX) may help identify the mechanism causing these symptoms, allowing appropriate management.<br/><br/>Methods: This was a retrospective analysis of patients attending a specialist-provided service for difficult asthma who proceeded to CPX as part of our evaluation protocol. Patient demographics, lung function, and use of health care and rescue medication were compared with those in patients with refractory asthma. Medication use 6 months following CPX was compared with treatment during CPX.<br/><br/>Results: Of 302 sequential referrals, 39 patients underwent CPX. A single explanatory feature was identified in 30 patients and two features in nine patients: hyperventilation (n = 14), exercise-induced bronchoconstriction (n = 8), submaximal test (n = 8), normal test (n = 8), ventilatory limitation (n = 7), deconditioning (n = 2), cardiac ischemia (n = 1). Compared with patients with refractory asthma, patients without ���pulmonary limitation��� on CPX were prescribed similar doses of inhaled corticosteroid (ICS) (median, 1,300 ��g [interquartile range (IQR), 800-2,000 ��g] vs 1,800 ��g [IQR, 1,000-2,000 ��g]) and rescue oral steroid courses in the previous year (median, 5 [1-6] vs 5 [1-6]). In this group 6 months post-CPX, ICS doses were reduced (median, 1,300 ��g [IQR, 800-2,000 ��g] to 800 ��g [IQR, 400-1,000 ��g]; P &lt; .001) and additional medication treatment was withdrawn (n = 7). Patients with pulmonary limitation had unchanged ICS doses post CPX and additional therapies were introduced.<br/><br/>Conclusions: In difficult asthma, CPX can confirm that persistent exertional breathlessness is due to asthma but can also identify other contributing factors. Patients with nonpulmonary limitation are prescribed inappropriately high doses of steroid therapy, and CPX can identify the primary mechanism of breathlessness, facilitating steroid reduction.

The Effect of Liposome Encapsulation on the Pharmacokinetics of Recombinant Secretory Leukocyte Protease Inhibitor (rSLPI) Therapy after Local Delivery to a Guinea Pig Asthma Model

Inhaled recombinant Secretory Leukocyte Protease Inhibitor (rSLPI) has shown potential for treatment of inflammatory lung conditions. Rapid inactivation of rSLPI by cathepsin L (Cat L) and rapid clearance from the lungs have limited clinical efficacy. Encapsulation of rSLPI within 1,2-Dioleoyl-sn-Glycero-3-[Phospho-L-Serine]:Cholesterol liposomes (DOPS-rSLPI) protects rSLPI against Cat L inactivation in vitro. We aimed to determine the effect of liposomes on rSLPI pharmacokinetics and activity in vitro and after local delivery to the airways in vivo.

The 'Unified airway': The RCPCH care pathway for asthma/or rhinitis

Abstract Aims The Royal College of Paediatrics and Child Health (RCPCH) Science and Research Department was commissioned by the Department of Health to develop national care pathways for children with allergies: the asthma/rhinitis care pathway is the third such pathway. Asthma and rhinitis have been considered together. These conditions co-exist commonly, have remarkably similar immuno-pathology and an integrated management approach benefits symptom control. Method The asthma/rhinitis pathway was developed by a multidisciplinary working group and was based on a comprehensive review of evidence. The pathway was reviewed by a broad group of stakeholders including the public and was approved by the Allergy Care Pathways Project Board and the RCPCH Clinical Standards Committee. Results The pathway entry points are defined by symptom type and severity at presentation. Acute severe rhinitis and life-threatening asthma are presented as distinct entry routes to the pathway, recognising that initial care of these conditions requires presentation-specific treatments. However, the pathway emphasises that ideal long term care should take account of both conditions in order to achieve maximal improvements in disease control and quality of life. Conclusions The pathway recommends that acute presentations of asthma and/or rhinitis should be treated separately. Where both conditions exist, ongoing management should address the upper and lower airways. The authors recommend that this pathway is implemented locally by a multidisciplinary team (MDT) with a focus on creating networks. The MDT within these networks should work with patients to develop and agree on care plans that are age and culturally appropriate.

Glucocorticoid receptor �� and histone deacetylase 1 and 2 expression in the airways of severe asthma.

<br/>Rationale Upregulation of glucocorticoid receptor �� (GR��) has been implicated in steroid resistance in severe asthma, although previous studies are conflicting. GR�� has been proposed as a dominant negative isoform of glucocorticoid receptor a (GRa) but it has also been suggested that GR�� can cause steroid resistance via reduced expression of histone deacetylase 2 (HDAC2), a key regulator of steroid responsiveness in the airway. <br/><br/><br/>Objectives To examine GR��, GRa, HDAC1 and HDAC2 expression at transcript and protein levels in bronchial biopsies from a large series of patients with severe asthma, and to compare the findings with those of patients with mild to moderate asthma and healthy volunteers. <br/><br/><br/>Methods Bronchoscopic study in two UK centres with real-time PCR and immunohistochemistry performed on biopsies, western blotting of bronchial epithelial cells and immunoprecipitation with anti-GR�� antibody. <br/><br/><br/>Measurements and main results Protein and mRNA expression for GRa and HDAC2 did not differ between groups. GR�� mRNA was detected in only 13 of 73 samples (seven patients with severe asthma), however immunohistochemistry showed widespread epithelial staining in all groups. Western blotting of bronchial epithelial cells with GR�� antibody detected an additional ���cross-reacting��� protein, identified as clathrin. HDAC1 expression was increased in patients with severe asthma compared with healthy volunteers. <br/><br/><br/>Conclusions GR�� mRNA is expressed at low levels in a minority of patients with severe asthma. HDAC1 and HDAC2 expression was not downregulated in severe asthma. These data do not support upregulated GR�� and resultant reduced HDAC expression as the principal mechanism of steroid resistance in severe asthma. Conflicting GR�� literature may be explained in part by clathrin cross-reactivity with commercial antibodies. <br/>