Garry Meakin

The utility of exhaled nitric oxide in patients with suspected asthma

The value of FENO measurements in patients with symptoms suggestive of asthma is unclear. We performed an observational study to assess the ability of FENO to diagnose asthma and to predict response to inhaled corticosteroids (ICS). Our findings suggest FENO is not useful for asthma diagnosis but is accurate at predicting ICS response.

A randomised controlled trial of small particle inhaled steroids in refractory eosinophilic asthma (SPIRA)

Background Some patients with refractory asthma have evidence of uncontrolled eosinophilic inflammation in the distal airways. While traditional formulations of inhaled steroids settle predominantly in the large airways, newer formulations with an extra-fine particle size have a more peripheral pattern of deposition. Specifically treating distal airway inflammation may improve asthma control. Methods 30 patients with refractory asthma despite high dose inhaled corticosteroids were identified as having persistent airway eosinophilia. Following 2 weeks of prednisolone 30 mg, patients demonstrating an improvement in asthma control were randomised to receive either ciclesonide 320 µg twice daily or placebo in addition to usual maintenance therapy for 8 weeks. The primary outcome measure was sputum eosinophil count at week 8. Alveolar nitric oxide was measured as a marker of distal airway inflammation. Results There was continued suppression of differential sputum eosinophil counts with ciclesonide (median 2.3%) but not placebo (median 4.5%) though the between-group difference was not significant. When patients who had changed their maintenance prednisolone dose during the trial were excluded the difference between groups was significant (1.4% vs 4.5%, p=0.028). Though alveolar nitric oxide decreased with ciclesonide the value did not reach statistical significance. Conclusions These data demonstrate that patients with ongoing eosinophilic inflammation are not truly refractory, and that suppression of airway eosinophilia may be maintained with additional inhaled corticosteroid. Further work is needed with a focus on patient-orientated outcome measures such as exacerbation rate, with additional tests of small airway function. Trial registration number NCT01171365. Protocol available at http://www.clinicaltrials.gov.

The Effects of Azithromycin in Treatment-Resistant Cough: A Randomized, Double-Blind, Placebo-Controlled Trial

BACKGROUND Chronic cough is a common clinical problem worldwide. Although many patients have underlying precipitating conditions such as asthma, gastroesophageal reflux, or rhinitis, many remain symptomatic despite treating these conditions. New approaches are needed for the treatment of this group of patients. METHODS We conducted a randomized, double-blind, placebo-controlled trial to determine whether 250 g of azithromycin three times a week for 8 weeks would affect the Leicester Cough Questionnaire (LCQ) score in 44 patients with treatment-resistant cough. Cough severity on a visual analog scale and bronchial exhaled nitric oxide were measured as secondary outcomes. RESULTS There was a clinically important improvement in LCQ score with azithromycin (mean change, 2.4; 95% CI, 0.5 to 4.2) but not placebo (mean change, 0.7; 95% CI, -0.6 to 1.9), but the between-group difference was not statistically significant (P = .12). There were no significant between-group differences for any of the secondary outcome measures. Looking at subgroups of responders, there was a large and significant improvement in LCQ score in patients with chronic cough and a concurrent diagnosis of asthma who were treated with azithromycin (mean, 6.19; 95% CI, 4.06 to 8.32). CONCLUSIONS Treatment with low-dose azithromycin for 8 weeks did not significantly improve LCQ score compared with placebo. The use of macrolides for treatment-resistant cough cannot be recommended from this study, but they may have a place in the treatment of chronic cough associated with asthma; this is worthy of further investigation. TRIAL REGISTRY WHO International Clinical Trials Registry; No.: ISRCTN75749391. URL: http://apps.who.int.

Exhaled nitric oxide and inhaled corticosteroid dose reduction in asthma: a cohort study

To the Editor: Inhaled corticosteroids (ICS) reduce airway inflammation; however, guidelines recommend titrating ICS dose based on symptoms [1], which are not closely associated with airway inflammation [2]. Once symptoms are controlled for ≥3 months, ICS reduction is recommended [3] but step-down is often not implemented. Studies suggest that the majority of patients treated with ICS can have their therapy stepped down, although there is no clear evidence on how best to achieve this [4]. We assessed whether exhaled nitric oxide fraction ( F eNO) measurements could predict a loss of symptom control or exacerbation following a reduction in ICS dose in a cohort study of people with well-controlled asthma recruited from primary care. All participants had a recorded asthma diagnosis, were aged 18–75 years, and had received at least one ICS prescription in the last year. The study was restricted to nonsmokers ( 1.5 at visit 1 (indicating poor control) were excluded. Participants were seen at the same time of day on four occasions: days 0, 14, 21 and 110. At each visit, ACQ-5, F eNO (Flex Flow; Aerocrine, Solna, Sweden) and spirometry were performed. Symptoms were assessed using the ACQ-5 [6]. Airway inflammation was measured using F eNO at 50 mL·s−1; participants were blinded to their measurements. Differential …

Home interventions and light therapy for the treatment of vitiligo (HI-Light Vitiligo Trial): study protocol for a randomised controlled trial

Introduction Vitiligo is a condition resulting in white patches on the skin. People with vitiligo can suffer from low self-esteem, psychological disturbance and diminished quality of life. Vitiligo is often poorly managed, partly due to lack of high-quality evidence to inform clinical care. We describe here a large, independent, randomised controlled trial (RCT) assessing the comparative effectiveness of potent topical corticosteroid, home-based hand-held narrowband ultraviolet B-light (NB-UVB) or combination of the two, for the management of vitiligo. Methods and analysis The HI-Light Vitiligo Trial is a multicentre, three-arm, parallel group, pragmatic, placebo-controlled RCT. 516 adults and children with actively spreading, but limited, vitiligo are randomised (1:1:1) to one of three groups: mometasone furoate 0.1% ointment plus dummy NB-UVB light, vehicle ointment plus NB-UVB light or mometasone furoate 0.1% ointment plus NB-UVB light. Treatment of up to three patches of vitiligo is continued for up to 9 months with clinic visits at baseline, 3, 6 and 9 months and four post-treatment questionnaires. The HI-Light Vitiligo Trial assesses outcomes included in the vitiligo core outcome set and places emphasis on participants’ views of treatment success. The primary outcome is proportion of participants achieving treatment success (patient-rated Vitiligo Noticeability Scale) for a target patch of vitiligo at 9 months with further independent blinded assessment using digital images of the target lesion before and after treatment. Secondary outcomes include time to onset of treatment response, treatment success by body region, percentage repigmentation, quality of life, time-burden of treatment, maintenance of response, safety and within-trial cost-effectiveness. Ethics and dissemination Approvals were granted by East Midlands—Derby Research Ethics Committee (14/EM/1173) and the MHRA (EudraCT 2014-003473-42). The trial was registered 8 January 2015 ISRCTN (17160087). Results will be published in full as open access in the NIHR Journal library and elsewhere. Trial registration number ISRCTN17160087.

LB1.5 The efficacy and safety of gentamicin for the treatment of genital, pharyngeal and rectal gonorrhoea: a randomised controlled trial

Introduction Gentamicin is effective against N. gonorrhoeae in vitro and systematic reviews have reported cure rates of 62%–98% but the quality of studies was low and there are few data on pharyngeal or rectal infections. A recent large non comparative trial reported a cure rate of 100% when gentamicin was combined with 2g oral azithromycin, but a high incidence of gastrointestinal adverse effects limited tolerability and few extra-genital infections were included. The aim of this study was to evaluate the efficacy and safety of gentamicin versus ceftriaxone, each combined with 1g of azithromycin, for the treatment of gonorrhoea. Methods A multi-centre, blinded, randomised controlled trial in participants with genital, pharyngeal or rectal gonorrhoea who received either gentamicin 240 mg or ceftriaxone 500 mg (each as a single intramuscular injection). The diagnosis of gonorrhoea was based on a positive nucleic acid amplification test (NAAT) or gram stained smear on microscopy. The primary endpoint was microbiological cure based on NAAT two weeks after treatment. The trial had 90% power to detect non-inferiority with a lower CI for an absolute risk difference of 5%. Data collection was completed in March 2017. Results 720 patients from 14 sexual health clinics in England were randomised to receive ceftriaxone (n=362) or gentamicin (n=358). Baseline characteristics of the two groups were well balanced. 306 participants randomised to ceftriaxone (85%) and 292 randomised to gentamicin (82%) had primary outcome data available. 98% (299/306) and 91% (267/292) of participants randomised respectively had clearance of gonorrhoea at 2 weeks – adjusted risk difference −6.4% (95% CI −10.4%, −2.4%). Pre-specified sensitivity analyses supported this result. Clearance at the genital site was 98% and 94%, at pharynx 96% and 80% and at rectum 98% and 90%. The frequency of side effects was similar between treatment groups. Conclusion Gentamicin is not non-inferior to ceftriaxone for the treatment of gonorrhoea.

Assessment of a rapid liquid-based cytology method for measuring sputum cell counts

Differential sputum cell counting is not widely available despite proven clinical utility in the management of asthma. We compared eosinophil counts obtained using liquid-based cytology (LBC), a routine histopathological processing method, and the current standard method. Eosinophil counts obtained using LBC were a strong predictor of sputum eosinophilia (≥3%) determined by the standard method suggesting LBC could be used in the management of asthma.

Conducting a randomised trial during an influenza pandemic: an example of a trial set up and ‘hibernated’ ready to activate and recruit within 4 weeks

Background No randomised controlled trial has been successfully conducted during an influenza pandemic. The ASAP trial (Adjuvant Steroids in Adults with Pandemic Influenza) aims to use the novel strategy of set-up in advance of an influenza pandemic, and ‘hibernation’ in readiness for activation in a pandemic. Upon activation, the trial needs to recruit the first participant within 4 weeks, and to complete recruitment of 2200 participants within the first pandemic wave of approximately 6 weeks.

P106 Tissue factor pathway inhibitor (TFPI) is cleaved by multiple proteases in COPD lungs to affect circulating TFPI levels

Background Tissue factor pathway inhibitor (TFPI) attenuates intravascular coagulation, a function limited by its proteolysis. Airway inflammation in COPD is associated with protease activity and intravascular thrombotic events, yet the link between proteolysis of TFPI in the airways and intravascular thrombosis in COPD is unexplored. Aims To explore the presence and processing of TFPI in COPD airways and its relationship to plasma TFPI levels. Methods COPD sputum and blood were collected at exacerbation and when stable. In vitro cleavage of TFPI was explored by incubation with proteases and Western blotting. TFPI presence and cleavage in sputum was detected by Western blotting. To determine the main protease/s involved in TFPI cleavage, sputum was spiked with recombinant TFPI in the presence of protease inhibitors, followed by Western blotting. Results TFPI was cleaved in vitro by Matrix Metalloproteinase (MMP)-12, Neutrophil Elastase (NE) and urokinase-type plasminogen activator (uPA) to <20. Conclusion TFPI is cleaved by NE in COPD airways, leading to lower circulating levels. Further studies are needed to determine if lower circulating TFPI levels lead to increased intravascular thrombotic events in COPD.

S129 A two species proteomics approach to determine MMP-12 substrates in COPD

Background Genetic variability in MMP-12 is associated with COPD; the matrix Metalloproteinase (MMP)-12 knockout (KO) mouse is resistant to emphysema despite cigarette smoke exposure, strongly implicating MMP-12 in COPD pathogenesis. However, the complete MMP-12 substrate profile (degradome) in COPD remains unknown. Terminal amine isobaric labelling of substrates (TAILS) is a novel proteomic technique allowing identification of a protease degradome on an organism-wide scale. Identification of the MMP-12 degradome will lead to novel drugs, desperately needed in COPD. Objectives To identify the MMP-12 degradome in COPD by comparing cigarette smoke exposed MMP-12 KO and wildtype (WT) controls by TAILS and validating these targets against the human COPD sputum proteome during exacerbations and stable disease. Methods C57BL/6J MMP-12 KO and WT mice (n = 4) were exposed to cigarette smoke and airways sampled by bronchoalveolar lavage (BAL). BAL fluid was analysed by TAILS, high performance liquid chromatography (HPLC) and tandem mass spectrometry (MS/MS). Matched COPD exacerbation and stable disease sputum samples (n = 9) were analysed by TAILS, HPLC and MS/MS. Results The following new MMP-12 targets in the COPD mouse model were identified: alpha-2-HS glycoprotein, anti-thrombin III, clusterin, complement C3, complement C4b, complement factor H-related protein-1, hemopexin, serotransferrin and serum albumin, alpha-2-macroglobulin, beta-1, 4-galactosyltransferase 2, transmembrane protease 7, DEP domain-containing mTOR-interacting protein, kininogen-1, tumour necrosis factor ligand superfamily member 11. Of these, alpha-2-HS-glycoprotein, anti-thrombin III, complement factors C3 and C4B, hemopexin and serum albumin were identified in both exacerbation and stable COPD human sputum. Furthermore, 1,116 peptides were identified in COPD exacerbation and stable disease sputum, grouped into the following categories: cell adhesion/migration, complement system, acute phase response, extracellular matrix structure/function, anti-microbicidal activity, cytoskeletal function/remodelling, carbohydrate metabolism, oxidoreductase activity, cell death regulation/DNA synthesis/repair, immune response, protease activity, protease inhibition and ATP synthesis/function. Conclusion This study identifies the MMP-12 degradome in COPD and provides the most comprehensive analysis of the proteome of COPD sputum at exacerbation and stable disease. It suggests a role for MMP-12 in complement regulation and haemostasis in COPD. Thus an important peptide library has been unravelled, providing an ideal tool in developing drugs and understanding COPD pathogenesis.