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Spoken Sessions

Background: The incidence of TB in new entrants aged 16–34 with positive tuberculin tests but normal chest x ray/examination after initial entry is uncertain and has been estimated for the NICE economic appraisal of new entrant screening.

Methods: New entrants aged 16–34 years predominantly from South Asia with tuberculin tests inappropriately positive for BCG history from 1989–2001 were studied and matched to the local notification database to July 2006.

Results: 479 entrants with normal chest x rays were identified. Median age was 24.0 years, 19% had prior BCG. The observation time was 4668.5 years. 49 developed clinical TB up to July 2006. The median detection of TB was 47 months, 75% by 79 months and none after 156 months. The incidence density of cases was 1050/100 000 person years (95% CI 756 to 1344), an annual risk of 1.05% (10.5% at 10 years; 15.8% at 15 years). 5% of individuals mainly students had moved out of the area. Of the remainder 29% were definitely shown still to be locally GP registered. Efforts are continuing to assess the remaining 312 individuals.

Conclusion: These patient-derived data show a minimum risk of TB disease of 10.5% at 10 years. The true rate could be even higher because (a) some persons may have moved/not been notified locally and (b) gamma-interferon test would now remove false positives. The NICE Guidelines section 12.2.8 (p 168) states "The health economic model shows cost-effectiveness when risk over 15 years after entry in the UK exceeds 12%". These data show that this cohort of South Asian entrants have TB levels of a minimum of 10.5% suggesting it would be cost effective to screen such entrants (currently excluded) for latent TB infection.

THE EPIDEMIOLOGY AND TREATMENT OF ENVIRONMENTAL MYCOBACTERIA IN THE PORTSMOUTH AREA
J. Graves, S. Scrivener. Queen Alexandra Hospital, Portsmouth, UK

Introduction: The occurrence of environmental mycobacteria in patients’ microbiological samples processed at The Queen Alexandra Hospital in Portsmouth was investigated. The numbers and types of organisms identified were noted, and whether these patients were investigated and treated in accordance with the 2000 BTS guidelines. Further information on tolerance and success rates of treatment was also gathered where applicable.

Methods: The microbiology department generated a list of all the patients who had grown an atypical mycobacterium, from any site, between 1/5/2004 and 31/5/2006. All of these patients’ case notes were reviewed by a clinician. Information was collected on organism type, site of infection, number of positive samples, patients immune status, presence of chronic lung disease, chest radiograph appearances, symptoms, whether the patient was treated, with which drugs, duration of treatment, success rate (conversion to culture negative) and tolerance of treatment.

Results: 79 patients were identified, with a total of 11 different organisms. 57% were male and 43% were female. Out of the environmental mycobacterium that can more commonly cause disease, MAI (31%) was the commonest organism identified. This was followed by M. Xenopi (18%), M. Chelonae (13%), M. Malmoense (7%) and M. Kansasii (2%). Bronchiectasis was the commonest concomitant lung disease identified (32%). 22% of the patients had some form of immunocompromise. Only 30% of the patients growing an environmental mycobacterium were treated. 55% of those treated had MAI, 25% had M. Xenopi, 10% had M. Chelonae and 5% each had M. Kansasii and M. Malmoense. The ‘rapid-grower’ M. Chelonae patients were all Cystic Fibrosis Paediatric patients. Advice was taken from King’s College Paediatric TB Team regarding treatment. Neither patient became culture negative and treatment was abandoned. Out of the ‘slow-growers’ (MAI, Xenopi, Kansasii and Malmoense) antibiotics consistent with the guidelines were prescribed 94% of the time and the intended duration of treatment was consistent with the guidelines in 83% of patients. However, the intended duration of treatment was only met in 50% of cases and only 33% were culture negative at the end of treatment. 33% of patients did not tolerate the treatment. Reasons given included diarrhoea with lethargy, peripheral neuropathy, renal and liver toxicity and decreased visual acuity. Of the 70% of patients not treated, the commonest reason cited was that the organism was felt to be a contaminant (60%). Other reasons included death and concomitant treatment for mycobacterium tuberculosis.

Discussion: Environmental mycobacteria are widely distributed in nature and are often found without evidence of disease. There is much debate as to which patients require treatment, with which drugs and for how long. The current guidelines are complex and do not include evidence from recent trials and hence clinicians have been uncertain or reluctant to follow them. Our survey found that MAI was the commonest organism identified. Although the antibiotics and intended duration of treatment stated at the start were usually consistent with the guidelines, we found that only 50% of cases complied with this, with about 1/3 becoming culture negative at the end of treatment. It should be noted that 1/3 of our patient remained on their treatment at the time of the survey, which may therefore underestimate this cure rate. Up to date guidelines are needed for management of these patients, and management by physicians with experience and expertise in this field is essential in order to provide the best service for these complex patients who frequently have significant other co-morbidities.

INCREASING ANTI-TUBERCULOSIS DRUG RESISTANCE IN THE UK
M. E. Kruijshaar³, J. M. Watson³, F. Drobniewski⁴, C. Anderson³, J. G. Magee², E. G. Smith¹, I. Abubakar³. ¹Health Protection Agency, Centre for Infections, London, UK; ²Health Protection Agency, Mycobacterium Reference Unit, London, UK; ³Health Protection Agency, Regional Centre for Mycobacteriology, Newcastle, UK

Background: The incidence of tuberculosis is increasing in England, Wales and Northern Ireland. This study examines the recent trends in, and factors associated with, anti-tuberculosis drug resistance in these three countries.

Methods: Information on drug susceptibility for Mycobacterium tuberculosis complex isolates was obtained from UK reference laboratories. Isolates were matched to tuberculosis cases reported to the enhanced tuberculosis surveillance system, which contains clinical and demographic information. Trends in drug resistance and associated factors were analysed using logistic regression. Strain typing information for cases with multi-drug resistant tuberculosis (MDR-TB) were obtained from the reference laboratories.

Results: The proportion of culture-confirmed cases with MDR-TB remained stable between 1998 and 2005 at around 1%. Resistance to isoniazid increased from 5% to 7% in the first five years of this period. Rifampicin, ethambutol and pyrazinamide resistance remained stable at around 1.2%, 0.4% and 0.6% respectively. The increase in isoniazid resistance outside London was a result of changes in place of birth and ethnicity of cases. In London, the rise was related to an outbreak. For cases with MDR-TB susceptibility to second line drugs was available for cases reported in 2002 (84% of cases), 2003 (86%), 2004 (95%) and 2005 (100%). One case was identified as extensively drug resistant (XDR). This case was reported in 2003. Strain typing information was available for 42% of MDR-TB cases reported in 2004–5. The proportion clustered was 20%.

Conclusions: The level of MDR-TB has remained stable despite increases in isoniazid resistance. Strain typing data suggest that some transmission of MDR-TB may be occurring, but the data are limited and most cases for which data were available were unclustered. The increase in isoniazid resistance reflects changes in the characteristics of cases and inadequate control of transmission in London. The observed increases highlight the need for early case detection, rapid drug susceptibility testing and improving treatment completion. Universal strain typing will facilitate the investigation of these trends.

A COMPARISON OF TUBERCULOSIS CASE RATES IN THE HOME-BORN WHITE POPULATIONS OF THE UK AND USA: AN INCREASING DISPARITY
S. Durairaj, N. Schluger, M. Asim, N. Sinnott, P. D. O. Davies. Cardio-thoracic Centre, Liverpool, UK

Introduction: In 2005 we presented data regarding the increasing TB rates in England compared with a decreasing trend in USA. (Duraira, Davies PDO. Increasing tuberculosis in England and Wales compared with a decreasing trend in the USA: a matter of migration. Thorax 2005;60:ii20.) We have now carried out a further analysis to compare case rates in the home-born White populations of the UK and USA.

Methods: Data were compared using government based websites www.cdc.gov for USA statistics and www.hpa.org.uk for the UK.

Results: We compared the rate of TB in the home-born White populations of the UK and USA over the most recent 12-year period for which data are available. The data show that in 1993, the rates/100 000 for the US born White population was 3.6, compared with 4.78 for the equivalent population in UK. By 2001 the rate in the White home-born US population was 1.5 compared with the equivalent UK figure of 3.6. The latest available data are for 2005. In this year the rate in US White home-born population had declined further to 1.3 compared with the UK figure which had remained static at 3.6 (see fig). The difference in the rates in similar population groups are therefore nearly three times higher in UK compared with the USA. As seen in the figure the US rates continue to decline in the home born White population compared with rates in UK.

Conclusion: There is a widening disparity between rates of TB in the White home-born US population compared with the equivalent UK population. Rates in the UK group seem to have stopped declining. The reasons for the disparity is not yet clear. It is possible that the more aggressive policy of giving preventive therapy to individuals with latent tuberculosis in the US may be making some contribution. One possible explanation could be that there may be unidentified transmission from immigrants to the White population within the UK where TB among some ethnic minority groups is rising, whereas rates among all groups in the US continue to fall (Duraira et al, 2005).

ACCURATE DATA COLLECTION: IMPACT ON TREATMENT OUTCOMES AT A RURAL TB PROJECT IN ZIMBABWE
R. M. Smith¹, K. M. Scott², R. D. Barker¹, F. J. C. Millard¹, M. Glenshaw³, E. Manomano³. ¹Department of Respiratory Medicine, King’s College Hospital; ²King’s College, London School of Medicine at Guy’s, King’s and St Thomas’s Hospitals, London, UK; ³Murambinda Mission Hospital, Buhera, Zimbabwe

Introduction: Our first attempts to determine treatment outcomes for the rural TB project in Buhera district, Zimbabwe showed poor case detection; during 2004 the TB detection rate was 422/100 000/year (64% of WHO estimate). However, treatment outcomes for those registered appeared suspiciously good considering the high HIV prevalence (see table). We wished to improve the accuracy of data collection to determine "true" outcomes.

Methods: Two data managers have been employed. They have made concerted efforts to establish accurate treatment outcomes by regularly visiting the district’s primary healthcare clinics and supporting the home-based care team with defaulter follow-up.

Results: Treatment outcomes reported for 2005 were worse than for 2004; only 44% achieved treatment success in 2005 and 46% defaulted. We believe this apparent deterioration in outcomes is a reflection of increasingly accurate data recording. Patients had been recorded as treatment complete when their outcomes were unknown. Revised results following intensive activities to gain true outcomes for those treated in 2005, and data from 2006 will be presented.

Conclusions: TB notifications in the district remain below WHO estimates. The data are likely to be more accurate than previously reported. It is essential that true outcomes are recorded in order that the problems can be defined and appropriate strategies for improving TB control implemented. These "truer" TB treatment outcomes are far from meeting the Stop TB Partnership Targets. Treatment success rates are low, and very few patients achieve "cure". Follow-up of defaulters is difficult in such rural settings but essential in order to avoid emergence of drug-resistant TB. Systems previously in place for follow-up of defaulters have largely disintegrated owing to the political and economic situation. Further research is necessary. However, a picture is emerging of poor access to chronically under-resourced healthcare services leading to poor case detection and case holding. Local and national initiatives are needed, including improved access to diagnosis by decentralisation of sputum collection, support of the national laboratory in provision of culture and DST, collaboration with the HIV service and continued strengthening of patient follow-up at the community level. We in the UK can help by providing financial and technical support for these interventions.

INCREASING TREND OF NON-TUBERCULOUS MYCOBACTERIA IN ENGLAND, WALES AND NORTHERN IRELAND 1995–2006: REAL OR ARTEFACT?
R. M. Smith¹, K. M. Scott², R. D. Barker¹, F. J. C. Millard¹, M. Glenshaw³, E. Manomano³. ¹Department of Respiratory Medicine, King’s College Hospital; ²King’s College, London School of Medicine at Guy’s, King’s and St Thomas’s Hospitals, London, UK; ³Murambinda Mission Hospital, Buhera, Zimbabwe

Introduction: Since the late 1980s, the number of cases of tuberculosis has increased in England, Wales and Northern Ireland. In light of this, reports of infections with non-tuberculous mycobacteria were investigated to see whether such infections showed similar trends.

Methods: Hospital laboratories in England, Wales and Northern Ireland voluntarily report mycobacterial infections to the Health Protection Agency Centre for Infections. Details routinely reported include age and sex of the patient, species and specimen type. All records of non-tuberculous mycobacterial infection between 1995 and 2006 were extracted and analysed.

Results: The number of reported infections rose from 460 in 1995 to 1609 in 2006, an increase of 350%. Nine out of fourteen species reported increased in numbers over the period studied. The six most commonly reported species in 2006 were M avium-intracellulare, M gordonae, M kansasii, M malmoense, M chelonae and M xenopi. These species account for 82% of all infections. Most infections were in males (60%) and in older age groups (51% were over 60) and 73% were isolated from pulmonary specimens.

Conclusions: The total number of non-tuberculous mycobacterial infections reported has increased considerably since 1995. This may be due to changes in diagnostic and reporting practices and the rise in HIV infection and other causes of immunosuppression in the population. An investigation into possible contributions to this increase will be presented.

Asthma: clinical aspects
THE EFFECT OF MECHANICAL HEAT RECOVERY VENTILATION ON THE CONTROL OF ASTHMA: A RANDOMISED CONTROLLED TRIAL
G. R. Wright¹, S. G. Howieson², C. Mcsharry¹, A. D. Mcmahon¹, R. Chaudhuri¹, J. Thompson¹, I. Fraser¹, L. Mcalpine³, S. Wood¹, N. C. Thomson¹. ¹University of Glasgow; ²University of Strathclyde; ³Monklands General Hospital, Loncashire, UK

Background: Sensitivity to the house dust mite allergen Dermatophagoides pteronyssinus 1(Der p1) is commonly associated with asthma in the UK. The warm, humid environment of modern homes favours the house dust mite population, but the effect of improved domestic ventilation on the control of asthma is uncertain.

Methods: We conducted a randomised double-blind placebo-controlled trial of the installation of mechanical heat recovery ventilation in the homes of 120 adults with asthma who were sensitive to Der p1. Activation of the unit was concealed from the subjects; half were activated at randomisation, the others were inactive for the 12 months of the study. All subjects had conventional allergen avoidance at baseline. The primary outcome measure was morning peak expiratory flow at 12 months. Secondary outcome measures included evening peak expiratory flow rate, asthma control questionnaire score, St George’s Respiratory Questionnaire score, courses of oral corticosteroids, hospitalisation, rhinitis visual analogue scores, relative humidity, Der p1 levels, and specific IgE to house dust mite.

Results: At 12 months, the change in mean morning peak expiratory flow, as compared with baseline, did not differ between the mechanical ventilation group and the control group (mean difference 13.59 l/min, 95% CL –2.66 to 29.85, p = 0.100). However, evening mean peak expiratory flow was significantly improved in the mechanical ventilation group (mean difference 24.56 l/min, 95% Cl 8.97 to 40.15, p = 0.002) and there were fewer hospitalisations for asthma. (0 vs 4, p = 0.029). Values for other clinical outcome measures did not differ between the two groups at 12 months. Nasal symptoms significantly improved in the MHRV group compared to the control group at 6 months (nasal discharge mean difference –1.36, 95% Cl –2.30 to –0.42, p = 0.005), but not at 12 months (mean difference –0.46, Cl –1.47 to 0.55, p = 0.371). Indoor relative humidity was reduced more effectively in the bedrooms of mechanically ventilated homes in winter months. Der p1 analysis is awaited.

Conclusion: Installation of mechanical ventilation in the homes of adults with chronic asthma and sensitivity to house dust mite results in an improvement in some indices of asthma control.

EXAMINING THE RELATION BETWEEN ASTHMA AND RHINITIS RESPONSE FOLLOWING OMALIZUMAB THERAPY
L. P. Boulet¹, R. Niven². ¹Institut de Cardiologie et de Pneumologie de l’Universite Laval, Qubec, Canada; ¹North West Lung Centre, Manchester, UK

Background: Omalizumab, an anti-IgE antibody, has proven efficacy as add-on therapy in the treatment of severe persistent allergic (IgE-mediated) asthma, reducing exacerbations, emergency visits, and improving quality of life. Additionally, improvements in rhinitis control have been seen in patients with persistent allergic rhinitis. We investigated the relationship between efficacy of omalizumab on lung and nasal outcomes in patients with co-existing allergic (IgE-mediated) asthma and rhinitis.

Methods: This post hoc analysis of the SOLAR study examined whether a response to omalizumab in terms of asthma control predicted a higher likelihood of a large rhinitis response. Patients were classified as asthma responders if they were judged by the physician to have achieved complete or marked improvement in asthma control according to a five-level evaluation (complete control; marked improvement in control; discernable but limited control; no appreciable change; worsening in control), based on multiple aspects of response including patient interviews, review of medical notes, spirometry and diaries of symptoms, rescue medication use and peak expiratory flow. Patients were classified as having a large rhinitis response if they achieved a 1.5-point improvement in Rhinitis Quality of Life Questionnaire (RQLQ) overall score. The RQLQ self-administered questionnaire contains 28 items covering eight domains (overall, activity limitation, sleep impairment, non-nasal or non-ocular symptoms, practical problems, nasal symptoms, eye symptoms, emotional function), and assesses the previous seven days.

Results: Data were available for 207 omalizumab patients (123 (59.4%) asthma responders, 84 (40.6%) asthma non-responders) and 192 placebo patients. Overall, 90% of patients had severe persistent asthma according to GINA 2002 classification. The likelihood of a large rhinitis response (1.5-point improvement in RQLQ) was significantly greater in omalizumab-treated asthma responders than in the placebo group (64.2% vs 35.4%, p<0.001). In patients who did not respond to omalizumab in terms their asthma, the percentage of patients who responded in terms of their rhinitis (32.1%) was similar to placebo. The odds ratio for a large rhinitis response in omalizumab-treated asthma responders vs asthma non-responders was 3.79 (95% CI 2.11 to 6.82).

Conclusions: Response to omalizumab therapy in terms of improvement in asthma control is associated with a significantly increased probability of improvement in quality of life associated with rhinitis symptoms. Omalizumab-treated asthma responders are 3.8 times more likely to experience a large (1.5 point) improvement in rhinitis related quality of life scores than omalizumab-treated asthma non-responders.

EFFECT OF INHALED CORTICOSTEROIDS ON SMALL AIRWAY DYSFUNCTION IN MILD TO MODERATE PERSISTENT ASTHMATICS
D. Menzies, S. Ismail, P. Hopkinson, A. Nair, B. Lipworth. University of Dundee, Dundee, UK

Background: Small airway dysfunction in asthma is poorly characterised. We have investigated the effect of inhaled corticosteroids (ICS) on small airway inflammation and calibre in adult asthmatics.

Methods: After withdrawal of usual treatment and a steroid free run-in, mild to moderate persistent asthmatics underwent four weeks of prospective treatment with 800 µg per day of inhaled beclometasone. Healthy volunteers acted as a control group. Airway inflammation was quantified using tidal (FE_NO) and alveolar (C_ALV) nitric oxide, and bronchial flux (J_NO). Impulse oscillometry was used to determine total, central and peripheral airway resistance.

Results: Compared with healthy volunteers (n = 27), asthmatics (n = 21) after withdrawal of usual ICS treatment had significantly different values for FE_NO (median 10.7 ppb; IQR 17.9 to 17.7 vs 33.8 ppb; 16.8 to 52.5, p<0.001); J_NO (0.48 nl/s; 0.37 to 0.89 vs 1.71 nl/s; 0.67 to 2.55, p<0.001); C_ALV (1.27 ppb; –1.00 to 2.07 vs 2.14 ppb; 1.49 to 3.95, p = 0.009); total resistance (0.49 kPa/sl; 0.36 to 0.64 vs 0.36 kPa/sl; 0.30 to 0.41, p = 0.002); and peripheral resistance (0.09 kPa/sl; 0.02 to 0.16 vs 0.01 kPa/sl; –0.01 to 0.03, p<0.001); but not central resistance (0.38 kPa/sl; 0.35 to 0.47 vs 0.36 kPa/sl; 0.29 to 0.39, p = 0.099). ICS attenuated FE_NO (p<0.001), J_NO (p<0.001) and C_ALV (p = 0.012), such that values were no longer significantly different from HV (p = 0.59, 0.79 and 0.66 respectively). There were no commensurate changes in peripheral airway resistance or spirometry indices.

Conclusion: Treatment with ICS suppresses peripheral inflammation in mild to moderate asthmatics, but has no effect on airway calibre.

THE LONGITUDINAL CORRELATION BETWEEN FRACTIONAL EXHALED NITRIC OXIDE AND SPUTUM EOSINOPHIL COUNTS IN REFRACTORY ASTHMA
P. Haldar, S. Birring, M. Berry, C. Brightling, P. Bradding, A. Wardlaw, I. Pavord, R. Green. Institute for Lung Health, Leicester, UK

Introduction: Fractional exhaled nitric oxide (FeNO) concentrations correlate significantly with sputum eosinophil counts in cross-sectional studies of asthma and have been proposed as a simple clinical tool for monitoring eosinophilic airway inflammation. However, little is known of the longitudinal correlation between these parameters. We investigated this relation in 88 patients with refractory asthma who are current non-smokers regularly attending the Glenfield Hospital Difficult Asthma Clinic.

Methods: All patients had 3 or more paired measurements of FeNO at 50 ml/s and induced sputum eosinophil counts over time. Longitudinal correlation coefficients (L_c) were calculated from within subject analysis of covariance of log transformed FeNO and % sputum eosinophil counts.

Results: 504 paired measurements were obtained (median 5/subject (range 3–12)). Baseline correlation between the parameters was weak but significant (r = 0.39, p<0.001). The overall within subject longitudinal correlation was weaker (L_c = 0.28, p<0.001). After stratifying the cohort according to concordance between FeNO and sputum eosinophils at baseline, subjects that exhibited concordance had superior longitudinal correlation (concordant group L_c = 0.34 vs discordant group L_c = 0.19). Within the discordant group, subjects expressing sputum eosinophilia without elevation of FeNO showed the poorest longitudinal correlation between the variables (L_c = 0.08, p = 0.48). We also explored the longitudinal correlation in measurements performed when subjects had concomitant symptoms (Juniper asthma control score >1.57). No significant longitudinal correlation was seen between the parameters during expression of symptoms (L_c = 0.05 calculated from 240 measurements in 68 patients, p = 0.471). This dissociation was mainly due to persistent elevation of FeNO in the absence of sputum eosinophilia (seen with 47.7% of measurements). Compared with the entire cohort, the subgroup of patients expressing this pattern (n = 16) were predominantly female (87% vs 44%, p = 0.002), younger (mean age 39 vs 49.8 yrs, p = 0.002) with minimal eosinophilic inflammation (GM Eos 0.67% vs 4,5%, p = 0.001).

Conclusion: Although a significant longitudinal correlation exists between FeNO and sputum eosinophil counts this is of weaker magnitude than cross-sectional measurements. In a subgroup of patients with uncontrolled asthma symptoms there is no longitudinal correlation between FeNO and sputum eosinophils. The clinical applicability of FeNO guided therapy for refractory asthma may therefore be limited.

A QUALITATIVE ANALYSIS OF HRCT SCANS IN DIFFICULT ASTHMA
S. Gupta¹, S. Siddiqui¹, P. Haldar¹, M. Berry¹, R. Green¹ J. Entwisle², I. Pavord¹, A. Wardlaw¹, C. Brightling¹. ¹Institute for Lung Health, Glenfield Hospital; ²Glenfield Hospital, University Hospitals of Leicester, UK

Aim: Bronchial wall thickening (BWT) and bronchiectasis (BE) are familiar radiological features in asthma. We sought to identify the prevalence of these airway geometry changes in a large difficult asthma cohort and to explore the association between BWT, BE and clinical characteristics.

Materials and Methods: Patients attending our "Difficult Asthma Clinic" are extensively characterised in terms of history, lung function, health status and airway inflammation. Out of 463 patients attending our clinic between February 2000 and November 2006, 185 had HRCT scans and were included in the study. Thoracic radiologists determined the presence of BWT or BE. Patients were categorised into those with neither BWT or BE (BWT-/BE-), BE only (BWT-/BE+), BWT only (BWT+/BE-) or both (BWT+/BE+).

Results: The difficult asthma cohort (n = 185) had a mean (SEM) age 49.75 (1.0) years, male: female ratio 73:112, disease duration 26.2 (1.4) years and smoking history of 6.77 (1.0) pack years. Other clinical characteristics for the whole cohort were: FEV₁/FVC ratio 69.69 (1.1), FEV1 % predicted 72.38 (2.0), bronchodilator response (BDR) 8.59 (1.0)%, BDP equivalent 2289 (237.5), sputum neutrophils 61.76 (2.1) %, sputum eosinophils (geometric mean 2.06 (95% CI 1.6–2.7)%. Four distinct groups were formed based on presence or absence of bronchiectasis and bronchial wall thickening. Clinical characteristics of each group were as shown in the table.

Conclusion: Bronchiectasis independent of bronchial wall thickening is associated with airflow limitation, longer disease duration and higher age in difficult asthma. Further quantitative and longitudinal studies are required to assess airway calibre in this disease cohort.

THE RELATIONSHIP BETWEEN GASTRO-OESOPHAGEAL REFLUX AND VOCAL CORD DYSFUNCTION IN A CLINICAL SETTING
N. J. Pargeter, A. H. Mansur. Severe Asthma Unit, Birmingham HeartlandsHospital, UK

Introduction: Vocal cord dysfunction (VCD) represents paradoxical inspiratory vocal cord adduction and is commonly misdiagnosed as asthma. Various case reports have implicated gastro-oesophageal reflux disease (GORD) in triggering VCD. However, the exact prevalence of GORD in VCD has not been previously reported, which is the subject of this study.

Method: Eighty patients (66 females, 14 males, mean age 47.7, age range 16–79) consecutively referred to a VCD clinic were studied using a pre-designed protocol that included in-depth interviews and flow volume loops. Diagnosis of VCD was made via nasendoscopy. The cohort comprised three groups: confirmed VCD (by nasendoscopy); suspected VCD (not seen on nasendoscopy but suggestive from flow volume loops and/or classical symptoms); excluded VCD. Diagnosis of GORD was made by barium swallow and/or 24-h pH monitoring. GORD positive patients (60/80, 75%) received at least eight weeks of twice-daily, high-dose proton pump inhibitor (PPI) therapy. Due to poor GORD symptom control 6/60 (10%) went on to have anti-reflux fundoplication surgery, in line with their physicians’ recommendations. Patients were asked for feedback on their throat symptoms pre and post GORD treatment.

Results: VCD diagnosis was confirmed in 34 patients (42.5%), of which, 28 (82%) had physician diagnosed asthma and 27 (79%) had GORD. In the GORD positive group, nasendoscopy showed refluxive change in the larynx in 20/27 patients (74%). 22/27 patients (81.5%) attributed reflux as a trigger of VCD. However, only 6/27 (22.2%) reported improvement in VCD symptoms following anti-reflux treatment. Thirty one patients conformed to suggestive VCD diagnosis. In this group, 28 (90%) had physician diagnosed asthma. 25/31 patients (81%) had GORD and 18/25 (72%) had laryngeal refluxive change on nasendoscopy. 22/25 (88%) reported reflux as a common trigger of VCD, but only 9/25 (36%) reported improvement in symptoms following anti-reflux treatment. VCD was excluded in 15 patients whose symptoms were attributed to throat irritation 9/15 (60%) and globus pharyngeus 6/15 (40%). In this group, 9 patients (60%) also suffered from asthma and 8/15 (53%) had GORD. Laryngeal refluxive change was observed in 2/8 (25%) cases. 3/8 patients (37.5%) reported symptom improvement following anti-reflux treatment.

Conclusion: GORD is common in patients with confirmed and suspected cases of VCD and is reported as a trigger for VCD in the majority of patients in this group. However, anti-reflux treatment seems to be effective in a minority of GORD confirmed cases, which would implicate other factors in VCD aetiology.

Clinical trials in NIV
NON-INVASIVE VENTILATION IN PATIENTS WITH ACUTE CARDIOGENIC PULMONARY OEDEMA: THE 3CPO TRIAL (A MULTICENTRE RANDOMISED CONTROLLED TRIAL)
A. Gray¹, M. W. Elliott⁴, S. Goodacre³, D. E. Newby², F. Sampson³, J. Nicholl³, M. Masson¹. ¹Royal Infirmary of Edinburgh; ²University of Edinburgh; ³University of Sheffield; ⁴St James’s University Hospital, Leeds, UK

Introduction: This open prospective randomised trial of the early management of acute cardiogenic pulmonary oedema (ACPO), aimed to determine (a) the clinical effectiveness of non-invasive ventilation (CPAP or NIPPV) and standard therapy against standard therapy alone, and (b) the comparative effectiveness of CPAP and NIPPV.

Setting: Emergency Departments of 26 centres between July 2003 and April 2007. Entry criteria: Clinical/radiological characteristics of ACPO, respiratory rate>20/min, arterial hydrogen ion >45 nmol/l (pH<7.35). Intervention: standard therapy, non-invasive positive pressure ventilation (NIPPV; inspiratory pressure 8–20 CmH2O, expiratory pressure 4–10 cmH₂O) or (CPAP; 5–15 cmH₂O). All patients received standard medical treatment at discretion of treating physician. Oxygen was titrated to a maximum of 60%.

Outcomes: Primary: 7-day mortality for standard therapy versus non-invasive ventilation. Secondary: 30-day mortality, combined 7-day mortality and intubation rate. Ancillary: Improvement in physiology, symptoms, myocardial infarction and intubation rates. Power calculation: Sample size 1,200 to detect 6% mortality difference with 80% power. Intention-to-treat analysis.

Results: 1069 patients (mean age 78 years; 43% male) were recruited and randomised to standard therapy (n = 367), CPAP (n = 346; 10 (4) cmH₂O) or NIPPV (356; 14 (5)/7 (2) cmH₂O). At entry patients were tachycardic (heart rate 113 (22)/min), acidotic (pH 7.25 (0.11)), tachypnoeic (respiratory rate 32 (7)/min) and hypoxic (oxygen saturation 90 (8)%). Compared to standard therapy, non-invasive ventilation was associated with greater improvements in tachycardia (102 (23) vs 96 (22)/min, p<0.001), acidosis (pH 7.33 (0.11) vs 7.36 (0.11), p = 0.002) and tachypnoea (26 (6) vs 25 (6), p = 0.023) at one hour. The 7-day and 30-day mortality was similar for standard therapy and non-invasive ventilation (9.8% versus 9.5% (p = 0.869) and 16.6% versus 15.6% (p = 0.685) respectively). Combined end-point 7-day death or intubation rate was similar for both forms of non-invasive ventilation (11.7% vs 11.1%, CPAP vs NIPPV; p = 0.806).

Conclusions: In patients with ACPO, non-invasive ventilation induces a faster improvement in respiratory distress and metabolic disturbance, but has no effect on short-term mortality. CPAP and NIPPV appear to be equally efficacious.

Funding: This project was funded by the NIHR Health Technology Assessment Programme (project number 01/43/01). The views and opinions expressed are those of the authors and do not necessarily reflect those of the Department of Health.

SHORT- AND LONG-TERM MORTALITY FOLLOWING NON-INVASIVE VENTILATORY SUPPORT FOR ACUTE TYPE II RESPIRATORY FAILURE
J. C. Bright, R. Karadi, P. M. Turkington, B. R. O’Driscoll. Salford Royal NHS Foundation Trust, UK

Background: Non-invasive ventilation (NIV) is now widely available in the UK for the support of type II respiratory failure. Ventilatory support for COPD and OHVS (obesity hypoventilation) is accepted but its use in acute pulmonary oedema (APO) and pneumonia remains controversial. Despite this "real world" usage of NIV is increasing.

Aims: To determine the outcome for patients who presented to the acute medical on-call service with Acute Type II Respiratory Failure requiring NIV.

Methods: Retrospective analysis of admissions to Salford Royal Hospital’s Medical High Dependency March 2001–August 2006 with Type II respiratory failure who required non-invasive bi-level ventilation (BiPAP). Only acute presentations were reviewed. All information was obtained from electronic patient hospital records (i SOFT).

Results: 67% of admitting physicians were non-respiratory trainees. 297 patients (140 male, 157 female) with 331 admissions (282 new and 49 repeat) were studied. Admission diagnosis: acute pulmonary oedema (APO) 31, COPD 199 (COPD alone 143), COPD+OHVS 22, OHVS 21, pneumonia 18, others 40.

Conclusions: Despite the use of ventilatory support, Type II respiratory failure is still associated with a poor short- and long-term prognosis. The high early mortality may reflect poor patient selection by the admitting physician. If the findings are reproducible consideration of formal training in ventilatory support for all general physicians participating in the acute on call is warranted. The worst prognosis was observed in the APO and pneumonia cohorts. OHVS cohort had the best outcome.

PREDICTORS OF A SUCCESSFUL OUTCOME IN NON-INVASIVE VENTILATION FOR ACUTE HYPERCAPNIC RESPIRATORY FAILURE: A PROSPECTIVE OBSERVATIONAL STUDY
B. Chakrabarti¹, R. M. Angus², S. Agarwal², S. Lane³, P. M. A. Calverley¹. ¹Clinical Sciences Centre, University Hospital Aintree; ²Aintree Chest Centre, University Hospital Aintree; ³Department of Medical Statistics, University of Liverpool, UK

Introduction: Non-invasive ventilation (NIV) reduces both the need for intubation and mortality in acute hypercapnic respiratory failure (AHRF). We have prospectively identified variables associated with an increased likelihood of NIV failure in AHRF to determine whether hyperglycaemia has an independent effect on outcome.

Methodology: All patients receiving NIV within 24 h of admission for respiratory acidosis complicating AHRF (pH<7.35; PaCO₂ >6 kPa) at University Hospital Aintree between June 2006 and June 2007 were studied. On admission, blood samples including random blood glucose (RBG) were taken before NIV began.

Results: 100 consecutive episodes in 88 patients fulfilled the entry criteria; COPD exacerbations ± pneumonia accounting for 86%. NIV failure occurred in 16%. On univariate analysis, NIV failure was associated with increasing age (76 vs 68 years; p = 0.013), elevated RBG (8.99 mmol/l vs 6.86 mmol/l; p = 0.002), baseline RR (33 vs 26; p = 0.001), APACHE 2 score (18.75 vs 14.39; p = 0.001) and mean 1- and 4-h pH (7.25 vs 7.29; p = 0.028; 7.32 vs 7.27; p = 0.017); a possible relation existed with baseline pH (7.26 vs 7.21; p = 0.097), female gender (p = 0.051) and lower GCS (p = 0.08). NIV failure occurred in 31% (15/48) when RBG was 7 mmol/l compared to 2% (1/50) where RBG 6.9 mmol/l (p = 0.003). NIV failure was not associated with pneumonia, lung function, delay in NIV administration and a previous diagnosis of diabetes mellitus (p>0.1). On multivariate analysis, baseline RR (p = 0.019), RBG 7 mmol/l (p = 0.028), female gender (p = 0.010), 1-h pH (p = 0.049) and 4-h pH (p = 0.007) emerged significant correctly classifying 99% of successes and 75% of failures. An ROC curve was constructed between RR and NIV outcome (area under curve 0.775; p = 0.001). The success rate of NIV reached 98% (43/44) in the subgroup with combination of baseline RR 30/min and RBG <7 mmol/l contrasting to just 42% (8/19) in the sub-group with baseline RR >30/min and RBG 7 mmol/l.

Conclusions: Glycaemia on admission is independently associated with failure of NIV in acute AHRF. Success of NIV in AHRF is more likely in patients with a baseline respiratory rate 30/minute and a random glucose <7 mmol/l.

NON-INVASIVE VENTILATION IN MOTOR NEURON DISEASE: AN AUDIT OF CURRENT PRACTICE
B. Green, K. Adeniji, J. Wilkinson. Southampton General Hospital, UK

Background: The use of non-invasive ventilation (NIV) for symptom palliation in motor neuron disease (MND) is now well recognised, however uptake and access to NIV services shows significant regional variation. An MND NIV service was established in Southampton in 2004 for patients with respiratory symptoms or declining lung function. The possible benefits of NIV use in MND are discussed at initial assessment. Patients are offered a trial of NIV on the basis of orthopnea or symptoms of hypercapnia.

Objective: To evaluate referral outcome and degree of respiratory compromise at the time of referral by retrospective notes audit.

Results: Fifty two referrals were identified over a three-year period. 22 (42.3%) received a trial of NIV. 16 (72.7%) tolerated NIV trial. 10 died before the trial, 2 were inappropriate for, and 5 declined an NIV trial. 13 received active follow-up. 15 (28.8%) accepted long-term NIV. 28 died over the audit period. Median survival from time of diagnosis for patients who accepted home NIV was 26 months compared to 13 months for patients who failed to tolerate NIV (p = 0.03). There was no significant correlation between time to referral, BMI, bicarbonate, PaCO2, forced vital capacity (FVC)% predicted, bulbar score, orthopnea or hypercapnic symptoms, and overall outcome of the referral. Patients tolerating NIV had higher mean arterial bicarbonate (28.1 vs 25.1 mmol/l, p = 0.04) and higher PaCO2 (5.85 vs 5.12 kPa, p = 0.05) than patients that failed NIV trials. Patients who failed an NIV trial had a mean FVC% predicted of 51% compared to 36% in patients who accepted NIV (p = 0.014). No significant correlation between toleration of NIV and bulbar dysfunction score was seen (p = 0.265).

Conclusions: When an NIV service is available to MND patients its use is widely applicable and well tolerated. We observed a significant survival advantage in patients who accept home NIV although the aim of the treatment is symptom palliation. Although severity of bulbar dysfunction has previously been cited as a limitation to the use of NIV our findings do not support this. NIV was better tolerated in patients with worse respiratory function as measured by lower FVC% predicted, higher bicarbonate and higher PaCO₂.

LONG-TERM OUTCOME OF VENTILATORY SUPPORT IN PATIENTS WITH RESPIRATORY FAILURE DUE TO DUCHENNE MUSCULAR DYSTROPHY
M. Ali, I. E. Smith, T. Quinnell, J. M. Shneerson. ¹Papworth Hospital NHS Trust, Cambridge, UK

Introduction: Duchenne muscular dystrophy (DMD) is an X-linked recessive disease characterised by progressive muscle weakness. Respiratory muscle weakness is inevitable and often leads to hypercapnic respiratory failure. Non-invasive ventilation (NIV) has been shown to improve quality of life and survival of patients with DMD who develop respiratory failure. One previous study from the UK has reported a five-year survival of 85% for hypercapnic DMD patients who were treated with NIV.

Aim: To evaluate the characteristics and long-term outcomes of patients with DMD referred to a specialist service.

Method: Patients were identified from the database. Thirty two case notes (between March 1985 and March 2007) were available for a retrospective review. Patients with Becker muscular dystrophy were excluded.

Results: All were males (mean age of 20 yrs at the time of referral). All were unable to walk. Eighteen (56%) had scoliosis. Median FEV1/FVC at the time of referral was 0.5 l/0.6 l (n = 14). Mean peak inspiratory and expiratory pressures were 35 and 32 cm H₂O (n = 7 and 10 respectively). Eighteen (56%) had abnormalities detected on ECG or echocardiogram. Twenty two (69%) were given NIV over the period of study (including 19 who were given NIV at their first assessment)—13 had daytime hypercapnia, 3 had already been trialled on NIV, 2 had only nocturnal hypoventilation and 4 were weaned to long-term NIV after prolonged invasive ventilation. One failed to be weaned and required long-term tracheostomy ventilation. Median survival following NIV was 7 years (95% CI 1 to 12). Following NIV, one survived for 12 years and another was still alive 22 years later. Mean age at death for NIV users was 27 years. Among 22 NIV users, 10 reported pressure sores from the mask or nasal symptoms but all continued to use NIV.

Conclusion: This study reports the survival of DMD patients following NIV over a longer period than previously reported from the UK. Following NIV, median survival was 7 years whereas 2 patients were still alive at 10 years. Following prolonged invasive ventilation, 4 out of 5 were weaned successfully to long-term NIV.

PROSPECTIVE STUDY OF INITIATION OF HOME MECHANICAL VENTILATION TO INVESTIGATE THE CHANGES IN PATIENT DEMOGRAPHICS OVER A TWO-YEAR PERIOD
M. Jheeta, A. J. Williams, N. Grey, A. C. Davidson, N. Hart. Lane FoxRespiratory Unit St Thomas’ Hospital, London, UK

Background: Home mechanical ventilation (HMV) is an established treatment for patients with chronic hypercapnic respiratory failure due to a variety of conditions. Although the evidence for the treatment of obstructive airways disease (OAD) is limited (Meecham-Jones et al, 1995), there is evidence that HMV is useful for the management of chronic respiratory failure complicating neuromuscular disease (NMD) and chest wall disease (CWD) (Leger et al, 1994; Simonds and Elliot, 1995). More recently with the increasing numbers of obese patients presenting with chronic hypercapnic respiratory failure, HMV has been shown to be an effective therapy (Masa et al, 2001; Prez de Llano et al, 2005). Although the Eurovent survey (Lloyd-Owen et al, 2005) highlighted the differences in the demographics of HMV users across Europe, there was no particular focus on the patients with obstructive sleep apnoea and obesity hypoventilation syndrome (OSA/OHS). The aim of the current study was to assess the changes in HMV-user demographics in a regional centre over a two-year period.

Method: The data were collected from the electronic discharge summary database. In addition to basic patient details, information was collected about the admission episode including admission urgency, length of stay, diagnostic group, specific diagnosis, ventilator used and settings and interface. The groups were NMD, OAD, CWD, OSA/OHS, and other. We compared the data between May 2005 to May 2006 and May 2006 to May 2007.

Results: See table. Although there was no change in age, sex or admission urgency over the two-year period, there was a 14% increase in the number of patients initiated on HMV. Furthermore, there was a 23% decrease in the number of patients with NMD initiated on HMV. This was reflected by a fall in all of the specific neuromuscular disease groups. However, there was an increase of over 90% in the patients initiated on HMV with OSA/OHS. All other diagnostic groups remained relatively unchanged.

Conclusion: In addition to an overall increase in initiation of HMV over a two-year period, we have observed a change in the type of patients that are commenced on HMV. There has been a decrease in the NMD group, which was more than matched by an increase in the OSA/OHS group. This increase in activity and change in HMV-user demographics is likely to have significant implications on the structure of the service which will need to be modified in terms of nursing, medical and technical provision in order to adequately manage these differing patient groups.

Acknowledgement: MJ is a medical student at Guy’s, King’s & St Thomas’ School of Medicine who undertook this project as part of an extended Special Study Module.

Lung cancer: basic mechanisms
FOURIER TRANSFORM INFRARED SPECTROSCOPY MEASURING METABOLIC MARKERS IN SPUTUM IN PATIENTS WITH AND WITHOUT LUNG CANCER
R. Ghosal¹, K. E. Lewis², P. Kloer¹, R. Mehta³, D. Parry³, C. Llewellyn-Jones¹, S. L. Prior², L. A. J. Mur⁴, P. D. Lewis². ¹Respiratory Unit, Carmarthenshire NHS Trust; ²School of Medicine, ILS, University of Swansea; ³Bro Morganwwg NHS Trust, Brigend; ⁴Institute of Biological Sciences, University of Wales,Aberystwyth, UK

Introduction: There are 1.3 million worldwide and over 37 000 new cases of lung cancer diagnosed in the UK each year. The incidence of lung cancer is higher in Wales than the UK average. MEDLUNG is a long-term study measuring different combinations of metabolic biomarkers for early detection of lung cancer. Biofluids, including sputum and serum, and biopsy tissue are being collected prospectively from people undergoing bronchoscopy for suspected lung cancer. A key objective of this project is to evaluate Fourier transform infrared (FTIR) spectroscopy for metabolic markers in sputum. FTIR is an established, cost effective technique that enables rapid, high-throughput analysis of different sample types. FTIR has great potential as a metabolic fingerprinting technique and has been applied in a wide variety of clinical settings. We have carried out a preliminary study to evaluate: (1) suitability of sputum as a biofluid for easy/cost effective processing for FTIR (2) ability of FTIR to distinguish between primary lung cancer and non-cancer cases from sputum.

Method: Patients: Five (biopsy proven) non-small cell lung cancer (cases) and 26 non-cancer controls (mixture of stable COPD patients, "healthy" smoking and non-smoking members of staff). Procedure: sputa was collected prior to bronchoscopy (cases) or in clinic (controls) and were frozen within 2–3 h. Sputum cells were isolated by centrifugation and freeze dried. Bronchial cell presence in sputum was confirmed by microscopy. Freeze dried cell extracts were processed in triplicate for FTIR. FTIR spectra data processing and multivariate analysis were performed using Matlab software.

Results: All sputum samples contained bronchial cells and lung cancer patients did not have more bronchial component. This suggests the difference in metabolites is due to different expression rather than cases just producing more sputum (cells).

Conclusion: This pilot suggests that (1) sputum is suitable as a biofluid for easy/cost effective processing for FTIR and (2) FTIR can potentially distinguish between cancer and non-cancer cases in sputum. Greater recruitment and longer term (10-year) follow-up is now assessing combinations of biomarkers in not only diagnosing lung cancer, but detecting pre-cancerous lesions and monitoring response to treatment.

DEGRANULATION OF STROMAL MAST CELLS OF THE TRYPTASE-ONLY PHENOTYPE IS ASSOCIATED WITH IMPROVED PROGNOSIS IN NON-SMALL CELL LUNG CANCER
C. M. Ohri, A. Shikotra, T. Welsh, D. Waller, P. Bradding. Institute for Lung Health, Glenfield Hospital, Leicester, UK

Introduction: It is unclear whether mast cells play a role in preventing cancer formation. We have previously identified a survival advantage for patients with non-small cell lung cancer (NSCLC) who have mast cell infiltration of tumour islets compared to patients who do not.

Methods: The aim of this study was to identify the phenotype of mast cells (either MC_TC, expressing both chymase and tryptase, or MC_T, expressing tryptase only) and their state of degranulation in the tumour stroma and islets in NSCLC, using immunohistochemical analysis. The degree of each mast cell degranulation was evaluated using a degranulation index (DI) as follows: 0 = no degranulation, 1 = less than one third degranulation, 2 = one to two thirds degranulation, 3 = more than two thirds degranulation. We compared 20 patients with above median survival (mean survival = 1452 days) versus 20 patients with below median survival (mean survival = 256 days), (p<0.0001).

Results: The mean densities of MC_TC and MC_T in tumour islets were higher in patients with a survival above the median (1.2 (0.48) and 2.58 (0.40) cells/mm² respectively) compared to those below the median (0.05 (0.02) and 0.19 (0.08) cells/mm² respectively) (p = 0.003 for both MC_TC and MC_T). In patients with above median survival, the MC_T phenotype in the stroma were degranulated to a greater degree than in those with below median survival (mean DI = 2.29 (0.073) versus 1.89 (0.112) respectively) (p = 0.007), as seen in figure 1. In figure 2, a ROC curve demonstrates five-year survival with regards to MC_T DI in the stroma (area under curve = 0.798, 95% CI 0.661 to 0.934).

Conclusions: Both MC_T and MC_TC mast cells infiltrate the tumour islets in patients with NSCLC and good prognosis. While increasing islet infiltration by mast cells also predicts good prognosis, this is accompanied by a higher degree of MC_T degranulation in the NSCLC stroma. Taken together, degranulating mast cells in the tumour stroma, when accompanied by mast cells infiltrating the tumour islets, contribute to an immune response which protects against tumour dissemination.

PROTEOMIC ANALYSIS OF RESECTABLE NON-SMALL CELL LUNG CANCER: IMPACT OF SMOKING, HISTOLOGICAL TYPE AND STAGE OF DISEASE
S. Rathinam¹, S. Nyangoma², D. Ward², A. Alzetani¹, J. Starczynski¹, A. Martin², P. Johnson², N. D. James², P. B. Rajesh¹. ¹Birmingham Heartlands Hospital, Foundation Trust; ²Cancer Research UK Institute for Cancer Studies, University of Birmingham, UK

Background: Surface Enhanced Laser Desorption Ionisation Time of flight Mass Spectrometry (SELDI-TOF-MS) is a mass spectrometry method used to generate "proteomic profiles" of body fluids such as serum. We have used this technique to produce serum proteomic profiles of non small cell lung cancer (NSCLC).

Aim: To determine the impact of smoking, histopathology of the tumour and staging on the proteomic profiles in NSCLC.

Methods: This analysis was performed as a part of the carcinoma of the lung biomarker (CLuB) Study, a prospective observational study with LREC, R&D Approval and NCRN support. The target group were patients undergoing surgery for lung cancer and the controls were from matched non-cancer subjects. Serum samples were analysed using SELDI-TOF-MS. Peak intensities were extracted from the proteomic profiles and a multiple linear regression model was used to evaluate how smoking, cancer type and stage affects the proteome. The p values from t tests of the significance based on the corresponding parameter estimates were used to identify their associated effects on peak intensities. These changes were further evaluated using two-sample t test.

Results: Between January 2005 -September 2006, 70 patients (66% male, median age 65.5 (SD10.0)) and 75 control subjects (70% male, median age 62.9 (SD 12.5)) were recruited. 131 peaks were detected in the SELDI analysis, of which 40 showed significant differences between cancer patients and controls (p<0.01).The smoking status is in table 1. The histology and stage distribution is shown in tables 2 and 3. There was a correlation between the stage of NSCLC and the intensity of certain peaks in the serum proteomic profiles. The differences between adeno and squamous carcinoma were modest. Smoking also had a clearly detectable influence on the profiles. Some peaks were found to be influenced by cancer alone, some by smoking alone and some by both cancer and smoking.

Conclusions: There was a correlation between the stage of the disease and the intensity of certain peaks in the serum proteomic profiles of patients with NSCLC however the differences between adeno and squamous carcinoma were modest. Smoking also had a clearly detectable influence on the profiles.

QUALITY OF RNA EXTRACTED FROM BIOPSIES OF NON-SMALL CELL LUNG CANCER COLLECTED USING DIFFERENT TECHNIQUES
M. H. Lawson¹, D. Rassl², J. Brenton¹, J. Hadfield¹, M. Goddard², N. Screaton², G. Murphy³, R. C. Rintoul². ¹CRUK Cambridge Research Institute; ²Papworth Hospital NHS Foundation Trust; ³University of Cambridge, UK

Introduction: Analysis of RNA using high throughput methods offers a powerful tool for research. However the gene expression profiles generated by such methods are influenced by the quality of the starting RNA which can be influenced by the collection procedure, storage and method used for extraction as well as the type of tissue. At Papworth prospective banking of lung cancer biopsy specimens for use in future research projects has recently begun. This project aims to compare the quality and yield of RNA extracted using a standard method, from non-small cell lung cancer (NSCLC) biopsy specimens collected by different techniques.

Methods: NSCLC biopsy specimens were collected by fibre-optic bronchoscopy (FOB), endobronchial ultrasound guided biopsy (EBUS) or CT-guided needle biopsy. The specimens were snap frozen in liquid nitrogen and stored at –80°C until analysis. RNA was extracted using an RNeasy Mini kit (Qiagen) according to the manufacturer’s instructions. Yield and quality were assessed using a Nanodrop spectrophotometer and by capillary electrophoresis using an Agilent Bioanalyzer.

Results: Yield and quality of extracted RNA was dependent on both the type of biopsy analysed and the quality of each biopsy. Needle biopsy provided the smallest samples and the least RNA. FOB provided the highest yield of RNA and the best quality RNA. The EBUS samples were the largest but did not yield more RNA than FOB samples.

Discussion: It is accepted that the quality of RNA analysed can significantly influence the results of gene expression analysis. Therefore ensuring uniform RNA quality is important in any investigation of comparative gene expression. We have demonstrated that different methods of biopsy collection for lung cancer specimens can result in differences in the quality of RNA when using a standardised extraction protocol. The tissue disruption and homogenisation step of the extraction may need to be optimised for each biopsy type to improve RNA quality. However much of the RNA degradation may be a result of unavoidable tissue crushing during collection activating RNases. The implication is that the most robust design would ensure uniform RNA quality by matching biopsy types for comparison.

THE ASSOCIATION OF LUNG CANCER AND SINGLE NUCLEOTIDE POLYMORPHISMS IN CODON 178 AND THE FIRST INTRON OF THE DNA REPAIR GENE O⁶-ALKYLGUANINE-DNA ALKYLTRANSFERASE
P. A. J. Crosbie¹, G. Mcgown², M. Thorncroft², P. N. S. O’Donnell¹, S. Lewis³,K. Harrison³, R. Agius³, M. Santibanez-Koref⁴, G. Margison², A. Povey³, P. V. Barber¹. ¹Wythenshawe Hospital; ²Carcinogenesis Group, Paterson Institute for Cancer Research; ³Centre for Occupational and Environmental Health, University of Manchester; ⁴Institute of Human Genetics, University of Newcastle, UK

Introduction: Chronic exposure to tobacco smoke is associated with over 90% of lung cancer cases in the UK. Interindividual differences in the ability to repair DNA damage, caused by carcinogens in tobacco smoke, may be a factor in determining the risk of developing lung cancer. One important component of the bodies defence against a subgroup of carcinogens, known as alkylating agents, is the DNA repair protein O⁶-alkylguanine-DNA alkyltransferase (MGMT). Previous work has shown that two single nucleotide polymorphisms (SNP) are significantly associated with MGMT DNA repair activity: within intron 1 (rs12268840) and in codon K178R (rs2308327). The association with lung cancer risk and these SNPs were investigated using three hospital case control studies.

Methods: Genotyping was undertaken on 617 subjects of whom 255 had lung cancer. All subjects were recruited from the Bronchoscopy Unit, Wythenshawe Hospital over a ten year period. All subjects were aged 40 or older; cases were defined as having an incident diagnosis of lung cancer and controls were cancer free. The majority of the population had a smoking history (89%) and were male (62%). Cases (n = 255) were older (n = 362) (68.9 (10.2) vs 64.4 (10.7) years, p<0.001) and had smoked significantly more than controls (52.4 (32.7) vs 46.6 (33.3) pack-years).

Results: The presence of the 178R allele was associated with a reduced risk of lung cancer in two of the three studies (p<0.05). In a meta-analysis, the odds ratio (95% CI) associated with the 178R allele relative to the 178K allele was 0.64 (0.45 to 0.92; p = 0.01) and 0.51 (0.24 to 1.11; p = 0.09) in fixed effects and random effects models respectively. A pooled analysis, which was adjusted for age, gender, smoking exposure (pack-years) and case-control series, revealed a reduced odds ratio (OR, 95% CI) for codon 178R heterozygotes (0.67, 0.45 to 1.01) and homozygotes (0.10, 0.01 to 0.94): the trend for a decreased risk with the number of R alleles was significant (p = 0.008). This trend was especially significant in subjects with above median smoking exposure (trend test p = 0.003) but not in those with below median exposure (p = 0.73). There was no evidence of an association between the intronic polymorphism and lung cancer risk.

Conclusions: These results provide evidence of a protective effect of the codon 178R allele with respect to lung cancer risk, especially in heavy smokers. This effect may be due to the polymorphism affecting the function of the MGMT protein and/or levels in MGMT activity.

Improving outcomes in smokingcessation
IMPORTANT FACTORS IN SMOKING CESSATION IN OLDER PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE VERSUS CRITICAL LIMB ISCHAEMIA
P. Gleeson¹, A. Johnson². ¹Kent & Canterbury Hospital; ²Guy’s & St Thomas’ NHS Foundation Trust, London, UK

Introduction: Smoking cessation is a most important part of management for patients with COPD and peripheral vascular disease (PVD). Little is known about the effectiveness of various smoking cessation interventions in older patients (60 years and above) with these conditions and whether there is any correlation between smoking cessation and diagnosis.

Aim: To assess the effectiveness of smoking cessation interventions in older patients with COPD or critical limb ischaemia; to ascertain if the diagnosis was a factor in giving up smoking and if not, to understand the reasons behind starting and stopping nicotine use.

Patients and Methods: Forty patients admitted to hospital with either an acute exacerbation of COPD (n = 20) or critical leg ischaemia (n = 20) manifested as ischaemic rest pain, ulceration or gangrene with/without amputation were recruited from SE London (St Thomas’ Hospital (STH)) and Kent (Kent & Canterbury Hospital, K&CH). Only those of 60 years of age or older who had stopped smoking before admission were included in the study. Patients were asked a series of 25 questions focussing on demographics, smoking history, reasons for starting smoking and age at starting, reasons for stopping, when and how, and knowledge and attendance (if any) at a smoking cessation clinic. Patients were also asked if they regretted smoking. The questionnaire was a mixture of specific closed questions and broad open questions allowing participants to express their views.

Results: 80% of vascular and 75% of respiratory patients were male and the median age was 70 years. 67.5% had been manual labourers but 27.5% had been in either office or professional employment. 16/40 patients had smoked 16–20 cigarettes per day, one had smoked <5 and four >30 per day. All patients had started smoking before the age of 20 years, two when under 10. All patients gave similar reasons for starting—peer pressure, part of the job, cheap cigarettes, advertising, the War. Most patients had stopped smoking in the last few weeks to 10 years but two had stopped 30 years before. 13/40 patients had stopped within the previous six months. Both vascular and respiratory patients reported stopping because of episodes of shortness of breath and in addition, half of the vascular patients stopped because of fear of immobility due to amputation. Hospitalisation was a potent trigger to quit (the sheer size of STH making it difficult to smoke) while patients at K&CH were afraid they would not be treated if they continued to smoke. Of those who had stopped years before, respiratory symptoms of breathlessness and coughing in public were important in 44% of COPD and 18% of vascular patients. Financial hardship was important for some patients in Kent while family support helped patients in both areas to stop. 60% of all patients had tried to quit more than once. Only 9/40 had tried nicotine patches, three regarding them as key to success. Only three had used other products without success. Most patients had not used anything to help them give up and relied on willpower. Only three had attended a smoking cessation clinic and two found it helpful. 75% of patients were not aware of any smoking cessation clinic in their area. 52.5% of patients regretted smoking but the remainder had no regrets.

Conclusions: Shortness of breath frightened people most and was a strong motivating force to quit, but the threat of amputation along with other medical conditions were also important. Most patients in this age group had not made use of aids to stop smoking and the majority were not aware of smoking cessation clinics. Most relied on willpower to stop. Smoking cessation interventions need to be offered to older smokers both in the primary care setting and also in hospital. Older patients perceive the urgency of stopping smoking and can therefore be highly motivated and receptive to smoking cessation advice and interventions. A period of hospitalisation should be used to encourage and inform elderly patients.

SMOKING CESSATION ADVICE FOR HOSPITAL IN-PATIENTS: ROOM FOR IMPROVEMENT
E. L. Roddy, K. Mortimer, K. Allen, R. Thomas, M. J. Ward, G. M. Cox. Kingsmill Hospital, Nottinghamshire, UK

Introduction: The widely publicised Thorax smoking cessation guidelines state that "all health professionals should give brief advice on smoking cessation" to all patients who smoke, and hospital admission is an ideal opportunity for health professionals, including doctors, to advise patients to give up smoking and provide practical support in the form of nicotine replacement therapy and referral to specialist services.

Methods: We conducted a snapshot survey of all medical, surgical and obstetric/gynaecology inpatients at our medium-sized district general hospital located in a deprived ex-mining area of the East Midlands. The authors visited all medical, surgical and obstetric/gynaecology wards and undertook a short questionnaire with those patients who were willing and able to participate. We asked about smoking status, whether smokers had been advised to quit on this admission and if so by whom, whether they had been offered nicotine replacement therapy and where they obtained their cigarettes. All responses were anonymous.

Results: Many of those questioned were ex-smokers, particularly on cardiac and respiratory wards, although we did not collect specific data on this. Some smokers had been offered NRT which was not then prescribed, and many smokers who had not been advised to quit commented that they felt they should have been, particularly in surgery. Most patients who had been advised to quit had been advised by doctors, and some by specialist nurses.

Conclusion: These "real-life" results show that despite guidelines, and the wide availability of nicotine replacement therapy, many smokers especially in non-medical specialties are still not being given adequate help and support to quit during inpatient attendances. They also show that smuggled cigarettes remain widely available, which may be related to the deprived area that the hospital is situated in. More work needs to be done to educate health professionals from all specialties to advise and assist patients to quit smoking in hospital.

A QUESTIONNAIRE SURVEY ON SMOKING POLICY AND SMOKING CESSATION TOOLS IN UK SECONDARY SCHOOLS
J. T. Samuel¹, K. E. Lewis¹, L. G. Mcalpine². ¹Basildon University Hospital, Essex, UK; ²Monklands Hospital, Airdrie, UK

Introduction: 70–80% of smokers start when they are of school age. Smoking cessation (SC) is part of health education in schools but its delivery and implementation is variable. On behalf of the British Thoracic Society (BTS) Tobacco Committee (TC), we surveyed schools across the UK regarding their policies on smoking and what services/teaching they employ.

Methods: A cross-sectional survey of secondary schools local to members of the TC between October and December 2006. Following initial telephone contact, anonymous self-addressed questionanaires were posted to the lead for Professional, Social and Health Education in each school.

Results: Sixty questionnaires were sent out and 49 replies were received (response rate of 82%). All responders said they had a complete smoking ban for students in the school premises. 88% had a policy for staff smokers. 61% reported policy breach by students and 16% by staff. 82% reported time specifically dedicated to SC in the curriculum. 37% reported that staff were not comfortable with their level of knowledge of tobacco smoking and SC and only 41% had access to any training in SC education. Although 47% said their available education tools were of a high standard, only 27% reported they had the appropriate skills to motivate and assist pupils who smoke to quit. 92% of schools felt that the BTS could help them educate on the effects of smoking on health and deliver SC advice.

Conclusion: Individual school policies on smoking do exist but are frequently breached, mainly by pupils but also by staff. A significant proportion of responding schools did not feel comfortable with their levels of knowledge and skills with less than half saying they had access to appropriate training. Three in four responders felt they did not have the skills to assist pupils who smoke to quit. Help from the BTS was welcome by most schools. Utilising the expertise of members of the newly formed British Association of Stop Smoking Practitioners (BASSP) in secondary schools perhaps concentrating on staff education and confidence building is being considered.

EARLY EXPERIENCE WITH VARENICLINE IN A HOSPITAL-BASED SMOKING CESSATION CLINIC
J. Ryder, R. Angus, L. Davies. Aintree Chest Centre, Liverpool, UK

Background: University Hospital Aintree is a large, teaching hospital in Liverpool. The local adult smoking prevalence is 34%, rising to almost 60% in one of our catchment PCTs. The local SMR for lung cancer is more than 200, and we see 1500 admissions annually with COPD exacerbations.

Methods: In 2001, a hospital-based smoking cessation clinic was established. Specialists see in-patients, out-patients and staff, and the intervention consists of initial assessment, pharmacological support and intensive counselling. In January 2007, varenicline was added to the hospital formulary. According to our protocol, smokers were initially offered NRT to aid their quit attempt. If they had used NRT in the past, or the quit attempt failed, varenicline or bupropion was offered.

Results: From January to June 2007, 463 new referrals (72% female) were seen. 74 (16%) were prescribed varenicline. Mean (SD) age 55 (10.6) years, 59 (80%) female. Fourteen smokers were staff members, 60 were patients with an underlying respiratory diagnosis. Only one patient was thought suitable for varenicline by the specialist but was refused on medical grounds. Varenicline was prescribed for mean (SD) 8.3 (5.8) weeks. 37 (50%) reported side effects (see table). There was no difference in side-effects between women and men. Twelve (16%) discontinued the medication due to nausea and/or vomiting within the first 4 weeks. A further five patients discontinued through choice. 52/74 (72%) had sustained quit attempts at 4 weeks compared with 98/160 (61%; ² NS) smokers using NRT in the same period.

Conclusion: Varenicline is acceptable to and well tolerated by smokers attending a hospital based smoking cessation clinic. The drug is suitable for most hospital patients. As this is a report of clinical practice, rather than a randomised controlled trial, many of the reported side effects could be due to nicotine withdrawal. However, in keeping with previous studies of "healthy smokers", nausea was a common problem. In our clinic, approximately 1:6 stopped the drug due to nausea and/or vomiting. It remains to be seen how well sustained these quit attempts will be at 6 and 12 months, but our early experience is certainly encouraging.

ACHIEVING A SMOKE-FREE SITE IN A DISTRICT GENERAL HOSPITAL: A SURVEY OF PERCEPTIONS OF HEALTHCARE WORKERS
M. D. Shipley, R. Allcock. Gateshead Health NHS Trust, UK

Background: In December 2006 all UK NHS trusts introduced smoke-free regulations prohibiting smoking on all NHS sites. These rules are to be implemented by all NHS trust staff. We have investigated barriers to the implementation and enforcement of these regulations.

Methods: Study participants were 85 medical and nursing staff working in acute medicine at the Queen Elizabeth Hospital, Gateshead. They completed a questionnaire reporting their behaviour when exposed to smokers on NHS hospital sites.

Results: Over 50% of medical and nursing staff reported that they would not challenge patients, staff or visitors smoking on NHS trust sites. Employees appeared more likely to challenge patients than visitors, and were more likely to challenge visitors than other staff. Fear of aggression was the most commonly reported reason for not challenging smokers.

Conclusions: This study has highlighted perceived barriers to the implementation of a smoke free NHS in a district general hospital medical unit. Most medical and nursing staff do not enforce NHS policy. Most medical and nursing staff would not challenge patients, staff, and visitors to stop smoking on a hospital site. There are perceived barriers to the implementation of NHS smoke free regulation by medical and nursing staff working in medical units at District General Hospitals in the North East of England. Many staff report non-compliance with NHS and local policies for enforcement of smoke free hospitals. There is scope to improve this through training in NHS policy and how to avoid aggression.

ATTITUDES OF CURRENT AND EX-SMOKERS TO THE BANNING OF SMOKING IN PUBLIC AND ENCLOSED SPACES IN ENGLAND
H. Burhan, J. Ryder, K. Dowd, S. Haworth, B. Brockway, L. Davies. Aintree Chest Centre, University Hospital Aintree, Liverpool, UK

Introduction: Patients attending Smoking Cessation Clinics often attend with partners or supporters who themselves may be current or ex-smokers. Are there differences between these two groups in attitudes towards the ban on smoking in enclosed public spaces and workplaces in England? We assessed awareness of the ban in the six weeks prior to its implementation in 71 Smoking Cessation Clinic attenders to see whether current smokers, and accompanying ex-smokers differed in their perceptions of the value of the ban.

Results: See table. All respondents were aware of the smoking ban prior to the legislation being enacted. The most frequently cited reasons for quitting in ex-smokers were ill health or hospital admission (55.5%), cost (18.6%), and family pressure (11.1%). Most current smokers (61.4%) had made 2–5 attempts to quit previously; 20.4% of ex-smokers claimed to have quit at their first attempt. There was a statistically significant difference between current and ex smokers’ responses (p<0.05); student t test. No significant differences were observed between smokers and ex-smokers in response to the question "Do you think the ban on smoking in enclosed and public spaces would help you quit?" (p = 0.44). Ex-smokers were significantly more likely to be bothered by a smoky atmosphere in a pub, club or bar than smokers (20 (74.1%) vs 17 (38.6%), p = 0.004); this difference was less significant when asked regarding smoky restaurants or cafes (23 (52.3%) vs 21 (77.8%), p = 0.06). Current smokers were significantly more likely to disagree with the comment "the smoking ban will make me more likely to eat out" (p = 0.01).

Conclusions: All those surveyed were aware of the imminent smoking ban. Both smokers and ex-smokers felt that the ban would be helpful in giving up smoking. Despite this there were statistically significant differences in opinion as to whether the ban was a good idea. Current smokers were less bothered by smoky environments than ex-smokers, and did not feel the ban would encourage them to eat out more frequently.

Pulmonary circulation: assessmentand treatment
BOSENTAN FOR INOPERABLE CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION: A RANDOMISED, PLACEBO-CONTROLLED TRIAL—BENEFIT
J. Pepke-Zaba¹, E. Mayer⁵, G. Simmoneau⁷, L. J. Rubin⁶, I. Lang⁴,M. M. Hoeper³, H. A. Ghofrani². ¹Papworth Hospital, Cambridge, UK; ²University Hospital, Giessen, Germany; ³University of Hanover Medical School; ⁴Medical University of Vienna, Austria; ⁵Johannes Gutenberg University Medical School, Mainz, Germany; ⁶University of California, USA; ⁷Antoine Beclere Hospital, Clamart, France

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening condition, characterized by obstruction of the pulmonary vascular bed causing increased pulmonary vascular resistance (PVR) and progressive pulmonary hypertension (PH). The treatment of choice is pulmonary endarterectomy (PEA), and is potentially curative. However, up to 50% of patients referred for surgery are not eligible. Additionally, 10–15% of patients experience post-operative persistent or recurrent PH. Since arteriopathy in CTEPH shares pathology with pulmonary vascular changes in pulmonary arterial hypertension (PAH), the efficacy and safety of the dual endothelin receptor antagonist, bosentan, has been evaluated in patients with inoperable CTEPH or with persistent or recurrent postoperative H.

Methods: BENEFiT is the first multicentre, prospective, double-blind, placebo-controlled study of medical treatment for inoperable CTEPH or PH after PEA. Patients were randomised to receive bosentan or placebo for 16 weeks (62.5 mg twice daily increasing to 125 mg twice daily after 4 weeks). Independent co-primary endpoints: percentage change from baseline in PVR at rest at week 16 OR change from baseline to week 16 in 6MWD. Other endpoints included: change from baseline to week 16 in WHO functional class (FC), haemodynamics, time to clinical worsening, SVO₂, change from baseline in NT-pro-BNP and Borg dyspnea index.

Results: 157 patients were randomised to bosentan or placebo. The PVR analysis set excluded 20 patients (9 placebo, 11 bosentan) and the 6MWD analysis 17 patients (7 placebo, 10 bosentan) because they were considered "operable" post-randomisation or due to a missing baseline or post-baseline assessment. Co-primary endpoints: change in PVR from baseline to week 16 was +30 dynxsec/cm⁵ in the placebo group compared to –146 dynxsec/cm⁵ in the bosentan group, a significant treatment effect of 24.1% (95% CI –31.5 to –16.0; p<0.0001) (fig). No treatment effect was observed on 6MWD at 16 weeks, which increased in the placebo group by 0.8 m compared to 2.9 m in the bosentan group. Other endpoints are shown in table 1. Safety results were consistent with the established safety profile for bosentan from other trials.

Conclusions: These results suggest that bosentan improves haemodynamics in patients with inoperable CTEPH or with persistent or recurrent PH after PEA.

PULMONARY ARTERY OCCLUSION PRESSURE ANALYSIS IN CHRONIC THROMBOEMBOLIC AND IDIOPATHIC PULMONARY HYPERTENSION
M. Toshner¹, J. Suntharalingam², E. Soon¹, K. K. Sheares¹, P. White¹, R. Hughes², P. Fesler³, R. Naeije⁴, J. Pepke-Zaba¹. ¹Papworth Hospital, Cambridge, UK; ²Royal United Hospital, Bath, UK; ³Montpelier University Hospital, France; ⁴Erasme University Hospital, Brussels, Belgium

Introduction: Pulmonary artery occlusion pressure (PAOP) waveform analysis is emerging as a useful tool for partitioning pulmonary vascular resistance. Previous work in chronic thrombo-embolic pulmonary hypertension (CTEPH) has suggested that it can identify patients at high risk of operative mortality and residual distal disease. The selection of patients suitable for pulmonary endarterectomy (PEA) is critical given that small vessel disease and arteriopathy account for over one third of operative deaths. To determine if PAOP analysis could discern between predominantly proximal and distal disease we examined patients with operable proximal CTEPH, inoperable distal CTEPH, and idiopathic pulmonary arterial hypertension (IPAH) including connective tissue associated PAH where the vascular obstruction is distal in nature.

Methods: All subjects were diagnosed using standard Venice classification criteria and assessed by the surgical team. PAOP were performed at right heart catheter and analysis of waveforms were undertaken blinded using a computer model as previously described and expressed as an upstream % (Rup). Statistical analysis between groups was by ANOVA.

Results: Of 35 patients recruited 14 were proximal operable CTEPH, 7 distal inoperable CTEPH and 13 IPAH/CTD. Mean Rup was significantly higher in operable, mean 86% (SD 7.6), versus inoperable disease mean 69.9% SD (8.7) p = 0.001. Postoperatively two patients died. These two patients were the lowest flow directed Rups in the operative group. IPAH mean Rup 77% (SD 8.6) was also significantly lower than proximal isease p = 0.008.

Conclusions: PAOP analysis continues to show potential for discriminating between surgically operable predominantly proximal and inoperable distally distributed disease and we confirm the observation that a low Rup is a risk factor for mortality post PEA. In IPAH as hypothesised the Rup was lower than proximal disease but not with sufficient sensitivity to distinguish between the two groups.

A RANDOMISED CONTROLLED TRIAL TO INVESTIGATE THE EFFECTS OF A PHYSIOTHERAPIST-LED REHABILITATION PROGRAMME ON EXERCISE CAPACITY AND QUALITY OF LIFE MEASURES IN PATIENTS WITH PULMONARY HYPERTENSION
A. Wilkinson¹, C. A. Elliot², S. Mawson¹, I. Armstrong², C. Billings², D. G. Kiely². ¹Department of Physiotherapy, Royal Hallamshire Hospital; ²Sheffield Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital, Sheffield, UK

Introduction: Pulmonary rehabilitation has been demonstrated to be an effective intervention in a number of cardiopulmonary diseases. In pulmonary hypertension a recent study has demonstrated an improvement in exercise capacity following a period of intensive in-patient rehabilitation.

Methods: In a randomised-controlled trial we examined the effects of an out-patient based physiotherapist led rehabilitation programme. 40 patients with pulmonary hypertension were recruited. All patients had been stable for at least six weeks. Patients were excluded if on continuous oxygen, in NYHA Class IV, or with severe mobility or balance problems. Patients were randomised into two groups; control group receiving standard best practice and a rehabilitation group receiving best practice plus a physiotherapist-led rehabilitation programme. Patients were seen by the physiotherapist in a single one to one class and given a prescribed set of exercises tailored to the individual needs of the patient. The patient was followed up with telephone support during the 3-month period and the patient was encouraged to continue with their regular exercise regime. Blind assessment was undertaken pre intervention and following 3 months. Outcome measures included distance walked on incremental shuttle (ISWT) and endurance shuttle (ESWT) and SF-36 and CAMPHOR quality of life questionnaires. Data are presented as mean (standard deviation). Analyses were made using the t test and p<0.05 (two-tailed) was considered significant.

Results: After 3 months there was a statistically significant increase in the ISWT distance in the rehabilitation group compared to baseline 278 (151 versus 255 (141) m, p = 0.028, and a trend towards an improvement in the ESWT 493 (473 m compared to 382 (465) m, p = 0.07. There was no significant difference in the Control group: for the ISWT 261 (132 compared to 262 (142) m at baseline and the ESWT 411 (409 compared to 471 (431) m at baseline. There were no statistically significant differences in quality of life measures.

Conclusions: This pilot study suggests that a physiotherapy-led rehabilitation programme for patients with pulmonary hypertension can be safely performed in the home setting and has the potential to improve exercise capacity through education and controlled exercise and a multicentre trial is planned.

Acknowledgement: This study was supported by a grant from the PHA-UK.

NON-INVASIVE ASSESSMENT OF PULMONARY BLOOD FLOW USING AN INERT GAS REBREATHING DEVICE IN PATIENTS WITH PULMONARY HYPERTENSION
L. E. R. Mclure, A. Brown, A. Peacock, M. K. Johnson. Scottish Pulmonary Vascular Unit, Glasgow, UK

Objective: Cardiac output (CO) is an important prognostic marker in pulmonary hypertension (PHT). A non-invasive measure of CO would be valuable in monitoring disease progression. Inert gas rebreathing using acetylene is a well established method for the non-invasive measurement of pulmonary blood flow (PBF) and has been validated in patients with PHT. Recently a new rebreathing technique (Innocor, Innovision, Denmark) using nitrous oxide analysed by a rapid photoacoustic method has been developed. The device is small, portable and convenient for use during exercise. This technique has been validated for patients with left heart failure. The aim of this study was to investigate the accuracy of this new inert gas rebreathing technique in patients under investigation for PHT.

Methods: Twenty three patients (14 female, 9 male) under assessment at the Scottish Pulmonary Vascular Unit had CO measured by three methods: inert gas rebreathing (Innocor) giving PBF, cardiac magnetic resonance (CMR) imaging giving pulmonary artery flow and thermodilution (TD) during right heart catheterisation (RHC) giving right-sided cardiac output. All the subjects had a provisional diagnosis of PHT by echocardiography. CMR imaging (using cine imaging with steady state free precession and phase contrast velocity encoding sequences) and RHC were performed within 48 h of Innocor measurements. PHT was confirmed in 16 patients (8 idiopathic, 5 chronic thromboembolic, 3 connective tissue disease associated). PBF and CO were expressed as volumes by dividing by heart rate, giving estimates of stroke volume (SV). Agreement between techniques was assessed using Bland-Altman analyis and correlation.

Results: All three methods showed good correlation for stroke volume estimates (Innocor vs CMR, r = 0.91; Innocor vs TD, r = 0.89, CMR vs TD, r = 0.95). Bland-Altman analysis showed that the best agreement was obtained between CMR and TD SV with bias (limits of agreement) of –3.2 ml (–19.4 to +12.9 ml). However, the inert gas rebreathing technique also provided values of reasonable accuracy. Innocor vs MRI SV gave bias (limits of agreement) of –2.5 ml (–23.5 to +18.5 ml) (see fig 1) whereas Innocor vs TD SV gave bias (limits of agreement) of –7.4 ml (–30.9 to +16.2 ml).

Conclusion: Inert gas rebreathing using the Innocor device provides an accurate, non-invasive means of assessment of pulmonary blood flow in patients with suspected PHT.

ISCHAEMIC STROKES AND PULMONARY ARTERIOVENOUS MALFORMATIONS (PAVMS): PAVM EMBOLISATION REDUCES STROKE RISK
C. L. Shovlin¹, J. E. Jackson², E. Kulinskaya¹. ¹Imperial College and Hammersmith Hospital; 2Hammersmith Hospital, London, UK

Background: Pulmonary arteriovenous malformations (PAVMs) provide a right-to-left (R-L) shunt between the pulmonary arterial and venous circulations. Paradoxical embolic strokes affect high proportions of PAVM patients. Embolisation can be used to treat PAVMs if the condition is recognised, however, until now, no direct evidence for reduction of stroke incidence has been presented.

Methods: A cohort study of 219 consecutive individuals with PAVMs was performed. Six markers of PAVM severity (respiratory symptoms; oxygen saturation; R-L shunt (by radionucleide scan); size of largest feeding artery to PAVMs; presence of small PAVMs; and PAVM multiplicity); 12 patient or HHT-