D Ryan

P243 Specific antibody deficiency to streptococcus pneumoniae and haemophilus influenzae in asthma and fungal disease

Introduction Recurrent exacerbations are a characteristic feature of uncontrolled asthma, often due to viral or bacterial infections. We have reported in a retrospective study that immune deficiency is common in asthma and correlates with reduced lung function. We set up a prospective study to determine if this predisposes to a more severe disease. Aim Our aim is to ascertain if immune deficiency is associated with a more severe disease potentially with radiological changes and clinically with low lung function and frequent exacerbations. Methods We prospectively collected data from new patients attending the regional asthma and fungal clinics. Demographics, markers of disease severity and specific antibody levels to Haemophilus iInfluenzae (HI), and Streptococcus pneumoniae (SP), were recorded. Patients with specific antibody deficiency (HI: ≤ 0.15 iu and SP: ≤ 0.35 iu to 6+ of 12 strains tested) received appropriate vaccination(s) in primary care (Pneumovax® and Meniotrix®), with repeat samples collected two months later. We also recorded blood and sputum eosinophil counts, radiological findings such as bronchiectasis and bronchial wall thickening, total IgE, smoking status, exacerbations in the last year and ITU admissions. Results 101 patients were followed up (69 asthma, 32 fungal) 67 female, mean (SD) age 53 (15) years, FEV1 69 (21.9)% predicted, ICS dose 1818 (1244) μg, and BMI 29.9 (8.9) kg/m2. Specific antibody levels and responses to vaccination are presented in Figure 1. Immune deficiency at baseline and post vaccination did not correlate with lung function, radiological findings such as bronchial wall thickening or exacerbation frequency. Conclusion Specific antibody deficiency is commonly seen in patients with asthma and fungal disease. Vaccination can provide protection and should be considered in this patient group. We need further analysis with a larger cohort of patients to study the association between antibody deficiency, lung function, radiological changes and disease progression. Abstract P243 Figure 1 Specific antibody levels at baseline and following vaccination for Haemophilus influenza and streptococcus pneumonia

P240 Low ige and not blood eosinophils predicts lack of response to omalizumab in uhsm cohort

Background Omalizumab is an anti-IgE monoclonal antibody therapy used in patients with inadequately controlled persistent allergic IgE mediated asthma who require continuous or frequent treatment with oral corticosteroids. Previous studies have tried to predict a patient’s response to omalizumab based on pre-treatment baseline characteristics. Most recent data has suggested that baseline blood eosinophils, serum periostin or FeNO may be predictive of response to omalizumab in the TH2 phenotype. Aims This study will attempt to identify a characteristic that may explain why some patients suffering with severe asthma in a single severe asthma centre do not achieve a response when treated with the anti-IgE monoclonal antibody, omalizumab. Methods The target population was represented by all patients previously treated or undergoing treatment with omalizumab at the Severe Asthma Service at University Hospital South Manchester (n = 185). The study population was those for whom records could be found within the study period (n = 154). Demographic and clinical data was collected retrospectively from patient medical records. Results 16.2% of patients at UHSM did not show response to omalizumab at 16 weeks. Baseline serum IgE levels in the non-response group were on average 77.28 kU/L lower than those in the response group, statistical analysis of the two groups show that this difference was significant (P = 0.04). Mean eosinophils in the true non-responder group were actually higher than those in the true responder group, however this difference was not statistically significant. No other demographic or disease specific measures predicted a lack of response to omalizumab. Discussion The results from the study indicate that a lower baseline serum IgE may predict non-response to treatment with omalizumab. The results also show that non-response rates at the NWLC were lower than those demonstrated in clinical trials (INNOVATE), were consistent with other real life studies (PERSIST/APEX I and APEX II) but markedly lower than those quoted in the eXpeRience registry. Abstract P240 Figure 1 Comparison of baseline IgE in true nonresponders and true responders

A clinically observed variability in serum total IgE in patients being considered for omalizumab therapy

Intro: Omalizumab (Xolair) is licensed for the treatment of severe allergic asthma patients with IgE mediated disease. Dose calculation is governed by total IgE and weight. Stringent controls in prescribing mean patients deemed clinically appropriate to commence treatment are illegible as consequence of IgE levels outside of the dosing table. Our aim was to identify the fluctuation of IgE, to ascertain if a degree of flexibility should be considered when prescribing Omalizumab. Methods: Retrospectively the total serum IgEs of patients whom were referred to potentially start therapy were reviewed. Patients with 2 or more IgEs within a six month period were included. The range of variability of IgE and percentage of variability between the two IgEs were recorded. Results: n=29. IgE 1 median=460 (IQR 155.5-870.0), IgE 2 median=340 (IQR 140.0-885). All IgE9s varied with 14 increasing and 15 decreasing. The average IgE variation was 89 IU/ML (IQR 75-123, median 98). This equated to an average percentage variation of 36.6% (IQR 13.5%-40.7%, median 23.1%). There was no statistically significant difference between IgE 1 and 2 yet, the variation in IgE 2 resulted in an additional 4 of the 29 patients becoming eligible for treatment and the dose could have been altered in 8 of the 19 patients whose IgE 1 was in the dosing range. This would mean that overall 79% of patients were eligible for Omalizumab instead of 66%. Conclusion: Our data collected shows that Serum IgE has significant variability, and therefore frequent testing of IgE in patients whom are potential for Omalizumab therapy and do not meet dosing criteria on initial review should have repeat measures of serum IgE.

S130 Axl receptor tyrosine kinase on airway macrophages has a key role in lung immune homeostasis

Rationale Apoptotic cell uptake (efferocytosis) by airway macrophages (AMs) is critical for lung immune homeostasis and is defective in chronic lung diseases, including asthma,1 although the molecular mechanism behind this remains unknown. The TAM (Tyro3, Axl, MerTK) receptor tyrosine kinases are one of the main receptor classes that mediate efferocytosis but little is known about their regulation and function in inflammatory lung diseases. Aim To investigate expression profile of TAM receptors and their ligand Gas6 in human AMs and analyse potential defects in TAM receptor expression in chronic lung inflammation. Methods AMs from the sputum of patients with asthma (BTS step 3–5) (n = 30) or healthy donors (HD) (n = 12) were enriched by plastic adhesion. Monocytes were isolated from matched whole blood samples by CD14 positive selection and differentiated into monocyte-derived macrophages (MDMs). Total RNA was extracted from all purified cell populations and mRNA expression analysed by qPCR. HD MDMs were stimulated with Th2 cytokines in vitro and TAM receptor expression was analysed using qPCR and ELISA.Abstract S130 Figure 1 mRNA expression of Axl in airway macrophages of healthy donors and patients with asthma Main results Axl was the dominant TAM receptor expressed in HD AMs whereas monocytes and MDMs predominantly expressed MerTK. Axl expression was significantly reduced in AMs from patients with asthma compared to HD (p < 0.0001), while mRNA levels of MerTK and Gas6 was similar in both groups. We found no differences in Axl and MerTK expression in monocytes and MDMs from HD and patients with asthma, indicating that the observed differences were restricted to the site of inflammation. In vitro, MDM stimulation with IL-4 or IL-13 downregulated Axl mRNA and protein expression in a time-dependent manner. Conclusions We have shown for the first time that Axl is the principal TAM receptor expressed in human AMs. Significant reduction of Axl expression in AMs from patients with asthma might be responsible for inefficient clearance of apoptotic cells from the inflamed airways and contribute to persistent airway inflammation. Strategies aimed at restoration of Axl expression or activity may represent a novel therapeutic strategy in asthma and other chronic lung diseases. Reference 1 Simpson JL, Gibson PG, Yang IA et al. Impaired macrophage phagocytosis in non-eosinophilic asthma. Clin Exp Allergy. 2013;43:29–35

P74 Prevalence of Specific Antibody Deficiency in Severe Asthma

Introduction Patients with asthma are prone to recurrent infective exacerbations, due to viral or bacterial infections. We have previously presented retrospective data, demonstrating significantly reduced lung function in severe asthma patients with specific antibody deficiency. The prevalence and impact of specific antibody deficiency in this patient group is not known. Aim We aimed to determine the prevalence of specific antibody deficiency and its association with markers of disease severity. Methods We prospectively collected data from all new patients attending the regional severe asthma clinic. We recorded demographic details and markers of disease severity including: BTS treatment step, inhaled corticosteroid (ICS) dose, spirometry, blood and sputum eosinophil count, radiological findings such as bronchiectasis and bronchial wall thickening, exacerbations in the last year and ITU admissions. Specific antibody levels to Haemophilus Influenzae (Streptococcus Pneumoniae (<0.35 μg/ml to at least 6 of the 12 serotypes classed as deficient) were measured. Results Data for 53 patients (39F), mean (SD) age 49.6 (15.9) years were available. Mean (SD) FEV1 was 69 (22)% predicted, ICS dose 1914 (1337) micrograms, and BMI 31.5 (8.6) kg/m2. All were at BTS step 3–5. Information on specific antibody levels was available for 43 and 45 patients for H Influenzae and S pneumoniae respectively and for both in 42 patients. Overall out of the 42 patients 35 (83%) were deficient to one or both the organisms. Of these 13 (31%) were deficient to H Influenzae alone, 5(12%) to S pneumoniae alone, and 17 (40.5%) to both. Looking at each organism separately 30 (70%) out of 43 were deficient to H Influenzae and 23 out of 45 (51%) were deficient to S pneumoniae. Of the 32 patients for whom data were available 20 (63%) had 7 or more exacerbations in the preceding year and two thirds of these had bronchial wall thickening on their CT scans. A third of patients (30%) reported at least one ITU admission. The presence of specific antibody deficiency did not correlate with any clinical or radiological findings.Abstract P74 Table 1 Prevalence of specific antibody deficiency and associated patient characteristics Prevalence Bronchial wall thickening on CT chest Bronchiectasis on CT chest ≥7 Exacerbations past year Total ITU admissions Percentage predicted FEV1 (%) Inhaled steroid (BDP equivalent) µg n = 45 n (%) n (%) n (%) n (%) n (%) Mean (SD) Mean (SD) Total H. influenzae deficient 30 (70) H. influenzae deficient alone 13 (31) 8 (23) 5 (5) - 14 4 (3) - 17 3 (3) - 18 57 (16) 2540 (2240) Total S. pneumoniae deficient 23(51) S. pneumoniae deficient alone 5 (12) 3 (8.5) 2 (2) - 6 1 (0) - 4 0 (2) - 0 77 (8) 1933 (1101) Combined Deficiency 17 (40) 11 (31) 6 (10) - 17 8 (3) - 33 4 (2) - 24 73 (23) 1837 (900) Competent Specific Antibody Levels 7 (13) 2 (6) 3 (2) - 8.5 2 (3) - 6 0 (3) - 0 70 (32) 1840 (607) Conclusion Specific antibody deficiency to H influenza and S pneumoniae is remarkably common in moderate to severe asthma. Further studies are required to determine the clinical significance of this finding.

P133 A Multidisciplinary Patient Education Programme Significantly Improves Asthma Control and Quality of Life in Patients with Severe Asthma

Background The impact of severe asthma upon quality of life is significant, as a consequence of unpredictable hospitalisations and life-threatening attacks. It is unknown whether patient education programmes in severe asthma improve self-management, quality of life or measures of asthma control. A 12 week patient education programme was piloted within a severe asthma multi-disciplinary team. Sessions were 2 h duration fortnightly. The aim of the programme was to enable patients to gain greater insight into their disease, treatment options and lifestyle management with emphasis on improving asthma control and quality of life. Aims Our aim was to assess the effect of the introduction of this programme upon participant’s asthma control and quality of life. Methods Prospective data collection was performed, including Asthma Quality of Life Questionnaire (AQLQ), Asthma Control Questionnaire (ACQ) and Hospital Anxiety and Depression (HAD) at week 1 and 12. Patient Satisfaction Evaluation forms were completed to facilitate ongoing programme development. Results 21 patients entered with 16 (76%) completing the 12 week programme (12 female, 4 male). Dropout was attributed to difficulty attending on a regular basis. There was an improvement in mean total AQLQ of 1.3 (minimal clinically important difference >0.5). There was notable improvement in the AQLQ domains; symptoms (0.8) and emotional (0.7). Mean ACQ improved by 0.7 (p < 0.05), mean HAD anxiety and depression scores fell but this did not reach statistical significance (Table 1).Abstract P133 Table 1 AQLQ Total(mean) AQLQ Symptoms(mean) AQLQ Activity(mean) AQLQ Emotional(mean) AQLQ Enviro(mean) ACQ 6(mean) HAD Anxiety(mean) HAD Depression(mean) Week 1 2.6 2.7 2.6 2.9 3.08 3.9 9.6 9.1 Week 12 3.9 3.5 3.1 3.6 3.22 3.2 8.5 7.5 Change from Baseline ↑1.3 ↑0.8 ↑0.5 ↑0.7 ↑0.1 ↓ 0.7- ↓1.1 ↓1.6 p value p = 0.06 p = 0.04 p = 0.1 p = 0.07 p = 0.3 p = 0.05 p = 0.27 p = 0.18 The patient evaluation forms demonstrated significant patient satisfaction with the programme, highlighting the positive impact that the sessions have had had upon their life. Conclusion A multidisciplinary patient education group for severe asthma patients significantly improves quality of life and asthma control. Longitudinal studies are required to determine impact upon exacerbations and hospitalisations.

P73 A pilot study to investigate the use of serum inhaled corticosteroid concentration as a potential marker of treatment adherence in severe asthma

Background Inhaled anti-inflammatory therapy is fundamental to asthma management, but adherence is very poor. This increases the risk of exacerbations and poor symptom control. Currently there is no direct way of assessing adherence to inhaled steroids accurately. The primary aim of this project was to determine whether liquid chromatography tandem mass spectrometry could be used to detect fluticasone propionate (FP) in human serum as a potential aid to therapeutic monitoring. The secondary aim was to relate serum levels of FP to markers of asthma severity. Methods We collected blood samples over an 8 hr period from inpatients with severe asthma on a stable dose of inhaled FP. Following baseline (trough) sampling, patients were observed using their inhaler, with inhaler technique documented. Subsequent samples were obtained 1, 2s, 4 and 8 hrs post inhalation. Demographic details and spirometry were also recorded. Results Thirteen patients were recruited: 8 males, 5 females; age range 22–64 yrs; FEV1 range 53–101% predicted; 10 patients on 1000 mcg/day, and three on 2000 mcg/day FP. The mean concentration of FP at 1 hr post inhaler (peak in 7/13 patients) was 95.5 (SD 89.1) ng/L. The mean pre-dose trough concentration was 32.9 (SD 41.5) ng/L. Two patients were noted to have poor inhaler technique; these patients had some of the lowest serum FP levels recorded. The FEV1% predicted was found to be strongly correlated with the peak serum FP concentration (Pearson’s r = 0.8, p = 0.001). Conclusion We have demonstrated that FP can be detected in the blood of patients with severe asthma following directly observed therapy; this could have a potential future application as a direct measure of adherence and perhaps inhaler technique. We also demonstrated a profound effect of reduced lung function predicting low serum FP levels. Future work will explore whether poor absorption reflects relatively poor efficacy in the most severe patients.Abstract P73 Figure 1 Serum concentration of FP at sampling timepoints; dashed lines represent individual patients; solid line group mean