H Parfrey

Development of a Consensus Statement for the Definition, Diagnosis, and Treatment of Acute Exacerbations of Idiopathic Pulmonary Fibrosis Using the Delphi Technique

IntroductionThere is a lack of agreed and established guidelines for the treatment of acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF). This reflects, in part, the limited evidence-base underpinning the management of AE-IPF. In the absence of high-quality evidence, the aim of this research was to develop a clinician-led consensus statement for the definition, diagnosis and treatment of AE-IPF.MethodsA literature review was conducted to obtain published material on the definition and treatment of AE-IPF. The results of this review were circulated to an online panel of clinicians for review. Statements were then shared with ten expert respiratory clinicians who regularly treat patients with IPF. A Delphi technique was then used to develop a consensus statement for the definition, diagnosis and treatment of AE-IPF. During the first round of review, clinicians rated the clarity of each statement, the extent to which the statement should be included and provided comments. In two subsequent rounds of review, clinicians were provided with the group median inclusion rating for each statement, and any revised wording of statements to aid clarity. Clinicians were asked to repeat the clarity and inclusion ratings for the revised statements.ResultsThe literature review, online panel discussion, and face-to-face meeting generated 65 statements covering the definition, diagnosis, and management of AE-IPF. Following three rounds of blind review, 90% of clinicians agreed 39 final statements. These final statements included a definition of AE-IPF, approach to diagnosis, and treatment options, specifically: supportive measures, use of anti-microbials, immunosuppressants, anti-coagulants, anti-fibrotic therapy, escalation, transplant management, and long-term management including discharge planning.ConclusionThis clinician-led consensus statement establishes the ‘best practice’ for the management and treatment of AE-IPF based on current knowledge, evidence, and available treatments.FundingBoehringer Ingelheim Ltd., Bracknell, West Berkshire, UK.

Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study

Summary Background Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with high mortality, uncertain cause, and few treatment options. Studies have identified a significant genetic risk associated with the development of IPF; however, mechanisms by which genetic risk factors promote IPF remain unclear. We aimed to identify genetic variants associated with IPF susceptibility and provide mechanistic insight using gene and protein expression analyses. Methods We used a two-stage approach: a genome-wide association study in patients with IPF of European ancestry recruited from nine different centres in the UK and controls selected from UK Biobank (stage 1) matched for age, sex, and smoking status; and a follow-up of associated genetic variants in independent datasets of patients with IPF and controls from two independent US samples from the Chicago consortium and the Colorado consortium (stage 2). We investigated the effect of novel signals on gene expression in large transcriptomic and genomic data resources, and examined expression using lung tissue samples from patients with IPF and controls. Findings 602 patients with IPF and 3366 controls were selected for stage 1. For stage 2, 2158 patients with IPF and 5195 controls were selected. We identified a novel genome-wide significant signal of association with IPF susceptibility near A-kinase anchoring protein 13 (AKAP13; rs62025270, odds ratio [OR] 1·27 [95% CI 1·18–1·37], p=1·32 × 10−9) and confirmed previously reported signals, including in mucin 5B (MUC5B; rs35705950, OR 2·89 [2·56–3·26], p=1·12 × 10−66) and desmoplakin (DSP; rs2076295, OR 1·44 [1·35–1·54], p=7·81 × 10−28). For rs62025270, the allele A associated with increased susceptibility to IPF was also associated with increased expression of AKAP13 mRNA in lung tissue from patients who had lung resection procedures (n=1111). We showed that AKAP13 is expressed in the alveolar epithelium and lymphoid follicles from patients with IPF, and AKAP13 mRNA expression was 1·42-times higher in lung tissue from patients with IPF (n=46) than that in lung tissue from controls (n=51). Interpretation AKAP13 is a Rho guanine nucleotide exchange factor regulating activation of RhoA, which is known to be involved in profibrotic signalling pathways. The identification of AKAP13 as a susceptibility gene for IPF increases the prospect of successfully targeting RhoA pathway inhibitors in patients with IPF. Funding UK Medical Research Council, National Heart, Lung, and Blood Institute of the US National Institutes of Health, Agencia Canaria de Investigación, Innovación y Sociedad de la Información, Spain, UK National Institute for Health Research, and the British Lung Foundation.

P155 Use of mycophenolate mofetil and azathioprine in patients with chronic hypersensitivity pneumonitis

Background The optimal pharmacological management of chronic hypersensitivity pneumonitis (cHP) is unknown. Corticosteroids are often used as first line therapy but can be associated with side effects. There is a paucity of data examining the roln DLCO but not FVC (Morisset J et al. Chest. 2017). We aimed to determine the effece of steroid-sparing agents in cHP. A recent retrospective study demonstrated that treatment with either mycophenolate mofetil (MMF) or azathioprine (AZA) was associated with improvements it of MMF and AZA on lung function and prednisolone dose in cHP patients. Methods Patients initiated on either MMF or AZA following a MDT diagnosis of cHP were retrospectively identified from the ILD service Papworth Hospital, Cambridge. Changes in lung function in the 9–12 months before and after treatment initiation were analysed. Daily prednisolone dose at initiation and 9–12 months treatment was recorded. Results Twenty eight patients were identified between 2008 and 2016; 20 were treated with MMF (1–2 g daily) and 8 with AZA (25–150 mg daily). The mean age at drug initiation was 59.6±1.7 years and 61% were female. The mean duration from diagnosis to commencing MMF or AZA was 30.9±5.5 months. Twenty patients remained on either drug at 9–12 months and were include in the effectiveness analysis (FVC and TLCO data were available for 20 and 13 patients respectively). Five patients discontinued treatment due to drug side effects. Treatment with either MMF or AZA resulted in a significant reduction in prednisolone dose from 16.1±2.1 mg to 8.0±0.8 mg (p<0.001). MMF or AZA treatment for 9–12 months was associated with a significant improvement in TLCO (−0.62±0.3 vs+0.32±0.17 mmol/kPa/min, p<0.05). Although treatment reduced rate of FVC decline (−100±65 vs −30±66 mls), it was not significant (p=0.4). Conclusions In our cohort of cHP, treatment with either MMF or AZA was associated with an improvement in TLCO consistent with findings of a previous retrospective study. Moreover, the addition of MMF or AZA enabled a significant reduction in prednisolone dose.

S76 Endoplasmic reticulum stress correlates with fibrosis in interstitial lung disease

In interstitial lung disease (ILD), pulmonary fibrosis is associated with a poor prognosis. Distinct histological features differentiate between the ILDs, however it is unknown if there are shared pathogenic mechanisms for the development of fibrosis. Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of familial and sporadic idiopathic pulmonary fibrosis (IPF). In response to ER stress, cells trigger the integrated stress response and upregulate chaperones, such as BiP, and the phosphatase GADD34, which can regulate EMT, cell proliferation and survival. AIMS We hypothesise that ER stress may be involved in the pathogenesis of fibrosis in all interstitial lung diseases. Paraffin embedded lung biopsy sections from 8 patients with familial pulmonary fibrosis, 11 sporadic idiopathic pulmonary fibrosis (IPF), 12 non-specific interstitial pneumonia (NSIP) and 10 hypersensitivity pneumonitis (HP) were evaluated for BiP and GADD34 by immunohistochemistry. Using light microscopy, 6 high power fields were scored for fibrosis, inflammation, BiP and GADD34 using semi-quantitative analysis by 2 blinded, independent investigators. Data were analysed by linear regression using Prism software. BiP and GADD34 were localised to reactive type II pneumocytes and columnar epithelium within areas of fibrosis. GADD34 was also evident in the endothelium. No staining was detected in fibroblasts. Epithelial GADD34 correlated with extent of fibrosis in familial pulmonary fibrosis (r2 = 0.72, p < 0.001), IPF (r2 = 0.51, p < 0.0001) and NSIP (r2 = 0.46, p < 0.0001). In contrast, BiP was associated with fibrosis in IPF (r2 = 0.49, p < 0.0001) and HP (r2 = 0.59, p < 0.0001). These data show that ER stress and the unfolded protein response are associated with fibrosis in ILD. Hence targeting ER stress may be a novel therapeutic option for pulmonary fibrosis.

S21 Identification of clinical prognostic parameters in patients with idiopathic pulmonary fibrosis

Idiopathic Pulmonary Fibrosis (IPF) is a progressive, scarring lung disease with a poor prognosis and median survival of 3 years. It is a heterogeneous disorder with varying rates of progression which presents a challenge for accurate prognostic prediction. The composite physiologic index (CPI) and the Gender, Age and Physiology (GAP) score are validated scoring systems for prognostic determination in IPF. Our data suggest these scoring systems have limited usefulness and we have undertaken a modelling approach to evaluate clinical prognostic parameters. Methods Gender, age, smoking history, presence of emphysema on HRCT thorax and echocardiogram confirmed pulmonary hypertension were collected retrospectively from 253 IPF patients (in accordance with ATS/ERS criteria and MDT consensus) from a single centre in the UK between 19th April 2007 and 13th November 2014. Lung function including FEV1, FVC, DLco and 6 minute walk test (distance, resting and minimum oxygen saturation and maximum heart rate) were collected at baseline, 6 and 12 months of follow up. Survival data were censored at 1st January 2016. The relationship between GAP or CPI and survival was analysed by Spearman’s correlation, ROC area under the curve and Chi2 analysis. Multivariate analysis and linear regression were used for the modelling. Results Of the 253 patients included 188 were male (74%) with age 71.4 ± 8.3 years (mean ± SD). There were 164 (64.8%) ex-smokers and 12 (4.7%) current smokers. At presentation 19 patients had pulmonary hypertension and 35 had evidence of emphysema on HRCT thorax. Baseline lung function FEV1 79 ± 22% predicted, FVC 82 ± 19% predicted, DLco 45 ± 15% predicted (mean ± SD). Median survival was 1169 days (3.2 years). The association between survival and CPI (r2 0.59, p < 0.01) or GAP (r2 0.45, p < 0.01) was modest. However ROC curve analysis demonstrated that GAP and CPI were poor predictors of survival. Chi2 analysis shows there is no significant difference between these scoring systems. Multivariate analysis demonstrated that baseline% predicted DLco (r2 = 0.32, p = 6×10–20) (Figure 1) had the strongest association with survival. Conclusion Our data suggest that baseline percent predicted DLco may be a better predictor of outcome in patients with IPF. These results required validation by an independent cohort. Abstract S21 Figure 1

S44 Prognostic scoring systems for Idiopathic Pulmonary Fibrosis: Comparison of the composite physiologic index (CPI) and the GAP score

Idiopathic Pulmonary Fibrosis (IPF) is a progressive, scarring lung disease with a poor prognosis and median survival of 3 years. It is a heterogeneous disorder with varying rates of progression, which presents a challenge for accurate prognostic prediction. The CPI1 and the GAP2 score are validated scoring systems for prognostic determination in IPF. However, it remains unclear which is the optimal method for accurate prediction of mortality in IPF. Therefore, a comparison of the predictive ability of the GAP score and CPI was undertaken in a cohort of IPF patients. Methods Baseline data were collected retrospectively from 213 IPF patients (in accordance with ATS/ERS criteria and MDT consensus) from a single centre in the UK between 19th April 2007 and 14th July 2014. Thirty-eight patients were excluded, either because pulmonary function test results could not be obtained or the patient received a lung transplant during follow-up. Gender, age, FVC and DLCO were used to calculate the GAP score whilst FVC, FEV1 and DLCO were used for the CPI. Spearman’s correlation was used to analyse the relationship between GAP score or CPI and survival time. The ability of the scoring systems to predict survival at 1 and 3 years was assessed using ROC curve analysis. Results Of the 175 patients, 131 (75%) were male with a mean age of 71 ± 8 years (mean ± SD) at presentation. Overall 3-year mortality was 50%. The CPI demonstrated a better correlation with survival (r2 = 0.37, p < 0.01) compared to the GAP score (r2 = 0.24, p < 0.01). ROC curve analysis for 1-year mortality found that area under curve (AUC) was 0.726 for the GAP score and 0.783 for the CPI. For 3-year mortality AUC was 0.749 for the GAP score and 0.805 for the CPI. Conclusion These data show that the CPI more accurately predicts survival at presentation and 3-years than the GAP score in a UK IPF cohort.Abstract S44 Figure 1 Correlation of GAP score (1a) and CPI (1b) and survival in IPF References 1 Wells AU, et al. Am J Resp Crit Care Med. 2003;167:962 2 Ley B, et al. Ann Intern Med. 2012;156:684