Spiral.imperial.ac.uk
In Patients with Idiopathic Pulmonary Fibrosis the Presence of Hiatus Hernia is Associated with Disease Progression and MortalityJohn A Mackintosh1, Sujal R Desai1,2, Huzaifa Adamali3, Kinesh Patel1, Felix Chua1, Anand Devaraj1, Vasilis Kouranos1, Maria Kokosi1, George Margaritopoulos1, Elisabetta A Renzoni1,2, Athol U Wells1,2, Philip L Molyneaux1,2, Sacheen Kumar4, Toby M Maher1,2, Peter M George1,21 Royal Brompton and Harefield NHS Foundation Trust, London2 National Heart and Lung Institute, Imperial College London3 North Bristol NHS Trust, Bristol4 Royal Marsden Hospital, LondonCorresponding author:Dr Peter M GeorgeConsultant Respiratory PhysicianInterstitial Lung Disease UnitRoyal Brompton HospitalSydney St, London, SW3 6NPEmail: p.george@rbht.nhs.ukTake Home Messages:In patients with idiopathic pulmonary fibrosis (IPF) treated with anti-fibrotic therapy, the presence of hiatus hernia is associated with disease progression. This supports the exploration of pathogenic mechanisms associated with hiatus hernia in IPF. Author Contribution:PG, SD and JM – study designJM, SD, HA, KP, FC, AD, VK, MK, GM, EA, AW, PM, SK, TM, PG – data acquisition, statistical analysis, data interpretation, manuscript drafting and revision, final approval of manuscript.In idiopathic pulmonary fibrosis (IPF), the role of gastro-oesophageal reflux (GOR) and its treatment remain unclear ADDIN EN.CITE <EndNote><Cite><Author>Kreuter</Author><Year>2018</Year><RecNum>102</RecNum><DisplayText>[1]</DisplayText><record><rec-number>102</rec-number><foreign-keys><key app="EN" db-id="tszade5dv950dve2f5apte28evw9fww5xxp2" timestamp="1540046784">102</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kreuter, M.</author><author>Raghu, G.</author></authors></contributors><auth-address>Center for interstitial and rare lung diseases, Thoraxklinik, University of Heidelberg, Heidelberg, Germany and German Center for Lung Research (DZL).
Center for Interstitial Lung Diseases, University of Washington, Seattle, WA, USA.</auth-address><titles><title>Gastro-oesophageal reflux and idiopathic pulmonary fibrosis: the heart burn in patients with IPF can no longer be silent</title><secondary-title>Eur Respir J</secondary-title><alt-title>The European respiratory journal</alt-title></titles><periodical><full-title>Eur Respir J</full-title><abbr-1>The European respiratory journal</abbr-1></periodical><alt-periodical><full-title>Eur Respir J</full-title><abbr-1>The European respiratory journal</abbr-1></alt-periodical><volume>51</volume><number>6</number><edition>2018/06/23</edition><dates><year>2018</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0903-1936</isbn><accession-num>29929960</accession-num><urls></urls><electronic-resource-num>10.1183/13993003.00921-2018</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[1]. Both acid and non-acid components of GOR contribute to lung inflammation and fibrosisPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYXZhcmlubzwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+
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ADDIN EN.CITE.DATA [9]. Patient selection for WRAP-IPF was dependent on a positive DeMeester score, a measure of acid-reflux that has not been examined in relation to IPF outcomes. We aimed to assess the impact of HH and acid-reflux as measured by DeMeester score in IPF, hypothesising that HH, which is associated with both acid and non-acid GOR, may be an important contributor to IPF progression.A retrospective cohort of IPF patients receiving pirfenidone between 2011-2017 was analysed. The study was restricted to patients prescribed a single anti-fibrotic agent to minimise potential confounding. HH was scored qualitatively as “present” or “absent” and estimated for size on the first available chest computed tomography (CT) scan, by a thoracic radiologist (SRD) blinded to outcome measures, in a randomised order. A separate cohort of IPF patients, who underwent 24-hour oesophageal pH-impedance testing between 2008-2017 was analysed. The majority of pH-impedance studies were performed prior to the advent of anti-fibrotic therapy, therefore the few who received an anti-fibrotic drug were excluded to minimise confounding. A positive pH study for acid-reflux was defined using DeMeester score (>14.72) and Lyon Consensus Criteria (pH<4 for >6% time or >80 total events)PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Kb2huc29uPC9BdXRob3I+PFllYXI+MTk3NDwvWWVhcj48
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ADDIN EN.CITE.DATA [10, 11].Serial forced vital capacity (FVC) was calculated as change in mL at approximately 12 months from the first available test. Transplant-free survival was measured from the first date. Appropriate parametric (t-tests), non-parametric (Mann-Whitney U tests) and categorical (Chi-square) analyses were performed using SPSS version 25.0 (Armonk,NY:IBM). Survival was analysed using Kaplan Meier and Cox-proportional hazards methods.HH was present in 37/89 (42%) patients (Table 1). Patients with HH were significantly younger and experienced greater relative and absolute annual FVC decline (-250mL (-123 to -333mL) versus -36mL (-15 to -156mL), p=0.01). Prescription of PPIs was 86% and 71% in the HH present and absent groups respectively. HH size did not correlate with FVC decline. The median transplant-free survival was significantly shorter in patients with HH (31 versus 55 months, p=0.049). Using a Cox-proportionate hazard model, adjusted for PPI use, age, gender and Composite Physiologic Index (CPI), the hazard ratio for HH and transplant-free survival was 1.74 (95%CI 0.95 – 3.2, p=0.07). Patients with HH were no more likely to discontinue Pirfenidone. Patients with positive acid-reflux studies demonstrated no difference in FVC decline or survival (Table 1). Acid-reflux and HH are both common in IPF. However, in these IPF cohorts, only the presence of HH was associated with disease progression and mortality. Although the association between HH and worse outcomes in IPF has been previously describedPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ub3NzaWVyPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48
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ADDIN EN.CITE.DATA [8], this is the first study to reveal an association with annual FVC decline and to demonstrate this in the context of anti-fibrotic therapy. Despite similar baseline disease severity, patients with HH were younger, suggesting that HH may be a co-factor in the pathogenesis of IPF, potentially driving earlier presentation and worse outcomes. It might be considered that GOR symptoms associated with HH such as cough may result in earlier diagnosis; however, lead-time bias does not explain the more rapid decline and increased mortality observed. As a positive pH-impedance study did not identify patients at risk of disease progression, HH may exert a pathogenic role through a combination of acid and non-acid reflux. An alternative explanation is that HH occur due to the effects of progressive fibrosis on thoracic biomechanics, developing because of progressively more negative intrathoracic pressures. However, patients with HH did not have more advanced disease as defined by FVC or CPI and we found no suggestion that HH enlarged over time. This study was not designed to address this ‘cause or effect’ question, which could be evaluated by assessing the presence and impact of HH in interstitial lung abnormality (ILA) cohorts.If HH is indeed pathogenically linked to IPF progression, it is tempting to postulate that surgical correction of HH in early or even subclinical disease might modulate the natural history of IPF. Surgical management of reflux in the post-transplant setting has proven prognostic benefitsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYW50dTwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [8], had WRAP-IPF been targeted to those with HH, a larger effect may have been observed in terms of lung function stabilisation and potentially survival.A limitation of our study is that the cohort of patients undergoing pH-impedance was small and measures of non-acid reflux were not available. Patients with positive impedance studies received lifestyle advice alongside pharmacological therapy to address acid and non-acid reflux. We are therefore not able to definitively exclude the role of acid-reflux in IPF progression. Our data suggest that HH is associated with IPF disease progression and while the pathogenic mechanism may be through combined acid and non-acid reflux, prospective studies exploring upper gastrointestinal physiology are required to allow definitive conclusions. A multi-dimensional approach to GOR assessment, incorporating measures of acid and non-acid impedance, manometry and the presence of HH, similar to that recently proposed by Jones and colleagues deserves prospective evaluation ADDIN EN.CITE <EndNote><Cite><Author>Jones</Author><Year>2018</Year><RecNum>171</RecNum><DisplayText>[15]</DisplayText><record><rec-number>171</rec-number><foreign-keys><key app="EN" db-id="tszade5dv950dve2f5apte28evw9fww5xxp2" timestamp="1541767213">171</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jones, R.</author><author>Krishnan, A.</author><author>Zeybel, G. L.</author><author>Dookun, E.</author><author>Pearson, J. P.</author><author>Simpson, A. J.</author><author>Griffin, S. M.</author><author>Ward, C.</author><author>Forrest, I. A.</author></authors></contributors><auth-address>Northern Oesophago-Gastric Unit, Royal Victoria Infirmary, Newcastle-upon-Tyne, UK.
Joint first authors.
Institute of Cell and Molecular Biosciences, The Medical School, Newcastle University, Newcastle-upon-Tyne, UK.
Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle-upon-Tyne, UK.
Joint senior authors.
Dept of Respiratory Medicine, Royal Victoria Infirmary, Newcastle-upon-Tyne, UK.</auth-address><titles><title>Reflux in idiopathic pulmonary fibrosis: treatment informed by an integrated approach</title><secondary-title>ERJ Open Res</secondary-title><alt-title>ERJ open research</alt-title></titles><periodical><full-title>ERJ Open Res</full-title><abbr-1>ERJ open research</abbr-1></periodical><alt-periodical><full-title>ERJ Open Res</full-title><abbr-1>ERJ open research</abbr-1></alt-periodical><volume>4</volume><number>4</number><edition>2018/11/09</edition><dates><year>2018</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>2312-0541 (Print)
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ADDIN EN.CITE.DATA [4]. When controlling for PPI use however, the association between HH and mortality remained. Finally, CT is not the gold-standard test for HH, but while CT may miss small HH, this should not negate the associations observed for those with HH large enough to be detected non-invasively. We have demonstrated that HH is associated with disease progression and adverse survival in IPF patients treated with antifibrotic therapy. A mechanical rather than pathogenic explanation remains possible and further research is required to explore these associations. If confirmed in subsequent studies, identification of HH as a poor prognostic indicator in IPF should prompt clinicians to stratify these patients as being at higher risk for disease progression. Early treatment of acid and non-acid reflux alongside IPF therapy may improve outcomes. As PPIs only address one component of GOR, measures such as pro-kinetics and fundoplication may be effective alternative and/or adjunctive therapeutic strategies. It may be that the most effective strategy for reflux intervention in IPF utilises a personalised approach, based on multiple factors, including HH. Acknowledgments: nilReferences ADDIN EN.REFLIST 1. Kreuter M, Raghu G. Gastro-oesophageal reflux and idiopathic pulmonary fibrosis: the heart burn in patients with IPF can no longer be silent. The European respiratory journal 2018; 51.2. Savarino E, Carbone R, Marabotto E, Furnari M, Sconfienza L, Ghio M, Zentilin P, Savarino V. Gastro-oesophageal reflux and gastric aspiration in idiopathic pulmonary fibrosis patients. The European respiratory journal 2013; 42: 1322-1331.3. Perng DW, Chang KT, Su KC, Wu YC, Wu MT, Hsu WH, Tsai CM, Lee YC. Exposure of airway epithelium to bile acids associated with gastroesophageal reflux symptoms: a relation to transforming growth factor-beta1 production and fibroblast proliferation. Chest 2007; 132: 1548-1556.4. Kreuter M, Wuyts W, Renzoni E, Koschel D, Maher TM, Kolb M, Weycker D, Spagnolo P, Kirchgaessler KU, Herth FJ, Costabel U. Antacid therapy and disease outcomes in idiopathic pulmonary fibrosis: a pooled analysis. The Lancet Respiratory medicine 2016; 4: 381-389.5. Lee JS, Collard HR, Anstrom KJ, Martinez FJ, Noth I, Roberts RS, Yow E, Raghu G. Anti-acid treatment and disease progression in idiopathic pulmonary fibrosis: an analysis of data from three randomised controlled trials. The Lancet Respiratory medicine 2013; 1: 369-376.6. Fein M, Ritter MP, DeMeester TR, Oberg S, Peters JH, Hagen JA, Bremner CG. Role of the lower esophageal sphincter and hiatal hernia in the pathogenesis of gastroesophageal reflux disease. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract 1999; 3: 405-410.7. Noth I, Zangan SM, Soares RV, Forsythe A, Demchuk C, Takahashi SM, Patel SB, Strek ME, Krishnan JA, Patti MG, Macmahon H. Prevalence of hiatal hernia by blinded multidetector CT in patients with idiopathic pulmonary fibrosis. The European respiratory journal 2012; 39: 344-351.8. Tossier C, Dupin C, Plantier L, Leger J, Flament T, Favelle O, Lecomte T, Diot P, Marchand-Adam S. Hiatal hernia on thoracic computed tomography in pulmonary fibrosis. The European respiratory journal 2016; 48: 833-842.9. Raghu G, Pellegrini CA, Yow E, Flaherty KR, Meyer K, Noth I, Scholand MB, Cello J, Ho LA, Pipavath S, Lee JS, Lin J, Maloney J, Martinez FJ, Morrow E, Patti MG, Rogers S, Wolters PJ, Yates R, Anstrom KJ, Collard HR. Laparoscopic anti-reflux surgery for the treatment of idiopathic pulmonary fibrosis (WRAP-IPF): a multicentre, randomised, controlled phase 2 trial. The Lancet Respiratory medicine 2018; 6: 707-714.10. Johnson LF, Demeester TR. Twenty-four-hour pH monitoring of the distal esophagus. A quantitative measure of gastroesophageal reflux. The American journal of gastroenterology 1974; 62: 325-332.11. Gyawali CP, Kahrilas PJ, Savarino E, Zerbib F, Mion F, Smout A, Vaezi M, Sifrim D, Fox MR, Vela MF, Tutuian R, Tack J, Bredenoord AJ, Pandolfino J, Roman S. Modern diagnosis of GERD: the Lyon Consensus. Gut 2018; 67: 1351-1362.12. Cantu E, 3rd, Appel JZ, 3rd, Hartwig MG, Woreta H, Green C, Messier R, Palmer SM, Davis RD, Jr. J. Maxwell Chamberlain Memorial Paper. Early fundoplication prevents chronic allograft dysfunction in patients with gastroesophageal reflux disease. The Annals of thoracic surgery 2004; 78: 1142-1151; discussion 1142-1151.13. King TE, Jr., Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, Gorina E, Hopkins PM, Kardatzke D, Lancaster L, Lederer DJ, Nathan SD, Pereira CA, Sahn SA, Sussman R, Swigris JJ, Noble PW. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. The New England journal of medicine 2014; 370: 2083-2092.14. Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, Cottin V, Flaherty KR, Hansell DM, Inoue Y, Kim DS, Kolb M, Nicholson AG, Noble PW, Selman M, Taniguchi H, Brun M, Le Maulf F, Girard M, Stowasser S, Schlenker-Herceg R, Disse B, Collard HR. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. The New England journal of medicine 2014; 370: 2071-2082.15. Jones R, Krishnan A, Zeybel GL, Dookun E, Pearson JP, Simpson AJ, Griffin SM, Ward C, Forrest IA. Reflux in idiopathic pulmonary fibrosis: treatment informed by an integrated approach. ERJ open research 2018; 4.Table 1: Baseline Demographic, Serial Lung Function and Survival Data for Both Hiatus Hernia and Acid Reflux Analyses.IPF cohort scored for presence of hiatus herniaIPF cohort scored for 24 hour pH-study resultHH present(n=37)HH absent(n=52)pAcid Reflux Positive(n=19)Acid Reflux Negative(n=42)pGender30 male(81%)42 male(81%)15 male(79%)23 male(55%)Age(years)65.5 9.370.4 8.30.0166 1067 9PPI86%71%84%83%BMI28.2(24.9 – 28.2)28.2(23.8 – 28.2)27.2(22.3 – 28.1)28.1(22.3 – 28.1)Baseline FVC (%pred)65(51 – 65)69(52 – 69)74 1881 18Baseline DLco (%pred)36.7 11.437.7 10.049 1646 14CPI56.2 8.355.7 8.945.7 12.643.8 11.1Lung Function Interval (months)12(9 – 12)13(9 – 13)11(7 – 11)12(7 – 12)Proportion of lung function interval on Pirfenidone (%)94%(89 – 95)99%(91 – 97)0%0%Proportion of follow-up period on Pirfenidone(%)83%(73 – 95)74%(63 – 84)--Pirfenidone termination for gastrointestinal indication2/119/22--Absolute FVC decline(mL)-250(-333 to -123)-36(-15 to -156)0.01-87(-188 to +103)-183(-408 to -137)Relative FVC decline(%)-8.7(-10.2 to +8.7)-1.0(-8.2 to +1.0)0.01-2.2 11.7-9.9 15.4Absolute DLCO decline-0.32(-0.40 to +0.32)-0.4(-0.27 to + 0.40)-0.18(-0.66 to +0.18)-0.33(-0.20 to + 0.33)Relative DLCO decline(%)-10.1(-15.3 to +10.1)-12.8(-10.8 to +12.8)-3.7(-17.7 to +3.7)-9.3(-6.0 to +9.3)Median Survival(months)31(1 transplant, 24 deaths)55(1 transplant, 24 deaths)0.04950(1 transplant, 21 deaths)53(13 deaths)*Data are expressed as mean SD or median (interquartile range) unless otherwise stated. PPI, Proton Pump Inhibitor; BMI, Body Mass Index; CPI, Composite Physiologic Index (extent of disease on computed tomography = 91.0 – (0.65 x DLCO%pred) – (0.53 x FVC%pred) + (0.34 x FEV1%pred)). ................
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