FVC(%predicterd)

70

60

50

40

30

20

DLCO(%predicted)

Fig. 23.7  Change in forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) over time from initial diagnosis of idiopathic pulmonary brosis. After a signi cant drop in lung function

at 18 months after diagnosis, Nissen fundoplication was performed with stabilization of lung function and ongoing non-surgical interventions

Abnormal

•Standard of care including antifibrotic medications

•Non-pharmacologic reflux interventions

•Proton pump inhibitor

•Research trials

Gastroesophageal Reflux Studies

•24hr pH monitor

•Esophageal manometry

•Esophagogram

Follow-up q3-4 months with PFTs,

6-minute walk test, HRCT chest noncontrast (12 months)

If significant deterioration*

and persistent GER (with repeat GERstudies) despite PPI and non pharmacologic interventions

Normal

•Standard of care including antifibrotic medications

•Reasearch trials

Consider lung transplant and fundoplication

Laparoscopic fundoplication**

(in centers with experience and expertise in management of ILD and fundoplication surgery)

Fig. 23.8  Suggested management of GER in patients diagnosed with IPF Approach followed at the Center for ILD, University of Washington Medical Center based on evolved knowledge with evidence and experience : Patients with con rmed diagnosis of IPF [87] and willing to undergo a formal and thorough evaluation for the detection of abnormal GER are subjected to esophageal manometry and barium esophagogram immediately following 24 h pH monitoring at baseline. Those patients with abnormal testing are offered treatment with a combination of proton pump inhibitors and non-pharmacologic interventions

(described in detail in chapter text). Patients are followed up at regular intervals to monitor lung functional status with pulmonary function testing, 6-min walk test at 3–4-month intervals and chest imaging (every 12 months). Patients with signi cant deterioration* and previously documented abnormal refux are re-evaluated for the persistence of abnormal GER and if present are considered for laparoscopic anti-­ refux surgery in the absence of contraindications**. Such patients if considered for lung transplantation are also considered for anti-refux surgery in discussion with the lung transplant team

Summary and Future Directions

A close relationship between the pulmonary and gastrointestinal system exists beginning from the early stages of embryogenesis. This relationship is particularly important in individuals diagnosed with IPF because of the impact of gastroesophageal refux and microaspiration on disease pathogenesis and behavior. We have outlined the key mechanisms involved in the impact of gastric contents on the respiratory epithelium and their contributions to the development of pulmonary brosis. Several testing modalities are available to evaluate patients with IPF for clinically signi cant refux and should be implemented in a systematic, stepwise fashion. Several treatment options are available including anti-refux surgery which has been shown to be a safe intervention in carefully selected patients.

Further research is needed to better clarify the role of GER and microaspiration in the pathogenesis and progression of IPF. Changes in esophageal physiology have been

associated with increased age including decreased UES and LES pressures and impaired esophageal motility [86]. While many older individuals have signi cant refux, not all develop IPF. Are GER and microaspiration a contributing factor to brosis development in genetically predisposed individuals? Additionally, the impact of microaspiration on the lung microbiome and its effect on disease pathogenesis is an area needing further exploration. As identi ed in one of the previous sections there remains a need for carefully designed, prospective, randomized controlled trials that examine the effects of PPI use in patients with IPF. A large, multicenter clinical trial –TIPAL (ISRCTN13526307; the EudraCT number 2020–000041-14) is underway in the UK examining the therapeutic potential of omeperazole (PPI0 in patients with IPF).

As the understanding of IPF and its pathomechanisms continues to expand, the role of refux and microaspiration will be further clari ed allowing for individualized approaches to disease management.

References

1.\Vinson PP. Cardiospasm complicated by pulmonary abscess a case report. Am J Surg. 1927;2:359–61.

2.\Bartlett JG, Gorbach SL. The triple threat of aspiration pneumonia. Chest. 1975;68:560–6.

3.\Mays EE, Dubois JJ, Hamilton GB. Pulmonary brosis associated with tracheobronchial aspiration. A study of the frequency of hiatal hernia and gastroesophageal refux in interstitial pulmonary brosis of obscure etiology. Chest. 1976;69:512–5.

4.\Kahrilas PJ, Lee TJ. Pathophysiology of gastroesophageal refux disease. Thorac Surg Clin. 2005;15:323–33.

5.\Vakil N, Van Zanten SV, Kahrilas P, Dent J, Jones R, Bianchi LK, Cesario KB. The Montreal de nition and classi cation of gastroesophageal­ refux disease: a global evidence-based consensus. Am J Gastroenterol. 2006;101:ajg2006349.

6.\Behr J, Kreuter M, Hoeper MM, et al. Management of patients with idiopathic pulmonary brosis in clinical practice: the INSIGHTS-­ IPF registry. Eur Respir J. 2015;46:186–96.

7.\Raghu G, Amatto VC, Behr J, Stowasser S. Comorbidities in idiopathic pulmonary brosis patients: a systematic literature review. Eur Respir J. 2015;46:1113–30.

8.\Hyldgaard C, Hilberg O, Bendstrup E. How does comorbidity infuence survival in idiopathic pulmonary brosis? Respir Med. 2014;108:647–53.

9.\Raghu G, Freudenberger TD, Yang S, Curtis JR, Spada C, Hayes J, Sillery JK, Pope CE, Pellegrini CA. High prevalence of abnormal acid gastro-oesophageal refux in idiopathic pulmonary brosis. Eur Respir J. 2006;27:136–42.

10.\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 brosis. Eur Respir J. 2016;48:833–42.

11.\Schoenwolf GC, Bleyl SB, Brauer PR, Francis-West PH. Larsen’s human embryology. Philadelphia: Elsevier Saunders; 2019.

12.\Mendelson CL. The aspiration of stomach contents into the lungs during obstetric anesthesia. Surv Anesthesiol. 1994;38:185.

13.\Green eld LJ, Singleton RP, McCaffree DR, Coalson JJ. Pulmonary effects of experimental graded aspiration of hydrochloric acid. Ann Surg. 1969;170:74–86.

14.\Amigoni M, Bellani G, Scanziani M, Masson S, Bertoli E, Radaelli E, Patroniti N, Di LA, Pesenti A, Latini R. Lung injury and recovery in a murine model of unilateral acid aspiration. Anesthesiology. 2008;108:1037–46.

15.\Appel JZ, Lee SM, Hartwig MG, Li B, Hsieh CC, Cantu E, Yoon Y, Lin SS, Parker W, Davis RD. Characterization of the innate immune response to chronic aspiration in a novel rodent model. Respir Res. 2007;8:87.

16.\Perng DW, WuYC, Tsai CC, Su KC, Liu LY, Hsu WH, LeeYC. Bile acids induce CCN2 production through p38 MAP kinase activation in human bronchial epithelial cells: a factor contributing to airwaybrosis. Respirology. 2008;13:983–9.

17.\Lee JS, Song JW, Wolters PJ, Elicker BM, King TE, Kim DS, Collard HR. Bronchoalveolar lavage pepsin in acute exacerbation of idiopathic pulmonary fibrosis. Eur Respir J. 2012;39:352–8.

18.\Bathoorn E, Daly P, Gaiser B, Sternad K, Poland C, MacNee W, Drost EM. Cytotoxicity and induction of infammation by pepsin in acid in bronchial epithelial cells. Int J Infam. 2011;2011:1–5.

19.\Rosen R, Johnston N, Hart K, Khatwa U, Nurko S. The presence of pepsin in the lung and its relationship to pathologic gastro-­ esophageal refux. Neurogastroenterol Motil. 2012;24:129–e85.

20.\Kahrilas PJ, Dodds WJ, Dent J, Haeberle B, Hogan WJ, Arndorfer RC. Effect of sleep, spontaneous gastroesophageal refux, and a meal on upper esophageal sphincter pressure in normal human volunteers. Gastroenterology. 1987;92:466–71.

21.\Gleeson K, Maxwell SL, Eggli DF. Quantitative aspiration during sleep in normal subjects. Chest. 1997;111:1266–72.

22.\Lancaster LH, Mason WR, Parnell JA, Rice TW, Loyd JE, Milstone AP, Collard HR, Malow BA. Obstructive sleep apnea is common in idiopathic pulmonary brosis. Chest. 2009;136:772–8.

23.\Bosi M, Milioli G, Fanfulla F, et al. OSA and prolonged oxygen desaturation during sleep are strong predictors of poor outcome in IPF. Lung. 2017;195:643–51.

24.\Shepherd KL, James AL, Musk AW, Hunter ML, Hillman DR, Eastwood PR. Gastro-oesophageal refux symptoms are related to the presence and severity of obstructive sleep apnoea. J Sleep Res. 2011;20:241–9.

25.\Dickson RP, Erb-Downward JR, Prescott HC, Martinez FJ, Curtis JL, Lama VN, Huffnagle GB. Analysis of culture-dependent versus culture-independent techniques for identi cation of bacteria in clinically obtained bronchoalveolar lavage fuid. J Clin Microbiol. 2014;52:3605–13.

26.\Hewitt RJ, Molyneaux PL. The respiratory microbiome in idiopathic pulmonary brosis. Ann Transl Med. 2017;5:250.

27.\Souza DG, Vieira AT, Soares AC, Pinho V, Nicoli JR, Vieira LQ, Teixeira MM. The essential role of the intestinal microbiota in facilitating acute infammatory responses. J Immunol. 2004;173:4137–46.

28.\Rosen R, Hu L, Amirault J, Khatwa U, Ward DV, Onderdonk A. 16S community pro ling identi es proton pump inhibitor related differences in gastric, lung, and oropharyngeal microfora. J Pediatr.

2001;358:823–8.

31.\Mittal RK, McCallum RW. Characteristics of transient lower esophageal sphincter relaxation in humans. Am J Physiol. 1987;252:G636–41.

32.\Evidence A, Approach B, Memon MA. Hiatal hernia surgery; 2018. https://doi.org/10.1007/978-3-319-64003-7.

33.\Gordon C, Kang JY, Neild PJ, Maxwell JD. The role of the hiatus hernia in gastro-oesophageal refux disease. Aliment Pharmacol Ther. 2004;20:719–32.

34.\Frazzoni M, De Micheli E, Grisendi A, Savarino V. Hiatal hernia is the key factor determining the lansoprazole dosage required for effective intra-oesophageal acid suppression. Aliment Pharmacol Ther. 2002;16:881–6.

35.\Petersen H, Johannessen T, Sandvik AK, Kleveland PM, Brenna E, Waldum H, Dybdahl JD. Relationship between endoscopic hiatus hernia and gastroesophageal refux symptoms. Scand J Gastroenterol. 1991;26:921–6.

36.\Sweet MP, Patti MG, Leard LE, Golden JA, Hays SR, Hoopes C, Theodore PR. Gastroesophageal refux in patients with idiopathic pulmonary brosis referred for lung transplantation. J Thorac Cardiovasc Surg. 2007;133:1078–84.

37.\Tobin RW, Pope CE, Pellegrini CA, Emond MJ, Sillery J, Raghu G. Increased prevalence of gastroesophageal refux in patients with idiopathic pulmonary brosis. Am J Respir Crit Care Med. 1998;158:1804–8.

38.\Johnson LF, Demeester TR. Twenty-four-hour pH monitoring of the distal esophagus. A quantitative measure of gastroesophageal refux. Am J Gastroenterol. 1974;62:325–32.

39.\Johnson LF, DeMeester TR. Development of the 24-hour intraesophageal pH monitoring composite scoring system. J Clin Gastroenterol. 1986;8:52–8.

40.\Hobbs P, Gyawali CP. The role of esophageal pH-impedance testing in clinical practice. Curr Opin Gastroenterol. 2018;34:249–57.

41.\Kahrilas PJ, Bredenoord AJ, Fox M, et al. The Chicago classi - cation of esophageal motility disorders, v3.0. Neurogastroenterol Motil. 2015;27:160–74.

42.\Savarino E, Gemignani L, Pohl D, et al. Oesophageal motility and bolus transit abnormalities increase in parallel with the severity of gastro-oesophageal refux disease. Aliment Pharmacol Ther. 2011;34:476–86.

43.\Ribolsi M, Balestrieri P, Emerenziani S, Guarino MPL, Cicala M. Weak peristalsis with large breaks is associated with higher acid exposure and delayed refux clearance in the supine position in GERD patients. Am J Gastroenterol. 2014;109:46–51.

44.\Gao F, Hobson AR, Shang ZM, Pei YX, Gao Y, Wang JX, Huang WN. The prevalence of gastro-esophageal refux disease and esophageal dysmotility in Chinese patients with idiopathic pulmonarybrosis. BMC Gastroenterol. 2015;15:26.

45.\Kahrilas PJ, Pandol no JE. Ineffective esophageal motility does not equate to GERD. Am J Gastroenterol. 2003;98:715–7.

46.\Vinjirayer E, Gonzalez B, Brensinger C, Bracy N, Obelmejias R, Katzka DA, Metz DC. Ineffective motility is not a marker for gastroesophageal refux disease. Am J Gastroenterol. 2003;98:771–6.

47.\Levine MS, Rubesin SE, Laufer I. Barium esophagography: a study for all seasons. Clin Gastroenterol Hepatol. 2008;6:11–25.

48.\Metheny NA, Chang YH, Ye JS, Edwards SJ, Defer J, Dahms TE, Stewart BJ, Stone KS, Clause RE. Pepsin as a marker for pulmonary aspiration. Am J Crit Care. 2002;11:150–4.

49.\D’Ovidio F, Mura M, Tsang M, et al. Bile acid aspiration and the development of bronchiolitis obliterans after lung transplantation. J Thorac Cardiovasc Surg. 2005;129:1144–52.

50.\Starosta V, Kitz R, Hartl D, Marcos V, Reinhardt D, Griese M. Bronchoalveolar pepsin, bile acids, oxidation, and infammation in children with gastroesophageal refux disease. Chest. 2007;132:1557–64.

51.\Parameswaran K, Anvari M, Efthimiadis A, Kamada D, Hargreave F, Allen C. Lipid-laden macrophages in induced sputum are a marker of oropharyngeal refux and possible gastric aspiration. Eur Respir J. 2000;16:1119–22.

52.\Hunt R, Armstrong D, Katelaris P, et al. World gastroenterology organisation global guidelines. J Clin Gastroenterol. 2017;51:467–78.

53.\Kahrilas PJ, Jonsson A, Denison H, Wernersson B, Hughes N, Howden CW. Regurgitation is less responsive to acid suppression than heartburn in patients with gastroesophageal refux disease. Clin Gastroenterol Hepatol. 2012;10:612–9.

54.\Raghu G, Rochwerg B, Zhang Y, et al. An of cial ATS/ERS/JRS/ ALAT clinical practice guideline: treatment of idiopathic pulmonary brosis. An update of the 2011 clinical practice guideline. Am J Respir Crit Care Med. 2015;192:e3–e19.

55.\Dutta P, Funston W, Mossop H, et al. Randomised, double-blind, placebo-controlled pilot trial of omeprazole in idiopathic pulmonary brosis. Thorax. 2019;74:346–53.

56.\Jo HE, Corte TJ, Glaspole I, et al. Gastroesophageal refux and antacid therapy in IPF: analysis from the Australia IPF registry. BMC Pulm Med. 2019;19:84.

57.\Kreuter M, Wuyts W, Renzoni E, et al. Antacid therapy and disease outcomes in idiopathic pulmonary brosis: a pooled analysis. Lancet Respir Med. 2016;4:381–9.

58.\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 brosis: an analysis of data from three randomised controlled trials. Lancet Respir Med. 2013;1:369–76.

59.\Kreuter M, Spagnolo P, Wuyts W, et al. Antacid therapy and disease progression in patients with idiopathic pulmonary brosis who received Pirfenidone. Respiration. 2017;93:415–23.

60.\Raghu G, Crestani B, Bailes Z, Schlenker-Herceg R, Costabel U. Effect of anti-acid medication on reduction in FVC decline with nintedanib. Eur Respir J. 2015;70:OA4502.

61.\Liu B, Su F, Xu N, Qu T, Li M, Ju Y. Chronic use of anti-refux therapy improves survival of patients with pulmonary brosis. Int J Clin Exp Med. 2017;10:5805–10.

62.\Kreuter M, Ehlers-Tenenbaum S, Palmowski K, Bruhwyler J, Oltmanns U, Muley T, Heussel CP, Warth A, Kolb M, Herth FJF. Impact of comorbidities on mortality in patients with idiopathic pulmonary brosis. PLoS One. 2016;11:e0151425.

63.\Lee CM, Lee DH, Ahn BK, Hwang JJ, Yoon H, Shin CM, Park YS, Kim N. Protective effect of proton pump inhibitor for survival in patients with gastroesophageal refux disease and idiopathic pulmonary brosis. J Neurogastroenterol Motil. 2016;22:444–51.

64.\Ghebremariam YT, Cooke JP, Gerhart W, et al. Pleiotropic effect of the proton pump inhibitor esomeprazole leading to suppression of lung infammation and brosis. J Transl Med. 2015;13:249.

65.\Noth I, Zangan SM, Soares RV, et al. Prevalence of hiatal hernia by blinded multidetector CT in patients with idiopathic pulmonarybrosis. Eur Respir J. 2012;39:344–51.

66.\Lee JS, Ryu JH, Elicker BM, Lydell CP, Jones KD, Wolters PJ, King TE, Collard HR. Gastroesophageal refux therapy is associated with longer survival in patients with idiopathic pulmonarybrosis. Am J Respir Crit Care Med. 2011;184:1390–4.

67.\Raghu G, Yang STY, Spada C, Hayes J, Pellegrini CA. Sole treatment of acid gastroesophageal refux in idiopathic pulmonary brosis. A case series. Chest. 2006;129:794–800.

68.\Linden PA, Gilbert RJ, Yeap BY, Boyle K, Deykin A, Jaklitsch MT, Sugarbaker DJ, Bueno R. Laparoscopic fundoplication in patients with end-stage lung disease awaiting transplantation. J Thorac Cardiovasc Surg. 2006;131:438–46.

69.\Takagi T, Naito Y, Okada H, et al. Lansoprazole, a proton pump inhibitor, mediates anti-inflammatory effect in gastric mucosal cells through the induction of Heme Oxygenase-1 via activation of NF-E2-related factor 2 and oxidation of Kelch-like ECH-­associating protein 1. J Pharmacol Exp Ther. 2009;331:255–64.

70.\Cooper JD, Jeejeebhoy KN. Gastroesophageal refux: medical and surgical management. Ann Thorac Surg. 1981;31:577–93.

71.\Cao Z, Cai W, Qin M, Zhao H, Yue P, Li Y. Randomized clinical trial of laparoscopic anterior 180° partial versus 360° Nissen fundoplication: 5-year results. Dis Esophagus. 2012;25(2):114–20. https://doi.org/10.1111/j.1442-2050.2011.01235.x.

72.\Broeders JAJL, Mauritz FA, Ahmed Ali U, Draaisma WA, Ruurda JP, Gooszen HG, Smout AJPM, Broeders IAMJ, Hazebroek EJ. Systematic review and meta-analysis of laparoscopic Nissen (posterior total) versus Toupet (posterior partial) fundoplication for gastro-oesophageal refux disease. Br J Surg. 2010;97:1318–30.

73.\Raghu G, Morrow E, Collins BF, et al. Laparoscopic anti-refux surgery for idiopathic pulmonary brosis at a single centre. Eur Respir J. 2016;48:826–32.

74.\Raghu G, Pellegrini CA, Yow E, et al. Laparoscopic anti-refux surgery for the treatment of idiopathic pulmonary brosis (WRAP-­ IPF): a multicentre, randomised, controlled phase 2 trial. Lancet Respir Med. 2018;6:707–14.

75.\Collard HR, Ryerson CJ, Corte TJ, et al. Acute exacerbation of idiopathic pulmonary brosis an international working group report. Am J Respir Crit Care Med. 2016;194:265–75.

76.\Collard HR, Yow E, Richeldi L, et al. Suspected acute exacerbation of idiopathic pulmonary brosis as an outcome measure in clinical trials. Respir Res. 2013;14:73.

77.\Molyneaux PL, Cox MJ, Wells AU, Kim HC, Ji W, Cookson WOC, Moffatt MF, Kim DS, Maher TM. Changes in the respiratory microbiome during acute exacerbations of idiopathic pulmonary brosis. Respir Res. 2017;18:29.

78.\Meltzer AJ, Weiss MJ, Veillette GR, et al. Repetitive gastric aspiration leads to augmented indirect allorecognition after lung transplantation in miniature swine. Transplantation. 2008;86:1824–9.

79.\Young LR, Hadjiliadis D, Davis RD, Palmer SM. Lung transplantation exacerbates gastroesophageal refux disease. Chest. 2003;124:1689–93.

80.\Benden C, Aurora P, Curry J, Whitmore P, Priestley L, Elliott MJ. High prevalence of gastroesophageal refux in children after lung transplantation. Pediatr Pulmonol. 2005;40:68–71.

81.\Hopkins PM, Kermeen F, Duhig E, et al. Oil red O stain of alveolar macrophages is an effective screening test for gastroesophageal refux disease in lung transplant recipients. J Heart Lung Transplant. 2010;29:859–64.

82.\Davis CS, Gagermeier J, Dilling D, Alex C, Lowery E, Kovacs EJ, Love RB, Fisichella PM. A review of the potential applications and controversies of non-invasive testing for biomarkers of aspiration in the lung transplant population. Clin Transpl. 2010;24:E54–61.

83.\Gasper WJ, Sweet MP, Hoopes C, Leard LE, Kleinhenz ME, Hays SR, Golden JA, Patti MG. Antirefux surgery for patients with end-stage lung disease before and after lung transplantation. Surg Endosc Other Interv Tech. 2008;22:495–500.

84.\Burton PR, Button B, Brown W, Lee M, Roberts S, Hassen S, Bailey M, Smith A, Snell G. Medium-term outcome of fundoplication after lung transplantation. Dis Esophagus. 2009;22:642–8.

85.\Hartwig MG, Anderson DJ, Onaitis MW, Reddy S, Snyder LD, Lin SS, Davis RD. Fundoplication after lung transplantation prevents the allograft dysfunction associated with refux. Ann Thorac Surg. 2011;92:462–9.

86.\Shim YK, Kim N, Park YH, Lee JC, Sung J, Choi YJ, Yoon H, Shin CM, Park YS, Lee DH. Effects of age on esophageal motility: use of high-resolution esophageal impedance manometry. J Neurogastroenterol Motil. 2017;23:229–36.

87.\Raghu G, Remy-Jardin M, Myers JL, et al. Diagnosis of idiopathic pulmonary brosis. An of cial ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2018;198:e44–68.

Clinical Vignette (CV)

A 53-year-old man was evaluated for lung brosis. He was a past smoker. His medical history revealed asymptomatic thrombocytopenia (between 50,000 and 100,000/mm3), red cell macrocytosis (103 μm3) without anemia, liver cirrhosis, and a premature graying of his hair at the age of 25. He also had a familial history of lung brosis (in red, Fig. 24.1) and premature appearance of white hair (in blue, Fig. 24.1a). The CT scan showed a de nite usual interstitial pneumonia (UIP) pattern (Fig. 24.1b). The pulmonary function tests showed reduced forced vital capacity (FVC) at 61% and diffusing lung capacity for CO (DLCO) at 46% of the predicted values.

A diagnosis of idiopathic pulmonary brosis was made and the patient received pirfenidone for 3 months but developed a skin rash.

He refused to take nintedanib and subsequently presented with an increase in shortness of breath. The pulmonary function tests showed a rapid decline of FVC at 43% and DLCO at 41% of the predicted values, 1 year after initial diagnosis. The CT scan showed a progression of the lung brosis without evidence of an acute exacerbation.

Genetic analysis revealed a pathogenic RTEL1 mutation (c.2869C > T. p.Arg957Trp). Following discussion in multidisciplinary team, recommendations were made to offer genetic counseling to the family, and to discuss lung transplantation with the patient. The patient opted for lung transplantation evaluation and is currently on the waiting list.