Role of gastroesophageal reflux disease in lung transplantation

Table 1 Papers summarizing effects of gastroesophageal reflux disease on transplant outcomes

Ref.	Population	Definition GERD and/or aspiration	Outcomes evaluated	Adjunctive therapy
King et al[29], 2009	59 pts. Post-LTx	Abnormal acid and non-acid reflux on esophageal impedance monitoring	Effect of reflux on time to development of BOS via hazard ratio
Hadjiliadis et al[33], 2003	43 pts. Post-LTx, survived > 6 mo, and underwent pH and manometry testing	Abnormal acid exposure time on 24-h pH testing	Effect of reflux on FEV1 (via Pearson correlation coefficient for time of study, via multivariable linear regression to assess overall effect)	PPI d/c’ed > 5 d prior to testing, H2 blockers and pro-motility agents > 1 d prior to testing
Stovold et al[35], 2007	36 asymptomatic pts. Post-LTx vs 4 healthy volunteers vs 17 patients with chronic cough	Increased levels of pepsin in BALF	Presence of pepsin, association between level of pepsin and acute rejection	30 LTx patients on antireflux therapy
Blondeau et al[36], 2009	24 pts. Post-LTx	Abnormal reflux on 24-h impedance-pH testing, bile acids in BALF	Relationship between acid exposure, volume exposure, or reflux events and bile acids in BALF	PPI d/c’ed 1 wk prior to testing
D’Ovidio et al[37], 2005	120 pts. Post-LTx	Increased levels of bile acids in BALF	Relationship between increased levels of bile acids, IL-8, neutrophils on development of BOS
Benden et al[41], 2005	10 pts. Post-LTx	Abnormal reflux on 24-h pH testing	Prevalence of GERD in population
Fisichella et al[42], 2013	105 pts. Post-LTx with 257 BALF samples	24-h pH testing and DeMeester score calculation, Increased levels of pepsin in BALF	Association between aspiration and patterns of dysregulation of immune mediator concentrations and BOS	PPI d/c’ed 2 wk prior to testing, H2 blocker d/c’ed 3 d prior to testing
Young et al[56], 2003	23 pts. evaluated pre- and post-LTx	Total, upright, and supine acid exposure time on 24-h pH testing, esophageal manometry, gastric-emptying study	Paired comparison between pre-transplant and post-transplant results (paired t test)	Acid suppression and gastric motility meds discontinued before testing
D’Ovidio et al[57], 2006	70 pts. Post-LTx	Esophageal manometry, 24-h pH-testing (DeMeester score calculation, Castell’s method) and gastric emptying study; BALF analysis	Actuarial freedom from BOS, impact of aspiration on pulmonary surfactant collectin proteins	PPI d/c’ed 7 d prior, H2-blockers d/c’ed 2 d prior
Fisichella et al[58], 2012	61 pts. Post-LTx	Esophageal impedance-manometry, 24-h pH testing (DeMeester score calculation), EGD, barium swallow, gastric emptying study	Relationship between prevalence and extent of GERD and type of transplant (unilateral vs bilateral vs retransplant)	PPI d/c’ed 14 d prior to pH testing, H2 blockers stopped 3 d prior to pH testing
Fisichella et al[74], 2012	8 pts. Post-LARS and LTx in whom BALF had been collected	Esophageal 24-h impedance-pH testing (DeMeester score calculation), gastric emptying study	Comparison of BALF concentrations of leukocytes, immune mediators, and pepsin pre- and post-LARS and post-LTx	PPI d/c’ed 14 d prior to pH testing, H2 blockers stopped 3 d prior to pH testing
Blondeau et al[78], 2008	45 pts. Post-LTx off PPI, 18 pts. Post-LTx on PPI	Esophageal 24-h impedance-pH catheter, BALF analysis for pepsin and bile acids	Association between the prevalence and type of reflux and gastric aspiration in pts. with and without BOS	Antacids and promotility agents d/c’ed > 14 d prior to testing vs remained on for testing
Griffin et al[45], 2013	18 pts. Post-LTx	RSI, esophageal manometry and 24-h impedance-pH monitoring, BALF analysis	Quantification of reflux, aspiration, and allograft injury immediately post-operatively	Testing performed on PPI
Davis et al[84], 2013	100 pts Post-LTx with 252 BALF samples	BALF pepsin concentration, esophageal manometry, esophageal 24-h pH catheter (DeMeester score calculation), gastric emptying study	Association between concentration of pepsin in BALF and results of esophageal function testing, barium swallow and gastric emptying to identify risk factors for GERD	PPI d/c’ed 14 d prior to pH testing, H2 blockers d/c’ed 3 d prior to pH testing
Hartwig et al[71], 2006	7 models of rat lung transplantation	Weekly injection of gastric contents for 4-8 wk	Degree of pulmonary allograft dysfunction reflective of chronic aspiration	N/A
Li et al[72], 2008	9 models of rat lung transplantation	Weekly injection of gastric contents for 8 wk	Association between chronic aspiration and development of OB	N/A
Meltzer et al[73], 2008	3 models of swine lung transplantation	Daily injection of gastric contents for 50 d	Effect on chronic aspiration on the direct and indirect pathways of allorecognition	N/A

BALF: Bronchoalveolar lavage fluid; BOS: Bronchiolitis obliterans syndrome; OB: Obliterative bronchiolitis; RSI: Reflux severity index; GERD: Gastroesophageal reflux disease; N/A: Not available.

Table 2 Papers on the effect of pharmacologic reflux treatment on transplant outcome

Ref.	n	Population	Treatment type	Adjunctive treatments	Outcomes assessed
Yates et al[32], 2005	20	Post-LTx with diagnosis of BOS (n = 18) or potential BOS (n = 2)	AZI 250 mg QOD from time of BOS diagnosis to time of manuscript writing (mean 6.25 mo)	Immunosuppressive regimen, no additional antireflux agents specified	Effect on FEV1
Verleden et al[110], 2004	8	Post-LTx with significant decrease in their FEV1 attributed to BOS	AZI 250 mg qd × 5 d then 250 mg po QOD	Immunosuppressive regimen, no additional antireflux agents specified	Effect on FEV1
Verleden et al[111], 2006	14	Post-LTx with BOS	AZI 250 mg po qd × 5 d then AZI 250 mg po 3 × /wk × 3 mo	Immunosuppressive regimen, no additional antireflux agents specified	Reduction in airway neutrophilia and IL-8 mRNA, effect on FEV1
Mertens et al[112], 2009	12	Post-LTx on AZI with pH monitoring	AZI 250 mg PO 3 ×/wk	Immunosuppressive regimen, held antireflux treatments × 1 wk prior to testing	Effect on impedance-pH monitoring, gastric aspiration via BAL analysis
Blondeau et al[78], 2008	18	Post-LTx on PPI vs off PPI at time of testing (secondary cohort)	Omeprazole 20 mg PO BID	Immunosuppressive regimen	Prevalence of reflux on objective testing, effect on aspiration in BAL

n: Patients in the study in the treatment arm; BOS: Bronchiolitis obliterans syndrome; LTx: Lung transplant; AZI: Azithromycin; QOD: Every other day; FEV1: Forced expiratory volume in 1 s; BID: Twice a day.

Table 3 Papers of surgical antireflux procedures and lung transplant outcomes

Ref.	n	Population undergoing surgery	Type of surgical intervention (Type Nissen: n)	Outcomes assessed
Davis et al[32], 2003	43	Post-LTx with abnormal pH study (n = 39), severe reflux with normal manometry (n = 2), repetitive aspiration events leading to retransplant (n = 1) or pneumonia (n = 1)	Laparoscopic: 36 Open: 3 Partial Toupet: 4	In-hospital or 30-d mortality, FEV1 pre- and post-procedure
Cantu et al[40], 2004	74	Post-LTx with abnormal pH studies	Laparoscopic: 71 Open: 5 Partial Toupet: 4 Other: 51	In-hospital or 30 d mortality, freedom from BOS in early vs late fundoplication groups
Robertson et al[75], 2012	16	Post-LTx undergoing antireflux surgery	Laparoscopic: 16	Effect on quality of life, peri-operative mortality and complications, reduction in deterioration of lung function
Linden et al[117], 2006	19	Pre-LTx IPF with h/o reflux, symptoms, and severe reflux on pH and manometry testing	Laparoscopic: 19	Peri-operative complications, post-operative lung function
Lau et al[118], 2002	18	Post-LTx with documented GERD	Laparoscopic: 13 Open: 1 Partial Toupet: 4	Length of hospital stay, post-operative lung function, morbidity and mortality
Fisichella et al[119], 2011	29	Post-LTx with GERD dx on symptoms, BAL, or decreased lung function; with abnormal pH monitoring	Laparoscopic: 27	30-d morbidity and mortality, hospital readmissions
Fisichella et al[43], 2011	19	Post-LTx with GERD symptoms, aspiration on BAL, or unexplained decrease in lung function	Partial Toupet: 2 Laparoscopic: 19	decreased aspiration as defined by the presence of pepsin in the BALF
Fisichella et al[74], 2012	8	Post-LTx patients with GERD and evidence of reflux on ambulatory pH monitoring	Laparoscopic: 8	Quantification and comparison of pulm leukocyte differential and concentration of inflammatory mediators in BAL, freedom from BOS, effect on FEV1, and survival
Burton et al[120], 2009	21	Post-LTx with reflux confirmed on EGD, pH testing, or BALF	Laparoscopic: 5 Partial Toupet: 16	Patient satisfaction, symptom changes and side effects, effect on lung function, BMI, rate progression to BOS
O’Halloran et al[121], 2004	28	Post-LTx with reflux on pH testing and manometry	Laparoscopic: 28	Perioperative complications, length of stay, readmission rate, effect on lung function
Gasper et al[122], 2008	35	Pre-LTx in 15 patients, Post-LTx in 20 patients with GERD or delayed gastric emptying study	Laparoscopic: 27 Partial Toupet: 5 Other: 32	Length of stay, perioperative complications pre- or post-LTx
Kilic et al[17], 2013	401	Post-LTx who pursued elective antireflux procedure	Laparoscopic: 3383 Open: 23	Inpatient mortality, length of stay, perioperative complications, hospital costs
Hoppo et al[16], 2011	43	Pre-LTx in 19 patients, Post-LTx in 24 patients with documented symptoms or signs of GERD on EGD, barium, manometry, pH or impedance testing; or declining lung function	Laparoscopic: 24 Other: 174	Effect on lung function, number cases of pneumonia and acute rejection episodes
Hartwig et al[126], 2011	157	Post-LTx with abnormal acid contact times before or early after transplantation	Laparoscopic: 1573	Effect on lung function
Lo et al[103], 2016	48	Pre-LTx or Post-LTx patients with persistent symptoms on maximal PPI and with objective evidence of reflux on pH testing	Laparoscopic = 48	Time to early allograft injury in pre-LTx vs early vs late post-LTx groups
Patti et al[114], 2000	39	Pt with GERD and respiratory symptoms on H2 agents vs PPI vs pro-kinetic agents, ± bronchodilators (n = 3) and bronchodilators/prednisone (n = 4)	Laparoscopic = 39	Outcome of surgery on GERD-induced respiratory symptoms

¹Three cases Belsey-Mark IVs, 1 Toupet and 1 Nissen at OSH (without further information);

²Two cases had pyloroplasty without fundoplication, 1 case had hypotension at induction and was discharged without operation;

³Does not specify full Nissen vs partial toupet, only laparoscopic vs open approach;

⁴Seventeen cases underwent laparoscopic Dor procedure. n: Study patients in the fundoplication group specifically; LTx: Lung transplant; BALF: Bronchoalveolar lavage fluid; BOS: Bronchiolitis obliterans syndrome; GERD: Gastroesophageal reflux disease; BMI: Body mass index; EGD: esophagogastroduodenoscopy.