ORIGINAL PAPERS

Esophageal motor disorders are frequent during pre and post transplantation. Can they influence lung rejection?

Constanza Ciriza-de-los-Ríos1, Fernando Canga-Rodríguez-Valcárcel1, Alicia de-Pablo-Gafas1, Isabel Castel-de-Lucas1, David Lora-Pablos2 and Gregorio Castellano-Tortajada1 1Department of . Hospital Universitario 12 de Octubre. Madrid, Spain. 2Clinical Research Unit. IMAS12-CIBERESP. Hospital Universitario 12 de Octubre. Madrid, Spain

Received: 21/09/2017 · Accepted: 02/01/2018 Correspondence: Constanza Ciriza-de-los-Ríos. Department of Gastroenterology. Hospital Universitario 12 de Octubre. Av. de Córdoba, s/n. 28041 Madrid, Spain. e-mail: [email protected]

ABSTRACT INTRODUCTION

Background: lung transplantation (LTx) is a viable option Lung transplantation (LTx) is a viable option for most for most patients with end-stage lung diseases. Esophageal patients with end-stage lung diseases (1). Transplant failure motor disorders (EMD) are frequent in candidates for LTx, is frequently caused by the development of bronchiolitis but there is very little data about changes in esophageal obliterans syndrome (BOS), a devastating complication that post-LTx. accounts for 30% of all deaths within a three-year period post transplantation (1). Risk factors associated with the Aim: the aim of our study was to assess esophageal motor development of BOS include cytomegalovirus infection and disorders by high resolution manometry (HRM) both pre- positive antibodies to class I HLA. Gastroesophageal reflux LTx and six months post-LTx in patients with and without disease (GERD) is associated with other pulmonary diseases rejection. such as , cystic and pulmonary fibrosis and obstruc- tive sleep apnea syndrome (2). Therefore, pH, bile acid and Study: HRM (Manoscan®) was performed in 57 patients trypsin levels in GERD have been studied as biomarkers both pre-LTx and six months post-LTx. HRM plots were for chronic allograft dysfunction (3). GERD is also associ- analyzed according to the Chicago classification 3.0. ated with esophageal motor disorders (EMD), although it is not clear if GERD is the cause or the consequence of the Results: EMD were found in 33.3% and in 49.1% of patients esophageal motility impairment (4). Although GERD has pre-LTx and post-LTx, respectively, and abnormal peristal- been extensively studied as a factor associated with LTx sis was more frequently found post-LTx (p = 0.018). Hyper- rejection, there are some gaps with regard to the potential contractile was frequently found post-LTx (1.8% contribution to the abnormal motility of the esophagus. and 19.3% pre-LTx and post-LTx, respectively). Esophago- Esophageal dysmotility can impair esophageal clearance gastric junction (EGJ) morphology changed significantly and could favor retrograde movement of the esophageal pre-LTx and post-LTx; type I (normal) was more frequent content to the pharyngeal area. Therefore, the refluxate post-LTx (63-2% and 82.5% respectively, p = 0.007). EMD material is not necessarily the acid that comes from the were more frequent post-LTx in both the non-rejection and . In this respect, experimental studies performed in rejection group, although particularly in the rejection group rat lung transplant models (WKY-to-F344) showed that both (43.2% and 69.2% respectively, p = 0.09). EMD such as dis- acid (pH 2.5) and neutralized acid pH (pH 7.4) caused lesions tal spasm, hypercontractile esophagus and EGJ outflow consistent with obliterative bronchiolitis (5). Findings show obstruction were also observed more frequently post-LTx that impaired esophageal peristalsis and hypotensive lower in the rejection group. esophageal sphincter (LES) are more prevalent in LTx can- didates with GERD (6) and hypercontractile motor disorders -Conclusion: signifcant changes in esophageal motility were have been reported post-LTx (7). Patients who have under observed pre-LTx and particularly post-LTx; hypercontractile gone a bilateral lung transplantation or a re-transplanta- esophagus was a frequent EMD found post-LTx. EMD were more frequent in the group of patients that experienced organ rejection compared to the non-rejection group. EMD leading to an impaired esophageal clearance should be con- Ciriza-de-los-Ríos C, Canga-Rodríguez-Valcárcel F, De-Pablo-Gafas A, Cas- sidered as an additional factor that contributes to LTx failure. tel-de-Lucas I, Lora-Pablos D, Castellano-Tortajada G. Esophageal motor disor- ders are frequent during pre and post lung transplantation. Can they influence lung rejection? Rev Esp Enferm Dig 2018;110(6):344-351. Key words: Esophageal motility disorders. High resolution manometry. Lung transplantation. Hypercontractile esoph- DOI: 10.17235/reed.2018.5263/2017 agus. Lung rejection.

1130-0108/2018/110/6/344-351 • REVISTA ESPAÑOLA DE ENFERMEDADES DIGESTIVAS REV ESP ENFERM DIG 2018:110(6):344-351 © Copyright 2018. SEPD y © ARÁN EDICIONES, S.L. DOI: 10.17235/reed.2018.5263/2017 Esophageal motor disorders are frequent during pre and post lung transplantation. Can they influence lung rejection? 345

tion have a more pronounced delay in gastric emptying, pressure prior to recording. The previously described stan- impaired esophageal motility and delayed esophageal acid dard protocol was used (13). All subjects were studied fol- clearance as compared to patients who had undergone a lowing an overnight fast and after discontinuing medication unilateral lung transplantation (8). within 48 hours (except for immunosuppressant therapy post-LTx) that could affect the examination results. How- Esophageal high-resolution manometry (HRM) represents ever, all patients received a double dose of proton pump an unquestionable advance in esophageal manometry and inhibitors (PPI) post-LTx as per protocol and when the HRM allows a better characterization of EMD and esophagogas- was performed six months post-LTx. After calibrating the tric junction (EGJ) morphology (9). The Chicago classifica- equipment, the recording probe was introduced nasally and tions include the new data that HRM provides for the study the procedure was performed with the patient in the supine of EMD (10). position (14). Subsequently, the recording was started with a 30 second basal period (landmark) with no deglutitions The aim of the study was to assess esophageal motor dis- in order to obtain the sphincter pressures, followed by ten orders by high resolution manometry (HRM) both pre-LTx deglutitions of 5 ml every 20 seconds. If the first landmark and six months post-LTx, in patients with and without organ were not satisfactory, a second landmark was performed at rejection. the end of the study. Furthermore, if the patient swallowed twice or the interval between swallows was under 20 sec- onds, these deglutitions were not considered as valid for MATERIAL AND METHODS the analysis. The final analysis required ten valid degluti- tions (15). Patients

This was a single-center retrospective analysis of a prospec- 24h pH-monitoring protocol tively-collected database of 57 consecutive patients over 18 years of age referred to our esophageal motility laboratory Twenty-four hours ambulatory pH-monitoring without PPI both pre-LTx and six months post-LTx, between October was carried out pre-LTx. The sensor was placed 5 cm above 2009 and November 2016. Inclusion criteria were: a) signed the upper limit of the lower esophageal sphincter (LES) informed consent; 2) a minimum age of 18 years; and 3) determined by HRM. The study catheter was attached to an indication for LTx. The exclusion criteria was: a) patients ambulatory recorder (Matla Systems Inc, Madrid, Spain). who refused to sign the informed consent. Post-LTx, pH-monitoring was performed with a double dose of PPI as per protocol (Lung Transplantation Unit). The proxi- Gastrointestinal (GI) symptoms were evaluated both pre mal sensor was placed 5 cm above the upper limit of the LES and six months post-LTx using the modified DeMeester and the distal sensor on the stomach. Patients were encour- Questionnaire that evaluated , regurgitation and aged to carry out their normal diet and daily activities. . These were scored between 0-3 (0: none; 1: mild; 2: moderate; 3: very severe) (11). Data analysis Acute rejection was defined as a clinical, radiological or functional episode that was compatible with a histological Manometric data were analyzed using the Mano ViewTM demonstration according to the international classification analysis software version 2.1 (Given Scientific Instruments of the Lung Rejection Study Group, or without histological Inc. Los Angeles, CA, USA) and reanalyzed with the new demonstration but with a response to the specific treatment version 3.3. Two experienced researchers performed HRM for rejection (12). Chronic rejection was defined according and reviewed manually all the deglutitions of each patient. to the international guidelines. This was defined as a drop Finally, a manometric diagnosis was reached using the analysis algorithm recommended by the Chicago Classifi- in forced expiratory volume in one second (FEV1) < 80% of the maximum volume achieved after transplant. This was cation. Esophageal motor function was evaluated according on the condition that other etiologies such as infections, to the Chicago Classification v. 3.0 (10). Subsequently, the airway stenosis or native lung complications in single-lung EMD were classified into the following subtypes: normal, transplant recipients were excluded (12). Chronic rejection achalasia, hypercontractile esophagus, distal esophageal can present at any time after the transplant. spasm, absent and ineffective peristalsis (16).

The study was performed following the protocol proposed The following manometric measurements were analyzed: by the Lung Transplant Program approved by the Hospital basal pressure of the LES (normal values: 10-35 mmHg; Universitario 12 de Octubre. minimum pressure obtained with the sleeve device) (17), integrated relaxation pressure (IRP) (four seconds IRP nor- mal values [IRP4s]: < 15 mmHg) (10), pressurization pres- HRM protocol ence or absence (9), distal contractile integral (DCI) (normal values: 450-8,000 mmHgm.s.cm) (10), and distal latency HRM was performed both pre-LTx and six months post-LTx (DL) (normal values: > 4.5 s) (10). in all patients according to the protocol established at our hospital. HRM was performed using a solid-state manomet- The normal values (thresholds) applied were based on the ric assembly with 36 circumferential sensors with an outer Chicago Classification, except for the cut-offs for LES resting diameter of 4.2 mm spaced at 1-cm intervals (Given Scientif- pressure, as this was not considered in this classification. LES ic Instruments Inc., Los Angeles, CA, USA). The transducers was considered as normal (basal pressure was between 10 were calibrated at 0 and 300 mmHg by applying an external and 35 mmHg and IRP-4s < 15 mmHg), hypotensive (basal

REV ESP ENFERM DIG 2018:110(6):344-351 DOI: 10.17235/reed.2018.5263/2017 346 C. Ciriza-de-los-Ríos et al.

LES pressure was < 10 mmHg and IRP-4s < 15 mmHg) and median and interquartile range (IQR) for non-parametric hypertensive (basal pressure ≥ 35 and IRP-4s < 15 mmHg). variables. Qualitative data were expressed as absolute frequencies. Acute and chronic rejection patients were HRM diagnosis was divided into the following groups: nor- grouped for analysis purposes. Data were stratified for mal, ineffective peristalsis (≥ 50% weak and failed contrac- patients as rejection and non-rejection and the distribution tions; DCI < 450 mmHg.cm.s and DCI < 100 mmHg.cm.s was compared with the Mann-Whitney U test (non-normal respectively), absent peristalsis (100% failed contraction distribution) or Chi-squared test (categorical variables) or and IRP-4s < 15 mmHg), EGJ outflow obstruction (EGJOO) Fisher’s exact test, as appropriate. The statistical signifi- (IRP-4s ≥ 15 mmHg), achalasia (100% of failed contractions cance of paired differences between pre-LTx and post-LTx and IRP ≥ 15 mmHg), distal esophageal spasm (≥ 20% of HRM data was calculated using the Wilcoxon signed rank premature contractions; distal latency < 4.5 s) and hyper- test (non-normal distribution) or McNemar’s test (categor- contractile esophagus (≥ 20% of hypercontractile contrac- ical variables). The data analysis was generated using the tions; DCI ≥ 8000 mmHg.cm.s) (10). IBM SPSS statistics 22 software.

EGJ morphology was classified depending on the distance between the LES and crural diaphragm (CD) as follows: type I (normal), for distances < 1 cm; type II, for distances RESULTS between 1-2 cm; and type III (hiatal ), for distances over 2 cm (10,18). Fifty-seven patients were included and analyzed both pre-LTx and post-LTx. Forty-four (77.2%) did not expe- Patients were classified as having GERD when the total rience a rejection, nine (15.8%) had acute rejection and time at pH < 4 was over 4.5% according to the DeMeester four (7%), chronic rejection. Most patients had obstruc- reference values when the procedure was performed with- tive type end-stage lung disease both in the non-rejec- out PPI (19) and 1.6% when performed with PPI (20). The tion and rejection groups (53.2% and 46.2%). GI symp- association with reflux symptoms was not used in the final toms were very infrequent and the symptom score was diagnosis for GERD as most patients were asymptomatic. similar in both the pre-LTx and post-LTx groups. Over- pH data were not compared pre-LTx and post-LTx. all, 17.5% and 15.8% of patients had symptoms pre-LTx and post-LTx, respectively; heartburn and regurgitation were the most frequent. None of the patients had dys- Statistical analysis phagia either pre-LTx or six months post-LTx. However, two patients presented with dysphagia during follow up HRM quantitative data were described using the mean and after the initial six month period. Patient characteristics confidence intervals (CI) for parametric variables and the are shown in table 1.

Table 1. Patient characteristics pre-LTx and post-LTx according to the rejection vs. non-rejection groups

Clinical data Non-rejection (n = 44) Rejection (n = 13) p-value Age (mean [CI 95%], yr) Pre-LTx 52.6 (41.7-63.5) 55.1 (50.2-59.8) 0.962 Post-LTx 57.4 (46.4-68.3) 57.9 (53.1-62.8) 0.505 Male (n [%]) 28 (49.1%) 8 (61.5%) 0.890 BMI (mean; kg/m2) Pre-LTx 24.6 (22.1-27) 26.3 (23.9-28.6) 0.024 Post-LTx 24.7 (21.5-27.8) 35.7 (23.5-27.9) 0.025 Abdominal perimeter (mean; cm) Pre-LTx 94.5 (88.7-100.2) 95.2 (89.6-100.7) 0.487 Post-LTx 92.3 (82.9-101.5) 94.8 (89.1-100.6) 0.189 LTx indication (n [%]) Obstructive 23 (52.3%) 6 (46.2%) COPD 5 (21.7%) 6 (100%) Emphysema 9 (39.1%) 0 Cystic fibrosis 5 (21.7%) 0 Bronchiectasis 1 (4.4%) 0 0.414 Fibro emphysema 3 (13%) 0 Restrictive 13 (29.5%) 4 (30.8%) 1 (7.7) 4 (100%) Idiopathic pulmonary fibrosis 12 (92.3%) 0 Pulmonary hypertension 4 (9.1%) 3 (23%) Others (histiocytosis X, etc.) 4 (9.1%) 0 (Continue in the next page)

REV ESP ENFERM DIG 2018:110(6):344-351 DOI: 10.17235/reed.2018.5263/2017 Esophageal motor disorders are frequent during pre and post lung transplantation. Can they influence lung rejection? 347

Table 1 (Cont.). Patient characteristics pre-LTx and post-LTx according to the rejection vs. non-rejection groups

Clinical data Non-rejection (n = 44) Rejection (n = 13) p-value DeMeester score (mean) Pre-LTx 2.8 (0.9-4.5) Nd Post-LTx 1.9 (0.1-3.6) Nd GI and extraesophageal symptoms pre-LTx None 34 (77.3%) 13 (100%) Heartburn 4 (9.1) Heartburn and regurgitation 3 (6.8%) 0.611 Hoarnesses 1 (2.3%) 1 (2.3%) 1(2.3%) GI and extraesophageal symptoms post-LTx None 36 (81.8%) 12 (92.3%) Heartburn 3 (6.8%) 0 Heartburn and regurgitation 2 (4.5%) 0 0.318 Hoarnesses 0 0 Chest pain 2 (4.5%) 0 Cough 1 (2.3%) 1 (7.7%) pH-monitoring pre-LTx* Normal 31 (70.5) 5 (38.5%) 0.019 Abnormal 11 (25%) 8 (61.5%) Not performed 2 (4.5%) 0 pH-monitoring post-LTx* Normal 31 (70.5%) 10 (76.9%) 0.966 Abnormal 9 (20.5%) 3 (23.1%) Not performed 4 (9%) 0 LTx type (n [%]) Bilateral 28 (63.6%) 9 (69.2%) 0.933 Right lung 12 (27.3%) 3 (23.1%) Left lung 4 (9.1%) 1 (7.7%) BMI: body mass index; LTx: lung transplantation; GI: Gastrointestinal; Nd: no data (patients did not report symptoms). Statistical method: Mann-Whitney U, Chi-squared test. *Double channel esophageal pH monitoring pre-LTx was performed without PPI and double channel esophago-gastric pH monitoring post-LTx, with PPI as per protocol. pH data pre-LTx and post-LTx were not compared.

Analysis pre-LTx vs. post-LTx 19 (51.4%) patients had bilateral LTx and ten (50%) patients with unilateral had normal peristalsis (NS). HRM parameters and diagnosis are shown in table 2. EMD were found in 33.3% and 49.1% of patients pre-LTx and post-LTx respectively (p = 0.018); hypercontractile esoph- Analysis rejection vs. non-rejection group agus was the most relevant EMD post-LTx (p = 0.018). Accordingly, DCI was significantly higher post-LTx (p < EMD were more frequent post-LTx in both the non-rejection 0.001) (Fig. 1). Of the eleven patients with hypercontractile and rejection groups, but particularly in the rejection group esophagus post-LTx, three (27.3%) had abnormal pH moni- (43.2% and 69.2%, respectively; p = 0.09). Hypercontractile toring, two (18.2%) had EGJOO and one (9%) had abnormal esophagus was observed in 23% of the cases post-LTx in pH monitoring with EGJOO. There was no evidence of other the rejection group (Table 3). Accordingly, DCI tended to possible causes in the remaining five (45.5%) cases. be higher in the rejection group (Fig. 2). EGJ was more frequently classed as type I (normal) in the non-rejection An EGJ morphology change was observed pre-LTx and compared to the rejection group (86.4% vs. 69.2% respec- post-LTx; type I (normal) was more predominant post-LTx tively, NS) (Table 3). (63.2% and 82.5% respectively, p = 0.007). Accordingly, EGJ length was shorter post-LTx due to a decrease in the The HRM results were as follows in the nine patients with intrathoracic length. Hypotensive LES was more frequent acute rejection, three cases had no abnormalities, three had pre-LTx than post-LTx (33.3% and 17.5% respectively, p = hypercontractile esophagus (one of them had also EGJOO), 0.017) (Table 2). There were no differences in the frequency one had EGJOO and two, distal spasm. The three patients of EMD according to the type of LTx (bilateral or unilateral); with hypercontractile esophagus still had the same disorder

REV ESP ENFERM DIG 2018:110(6):344-351 DOI: 10.17235/reed.2018.5263/2017 348 C. Ciriza-de-los-Ríos et al.

Table 2. HRM parameters, EGJ morphology and EMD diagnosis pre-LTx and six months post-LTx

Pre-LTx Post-LTx HRM parameter p-value Median (IQR) Median (IQR) LES pressure (mmHg) 11.4 (6.9-18.9) 15.8 (10.7-26.3) < 0.001

IRP (mmHg) 6.9 (3.3-11.5) 7.4 (4.9-12.8) 0.324 EGJ total length (cm) 3.9 (3.4-4.2) 3.5 (3.3-4.1) 0.044 EGJ abdominal length (cm) 2.1 (1.8-2.5) 2.1 (1.9-2.7) 0.677 EGJ thoracic length (cm) 1.6 (1.3-2.3) 1.4 (1.1-1.7) 0.004 DCI (mmHg.cm.s) 1,503 (782.8-2,647.5) 2,559.8 (1,523.2-4,593) < 0.001 Distal latency (s) 6.3 (6-7.3) 7 (6-7.7) 0.029 Intrabolus pressure (mmHg) 15.4 (13-20.7) 17.8 (13.8-24.4) 0.155 LES basal pressure (n, %) Normal 37 (65%) 42 (73.7%) 0.017 Hypotensive 19 (33.3%) 10 (17.5%) Hypertensive 1 (1.7%) 5 (8.8%) EGJ morphology (n, %) Type I 36 (63.2%) 47 (82.5%) 0.007 Type II 19 (33.3%) 10 (17.5%) Type III 2 (3.5%) 0 Diagnosis (n, %) Normal 38 (66.7%) 29 (50.9%) EMD 19 (33.3%) 28 (49.1%) Ineffective peristalsis 6 (10.5%) 9 (15.8%) Absent peristalsis 4 (7%) 0 0.018 Hypercontractile esophagus* 1 (1.8%) 11 (19.3%) Distal spasm 3 (5.3%) 3 (5.3%) EGJOO 5 (8.8%) 5 (8.8%) Achalasia 0 0 HRM: high-resolution manometry; LES: lower esophageal sphincter; IRP: integral relaxation pressure; EGJ: esophagogastric junction; DCI: distal contractile integral; EGJOO: esophagogastric junction outflow obstruction; IQR: interquartile range. Statistical methods: Wilcoxon signed rank test and McNemar’s test. *Two patients with hypercontractile esophagus also had EGJOO post-LTx.

ed with endoscopic injection (Fig. 3). In addition, four patients had chronic rejection, two had weak peristalsis and one had EGJOO.

DISCUSSION

Patients with end stage lung disease pre-LTx have a high prevalence of EMD and hypotensive LES with a reported frequency of around 76.6% using HRM (1). We found a sim- ilar frequency in our series of 66.6% (including EMD and hypotensive LES). According to the Chicago Classification 3.0, the frequency of EMD pre-LTx in our series was 33.3%, and these alterations increased post-LTx up to 49.1%. The most frequent disorders found were ineffective peristalsis, hypercontractile esophagus and EGJOO. Previous studies Fig. 1. DCI pre-LTx and six months post-LTx. performed with water perfused manometry have reported dysmotility post-LTx in up to 44% of the patients. Although the results are not strictly comparable between conven- tional and HRM, the authors found similar findings, includ- one year post-LTx. Two of these patients presented with ing ineffective motility and (21). In dysphagia during follow up after six months and were treat- addition, we found significant changes in EGJ morphol-

REV ESP ENFERM DIG 2018:110(6):344-351 DOI: 10.17235/reed.2018.5263/2017 Esophageal motor disorders are frequent during pre and post lung transplantation. Can they influence lung rejection? 349

Table 3. HRM results with regard to the rejection vs. non-rejection group pre-LTx and six months post-LTx

HRM results Non-rejection (n = 44) Rejection (n = 13) Pre-LTx Post-LTx* Pre-LTx Post-LTx* EGJ morphology (n, %) Type I 27 (61.4%) 38 (86.4%) 9 (69.2%) 9 (69.2%) Type II 16 (36.4%) 6 (13.6%) 3 (23.1%) 4 (30.8%) Type III 1 (2.2%) 0 1 (7.7%) 0 Diagnosis (n, %) Normal 29 (65.9%) 25 (56.8%)* 9 (69.2%) 4 (30.8%)* EMD 15 (34.1%) 19 (43.2%) 4 (30.8%) 9 (69.2%) Type of EMD Ineffective peristalsis 6 (13.6%) 7 (15.9%) 0 2 (15.4%) Absent peristalsis 3 (6.8%) 0 1 (7.7%) 0 Hypercontractile esophagus 0 (0%) 8 (18.2%) 1 (7.7%) 3 (23%) Distal spasm 2 (4.5%) 1 (2.3%) 1 (7.7%) 2 (15.4%) EGJOO 4 (9.1%) 3 (6.8%) 1 (7.7%) 2 (15.4%) Achalasia 0 0 0 0 HRM: high-resolution manometry; EMD: esophageal motor disorder; EGJOO: esophagogastric junction outflow obstruction. *Comparison of post-LTx between the non-rejection and rejection group (normal vs. EMD, p = 0.09). Statistical methods: Chi-squared test or Fisher’s exact test, as appropriate.

The physiopathology of hypercontractile esophagus remains unclear and different hypotheses have been suggested, including mechanical EGJOO, occurrence secondary to reflux disease, primary esophageal muscle hypercontractility (25) and eosinophilic infiltration into the muscularis propria (26). In this regard, EMD was observed in one patient four weeks post-LTx, who nevertheless recov- ered without any specific treatment besides PPI (7).

In our series, all the patients received double doses of PPI as per protocol post-LTx and HRM was performed after six months. Therefore, the disorder was not correct- ed with PPI use. Furthermore, the small group of patients Fig. 2. DCI pre-LTx and post-LTx in the rejection vs. non- with complications post-LTx and EMD were followed up rejection groups. over six months and the disorder persisted in all cases. Therefore, we do not consider this as a transient problem. It was not possible to clarify the etiology of the disorder in 45.5% of the patients. In this respect, and according to ogy pre-LTx and post-LTx; more type I (normal) EGJ was previous reports (25), the disorder could have been initi- observed post-LTx, particularly in the non-rejection group. ated by neuromuscular stress induced by surgical trauma These changes could be related to the surgical changes and and perhaps, complicated by partial during LTx the improvement of pulmonary function. However, these leading to esophageal dysmotility. Some medications such findings were not present in the rejection group (Table 3). as azithromycin can influence esophageal motility (27), but none of the patients were under the effects of this medica- There is some evidence that demonstrates a link between tion during the procedure as this treatment was stopped at GERD and LTx rejection (8,22,23) that can occur early post-LTx least 48 hours previously. (21), but the potential implication of esophageal dysmotility in LTx rejection has not yet been clarified. The importance of The mechanism could be related to abnormal acid reflux EGJOO for chronic rejection has been recently reported (24). or EGJOO in the remaining 54.5% of patients. An abnor- In our series, EGJOO was observed pre-LTx in five patients, mal pH monitoring result was found in 27.3% of cases. two related with abnormal acid reflux. The disorder persisted EGJOO was a possible mechanism in 18.2% of cases with post-LTx in the same five patients and only one had abnormal hypercontractile esophagus, and abnormal GERD was pH-monitoring. When the data was analyzed considering the also found in one of these cases. Therefore, some of the rejection vs. non-rejection group, EGJOO was more frequent complications post-LTx could be related to GERD and oth- in the rejection group. On the other hand, hypercontractile ers could be a consequence of retained material in the esophagus was diagnosed more frequently than expected in esophagus due to an impaired esophageal clearance. A the post-LTx group, which was 19.3% (18.2% in the non-rejec- very recent finding supports our theory, namely, that poor tion and 23% in the rejection group). esophageal clearance is due to an abnormal post-reflux

REV ESP ENFERM DIG 2018:110(6):344-351 DOI: 10.17235/reed.2018.5263/2017 350 C. Ciriza-de-los-Ríos et al.

Fig. 3. High resolution manometry (HRM) plot pre-LTx and six months post-LTx. High resolution impedance manometry (HRiM) was performed three months later to follow up the esophageal motor disorder (EMD) previously treated with botulinum toxin (at the level of the esophagogastric junction [EGJ] and in the esophageal body) when the patient presented dysphagia and also acute rejection. A. HRM plot pre-LTx. B. HRM plot six months post-LTx with a diagnosis of hypercontractile esophagus and impaired EGJ relaxation. C. HRiM performed three months later, after treatment with botulinum toxin. Persistence of EMD and bolus retention can be observed.

swallow-induced peristaltic wave index associated with The main limitation of our study is the small number of obstructive chronic lung allograft dysfunction (24). PPI patients in the rejection group, although we still observed treatment is necessary in these types of patients due to significant changes pre-LTx and post-LTx and between the the high prevalence of GERD, although it would not be rejection vs. non-rejection group. Another limitation is the useful to prevent the aspiration of esophageal content. fact that HRiM and 24h pH/impedance was not performed Even though antireflux surgery has been demonstrated in all of the patients. to be safe post-LTx and leads to a stabilization of lung function in patients with reflux, there is no definitive data In conclusion, significant changes in esophageal motility supporting the hypothesis that it improves the survival can be observed pre-LTx and particularly post-LTx; hyper- rate (28). On the other hand, antireflux surgery has not contractile esophagus is a frequent EMD. EMD were more prevented acute rejection episodes (28). Although some frequent in the rejection group compared to the non-re- other factors can influence rejection, it is important to jection group. Esophageal motility alterations leading to appreciate that esophageal dysmotility which can impair impaired esophageal clearance should be considered as bolus transit, may also contribute to LTx failure. another factor that might contribute to LTx failure.

REV ESP ENFERM DIG 2018:110(6):344-351 DOI: 10.17235/reed.2018.5263/2017 Esophageal motor disorders are frequent during pre and post lung transplantation. Can they influence lung rejection? 351

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REV ESP ENFERM DIG 2018:110(6):344-351 DOI: 10.17235/reed.2018.5263/2017