Workup and management of upper gastrointestinal disorders in patients undergoing lung transplantation: a narrative review

Introduction

Background

The incidence of lung transplantation in the United States reached a record number of 3,026 in the 2023 calendar year (1). This marked the first time since the coronavirus disease 2019 (COVID-19) pandemic where the annual number of lung transplants exceeded pre-pandemic levels (Figure 1). Despite the enhanced volume, post-transplant survival has remained stable over the past decade, with 1-year mortality from 12–15% (2). However, long-term survival remains the lowest among the solid organ transplant population, with 5-year survival at 60% or less (2). As such, allograft preservation and mitigation of injury remain paramount. Patients deemed as suitable candidates for lung transplantation are carefully selected and undergo extensive preoperative testing to identify potential pathology that may lead to morbidity or graft dysfunction (3). From a gastrointestinal (GI) perspective, these include esophagogastroduodenoscopy (EGD), esophageal manometry and pH testing, impedance, gastric emptying, evaluation of diaphragm function, colonoscopy, and cross-sectional abdominal imaging. The utility and timing of these evaluations relative to transplantation will be discussed in detail below.

Figure 1 Number of lung transplants performed over time in the United States (publicly reported data retrieved and compiled from the Organ Procurement and Transplantation Network).

Acute rejection is characterized both clinically, as declining lung function, and histologically, as cellular or antibody-mediated rejection, between 1 week and 1 year post-transplant. Acute rejection occurs in up to 50% of cases, and is an independent risk factor for the later development chronic lung allograft dysfunction (CLAD), which occurs beyond 1 year (2). CLAD comprises both obstructive [i.e., bronchiolitis obliterans syndrome (BOS)] and restrictive [i.e., restrictive allograft syndrome (RAS)] forms of chronic rejection. BOS is a clinical entity that is comprised of inflammation, destruction, and fibrosis of small airways leading to obliterative bronchiolitis. Microscopically, this is a result of macrophage and myofibroblast infiltration, which induces fibrous obliteration, intimal thickening, and destruction of pulmonary vasculature (4,5). The International Society of Heart and Lung Transplantation (ISHLT) released a clinical practice guideline that defines BOS clinically as delayed (>3 months from transplant) allograft dysfunction with persistent decline in forced expiratory volume in 1 s (FEV₁) that is not caused by other known and potentially reversible causes of post-transplant loss of lung function (6). BOS is recognized as the predominant cause of delayed lung allograft dysfunction and remains one of the greatest impediments to long-term survival after lung transplantation, with 80% of transplant recipients ultimately affected by 5 years (7). Many risk factors have been associated with its development, including primary graft dysfunction (PGD), acute rejection, certain infections, and chronic aspiration secondary to gastroesophageal reflux disease (GERD), esophageal dysmotility, and/or gastroparesis (6).

The association between GERD and allograft injury/BOS is well-documented. At the cellular level, reflux-induced lung injury is precipitated by aspiration, causing local immunomodulation and histologic rejection, as reflective of allograft injury. As such, the ISHLT algorithm for declining lung function proposes evaluation for GERD in any patient with suspected BOS and FEV₁ <90% of post-transplant baseline (6). Interestingly, nearly two-thirds of end-stage lung disease patients report GERD symptoms pre-transplant, and at least 38% have documented pathologic acid reflux on objective testing (8) (Table 1). Consequently, the ISHLT also recommends pre-transplant evaluation for GERD in all patients who are being considered for listing (9). Post-transplant GERD is reported in 30–65% of cases, yet workup is less standardized, and often only occurs as a result of declining lung function or significant symptoms (10,11). However, symptoms alone are insufficient to guide the workup of GERD in this population. One study found that while pH testing was abnormal in the majority of transplant patients with GERD symptoms, 60% of patients without symptoms also had abnormal pH testing (12). This indicates that “silent aspiration” may persist undetected and contribute to allograft dysfunction, representing a missed opportunity for prevention or mitigation of injury.

Finally, other GI disorders, namely esophageal and gastric dysmotility, are also prevalent in both the pre- and post-lung transplant population. Vagal nerve injury or dysfunction is often implicated in motility disorders, with up to 83% of patients developing esophageal dysmotility and up to 60% with delayed gastric emptying (DGE) post-transplant (13,14). It has also been reported that at least two-thirds of patients with documented esophageal or gastric motility disorders post-transplant will develop rejection (13). Although a causal link has yet to be elucidated, this reiterates the increased risk for progressive graft dysfunction in this population.

Rationale and knowledge gap

Upper GI disorders are highly prevalent in both the pre- and post-lung transplant patient population, and their association with allograft injury is well-documented. Despite this, no consensus exists for standardized GI workup, nor the medical, endoscopic, and/or surgical management of these entities in this cohort. A nuanced treatment approach in these patients may improve long-term outcomes which have thus far remained unchanged.

Objective

The objective of this narrative review is to carefully examine the diagnosis and management of both pre-existing and acquired upper GI disorders in the adult lung transplant population, with a particular focus on reflux disease. Risk factors/stratification and corresponding treatment algorithms will be presented with a thorough investigation of contemporary literature in hopes of establishing a tailored approach to management of GI disease in this cohort. We present this article in accordance with the Narrative Review reporting checklist (available at https://ccts.amegroups.com/article/view/10.21037/ccts-25-12/rc).

Methods

A search was performed of all English publications in PubMed with the following keywords (all paired with “lung transplant”): “gastrointestinal pathology”, “gastrointestinal disorders”, “gastroesophageal reflux disease”, “esophageal dysmotility”, “gastric dysmotility”, “delayed gastric emptying”, “fundoplication”, “antireflux surgery”, “allograft dysfunction”, “rejection”, and “preoperative and postoperative testing”. Article types included clinical trials, case reports, case series, retrospective studies, and systematic reviews. Articles not available in English were excluded. The search yielded 74 articles between 1990 and 2024 with direct relevance to the chosen topic. The complete search strategy is detailed in Table 2.

Discussion

Pre-transplant GI disease prevalence, pathogenesis, and workup

Interestingly, a consensus document encompassing all recommended pre-transplant evaluations does not currently exist. However, the ISHLT has published a set of preoperative risk factors that have been associated with unfavorable short and/or long-term outcomes after lung transplant, and contemporary transplant candidate workup serves to identify and treat these conditions. From a GI perspective, these include pathologic GERD, esophageal dysmotility, and gastric dysmotility, with significant overlap between the three (15). Although standard workup varies by institution, traditional investigations include EGD and pH testing, impedance, esophageal manometry, gastric emptying assessment, diaphragmatic evaluation, colonoscopy, and cross-sectional abdominal imaging. The rationale for performing these evaluations, as well as the existing evidence supporting them, will be discussed in this section.

Initial surveillance endoscopy is part of standard workup for lung transplant candidates. EGD and colonoscopy are commonly performed concurrently. EGD is recommended regardless of presence or absence of reflux symptoms, as symptoms have been shown to be poor predictor of pathologic reflux (10), with a sensitivity of 67% and specificity of 26% (16). Pathologic reflux—traditionally defined as a DeMeester score of >14.72 or acid exposure time >6 minutes (17)—was present in the distal esophagus in 68% and proximal esophagus in 37% of pre-transplant patients (16). In restrictive lung disease patients (the most common indication for transplantation), even higher rates of distal (76%) and proximal (63%) reflux were observed (18). Thus, concurrent pH testing is recommended in nearly all patients, especially in those with endoscopic evidence of reflux and in those with significant symptoms. Potential biochemical markers for detecting pathologic reflux are also discussed in the following sections. While the pathogenesis of GERD in the end stage lung disease population is not fully elucidated and likely varies by disease type, numerous studies have proposed that the altered chest wall mechanics of advanced pulmonary disease causes disequilibrium of intra-thoracic and intra-abdominal pressures that leads to an increased pressure gradient across the LES (19,20). Additionally, diaphragmatic dysfunction also appears to contribute significantly to GERD in these patients, with loss of the “diaphragmatic pinch valve” exacerbating reflux physiology. Thus, many centers also require evaluation of diaphragm function as part of candidate workup. Indications for impedance testing are identical to the non-transplant population and include persistent symptoms despite acid-suppressing medications and suspicion of bile (non-acid) reflux. Management of pre- and post-transplant GERD is discussed subsequently. If no pathologic reflux is noted on initial evaluation, endoscopic surveillance may be performed at 3, 6, and 12 months post-transplant or with any instance of BOS.

It should be noted that lung transplant recipients are also at substantially increased risk of colonic adenoma formation (up to 39% pre-transplant and 50% post-transplant) and progression, compared to the general population (21). Adenoma formation is largely attributed to immunosuppression and occurs most commonly in the first 3 years after transplant. As a result, a baseline colonoscopy is recommended pre-transplant, with additional colonoscopic surveillance within 3 years post-transplant, unless high-risk adenomas are detected preoperatively [in which case, United States Preventive Services Task Force (USPSTF) guidelines are followed (22)].

Esophageal dysmotility is also highly prevalent in the advanced lung disease population (up to 35–45% of patients), with highest rates again seen in patients with restrictive lung disease (23). Dysmotility is observed concurrently with GERD in many patients, but can also exist in isolation. In the former, persistent abnormal acid exposure predisposes these patients to progressive cellular injury and resultant dysmotility. In the latter, the pathogenesis is poorly understood (except in cases of connective tissue disorders), although one study intriguingly observed that patients with obstructive lung disease were more likely to have hypermotility abnormalities whereas patients with interstitial lung disease were more likely to have hypomotility abnormalities (23). Moreover, intraoperative vagal nerve palsy or injury often leads to transient or permanent nerve dysfunction and post-transplant dysmotility, with up to 83% of patients developing esophageal dysmotility (13). Similarly, DGE was noted in half of lung transplant candidates, and in 63–74% of patients after transplant (14,24). While pre-existing lung disease is thought to play a role in its development, calcineurin inhibitors, weight loss, diabetes mellitus, and uremia have all been shown to worsen gastroparesis before and after transplantation. Moreover, both esophageal and gastric dysmotility were independently associated with the development of BOS in a 2012 report from a high-volume Canadian transplant center (24). Therefore, esophageal manometry (concurrent with initial endoscopy) and gastric emptying assessment are recommended at the majority of transplant centers.

Finally, cross-sectional abdominal and pelvic imaging is routinely combined with chest computed tomography (CT) for comprehensive assessment of GI pathology. Additionally, a recent study evaluated the association of CT-characterized abdominal skeletal muscle adipose deposition and outcomes after lung transplant. Interestingly, each ½ standard deviation decrease in abdominal muscle attenuation was associated with a significant decrease in 6-minute walk distance and 20% increased risk of death or delisting, providing an additional potential utility for abdominal imaging (25).

Management of gastroesophageal reflux disease pre- and post-transplant

As mentioned above, more than half of lung transplant candidates have some degree of pathologic gastroesophageal reflux, with an even higher proportion after receipt of transplant (11). Some have proposed that proximal esophageal acid exposure has the greatest correlation with the development of BOS; notwithstanding, the resultant deleterious effects of reflux disease on lung function are well-documented, even in cases of non-acidic reflux. Notably, this is independent of changes in manometry or gastric emptying (26). Thus, risk stratification and appropriate selection of those who are best managed with either medical or endoscopic/surgical intervention becomes paramount.

Medical treatment of reflux is identical to the non-transplant population revolves around acid suppression and consists predominantly of proton-pump inhibitors (PPIs), with prokinetic agents added in patients with concomitant DGE. Wedge pillows are also useful for nocturnal reflux. Additionally, recent publications have suggested that strict medical antireflux therapy may prolong survival and decrease the incidence of acute disease exacerbation in patients with idiopathic pulmonary fibrosis (IPF) (27). The role of newly introduced selective potassium channel blockers has yet to be delineated.

However, when medical therapy is ineffective in either controlling symptoms or in mitigating lung injury, procedural intervention is preferred. Antireflux intervention in this patient population consists of endoscopic or surgical fundoplication, with or without hiatal hernia repair (if present). While the specific criteria for selecting candidates for antireflux intervention remain undefined, generally accepted indications are declining lung function (with other treatable causes ruled out) and documented pathologic reflux by pH testing/impedance, endoscopic biopsies, and/or significant symptoms despite medical treatment. Recent studies have also sought to establish a link between biochemical markers and the presence of pathologic reflux. Bile acids appear to disrupt macrophage function and destroy cellular membranes of type II pneumocytes in in vitro studies, which increases susceptibility to injury and limits surfactant production (28). Bile acids were detected in a higher percentage (71%) of bronchoalveolar lavage (BAL) specimens in patients with BOS compared to patients without (31%), indicating that mucosal exposure to bile acids may contribute to BOS development (29). In addition, a report from the United Kingdom found that increasing levels of pepsin (a gastric proteolytic enzyme) in BAL specimens appeared to correlate with higher levels of histologic inflammation and ultimately allograft rejection (30). However, this and other studies found that some level of pepsin is present in all BAL specimens of lung transplant recipients, suggesting that aspiration of gastro-duodenal contents may be ubiquitous in this population (30,31). Its role, therefore, remains purely as a marker of reflux, with a possible concentration-dependent effect on lung injury.

The safety of surgical fundoplication has been well-established, even in this high-risk group. Many institutions favor intervention prior to lung transplant, as pre-transplant fundoplication has been shown to be safe (32,33) and can stabilize end-stage lung disease in some patients (34). This is especially true in those with large type III or type IV hiatal hernias, and those expected to have a long wait list time. The additional advantage of pre-transplant fundoplication is the early graft protection from reflux and aspiration upon transplantation. The safety of this procedure post-transplant has also been reported (34,35), with one study finding no difference in length of stay, complications, or readmissions between lung transplant and non-transplant patients who underwent minimally-invasive fundoplication for GERD (36).

The effectiveness of fundoplication for prevention of pulmonary injury has been consistently reported in the pre- and early post-transplant periods. A study from the Boston group assessed the development of allograft injury (defined both clinically as decline in pulmonary function and histologically as rejection) in three groups of patients who underwent fundoplication at different time points: (I) prior to transplant (mean 3.5 years prior); (II) within 6 months of transplant (mean 118 days); and (III) >6 months from transplant (mean 1.8 years) (37). The pre-transplant and early post-transplant groups experienced greater freedom from allograft injury compared with the late post-transplant group, without an increase in complications. The Duke transplant group has previously suggested a more narrow post-transplant fundoplication window of 90 days, as those who underwent fundoplication by this time interval experienced both greater freedom from BOS and improved survival compared to later fundoplication (38). This is concordant with prior reports suggesting that the prevalence of GERD after lung transplant increases with time (39).

Objective measures of pulmonary function also appear to be improved after fundoplication. Although a recent meta-analysis showed a small increase in raw FEV1 values post-fundoplication (pre: 2.02±0.89 vs. post: 2.14±0.77 L/1 sec; P=0.11), the rate of change in FEV1 was significantly worse in the pre-fundoplication group (pre: −2.12±2.76 vs. post: +0.05±1.19 mL/day; P=0.013) (40). Extended follow-up further supports early fundoplication, as a statistically significant difference in FEV₁ of 40.7% (P=0.019) was noted at 5 years between those who underwent early versus late fundoplication (41). Another study found that FEV1 after double lung transplant approaches that of single lung transplant in patients with persistently unmanaged reflux disease (42). This apparent preservation of pulmonary function post-fundoplication, as well as improved long-term survival, is reiterated in other large studies (43,44).

Finally, in addition to objective measures of pulmonary function preservation, patient satisfaction also appears to be more favorable after fundoplication. For instance, one study reported a significantly decreased prevalence of GERD symptoms following surgery (79% of patients pre- vs. 24% of patients post-surgery, P=0.002) with excellent patient-reported satisfaction measures (mean satisfaction score 8.8 out of 10) (45).

Endoscopic fundoplication (transoral incisionless fundoplication, or TIF) has gained popularity in both the transplant and non-transplant GERD populations. Although there are no current randomized controlled trials comparing endoscopic and surgical fundoplication, existing large retrospective studies and meta-analyses show encouraging results with regard to quality-of-life measures and objective reflux parameters in the short-term (46,47). However, various factors currently limit its widespread reach, including (I) required performance at a center capable of advanced endoscopy, (II) inability to perform concomitant procedures such as hiatal hernia repair, and (III) lack of robust data in the lung transplant population as well as long-term follow-up in any population. Moreover, distal esophageal pH fails to normalize in up to half of patients, and deterioration of the Hill grade is observed within 1 year, contesting both the short- and long-term durability of the TIF procedure (48).

Taken together, anti-reflux surgery in the pre-transplant and early post-transplant period is both safe and effective, and has consistently been associated with a decrease in the development of early allograft dysfunction. Fundoplication should be recommended in patients with declining lung function (with other treatable causes ruled out) and documented pathologic reflux by pH testing/impedance, endoscopic biopsies, and/or significant symptoms despite medical treatment (Figure 2A). In patients with mild reflux (acid exposure time <4–6%) with or without grade A esophagitis, maximal medical therapy is preferred, with fundoplication reserved for persistent decline in lung function not attributable to other cases. The timing of surgery relative to transplant is based on numerous factors; those with acceptable operative risk expected to have extended wait list times as well as those with large hiatal hernias may benefit from pre-transplant fundoplication, while those with tenuous respiratory status on the wait list may be deferred until after transplant, ideally within 6 months. Of note, patients with morbid obesity [body mass index (BMI) >35–40 kg/m²] have been shown to be at high risk of recurrence for both GERD and hiatal hernia; as a result, aggressive weight loss is often pursued by either medical or surgical means in this population prior to consideration of antireflux procedures (49).

Figure 2 Algorithm for the workup and management of (A) pathologic reflux and hiatal hernia, (B) esophageal dysmotility, and (C) delayed gastric emptying in lung transplant candidates and recipients. *, maximal medical therapy for GERD traditionally consists of twice-daily proton-pump inhibitors. If no pathologic reflux is noted on initial evaluation, endoscopic surveillance may be performed at 3, 6, and 12 months post-transplant or with any instance of BOS. **, supportive care for dysmotility includes diet modification and medications such as PPIs, calcium channel blockers, nitrates, and botulinum toxin for hypermotility, and withdrawal of phosphodiesterase-type 5 inhibitors for hypomotility. BOS, bronchiolitis obliterans syndrome; GERD, gastroesophageal reflux disease; G-POEM, gastric peroral endoscopic myotomy.

Management of esophageal dysmotility pre- and post-transplant

The term esophageal dysmotility encompasses a wide variety of pathology, each with variable significance in the lung transplant population. However, the spectrum of esophageal dysmotility is observed in a statistically greater proportion in lung transplant candidates and recipients than in the non-transplant population. In one study, a remarkable 76.7% of lung transplant candidates had any esophageal peristaltic dysfunction compared to 0% of random healthy controls (P<0.001) (50). Elevations in residual upper esophageal sphincter (UES) pressures were also noted, compared to controls (3.9 vs. 3.1 mmHg, P=0.015), and 80% of candidates with significant esophageal peristaltic dysfunction also had a hypotensive LES. Interestingly, all patients with post-transplant complications in this study had preoperative esophageal dysmotility, though further analysis was not performed due to low numbers. An increase in prevalence of esophageal dysmotility after lung transplant has also been variably reported. A Spanish transplant center reported an increased prevalence of both hypocontractile (49.1% vs. 33.3%, P=0.018) and hypercontractile (19.3% vs. 1.8%, P=0.018) esophagus post- versus pre-lung transplant, respectively (51). However, a smaller single center report showed that up to 65% of patients may demonstrate some recovery of esophageal peristalsis, attributed to improvement in thoracoabdominal pressure gradients and respiratory/GI equilibrium (52).

Although the consequences of esophageal dysmotility post-transplant are less well-characterized than those associated with GERD (in part because the former is less prevalent in isolation), many studies have demonstrated worse outcomes in these patients. The study from Spain mentioned above reported a 69.2% prevalence of esophageal dysmotility in the cohort who developed allograft rejection, compared with 43.2% in those without rejection (P=0.09) (51). Specifically, distal esophageal spasm, hypercontractile esophagus, and gastroesophageal junction (GEJ) outflow obstruction (both achalasia and non-achalasia types) were observed more frequently in those with rejection. Another study further characterized the negative effects of persistent esophageal dysmotility and found that inefficient bolus clearance and lower esophageal outflow obstruction precipitated the microaspiration and allograft injury cascade that is characteristic of CLAD (53). In contrast, those with improvement in peristalsis post-transplant experienced similar survival to those without esophageal dysmotility (52,54).

Unfortunately, aside from achalasia (discussed below), the management of isolated esophageal dysmotility is predominantly supportive, with diet modification and medications such as PPIs, calcium channel blockers, nitrates, and botulinum toxin having variable success for hypercontractile patients (55). Jackhammer esophagus exists at the severe end of the hypercontractile spectrum and has been seen in a larger proportion of post-lung transplant patients than expected (up to 25%), seemingly unrelated to preoperative manometry findings; management in this group is also predominantly supportive (56). The subgroup of patients with hypocontractility secondary to medications such as phosphodiesterase-type 5 inhibitors (PDE5i, a cornerstone of treatment for pulmonary hypertension) may see improvement or resolution after transplant once these medications are withdrawn (57).

Achalasia comprises a minority of cases (10–15%) of GEJ outflow obstruction in lung transplant patients, yet is much more significantly correlated with CLAD than non-achalasia cases [hazard ratio (HR) 3.99; 95% confidence interval (CI): 1.58–10.08, P=0.003 vs. HR 1.55 (95% CI: 1.01–2.37), P=0.04, respectively] (58). Although no standardized treatment approach exists to guide the management of achalasia in this small but extremely high-risk population, intervention should be prioritized both pre- and post-transplant to mitigate further pulmonary decline. Similar to the management of GERD in the transplant population, a surgical approach is preferred except in cases of a hostile abdomen (Figure 2B). Although an advantage of the per-oral endoscopic myotomy (POEM) is the lack of abdominal insufflation (and its associated negative respiratory effects), the post-POEM incidence of GERD approaches 50%, and is often not fully corrected by subsequent fundoplication (59). Finally, in patients with absent esophageal motility, a 180-degree fundoplication is reasonable after ruling out distal obstruction.

Management of gastric dysmotility pre- and post-transplant

In accordance with the spectrum of dysmotility in lung transplant patients, gastroparesis is observed at high rates in both the pre- and post-transplant population. The Toronto group assessed the prevalence of DGE over time among 139 lung-transplant candidates and recipients, and evaluated its association with BOS (24). DGE (t(1/2) >90 min) was documented in 50% of patients before transplantation, 74% of patients at three months post-transplant, and 63% at 12 months post-transplant. Among patients with pre-transplant DGE, 42% and 63% developed BOS by 24 and 36 months post-transplant, respectively, compared with 22% and 37% in non-DGE patients (P=0.08). Even after adjusting for indices of esophageal dysfunction and reflux, gastroparesis before (OR 1.05; 95% CI: 1.01–1.09, P=0.02) or within three months of transplant (OR 1.003; 95% CI: 1.001–1.005, P=0.01) was independently associated with the development of BOS. The correlation between DGE at 12 months and BOS was not assessed. Non-acid reflux was also thought to play a role, as evidenced by the association between BOS and levels of bile salts in BAL specimens.

The association between prevalence of postoperative gastroparesis and type of lung transplant performed (unilateral vs. bilateral) has also been studied, with mixed results. A 2015 study from Spain assessing 170 recipients found a higher rate of postoperative gastroparesis in double lung transplant recipients compared with single (40% vs. 22%, P=0.01) (60). In contrast, a larger (N=616), more recent study from a high-volume New York transplant center found that type of lung transplant was not a risk factor for the development of gastroparesis after adjustment for confounders (61). Given the discordant findings in these and other studies, it is likely that the extent of hilar and esophageal dissection, rather than the type of lung transplant performed, has a greater contribution to the development of postoperative gastroparesis. As such, protection of bilateral vagus nerves during dissection and retraction is paramount. Published techniques for avoiding nerve injury include ensuring meticulous hemostasis during the recipient pneumonectomy and hilar dissection, using bipolar cautery for coagulation, and using adjacent (usually ≥2 cm away) tissue as a “handle” during dissection (62,63).

Pre-transplant gastroparesis likely influences critical early events in the lung allograft, such as impaired absorption of oral immunosuppressive drugs and increased risk of aspiration. However, a portion of patients (up to 50%) with pre-transplant gastroparesis demonstrated improved gastric emptying after transplantation (64). Thus far, no report has delineated the risk factors for worsening gastroparesis, nor identified those whose DGE may improve post-transplant. Given the above and the existing evidence, it is reasonable to recommend procedural intervention in cases where gastroparesis is characterized as moderate or severe pre- or post-transplant. In contrast to achalasia and GERD, the management of DGE is largely endoscopic as gastric POEM (or G-POEM) is performed in the majority of cases, with encouraging results (complete emptying in up to 35% of patients) (65,66). Fundoplication may be performed as a concurrent or staged procedure if a hiatal hernia is also present (Figure 2C). In those with declining allograft function and mild DGE plus pathologic reflux, a fundoplication alone may improve gastric emptying by increasing intragastric pressure from decreased fundic compliance in the wrap. Mild DGE alone may respond to promotility agents, with botox injection as an alternative. G-POEM is often reserved until 1 year post transplant in these patients, to eliminate those who may improve prior to this time interval.

Special populations

The evidence referenced above largely includes lung transplant candidates and recipients as a whole, with end-stage lung disease secondary to restrictive disease, obstructive disease, pulmonary vascular disease, and cystic fibrosis (in order of decreasing indication for transplant) (2). Although a decreasing proportion of patients receive transplant for cystic fibrosis, and even fewer for connective tissue disease, they can be disproportionately affected by upper GI disorders, and the management of these patients is worth special consideration.

GERD and cystic fibrosis have historically been closely related. In one small case series, 91% of transplant candidates with cystic fibrosis had pathologic reflux on pH monitoring, with an average DeMeester score of 36.6±22.3 (normal <14.7) and symptom score of 5.8±6.5 (≥4 indicates symptomatic reflux) (67). Outcomes after fundoplication in cystic fibrosis patients appear to be similar to recipients with other causes of end stage lung disease, with statistically significant improvements in DeMeester scores and patient-reported quality of life metrics (68).

Although connective tissue diseases represent a rare indication for lung transplant, they are highly associated with dysmotility and reflux pathology. Existing studies of lung transplant patients with connective tissue disorders report abnormal distal esophageal acid exposure in 78–83% and proximal reflux in 30% (69,70). Esophageal dysmotility is also extremely common in systemic sclerosis, with aperistalsis reported in as many as 60–78% of patients (70,71). The prolonged acid exposure in these patients likely contributes to further dysmotility and precipitates a morbid cascade leading to significant aspiration events. Conventional anti-reflux surgery may be less suitable in this group due to concurrent esophageal dysmotility and/or gastroparesis, with modified fundoplication techniques and concurrent myotomy necessary in many cases. Despite this potential additional morbidity, outcomes after upper GI intervention are encouraging in connective tissue disease patients, possibly reflective of increased surveillance and prompt intervention (70,72,73).

Patients with medically refractory allograft dysfunction and persistent acceptable functional status may qualify for lung retransplantation. In this unique population, GERD is appears to be ubiquitous (100% of recipients in two studies) (10,36) and therefore aggressive surveillance and prompt management are paramount in order to protect the retransplanted graft.

Finally, patients with prior esophagectomy are usually not considered for lung transplant due to a non-modifiable risk of GERD and aspiration that may affect the integrity of the transplanted lung.

Proposed treatment algorithm

The pre- and post-transplant management of the above entities is extremely nuanced, and no current randomized trials exist to guide decision making. As a result, a consensus has not been reached on the standardized treatment approach for many of these comorbidities. Here we propose a treatment algorithm with the available evidence for the pre- and post-operative management of the disorders mentioned above, with the understanding that individual decisions should be made on a case-by-case basis (Figure 2A-2C).

Strengths and limitations of this work

This article serves as a central resource to guide the workup and management of upper GI disorders in lung transplant candidates and recipients. As the extent of the pre-transplant workup has historically varied by institution, we first propose a standardized workup for all lung transplant candidates with a focus on the identification of pre-existing upper GI disorders. Next, an exhaustive literature search was performed in order to characterize both the relative incidence and contemporary risk factors for the development of these disorders. This culminated in a detailed and comprehensive algorithm for the management of upper GI disorders in this group, with a particular focus on timing relative to transplant. While the management of these patients remains extremely nuanced, we hope the proposed algorithm provides a framework for clinicians to guide decision-making supported by the available evidence. As mentioned previously, the field lacks randomized clinical trials to validate the evidence-based management of upper GI disorders in this high-risk group; as a result, the current recommendations are based on the best available evidence which predominantly consists of retrospective reports and smaller case series.

Conclusions

Despite continued advances in the medical and surgical care of the lung transplant patient, survival remains significantly lower than for other solid organ transplantations. The primary factor limiting survival beyond the first year of lung transplantation is obliterative bronchiolitis. Numerous risk factors for BOS have been reported, with existing or acquired upper GI disorders and the associated aspiration events at the top of the list. There is substantial overlap in the pathogenesis and clinical manifestations between reflux disease, esophageal dysmotility, and gastric dysmotility, and likely a synergistic contribution to the development of BOS. After transplant, these entities often exist in larger proportions, and although a causative relationship between these and obliterative bronchiolitis has not been found, the existing literature increasingly supports the aggressive management of these GI disorders in hopes of mitigating their deleterious effects on allograft function. While the field is in dire need of randomized trials to guide decision making, we have proposed a treatment algorithm integrating the available evidence for the management of upper GI disorders in the lung transplant population, in hopes of improving the long-term outcomes that have thus far remained unchanged.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Haytham Elgharably) for the series “Lung Transplantation: New Frontiers” published in Current Challenges in Thoracic Surgery. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://ccts.amegroups.com/article/view/10.21037/ccts-25-12/rc

Peer Review File: Available at https://ccts.amegroups.com/article/view/10.21037/ccts-25-12/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://ccts.amegroups.com/article/view/10.21037/ccts-25-12/coif). The series “Lung Transplantation: New Frontiers” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Valapour M, Lehr CJ, Schladt DP, et al. OPTN/SRTR 2023 Annual Data Report: Lung. Am J Transplant 2025;25:S422-89. [Crossref] [PubMed]
2. Valapour M, Lehr CJ, Schladt DP, et al. OPTN/SRTR 2022 Annual Data Report: Lung. Am J Transplant 2024;24:S394-456. [Crossref] [PubMed]
3. Adegunsoye A, Strek ME, Garrity E, et al. Comprehensive Care of the Lung Transplant Patient. Chest 2017;152:150-64. [Crossref] [PubMed]
4. Hathorn KE, Chan WW, Lo WK. Role of gastroesophageal reflux disease in lung transplantation. World J Transplant 2017;7:103-16. [Crossref] [PubMed]
5. Wood RK. Esophageal Dysmotility, Gastro-esophageal Reflux Disease, and Lung Transplantation: What Is the Evidence? Curr Gastroenterol Rep 2015;17:48. [Crossref] [PubMed]
6. Meyer KC, Raghu G, Verleden GM, et al. An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome. Eur Respir J 2014;44:1479-503. [Crossref] [PubMed]
7. Kilic A, Shah AS, Merlo CA, et al. Early outcomes of antireflux surgery for United States lung transplant recipients. Surg Endosc 2013;27:1754-60. [Crossref] [PubMed]
8. D'Ovidio F, Singer LG, Hadjiliadis D, et al. Prevalence of gastroesophageal reflux in end-stage lung disease candidates for lung transplant. Ann Thorac Surg 2005;80:1254-60. [Crossref] [PubMed]
9. Leard LE, Holm AM, Valapour M, et al. Consensus document for the selection of lung transplant candidates: An update from the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2021;40:1349-79. [Crossref] [PubMed]
10. Davis CS, Shankaran V, Kovacs EJ, et al. Gastroesophageal reflux disease after lung transplantation: pathophysiology and implications for treatment. Surgery 2010;148:737-44; discussion 744-5. [Crossref] [PubMed]
11. Young LR, Hadjiliadis D, Davis RD, et al. Lung transplantation exacerbates gastroesophageal reflux disease. Chest 2003;124:1689-93. [Crossref] [PubMed]
12. Posner S, Zheng J, Wood RK, et al. Gastroesophageal reflux symptoms are not sufficient to guide esophageal function testing in lung transplant candidates. Dis Esophagus 2018; [Crossref] [PubMed]
13. Burlen J, Chennubhotla S, Ahmed S, et al. Investigating Defects of Esophageal Motility in Lung Transplant Recipients. Gastroenterology Res 2022;15:120-6. [Crossref] [PubMed]
14. Hirji SA, Gulack BC, Englum BR, et al. Lung transplantation delays gastric motility in patients without prior gastrointestinal surgery-A single-center experience of 412 consecutive patients. Clin Transplant 2017; [Crossref] [PubMed]
15. Yeager B, Minor E, Radlinski M, et al. S1126 Rate of Upper Gastrointestinal Motility Disorders Post Lung Transplantation. Am J Gastroenterol 2022;117:e820. [Crossref]
16. Sweet MP, Herbella FA, Leard L, et al. The prevalence of distal and proximal gastroesophageal reflux in patients awaiting lung transplantation. Ann Surg 2006;244:491-7. [PubMed]
17. Gyawali CP, Yadlapati R, Fass R, et al. Updates to the modern diagnosis of GERD: Lyon consensus 2.0. Gut 2024;73:361-71. [Crossref] [PubMed]
18. Raghu G, Freudenberger TD, Yang S, et al. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J 2006;27:136-42. [Crossref] [PubMed]
19. Sweet MP, Patti MG, Hoopes C, et al. Gastro-oesophageal reflux and aspiration in patients with advanced lung disease. Thorax 2009;64:167-73. [Crossref] [PubMed]
20. Allaix ME, Fisichella PM, Noth I, et al. The pulmonary side of reflux disease: from heartburn to lung fibrosis. J Gastrointest Surg 2013;17:1526-35. [Crossref] [PubMed]
21. Dameworth JL, Colburn L, Corrigan D, et al. Colorectal Cancer Prevention in Lung Transplant Recipients: The Need for an Enhanced Surveillance Protocol. J Am Coll Surg 2021;232:717-25. [Crossref] [PubMed]
22. US Preventive Services Task Force. Screening for Colorectal Cancer: US Preventive Services Task Force Recommendation Statement. JAMA 2021;325:1965-77. [Crossref] [PubMed]
23. Seccombe J, Mirza F, Hachem R, et al. Esophageal motor disease and reflux patterns in patients with advanced pulmonary disease undergoing lung transplant evaluation. Neurogastroenterol Motil 2013;25:657-63. [Crossref] [PubMed]
24. Raviv Y, D'Ovidio F, Pierre A, et al. Prevalence of gastroparesis before and after lung transplantation and its association with lung allograft outcomes. Clin Transplant 2012;26:133-42. [Crossref] [PubMed]
25. Anderson MR, Easthausen I, Gallagher G, et al. Skeletal muscle adiposity and outcomes in candidates for lung transplantation: a lung transplant body composition cohort study. Thorax 2020;75:801-4. [Crossref] [PubMed]
26. Young JS, Coppolino A. Esophageal disease in lung transplant patients. Ann Transl Med 2021;9:900. [Crossref] [PubMed]
27. Savarino E, Carbone R, Marabotto E, et al. Gastro-oesophageal reflux and gastric aspiration in idiopathic pulmonary fibrosis patients. Eur Respir J 2013;42:1322-31. [Crossref] [PubMed]
28. Oelberg DG, Downey SA, Flynn MM. Bile salt-induced intracellular Ca++ accumulation in type II pneumocytes. Lung 1990;168:297-308. [Crossref] [PubMed]
29. Blondeau K, Mertens V, Vanaudenaerde BA, et al. Gastro-oesophageal reflux and gastric aspiration in lung transplant patients with or without chronic rejection. Eur Respir J 2008;31:707-13. [Crossref] [PubMed]
30. Stovold R, Forrest IA, Corris PA, et al. Pepsin, a biomarker of gastric aspiration in lung allografts: a putative association with rejection. Am J Respir Crit Care Med 2007;175:1298-303. [Crossref] [PubMed]
31. Ward C, Forrest IA, Brownlee IA, et al. Pepsin like activity in bronchoalveolar lavage fluid is suggestive of gastric aspiration in lung allografts. Thorax 2005;60:872-4. [Crossref] [PubMed]
32. Sweet MP, Patti MG, Leard LE, et al. Gastroesophageal reflux in patients with idiopathic pulmonary fibrosis referred for lung transplantation. J Thorac Cardiovasc Surg 2007;133:1078-84. [Crossref] [PubMed]
33. Gasper WJ, Sweet MP, Hoopes C, et al. Antireflux surgery for patients with end-stage lung disease before and after lung transplantation. Surg Endosc 2008;22:495-500. [Crossref] [PubMed]
34. Linden PA, Gilbert RJ, Yeap BY, et al. Laparoscopic fundoplication in patients with end-stage lung disease awaiting transplantation. J Thorac Cardiovasc Surg 2006;131:438-46. [Crossref] [PubMed]
35. Hoppo T, Jarido V, Pennathur A, et al. Antireflux surgery preserves lung function in patients with gastroesophageal reflux disease and end-stage lung disease before and after lung transplantation. Arch Surg 2011;146:1041-7. [Crossref] [PubMed]
36. Fisichella PM, Davis CS, Shankaran V, et al. The prevalence and extent of gastroesophageal reflux disease correlates to the type of lung transplantation. Surg Laparosc Endosc Percutan Tech 2012;22:46-51. [Crossref] [PubMed]
37. Lo WK, Goldberg HJ, Wee J, et al. Both Pre-Transplant and Early Post-Transplant Antireflux Surgery Prevent Development of Early Allograft Injury After Lung Transplantation. J Gastrointest Surg 2016;20:111-8; discussion 118. [Crossref] [PubMed]
38. Cantu E 3rd, Appel JZ 3rd, Hartwig MG, et al. J. Maxwell Chamberlain Memorial Paper. Early fundoplication prevents chronic allograft dysfunction in patients with gastroesophageal reflux disease. Ann Thorac Surg 2004;78:1142-51; discussion 1142-51. [Crossref] [PubMed]
39. D'Ovidio F, Mura M, Ridsdale R, et al. The effect of reflux and bile acid aspiration on the lung allograft and its surfactant and innate immunity molecules SP-A and SP-D. Am J Transplant 2006;6:1930-8. [Crossref] [PubMed]
40. Davidson JR, Franklin D, Kumar S, et al. Fundoplication to preserve allograft function after lung transplant: Systematic review and meta-analysis. J Thorac Cardiovasc Surg 2020;160:858-66. [Crossref] [PubMed]
41. Biswas Roy S, Elnahas S, Serrone R, et al. Early fundoplication is associated with slower decline in lung function after lung transplantation in patients with gastroesophageal reflux disease. J Thorac Cardiovasc Surg 2018;155:2762-2771.e1. [Crossref] [PubMed]
42. Murthy SC, Nowicki ER, Mason DP, et al. Pretransplant gastroesophageal reflux compromises early outcomes after lung transplantation. J Thorac Cardiovasc Surg 2011;142:47-52.e3. [Crossref] [PubMed]
43. Leiva-Juarez MM, Benvenuto L, Costa J, et al. Identification of Lung Transplant Recipients With a Survival Benefit After Fundoplication. Ann Thorac Surg 2022;113:1801-10. [Crossref] [PubMed]
44. Green CL, Gulack BC, Keshavjee S, et al. Reflux Surgery in Lung Transplantation: A Multicenter Retrospective Study. Ann Thorac Surg 2023;115:1024-32. [Crossref] [PubMed]
45. Burton PR, Button B, Brown W, et al. Medium-term outcome of fundoplication after lung transplantation. Dis Esophagus 2009;22:642-8. [Crossref] [PubMed]
46. Jain D, Singhal S. Transoral Incisionless Fundoplication for Refractory Gastroesophageal Reflux Disease: Where Do We Stand? Clin Endosc 2016;49:147-56. [Crossref] [PubMed]
47. Pasam RT, Osman KT, Mohan BP, et al. Endoscopic versus surgical therapies for GERD: a systematic review and network meta-analysis. iGIE 2023;2:510-521.e12.
48. Canto MI, Diehl DL, Parker B, et al. Outcomes of transoral incisionless fundoplication (TIF 2.0): a prospective multicenter cohort study in academic and community gastroenterology and surgery practices (with video). Gastrointest Endosc 2025;101:90-102.e1. [Crossref] [PubMed]
49. Morgenthal CB, Lin E, Shane MD, et al. Who will fail laparoscopic Nissen fundoplication? Preoperative prediction of long-term outcomes. Surg Endosc 2007;21:1978-84. [Crossref] [PubMed]
50. Basseri B, Conklin JL, Pimentel M, et al. Esophageal motor dysfunction and gastroesophageal reflux are prevalent in lung transplant candidates. Ann Thorac Surg 2010;90:1630-6. [Crossref] [PubMed]
51. Ciriza de Los Ríos C, Canga Rodríguez-Valcárcel F, de Pablo Gafas A, et al. Esophageal motor disorders are frequent during pre and post lung transplantation. Can they influence lung rejection? Rev Esp Enferm Dig 2018;110:344-51. [Crossref] [PubMed]
52. Masuda T, Mittal SK, Csucska M, et al. Esophageal aperistalsis and lung transplant: Recovery of peristalsis after transplant is associated with improved long-term outcomes. J Thorac Cardiovasc Surg 2020;160:1613-26. [Crossref] [PubMed]
53. Tangaroonsanti A, Lee AS, Crowell MD, et al. Impaired Esophageal Motility and Clearance Post-Lung Transplant: Risk For Chronic Allograft Failure. Clin Transl Gastroenterol 2017;8:e102. [Crossref] [PubMed]
54. Ahmad U. Commentary: Esophageal aperistalsis should not preclude lung transplant candidacy in well-selected patients. J Thorac Cardiovasc Surg 2020;160:1629-30. [Crossref] [PubMed]
55. Wilkinson JM, Halland M. Esophageal Motility Disorders. Am Fam Physician 2020;102:291-6. [PubMed]
56. Cangemi DJ, Flanagan R, Bailey A, et al. Jackhammer Esophagus After Lung Transplantation: Results of a Retrospective Multicenter Study. J Clin Gastroenterol 2020;54:322-6. [Crossref] [PubMed]
57. Miller MS, Johnson SW, Opotowsky AR, et al. Iatrogenic esophageal dysmotility as a barrier to transplantation in pulmonary arterial hypertension. JHLT Open 2024;5:100098. [Crossref] [PubMed]
58. Ramendra R, Fernández-Castillo JC, Huszti E, et al. Oesophageal stasis is a risk factor for chronic lung allograft dysfunction and allograft failure in lung transplant recipients. ERJ Open Res 2023;9:00222-2023. [Crossref] [PubMed]
59. Ďuriček M, Demeter M, Bánovčin P. POEM in the esophagus - How to deal with the post-POEM reflux. Best Pract Res Clin Gastroenterol 2024;71:101917. [Crossref] [PubMed]
60. Riera J, Caralt B, López I, et al. Ventilator-associated respiratory infection following lung transplantation. Eur Respir J 2015;45:726-37. [Crossref] [PubMed]
61. Blackett JW, Benvenuto L, Leiva-Juarez MM, et al. Risk Factors and Outcomes for Gastroparesis After Lung Transplantation. Dig Dis Sci 2022;67:2385-94. [Crossref] [PubMed]
62. Robertson AG, Ward C, Pearson JP, et al. Lung transplantation, gastroesophageal reflux, and fundoplication. Ann Thorac Surg 2010;89:653-60. [Crossref] [PubMed]
63. Shah S, Derryberry S, Teman N, et al. What Happens in (the) Vagus, Stays in (the) Vagus. Heart Surg Forum 2020;23:E335-42. [Crossref] [PubMed]
64. Smit J, Glaudemans AWJM, Van Der Bij W, et al. Gastroparesis after Lung Transplantation: Prevalence, Reversibility and Relation with Outcome. The Journal of Heart and Lung Transplantation 2013;32:S264. [Crossref]
65. Ichkhanian Y, Hwang JH, Ofosu A, et al. Role of gastric per-oral endoscopic myotomy (G-POEM) in post-lung transplant patients: a multicenter experience. Endosc Int Open 2022;10:E832-9. [Crossref] [PubMed]
66. Rappaport JMP, Raja S, Gabbard S, et al. Endoscopic pyloromyotomy is feasible and effective in improving post-lung transplant gastroparesis. J Thorac Cardiovasc Surg 2022;164:711-719.e4. [Crossref] [PubMed]
67. Button BM, Roberts S, Kotsimbos TC, et al. Gastroesophageal reflux (symptomatic and silent): a potentially significant problem in patients with cystic fibrosis before and after lung transplantation. J Heart Lung Transplant 2005;24:1522-9. [Crossref] [PubMed]
68. Hartwig MG, Anderson DJ, Onaitis MW, et al. Fundoplication after lung transplantation prevents the allograft dysfunction associated with reflux. Ann Thorac Surg 2011;92:462-8; discussion; 468-9.
69. Bassotti G, Battaglia E, Debernardi V, et al. Esophageal dysfunction in scleroderma: relationship with disease subsets. Arthritis Rheum 1997;40:2252-9. [Crossref] [PubMed]
70. Gasper WJ, Sweet MP, Golden JA, et al. Lung transplantation in patients with connective tissue disorders and esophageal dysmotility. Dis Esophagus 2008;21:650-5. [Crossref] [PubMed]
71. Marie I, Dominique S, Levesque H, et al. Esophageal involvement and pulmonary manifestations in systemic sclerosis. Arthritis Rheum 2001;45:346-54. [Crossref] [PubMed]
72. Crespo MM, Claridge T, Domsic RT, et al. ISHLT consensus document on lung transplantation in patients with connective tissue disease: Part III: Pharmacology, medical and surgical management of post-transplant extrapulmonary conditions statements. J Heart Lung Transplant 2021;40:1279-300. [Crossref] [PubMed]
73. Miele CH, Schwab K, Saggar R, et al. Lung Transplant Outcomes in Systemic Sclerosis with Significant Esophageal Dysfunction. A Comprehensive Single-Center Experience. Ann Am Thorac Soc 2016;13:793-802. [Crossref] [PubMed]