Abstract
Introduction:
Gastroesophageal reflux and aspiration are risk factors for chronic lung allograft dysfunction in lung transplant recipients. Patients with systemic sclerosis are at an increased risk of aspiration due to esophageal dysmotility and an ineffective lower esophageal sphincter. The aim of this study is to understand the effect of fundoplication on outcomes in systemic sclerosis recipients.
Methods:
Between 2001 and 2019, 168 systemic sclerosis patients were referred for lung transplantation—51 (30.3%) were listed and 36 (21.4%) were transplanted. Recipients were stratified whether they underwent a fundoplication (n = 10, 27.8%) or not (n = 26, 72.2%). Freedom from chronic lung allograft dysfunction and survival were analyzed using log-rank test. Multivariable analysis for known risk factors was performed using a Cox-proportional hazards model.
Results:
Median time to fundoplication after transplantation was 16.4 months (interquartile range: 9.6–25.1) and all were laparoscopic (Dor 50%, Nissen 40%, Toupet 10%). There were no differences in acute rejection ⩾ A1 (26.9% vs 30%), or primary graft dysfunction grades 2–3 at 72 h (42.3% vs 40%) between groups. Recipients with fundoplication had an increased freedom from chronic lung allograft dysfunction (p = 0.035) and overall survival (p = 0.01). Fundoplication was associated with a reduced risk of mortality adjusting for other comorbidities (hazard ratio = 0.13; 95% confidence interval = 0.02–0.65; p = 0.014). Double and single lung transplant did not have different post-transplant survival.
Conclusion:
Fundoplication in systemic sclerosis lung transplant recipients is associated with greater freedom from chronic lung allograft dysfunction and overall survival. Screening for reflux and aspiration followed by early fundoplication may delay graft deterioration in this population.
Keywords: Lung transplantation, scleroderma, fundoplication, mixed connective tissue disorders
Introduction
Systemic sclerosis (SSc) is a connective tissue autoimmune disorder with a heterogeneous clinical presentation, mainly characterized by progressive fibrosis of the skin and internal organs.1,2 Among the earliest symptoms are signs of vasculopathy, causing an insufficient blood supply to organs. The gastrointestinal tract is affected in over 80% of patients, as collagen accumulation in the myenteric plexus leads to dysmotility throughout the gastrointestinal system.3,4 These events manifest clinically most frequently as esophageal aperistalsis, a hypotensive and incompetent lower esophageal sphincter, and esophageal dilation. This results in gastroesophageal reflux (GER), which is often promoted and potentiated by concomitant delayed gastric emptying and small bowel dysmotility in more advanced cases.
End-stage lung disease is recognized as the main cause of death in SSc, due to interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH). 3 Immunosuppressive and/or antifibrotic therapy remains the mainstay of ILD treatment in this population; however, many eventually will require lung transplantation. Recent studies have shown that transplantation is safe in this population and outcomes are comparable to other interstitial disorders.5,6
Despite the potential benefit of lung transplantation in SSc patients presenting with ILD, the GER and potential retrograde aspiration may lead to the development of chronic lung allograft dysfunction (CLAD). 7 For this reason, many centers have considered foregut involvement in SSc an absolute or relative contraindication to lung transplantation.
Early bile acid aspiration has been shown to predict outcomes after lung transplant, and is associated with an increased rate of airway infections, earlier CLAD development, and reduced overall survival.8,9 Anti-reflux procedures remain the most effective intervention to decrease GER, resulting in an improvement in gastric emptying and the prevention of aspiration of gastroenteric contents into the airways. 10 These have also been shown to be effective in the reduction of GER symptoms among patients with SSc-related esophageal dysmotility.11,12 While the data within this population are granular, a fundoplication is associated with 93% symptom control particularly among those with complete esophageal aperistalsis.
Studies have shown an increased overall and CLAD-free survival among patients that underwent a fundoplication after lung transplantation. 13 In addition, pulmonary function and the rate of forced expiratory volume at 1 s (FEV1) decline are improved among patients following fundoplication. Screening patients for GER and aspiration is institution dependent; however, data suggest that an early anti-reflux surgical approach is associated with an increased overall and CLAD-free survival. 14
All these data are, however, based on transplants with heterogeneous recipient diagnoses, which may have fundamental differences in GER pathophysiology in comparison to SSc-related ILD. Our study sought to elucidate the effects of fundoplication after transplant on the rate of CLAD and overall survival in patients with SSc.
Methods
Patients and selection
The study was approved the Columbia University Institutional Review Board (IRB: AAT0933). A single center retrospective review of electronic medical records was performed for lung transplants done between 2001 and 2019. A total of 552 patients with ILD-related end-stage lung disease who underwent single or double lung transplantation were screened, of which 36 patients (6.5%) with SSc were identified and analyzed. Patients were further stratified by those who underwent a fundoplication after transplant (n = 10, 27.8%) versus those who did not (n = 26, 72.2%).
General approach to selection and perioperative testing
Patients referred for lung transplant are evaluated by a multidisciplinary panel of thoracic surgeons, transplant pulmonologists, social workers, psychiatrists, financial specialists, and cardiologists individually. Each case is presented and the adequacy of the candidate is determined by all the involved specialists. As part of the regular workup for transplant, patients undergo barium swallow, esophageal manometry, upper gastrointestinal studies, pH monitoring, autoantibody testing, and gastric emptying nuclear scans, when time and the patient’s condition allowed it. None of the tests above were deemed an absolute contraindication to transplantation and the decision for listing was made based on the overall clinical condition and comorbidities of the candidate.
Per institution protocol, recipients were screened after transplant for GER through esophageal manometry and ambulatory esophageal pH testing through a Bravo™ probe (Medtronic, Fidley, MN) as clinical condition and follow-up status allowed. Recipients with evidence of GER and adequate functional status (defined in an individual basis) were referred for laparoscopic fundoplication. The type of fundoplication was decided based on the manometric results and gastric emptying study and included laparoscopic Nissen, Toupet, or Dor procedures. The choice of a partial (Dor or Toupet) versus a full wrap (Nissen) was decided based on the presence of esophageal dysmotility.
Outcomes of interest
The primary outcomes of interest were post-transplant freedom from CLAD and overall survival. CLAD was defined according to the International Society of Heart and Lung Transplantation guidelines (ISHLT).15,16 A distinction between bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS) was not made due to a non-uniform testing of total lung capacity in follow-up pulmonary testing after transplant. As secondary outcomes, the rates of primary graft dysfunction (PGD) at 72 h post-transplant and rates of acute cellular rejection (ACR) ⩾ A1 were recorded. These were also defined by ISHLT guidelines. 17 In addition, overall and CLAD-free post-transplant survival between SSc and non-SSc-ILD was recorded as a secondary outcome of interest.
Statistical analysis
Baseline characteristics were compared among patients who underwent a fundoplication versus those who did not using central tendency methods. Differences in baseline characteristics were compared between groups using a Mann–Whitney test or a chi-square test for continuous and categorical variables, respectively. Time-to-event rates were calculated using Kaplan–Meier curves and tested using a log-rank test. For the univariable and multivariable analysis of predictors for overall survival, a Cox proportional hazards model was used. All models were tested to meet the proportionality assumption based on Schoenfeld residuals. Variables for the model were chosen based on historic predictors of survival in the literature. A value of p < 0.05 was determined statistically significant. All statistical analyses were performed using Stata Version 14.0 (StataCorp, College Station, TX, USA).
Results
Patient selection and baseline characteristics
A total of 168 patients with a diagnosis of SSc were referred and evaluated by the lung transplant clinic. After workup and evaluation by the transplant selection committee, 51 (30.3%) were listed and 36 patients (21.4%) were transplanted (Figure 1). The most common reasons for failure to meet transplant criteria were poor clinical condition or multiple comorbidities (25.6%), failure to follow-up (22.2%), and intestinal dysmotility (12%). Of those transplanted, 10 (27.8%) underwent a posttransplant fundoplication and 26 (72.2%) did not. Risk factors and baseline characteristics were similar among those who underwent a fundoplication versus those who did not (Table 1).
Figure 1.
Study design.
SSc: systemic sclerosis; ESLD: end-stage lung disease; PRA: panel of reactive antibodies, GI: gastrointestinal; BMI: body mass index.
Table 1.
Recipient and donor demographics.
| No fundoplication (n = 26) | Fundoplication (n = 10) | p-value | |||
|---|---|---|---|---|---|
| n | % | n | % | ||
| Recipient age (years) | 56.5 | [52–61] | 52 | [50–62] | 0.559 |
| LAS | 51.4 | [44–64.5] | 51.1 | [49.2–63.4] | 0.621 |
| Recipient female gender | 15 | 57.7 | 6 | 60.0 | 0.9 |
| Gender mismatch | 9 | 34.6 | 2 | 20.0 | 0.394 |
| CMV mismatch | 5 | 19.2 | 1 | 10.0 | 0.506 |
| Explant pathology | |||||
| NSIP | 18 | 69.2 | 5 | 50.0 | 0.219 |
| UIP | 8 | 30.8 | 5 | 50.0 | |
| Bilateral transplant | 12 | 46.2 | 5 | 50.0 | 0.836 |
| Mixed CTD | 4 | 15.4 | 3 | 30.0 | 0.321 |
| Raynaud’s syndrome | 18 | 69.2 | 6 | 60.0 | 0.599 |
| Other CTD | |||||
| Dermatomyositis | 1 | 3.8 | 2 | 20.0 | 0.116 |
| Polymyositis | 0 | 0.0 | 2 | 20.0 | 0.019 |
| RA | 2 | 7.7 | 1 | 10.0 | 0.822 |
| SLE | 1 | 3.8 | 1 | 10.0 | 0.47 |
| Sjögren’s | 1 | 3.8 | 0 | 0.0 | 0.529 |
| PAH | 15 | 57.7 | 8 | 80.0 | 0.212 |
| Hiatal hernia | 13 | 50.0 | 6 | 60.0 | 0.590 |
| Heartburn | 18 | 69.2 | 9 | 90.0 | 0.197 |
| Smoker/ex-smoker | 15 | 57.7 | 4 | 40.0 | 0.341 |
| Antibodies | |||||
| ANA | 19 | 73.1 | 7 | 70.0 | 0.854 |
| RF | 8 | 30.8 | 5 | 50.0 | 0.282 |
| SSA | 3 | 11.5 | 3 | 30.0 | 0.183 |
| SSB | 2 | 7.7 | 1 | 10.0 | 0.822 |
| U1RNP | 2 | 7.7 | 1 | 10.0 | 0.822 |
| SCL-70 | 5 | 19.2 | 4 | 40.0 | 0.197 |
| Centromere | 1 | 3.8 | 0 | 0.0 | 0.529 |
| Jo-1 | 1 | 3.8 | 1 | 10.0 | 0.47 |
| Donor age (years) | 38.5 | [20–49] | 24 | [21–52] | 0.437 |
| Donor female gender | 18 | 69.2 | 8 | 80.0 | 0.518 |
| Donor smoker | 1 | 3.8 | 0 | 0.0 | 0.529 |
LAS: lung allocation score; CMV: cytomegalovirus; NSIP: non-specific interstitial pneumonia; UIP: usual interstitial pneumonia; CTD: connective tissue disorder; RA: rheumatoid arthritis; SLE: systemic lupus erythematosus; PAH: pulmonary arterial hypertension; ANA: anti-nuclear antibodies; RF: rheumatoid factor.
Continuous variables are presented as median [interquartile range].
Post-transplant outcomes and operative characteristics
The rates of post-transplant complications, ACR ⩾ A1 (26.9% vs 30%, p = 0.854), and PGD 2–3 at 72 h post-transplant (42.3% vs 40%, p = 0.9) were comparable between groups (Table 2). The median time to fundoplication after transplantation was 16.4 months (interquartile range (IQR): 9.6–25.1 months, actual range: 4.9–65.7 months). All fundoplications were done by laparoscopy (50% Dor, 40% Nissen, 10% Toupet). Of the four patients who underwent a Nissen fundoplication, three had normal esophageal motility by manometry and one had scleroderma-type esophagus with severe reflux.
Table 2.
Post-transplant outcomes.
| No fundoplication (n = 26) | Fundoplication (n = 10) | p-value | |||
|---|---|---|---|---|---|
| n | % | n | % | ||
| CLAD | 6 | 23.1 | 0 | 0.0 | 0.035 |
| Mortality | 12 | 46.2 | 2 | 20.0 | 0.01 |
| Episode of acute rejection ⩾ A1 | 7 | 26.9 | 3 | 30.0 | 0.854 |
| Post-transplant complications | |||||
| Arrhythmia | 6 | 23.1 | 3 | 30.0 | 0.667 |
| AKI | 4 | 15.4 | 2 | 20.0 | 0.606 |
| Delirium | 3 | 11.5 | 1 | 10.0 | 1.000 |
| Pneumonia | 2 | 7.7 | 2 | 20.0 | 0.221 |
| Airway complication | 3 | 11.5 | 1 | 10.0 | 1.000 |
| PGD grades ⩾ 2 at 72 h post-transplant | 11 | 42.3 | 4 | 40.0 | 0.900 |
CLAD: chronic lung allograft dysfunction; AKI: acute kidney injury, PGD: primary graft dysfunction.
The p-values for CLAD and mortality are based on a log-rank test.
Rates of gastroesophageal reflux disease and gastroparesis
Preoperative and postoperative esophageal studies were performed based on symptomatology and patient’s overall clinical status. The rates of pretransplant pH confirmed gastroesophageal reflux disease (GERD; 46.2% vs 40%, p = 0.199) and scleroderma-type esophagus (61.5% vs 30%, p = 0.154) were similar among patients without or with a fundoplication, respectively. All patients that underwent a fundoplication had proven GER by pH studies and 50% had scleroderma-type esophageal manometric findings.
Primary outcomes
The median overall and CLAD-free survival was 3 [IQR: 1.47–6.6] and 2.9 years [IQR: 1.1–6.2], respectively. The rate of CLAD was significantly increased in recipients who did not receive a fundoplication (0% vs 23.1%, p = 0.035; Figure 2(a)). Similarly, survival was significantly decreased in recipients without a fundoplication (20% vs 46.2%, p = 0.01; Figure 2(b)). When comparing non-SSc ILD to SSc, the former had an increased survival with fundoplication (p = 0.002) but no significant differences in freedom from CLAD among groups (p = 0.774; Figure 3(a) and(b)).
Figure 2.
Freedom from chronic lung allograft dysfunction (a) and survival (b) by fundoplication status.
CLAD: chronic lung allograft dysfunction.
Figure 3.
Freedom from chronic lung allograft dysfunction (a) and survival (b) by fundoplication status and diagnosis.
CLAD: chronic lung allograft dysfunction; SSc: systemic sclerosis; ILD: interstitial lung disease.
ILD refers to patients excluding SSc.
Predictors for mortality
To further describe predictors for mortality in this rare population, risk factors from the literature were analyzed. PAH, lung allocation score, cytomegalovirus mismatch, gender mismatch, donor and recipient age, or PGD grades 2–3 at 72 h post-transplant were not significant predictors of overall mortality (Table 3). In an unadjusted model and in an adjusted Cox proportional hazards model, post-transplant fundoplication remained a negative predictor of mortality (unadjusted hazards ratio (HR): 0.17, 95% confidence interval (CI): 0.04–0.77, p = 0.021, adjusted HR: 0.13, 95% CI: 0.02–0.65, p = 0.014). Double and single lung transplant did not have different post-transplant survival.
Table 3.
Multivariable analysis for mortality.
| Univariable | Multivariable | |||||||
|---|---|---|---|---|---|---|---|---|
| HR | 95% CI | p-value | HR | 95% CI | p-value | |||
| Fundoplication | 0.17 | 0.04 | 0.77 | 0.021 | 0.13 | 0.02 | 0.65 | 0.014 |
| Recipient age | 1.01 | 0.96 | 1.06 | 0.766 | 0.99 | 0.93 | 1.07 | 0.883 |
| Double lung transplant | 0.76 | 0.26 | 2.20 | 0.611 | 0.59 | 0.18 | 1.94 | 0.382 |
| PAH | 0.75 | 0.25 | 2.27 | 0.61 | 1.11 | 0.23 | 5.24 | 0.899 |
| LAS | 0.99 | 0.95 | 1.03 | 0.478 | 0.98 | 0.94 | 1.03 | 0.519 |
| CMV mismatch | 0.54 | 0.07 | 4.20 | 0.558 | 0.27 | 0.03 | 2.94 | 0.284 |
| Gender mismatch | 0.74 | 0.20 | 2.72 | 0.655 | 0.48 | 0.12 | 1.97 | 0.31 |
| Donor age | 1.01 | 0.98 | 1.05 | 0.556 | 1.00 | 0.95 | 1.05 | 0.858 |
| PGD grade 2–3 at 72 h | 0.77 | 0.23 | 2.53 | 0.665 | 0.97 | 0.24 | 3.88 | 0.966 |
HR: hazards ratio; CI: confidence interval; PAH: pulmonary arterial hypertension; LAS: lung allocation score; CMV: cytomegalovirus; PGD: primary graft dysfunction.
Discussion
This study is the first to report fundoplication after lung transplant for SSc patients is associated with increased freedom from CLAD and improved survival. Recipients that underwent a fundoplication had lower rates of CLAD and lower mortality despite similar perioperative comorbidities. The effect was present after adjusting for known risk factors of CLAD development or mortality. In addition, neither single lung transplantation nor PAH were significant predictors for CLAD or mortality in our cohort of recipients with SSc.
SSc is a disease associated with progressive pulmonary fibrosis, frequently accompanied by gastroesophageal and intestinal dysmotility. This often results in GER and micro aspiration of gastroenteric fluids along with increased airway inflammation and pulmonary infections. Some lung transplant centers have not transplanted patients with SSc due to the high risk of aspiration and allograft compromise. 18 However, several recent reports have shown that outcomes in this population are similar to those with other forms of ILD.19,20 The largest retrospective study by Bernstein and colleagues analyzed 229 patients with SSc from the UNOS database, and compared them to patients with either ILD or primary PAH. 5 They reported a lower 1-year survival in SSc-associated ILD compared to those with other forms of ILD but a comparable survival to PAH after adjustment of several baseline variables. Another single-center review of 72 patients looked at 5-year survival among patients with SSc and ILD. 21 They failed to detect a difference in overall survival and ACR-free survival. Furthermore, the data on single versus double lung transplantation for this disease are scarce with a predominance of bilateral transplantation, yet the type of transplantation has not been shown to be associated with mortality.5,6,22 This was consistent with our findings in which the type of transplantation was not a significant predictor of mortality in both univariable and multivariable models. Adjusted survival analysis with larger number of patients is needed to confirm these findings; however, these data suggest that allocating a single lung for transplantation is appropriate in SSc.
While lung transplantation has acceptable outcomes in this patient population, gastrointestinal comorbidities specific to SSc pose a challenge for their management. In addition to the intrinsic gastroesophageal and enteric dysmotility seen in SSc, restrictive lung disease can also promote GER by decreasing esophageal length and increasing the thoracoabdominal pressure gradient.23,24
A hallmark of SSc is an aberrant remodeling of interstitial tissues with progressive fibrosis. 25 This is also true for the gastrointestinal system, where autoantibody destruction of the myenteric plexus results in enteric dysmotility. 26 The esophagus is the most affected enteric organ presenting with a classic pattern of absent peristalsis and a hypotensive, ineffective lower esophageal sphincter. Gastrointestinal presentations may also frequently include delayed gastric emptying and in more advanced presentations small bowel dysmotility. On its own, delayed gastric emptying has been shown to be a risk factor for GER. 27 The combination of delayed gastric emptying, atonic lower esophageal sphincter, and non-peristaltic esophagus result in a condition with a common esophago-gastric cavity, which is subject to the thoracoabdominal pressure changes during respiration. This poses a greater risk for nocturnal aspiration events occurring while the patient is supine and the upper esophageal sphincter is relaxed. 28 This is further aggravated by pulmonary allograft denervation and impaired muco-ciliary clearance with loss of cough reflex.29,30 All these factors increase the propensity of aspiration-related complications after transplant.
The main cause of death after the first year in patients undergoing lung transplantation is CLAD. The latter condition is characterized by terminal bronchiolar fibrosis presenting clinically as a progressive decrease in FEV1. While the pathogenesis of this condition is poorly understood, it has a strong association with GER and aspiration. Patients with GER tend to have increased rates of CLAD and a decreased overall survival. 7 The pathophysiology behind this phenomenon may be multifactorial; however, data have shown an association between bile acid aspiration and development of CLAD. Increased levels of bile acids in bronchioalveolar lavage samples after lung transplant correlate with early development of CLAD. 8 Bile acid concentration in the airways, correlate with increased levels of neutrophils and IL-8 as well as decreased concentration of surfactant proteins. 9 The mechanism behind these findings suggest increased inflammation and decreased levels of surfactant. 31 This was recently confirmed in a multicenter study in which higher levels of bile acids at 3 months after transplant were associated with increased levels of IL-1β, IL-12p70, and CCL5. 32 Whether the relationship between aspiration from GER and CLAD is a matter of direct injury or indirect insults that result in further alloimmune injury requires further investigation.
Fundoplication involves mobilization and wrapping of the stomach fundus around the distal esophagus to recreate a functional distal esophageal sphincter. 33 These are generally classified as partial (<360 degrees) or complete (360 degrees). A complete, or Nissen type, fundoplication is the preferred approach for patients with normal esophageal motility, whereas partial wraps are generally used when there is evidence of esophageal dysmotility. The latter can be further classified into anterior (Dor) or posterior (Toupet) fundoplication based on the directionality of the fundal wrap.
Given the relationship of GER and CLAD, several groups have studied the effect of fundoplication on outcomes after transplant. This was first reported by Davis et al. 7 who showed an increase in survival and 1-year FEV1 volumes with fundoplication, particularly among those with an abnormal pH study. 13 Another study by Cantu et al. 14 correlated early fundoplication and increased CLAD-free survival. In this study, early fundoplication (within 3 months post-transplant) was associated with the highest overall and CLAD-free survival. Moreover, fundoplication has been shown to successfully decrease airway bile acid levels and proinflammatory cytokines. 32 Our study is consistent with these reports, showing a significant increased freedom from CLAD and overall survival in the fundoplication arm. The positive effect of fundoplication on survival remained independent after adjusting for other risk factors. All patients in the fundoplication arm were free of CLAD at the time of study, this contrasted to non-SSc ILD, which did not show a CLAD-free survival benefit. These data suggest an important association of fundoplication with long-term allograft function among patients with SSc, and identify a subpopulation within transplanted patients with ILD that may benefit the most from an anti-reflux procedure.
Limitations
There are several limitations to this study, which are intrinsic of its retrospective nature and small sample size. While rates of esophageal testing by manometry and/or pH testing were similar to other studies, these were not done routinely, which does not allow to gain meaningful conclusions on the role of esophageal dysmotility or GER in CLAD-free survival. In addition, pH testing did not include impedance studies, which does not allow differentiation of acid versus non-acid reflux. In an attempt to adjust for selection bias, we have reported adjusted hazards for survival based on common predictors of long-term mortality. However, this does not completely eliminate the possibility of selection of healthier patients toward the fundoplication arm. Small sample size will always be a challenge with rare diseases but data from this report should help further elucidate strategies for outcome improvement in this small, but high-risk population.
Conclusion
Fundoplication after lung transplant is associated with increased survival, related to a decreased incidence of CLAD among patients with SSc-related ILD. Furthermore, single or double lung transplantation is safe in patients with SSc-related ILD. Early screening for GER and fundoplication may delay graft deterioration in this population.
Acknowledgments
Andreacarola Urso is a student in the PhD program of Cardio-Nephro-Thoracic Sciences, Alma Mater Studiorum, University of Bologna, Italy.
Footnotes
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Ethical approval: This study was approved by the institutional review board of Columbia University Medical Center.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Patient consent: Patient consent was waivered by the institutional review board due to the retrospective nature of the study.
ORCID iD: Miguel M Leiva-Juárez 
https://orcid.org/0000-0002-7786-9623
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