Abstract
Background
Concomitant liver and lung transplant (ConLi-LTx) may be indicated for select pediatric patients with cystic fibrosis (CF). This study aims to analyze pre-transplant predictors and post-transplant outcomes of ConLi-LTx and lung transplant (LTx) only in pediatric patients with cystic fibrosis.
Methods
The ISHLT International Thoracic Organ Transplant Registry was queried for patients <18 years old with CF who underwent ConLi-LTx and LTx-only from 1994-June 2018. Data were propensity matched to LTx-only controls and analyzed with Fisher’s exact, Wilcoxon rank sum tests, Kaplan-Meier methods, and Cox proportional hazards where appropriate.
Results
We identified 18 ConLi-LTx who were compared to 72 LTx-only cases. No significant differences were identified in patient demographics, resting oxygen requirement prior to transplant, or six-minute walking distance at time of listing. Interestingly, ConLi-LTx patients demonstrated significantly improved overall (p=0.0220) and BOS-free survival (p=0.0167).
Conclusions
There were no differences in pre-transplant predictors of simultaneous liver and lung transplantation in pediatric patients with cystic fibrosis compared to those who received LTx-only. The noted survival benefits of ConLi-LTx remains uncertain, as patients who underwent simultaneous transplant are likely well-selected as candidates for such an extensive procedure, and we hypothesize that the liver may play a role in immunologic benefit. Further research is warranted regarding pre-transplant characteristics of pediatric cystic fibrosis patients who may be considered for concomitant liver with lung transplant.
Keywords: Concomitant transplant, Lung transplant, Cystic fibrosis, Pediatric
Introduction
Cystic fibrosis (CF) is an autosomal recessive defect of sodium channels, which may progress to obstructive lung disease and exocrine dysfunction of the pancreas, sometimes resulting in biliary cirrhosis.1 If CF patients develop cholestasis and biliary fibrosis, 4–10% will progress to advanced clinical liver failure.1, 2 Although the onset of multilobular cirrhosis in patient with CF occurs quite early, usually before 12 years of age, medical therapies have yet to demonstrate efficacy in preventing the development or progression of CF-related cirrhosis.1, 3 Rather, therapies are typically aimed at symptom control, such as ursodiol for relief of cholestatic symptoms.1 Nearly 60% of cystic fibrosis mortality can be attributed to pulmonary disease, and 3.4% of overall mortality resulting from CF can be attributed to liver disease.1 Given the high mortality associated with end-stage organ disease due to cystic fibrosis alongside the progressive nature of the disease, transplantation often serves as the final destination treatment for patients with CF.
Lung transplantation (LTx) among patients with CF has been well studied, with only 6.3% of transplants occurring in the pediatric population.1 However, timing of transplantation is crucial to success, especially if considering concomitant abdominal organ transplantation. Typically, liver transplant in CF patients occurs between ages 11 and 17, with LTx occurring later at a mean age of 30 years.4 In cases of simultaneous lung/liver transplantation, patients may be sicker at baseline as indicated by higher rates of diabetes and dialysis at time of transplant.4 While multiorgan recipients demonstrate higher mortality in the first year post-transplant, no significant difference has been noted in long-term survival when compared to LTx-only or liver-only patients.2, 4 Interestingly, combined lung/liver recipients exhibit lower rejection and bronchiolitis obliterans syndrome (BOS) rates when compared to LTx-only.5, 6
The current literature exploring combined lung/liver transplantation (ConLi-LTx) offers both single-center experiences and database reviews. However, results vary widely, and studies are often inclusive of adult patients which may affect overall conclusions. Therefore, the purpose of this study is to expand upon the current literature and provide, to the best of our knowledge, the largest analysis of prognostic factors and survival outcomes of combined lung/liver transplantation in the pediatric population with CF through the ISHLT International Thoracic Organ Transplant Registry database.
Materials and methods
IRB statement
This study was deemed exempt from formal review by the Mayo Clinic Institutional Review Board as all data was de-identified prior to receipt and was not classified as involving human subjects.
Study data
We retrospectively analyzed the ISHLT Transplant Registry database as of April 19, 2019 for pediatric (<18 years old) patients with CF who underwent simultaneous lung and liver transplantation between January 1, 1994 and June 30, 2018. In the context of this dataset, a “simultaneous transplant” refers to transplants of multiple organs from the same donor to the same recipient with the exclusion of kidney-pancreas and heart-lung transplants. LTx-only controls were matched (4:1) to ConLi-LTx recipients via propensity score matching using recipient age and year of LTx. Although propensity score matching greatly reduced the size of the control group, this allowed for a similar median age and range of the control group to ConLi-LTx cases for interpretation of results. Propensity scores were constructed using logistic regression and nearest neighbors were matched without replacement. Matching was carried out using the R language and environment for statistical computing (v4.3.2) and the matchit package (v4.5.5) (Figure 1).7, 8
Figure 1.
Consort diagram.
Statistical analysis
Fisher's exact tests were used to compare frequency distributions between groups. Nonparametric Wilcoxon rank sum tests compared continuous measures alongside medians and interquartile ranges. Kaplan-Meier methods were used for time-to-event estimates and corresponding confidence intervals (including overall and graft-failure free survival). Log-rank tests compared survival distributions. Unadjusted Cox proportional hazards models were considered to estimate hazard ratios between groups where model assumptions permitted their use and hazard ratios (HR) are reported with 95% confidence intervals (CI). P values less than 0.05 were deemed statistically significant.
Results
A total of 18 ConLi-LTx matched cases and 72 LTx-only controls were identified from the ISHLT database. Patient characteristics are outlined in Table 1. The median recipient age was 14 years for both ConLi-LTx and LTx-only groups. Recipient BMI was 17.7 kg/m2 in the ConLi-LTx group and 17.5 kg/m2 in LTx-only controls (p=0.8834). Both groups had a similar percentage of females (66.7% female in ConLi-LTx and 61.1% in LTx-only, p=0.7886).
Table 1.
Characteristics of LTx-only Controls and ConLi-LTx
| LTx-only (N=72) | ConLi-LTx (N=18) | Total (N=90) | p Value | |
|---|---|---|---|---|
| RECIPIENT | ||||
| Age, median (IQR) | 14 (13−16) | 14 (12−16) | 14 (13−16) | - |
| BMI (kg/mb), median (IQR) | 17.5 (15.6−19.2) | 17.7 (15.7−20.0) | 17.6 (15.6−19.5) | 0.8834a |
| Female, n (%) | 44 (61.1%) | 12 (66.7%) | 56 (62.2%) | 0.7886b |
| PRE-TRANSPLANT | ||||
| Chronic steroid use, n (%) | 6 (23.1%) | 2 (13.3%) | 8 (19.5%) | 0.8553b |
| History of diabetes, n (%) | 9 (24.3%) | 6 (40%) | 15 (28.8%) | 0.4098b |
| Recent hospitalization within 90 days prior to transplant admission, n (%) | 6 (54.5%) | 6 (85.7%) | 12 (66.7%) | 0.3156b |
| Recent serum creatinine (mg/dL), median (IQR) | 0.5 (0.4−0.6) | 0.5 (0.4−0.6) | 0.5 (0.4−0.6) | 0.9788a |
| Oxygen requirement at rest prior to transplant (L/min), median (IQR) | 3.0 (0.0−6.0) | 2.0 (0.5−3.0) | 2.0 (0.0−4.0) | 0.4078a |
| Six-minute walking distance at time of listing (m), median (IQR) | 891.0 (300−1170) | 1246.0 (909−1671) | 922.0 (700−1370) | 0.1731a |
| Ventilator support at time of transplant, n (%) | 2 (6.3%) | 3 (20.0%) | 5 (10.0%) | 0.3088b |
| Ischemic time (hours), median (IQR) | 5.2 (4.5−6.5) | 5.0 (4.2−6.3) | 5.1 (4.4−6.5) | 0.6944a |
| POST-TRANSPLANT | ||||
| Hospital length of stay (days), median (IQR) | 16.0 (11−27) | 26.5 (18.5−48) | 18.0 (13−33) | 0.0550a |
| Bronchiolitis obliterans syndrome, n (%) | 9 (40.9%) | 3 (23.1%) | 12 (34.3%) | 0.4630b |
| Post-transplant dialysis prior to discharge, n (%) | 0 (0.0%) | 1 (6.7%) | 1 (2.3%) | 0.4175b |
| Post-transplant stroke prior to discharge, n (%) | 1 (3.4%) | 0 (0.0%) | 1 (2.3%) | 0.6972b |
| Acute rejection, n (%) | 1 (7.1%) | 0 (0.0%) | 1 (5.3%) | 0.7162b |
| Chronic rejection, n (%) | 8 (57.1%) | 4 (80.0%) | 12 (63.2%) | 0.7162b |
ConLi-LTx = concomitant liver/lung transplant; LTx = lung transplant; IQR = interquartile range; P values reflect two-group comparisons between ConLi-LTx and LTx-only. Severe renal dysfunction defined as creatinine > 2.5 mg/dL, dialysis, or renal transplant.
Wilcoxon Rank Sum
Fisher Exact
For ConLi-LTx and LTx-only, respectively, there were no significant differences in chronic steroid use (13.3% vs 23.1%, p=0.8553), history of diabetes (40% vs 24.3%, p=0.4098), serum creatinine (0.5 mg/dL, p=0.9788), pre-transplantation hospitalization (85.7% vs 54.5%, p=0.3156) and oxygen requirement at rest (2 vs 3 L/min, p=0.4078) prior to transplantation. Similarly, there was no statistically significant difference in six-minute walking distance at time of transplant listing (1246 m ConLi-LTx vs 891 m LTx-only, p=0.1731) or necessity of mechanical ventilation pre-transplant (20% vs 6.3%, p=0.3088). Length of ischemic time was not significantly different between the two groups, with 5.2 h of ischemic time in LTx-only recipients and 5.0 h of ischemic time in ConLi-LTx (p=0.6944).
Post-transplant, ConLi-LTx cases had a median hospital length of stay of 26.5 days compared to 16 days in LTx-only cases which approached statistical significance (p=0.0550). Both groups exhibited similar rates of stroke (0% vs 3.4%, p=0.6972) and dialysis (6.7% vs 0%, p=0.4175) prior to discharge from the hospital for ConLi-LTx and LTx, respectively. No statistically significant difference was observed in either the rates of acute (0% vs 7.1%, p=0.7162) or chronic (80% vs 57.1%, p=0.7162) rejection, nor development of BOS (23.1% vs 40.9%, p=0.4630) for ConLi-LTx and LTx, respectively.
ConLi-LTx demonstrated improved long-term overall survival compared to LTx-only controls (p=0.0220, HR: 0.35 95%CI: [0.14, 0.89], Figure 2), although graft-failure free survival rates for ConLi-LTx recipients did not reach statistical significance compared to LTx-only patients (p=0.0575, HR: 0.48, 95%CI: [0.23, 1.04], Figure 3). Among the data available for this cohort, 61% of BOS status was missing (69% missing for LTx-only; 28% missing for ConLi-LTx). Despite the limited data and considering that only patients with observed BOS status and time were considered for BOS-free survival, it is interesting to note that ConLi-LTx patients showed significantly favorable outcomes where BOS-free survival was improved compared to LTx-only control (p=0.0167, HR: 0.29 [0.10, 0.84]) (Figure 4).
Figure 2.
Overall survival in pediatric ConLi-LTx recipients with CF compared to LTx-only controls.
Figure 3.
Overall graft-failure free survival in pediatric ConLi-LTx recipients with CF compared to LTx-only controls.
Figure 4.
Overall BOS-free survival in pediatric ConLi-LTx recipients with CF compared to LTx-only controls [61% of patient BOS status missing (69% missing for LTx-only; 28% missing for ConLi-LTx].
Discussion
In this study, we provide a comprehensive analysis of simultaneous liver and lung transplant in pediatric patients with cystic fibrosis based on the ISHLT database. For CF patients with severe liver and lung dysfunction, dual organ transplantation may be a safe and viable treatment option which may confer a long-term survival benefit (although our study is limited by sample size). The existing literature has noted select pre-transplant factors and immediate post-operative measures that may differ between the two groups, although long-term survival outcomes remain unclear among current studies.
Firstly, our study aimed to analyze pre-transplant patient characteristics and post-transplant outcomes associated with simultaneous liver/lung transplant. Our results indicate no significant differences in pre-transplant factors or post-transplant non-survival outcomes, although our propensity-matched cases may not be representative of the greater CF patient population receiving lung transplants. Existing studies including both adult and pediatric populations have identified that ConLi-LTx patients are younger and more often male than LTx-only counterparts.5 In some reports, ConLi-LTx patients require longer ICU and hospital length of stay post-transplant and may require longer periods of post-operative mechanical ventilation.5 Our study demonstrates similar results of longer hospital length of stay for ConLi-LTx patients with p values approaching significance. Additionally, use of extracorporeal circulation prior to transplant has been associated with decreased survival of pediatric patients after lung-only transplant due to critical health status approaching transplant and impaired coagulopathy.9
We next sought to examine graft outcomes post-transplant between ConLi-LTx and LTx-only recipients. Although the results of our analysis do not indicate a significant difference in the rates of BOS after transplant, nearly twice as many LTx-only recipients developed BOS compared to ConLi-LTx. BOS, a manifestation of chronic rejection, is a common complication of lung transplant, affecting nearly 50% of all recipients.6 Interestingly, the liver has been identified to behave as a protective organ against rejection in other combined organ transplants, such as liver/kidney transplant and in combined lung/liver transplants.3, 6, 10, 11 While not statistically significant, it is possible that the lower rates of BOS in ConLi-LTx recipients observed in this study may be, in part, due to an immunological benefit of combined transplant. In addition, we observed that ConLi-LTx recipients had significantly improved BOS-free survival compared to LTx-only counterparts, suggesting that there may be a survival benefit to concomitant transplant alongside lower rates of BOS post-transplant.
Finally, our study analyzed short- and long-term survival outcomes of ConLi-LTx and LTx-only recipients. The existing literature has largely shown no survival benefit of combined ConLi-LTx as compared to LTx-only pediatric recipients with CF. Studies exploring simultaneous ConLi-LTx transplant in pediatric patients by Faro et al and Desai et al demonstrate no statistically significant difference in patient survival when compared to either lung-only or liver-only transplant, although sample sizes were limited at 5 and 8 pediatric patients, respectively.6, 12 In comparisons between the pediatric and adult population with cystic fibrosis, Desai et al show survival benefits in pediatric patients (although not statistically significant).12 Even when analyzing both adults and children together, Arnon et al demonstrate no significant difference in graft or patient survival between liver-only and ConLi-LTx.2 When considering single-organ only transplant in pediatric CF patients, the course of the other non-transplanted organ in single-organ transplant remains unclear. After liver transplant in cystic fibrosis patients, there have been mixed results regarding lung function improvement.3 In some studies, native lung function as measured with FEV1 declined after orthotopic liver transplant (OLT) compared to matched, non-transplanted patients with cystic fibrosis.3, 13 While some patients demonstrated stable PFTs both prior to and after OLT, interestingly, some patients had an increase in FEV1 (average of 5.9%) and improvements in FVC (61 to 82%) after OLT.3, 14, 15 On the other hand, in lung-only transplant, underlying liver dysfunction may prohibit optimal results due to an increased risk for coagulopathy and hepatic decompensation.5 Therefore, the findings of our analysis are particularly notable for the improved survival of ConLi-LTx patients. This survival benefit of simultaneous liver/lung transplantation was also present when compared to the entire LTx-only control pool (n=1275) (Supplemental Figures 1–2). The improved survival of ConLi-LTx recipients may be indicative of patient selection – candidates who are selected for dual-organ transplant may be better suited to undergo the transplant process with successful outcomes. Nonetheless, the survival benefit after the first year post-transplant is encouraging for patients who are under consideration for ConLi-LTx.
The advent of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies has shifted the approach to management of CF. Drugs such as ivacaftor have been shown to slow the rate of pulmonary function decline and improve nutritional status, indicating that CF-related tissue injury may not be irreversible.16 Although there have been some reports of improved hepatic steatosis on ivacaftor, hepatic benefits of CFTR modulator therapy largely remain unclear.17 While these pharmacological interventions are certainly promising for the multi-system management of CF, with limited data availability, transplant remains at the forefront for definitively addressing pulmonary and liver dysfunction in these patients.
Our study is not without its limitations. Database limitations of captured variables challenge the analysis of transplant outcomes that are often multi-factorial. While database reviews can provide unique perspectives, there is a lack of granular and detailed data that limits the conclusions that can be drawn. In addition, the low sample size of 18 cases decreases the power of this study in determining statistical significance. Also, we do not have information regarding selection of the included patients for combined transplant or transplant strategy utilized in ConLi-LTx recipients.
Conclusion
In conclusion, while our study does not identify any pre-transplant factors or non-survival post-transplant outcome variations in simultaneous ConLi-LTx compared to LTx-only in pediatric patients with cystic fibrosis, the improved survival of ConLi-LTx recipients highlights this approach as a strategy to address the multi-system effects of this disease. With similar complication rates and lower overall mortality, pediatric cystic fibrosis patients should be recommended for dual lung/liver transplantation. Further research is needed regarding the granularity of dual-organ allocation and the ethical considerations that contribute to this decision.
Funding sources
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
CRediT authorship contribution statement
RW – Conceptualization, Data curation, Formal analysis, Investigation, Writing – original draft, Writing – review and editing; JAJ – Formal analysis, Writing – original draft, Writing – review and editing; JMF – Writing – review and editing; BL – Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Software, Writing – review and editing; BA – Supervision, Writing – review and editing; AO – Supervision, Writing – review and editing; JD – Supervision, Writing – review and editing; PRDS – Conceptualization, Data curation, Formal analysis, Investigation, Supervision, Writing – review and editing.
Acknowledgments
The data have been provided by the ISHLT Transplant Registry. The interpretation and reporting of these data are the responsibility of the user(s). The authors agree with and confirm that their study adheres to the principles of the World Medical Association Statement on Organ and Tissue Donation, the Declaration of Helsinki, and the Declaration of Istanbul.
Footnotes
Supplemental data associated with this article can be found in the online version at doi:10.1016/j.jhlto.2025.100212.
Appendix A. Supplemental material
Overall survival between Liver+Lung group and entire control pool
.
BOS-free survival between Liver+Lung group and entire control pool
.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Overall survival between Liver+Lung group and entire control pool
BOS-free survival between Liver+Lung group and entire control pool