Lung Transplantation For Cystic Fibrosis Research Articles

First Successful Pregnancy After Lung Transplantation in Poland—Case Report

Lung transplantation is well-established treatment for patients with advanced lung dysfunction in cystic fibrosis (CF). Pregnancy in CF lung transplant recipients is feasible, although it still remains challenging for even professionals and demands a multidisciplinary approach. We report the case of pregnancy in a 22-year-old woman after lung transplantation (LTx) due to end-stage respiratory failure in the course of CF. The interval from transplant to conception was 2.5 years. In 2019, orthotopic LTx was performed and a 3-drug immunosuppressive scheme was used-tacrolimus, mycophenolate mofetil, and prednisolone. There were no complications in the postoperative course. In April 2022, the patient was confirmed pregnant. All fetotoxic or teratogenic drugs were discontinued. Throughout the whole pregnancy, the patient was regularly monitored in the transplant and obstetrics centers. Due to the vaginal bleeding and irregular contractions at the 33 weeks of pregnancy, the course of steroids was administered. At 38 weeks and 5 days of gestation, she presented premature rupture of membranes. The caesarean section was performed because of breech presentation of the fetus. A live, term daughter was born and according to the screening test she does not have CF. Currently, 12 months after the delivery, the mother's lung function is good. Getting pregnant and having a safe pregnancy after LTx is possible, but it requires a specialized and individual approach. The patient should be well informed about possible complications and risks including graft failure. The patient's attitude and her cooperation with doctors play a major role.

Metabolic complications in lung transplantation for cystic fibrosis - A case control study

BackgroundMetabolic complications post-lung transplant are poorly understood and little is known about how these complications differ between patients with or without cystic fibrosis (pwCF and pwoCF). This study compared post-lung transplant outcomes between pwCF and pwoCF relating to survival and incidence of diabetes, dyslipidaemia, hypertension, and renal impairment. MethodsA retrospective (2004–2017) case-control study involving 90 pwCF and 90 pwoCF (age, sex and year of transplant matched) was conducted. Demographic variables, pre/post-transplant metabolic diseases, blood investigations and medications were extracted. Descriptive statistics were used to describe the cohort. Mann-Whitney U and Chi-squared tests were used to analyse morbidity and mortality data. Regression analyses were used to identity independent variables that impacted clinical outcomes. Kaplan Meier analysis with log-rank testing was used to compare survival. ResultsPwCF were younger, had lower BMIs, and were less likely to have pre-transplant extracorporeal membrane oxygenation (ECMO) use. A total of 37 pwCF and 41 pwoCF died (p = 0.65) during the period of observation with no differences in survival. Adjusting for covariates of age, sex and BMI via multiple logistic regression, CF status was associated with a dramatic increased risk of new-onset diabetes post-transplant (adjusted odds ratio 28.7; 95 % CI, 28.76 to 108.7). No other differences in adjusted risk were found. ConclusionsAs pwCF had a greater adjusted risk of developing new post-transplant diabetes and experienced metabolic complications at similar rates as pwoCF, the findings highlight the need for rigorous monitoring of pwCF for possible metabolic complications post-transplant.

Porcine-derived pancreatic enzyme replacement therapy may be linked to chronic hepatitis E virus infection in cystic fibrosis lung transplant recipients

ObjectivesIn high-income countries hepatitis E virus (HEV) is an uncommonly diagnosed porcine-derived zoonoses. After identifying disproportionate chronic HEV infections in persons with cystic fibrosis (pwCF) postlung transplant, we sought to...

Quality of locally designed surveys in a quality improvement collaborative: review of survey validity and identification of common errors

ObjectiveSurveys are a commonly used tool in quality improvement (QI) projects, but little is known about the standards to which they are designed and applied. We aimed to investigate the...

Self-reported engagement in everyday activities following bilateral lung transplantation in paediatric cystic fibrosis: a single centre study

IntroductionFollowing lung transplantation, it is unknown how children/adolescents self-assess their performance in everyday activities, importance of these activities, and whether resumption of everyday activities influences self-reported quality of life. The...

Telemonitoring: An opportunity in cystic fibrosis lung transplant recipients

IntroductionTelemedicine has been successfully employed in a wide range of conditions, such as such as chronic lung disease and COVID-19. This study evaluate the role of telemonitoring for the early diagnosis of acute lung allograft dysfunction in cystic fibrosis adults who underwent lung transplant (LuTx). Quality of life and functional level achieved during a 12 months follow up were assessed. MethodsPatients were randomized into two groups; control group received traditional hospital-based follow-up, whereas patients in the intervention group received, on top of standard care, a telemonitoring device, with a pulse oximeter and a spirometer integrated. Telemonitoring data were digitally transmitted to our centre. ResultsSixteen patients were enrolled in each group. No statistically significant difference was found between the two groups in terms of incidence of allograft dysfunction, time from onset of symptoms to diagnosis and time of occurrence from LuTx. Moreover, both groups achieved similar quality of life and functional level. With reference to the telemonitoring group: 1) hospital reported data were consistent with those being remotely registered; 2) adherence to telemonitoring decreased during the follow up; 3) the majority of patients reported a high degree of satisfaction. ConclusionThe COVID19 pandemic highlighted the necessity to investigate alternative practices to treat chronically ill individuals. Telemonitoring is a valuable tool to improve quality care to LuTx recipients.

Lung Transplantation in a New Era in the Field of Cystic Fibrosis.

Lung transplantation for people with cystic fibrosis (PwCF) is a critical therapeutic option, in a disease without a cure to this day, and its overall success in this population is evident. The medical advancements in knowledge, treatment, and clinical care in the field of cystic fibrosis (CF) rapidly expanded and improved over the last several decades, starting from early pathology reports of CF organ involvement in 1938, to the identification of the CF gene in 1989. Lung transplantation for CF has been performed since 1983, and CF now accounts for about 17% of pre-transplantation diagnoses in lung transplantation recipients. Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have been the latest new therapeutic modality addressing the underlying CF protein defect with the first modulator, ivacaftor, approved in 2012. Fast forward to today, and we now have a growing CF population. More than half of PwCF are now adults, and younger patients face a better life expectancy than they ever did before. Unfortunately, CFTR modulator therapy is not effective in all patients, and efficacy varies among patients; it is not a cure, and CF remains a progressive disease that leads predominantly to respiratory failure. Lung transplantation remains a lifesaving treatment for this disease. Here, we reviewed the current knowledge of lung transplantation in PwCF, the challenges associated with its implementation, and the ongoing changes to the field as we enter a new era in the care of PwCF. Improved life expectancy in PwCF will surely influence the role of transplantation in patient care and may even lead to a change in the demographics of which people benefit most from transplantation.

Results of Lung Transplantation for Cystic Fibrosis With Selected Donors Over 65Years Old.

Lung transplantation is limited by the shortage of suitable donors. Many programs have begun to use extended criteria donors. Donors over 65years old are rarely reported, especially for young cystic fibrosis recipients. This monocentric study was conducted for cystic fibrosis recipients from January 2005 to December 2019, comparing two cohorts according to lung donor age (<65years or ≥65years). The primary objective was to assess the survival rate at 3years using a Cox multivariable model. Of the 356 lung recipients, 326 had donors under 65years, and 30 had donors over 65years. Donors' characteristics did not differ significantly in terms of sex, time on mechanical ventilation before retrieval, and partial pressure of arterial oxygen/fraction of inspired oxygen ratio. There were no significant differences in post-operative mechanical ventilation duration and incidence of grade 3 primary graft dysfunction between the two groups. At 1, 3, and 5years, the percentage of predicted forced expiratory volume in 1s (p = 0.767) and survival rate did not differ between groups (p = 0.924). The use of lungs from donors over 65years for cystic fibrosis recipients allows extension of the donor pool without compromising results. Longer follow-up is needed to assess the long-term effects of this practice.

WS03.03 Clinical outcomes and long-term survival in cystic fibrosis (CF) lung transplant recipients in Belgium

Objectives: Lung transplantation (LTx) is a therapeutic option for cystic fibrosis (CF) patients suffering from end-stage lung disease. Our objective is to report the experience of LTx for CF in Belgium.

Effectiveness of an Oral Gastrografin Regimen for Complete Distal Intestinal Obstruction Syndrome.

To assess the effectiveness of oral Gastrografin treatment and outcomes in adult patients with complete distal intestinal obstruction syndrome (cDIOS). DIOS is an important gastrointestinal complication of cystic fibrosis (CF). Conservative treatment options for cDIOS are largely empirical, and the optimal management remains unclear. Surgery should be reserved for patients who have failed nonoperative treatment or have immediate indications for surgery. A retrospective single-institution cohort study was undertaken of adults with CF who had undergone lung transplantation and were admitted with an episode of cDIOS between 2004 and 2020. The outcomes of treatment in a high-volume CF transplant center with routine oral Gastrografin-based therapy were assessed. Forty-seven episodes of cDIOS were recorded in 29 (23.3%) of 124 patients who had undergone lung transplantation for CF, and mean age at cDIOS was 30.3 years (SD ±11.2). Mean follow-up post cDIOS was 75.6 months (SD ±45.5). Twelve patients had >1 cDIOS episode. One episode occurred during recovery after transplantation, and 5 patients were readmitted within 30 days posttransplant with cDIOS. A history of previous abdominal surgery was associated with the development of cDIOS (P < 0.001). Oral Gastrografin therapy was used in 95.7% of the episodes, at varying doses. Three patients (7.0%) were resistant to oral Gastrografin treatment, requiring laparotomy. There were no deaths due to DIOS. Oral Gastrografin is effective and safe for the treatment of cDIOS, with low treatment failure rates. It should be considered as a first-line treatment option for patients with CF presenting with complete distal intestinal obstruction.

Impact of extended sinus surgery on allograft infection, allograft function and overall survival in cystic fibrosis lung transplant recipients.

Studies investigating the impact of sinus surgery for cystic fibrosis (CF) patients performed early after lung transplantation (Ltx) are scarce. Recent studies evaluating frequency of respiratory infections and graft outcomes are not available. To determine whether there is a difference in allograft infection, allograft function and overall survival among CF lung transplant recipients with and without concomitant sinus surgery. Retrospective single-center study. We examined 71 CF patients who underwent Ltx between 2009 and 2019 at our center. Fifty-nine patients had sinus surgery before or/and after transplantation and twelve did not undergo sinus surgery. We assessed the survival, the diagnosis of chronic allograft dysfunction (CLAD) and all elevated (> 5mg/l) c-reactive protein episodes during the observed period. The infectious events of the upper and lower airways were categorized in mild infections (5-15mg/l CRP) and severe infections (> 15mg/l CRP). There was no difference in the long-time overall survival (p = 0.87) and no benefit in the short-term survival at 4 year post-transplant (p = 0.29) in both groups. There was no difference in both groups concerning CLAD diagnosis (p = 0.92). The incidence of severe upper and lower airway infections (CRP > 15mg/l) was significantly decreased in the sinus surgery group (p = 0.015), whereas in mild infections there was a trend to decreased infections in the sinus surgery group (p = 0.056). CF patients undergoing Ltx benefit from extended endoscopicsinus surgery (eESS) in terms of frequency of severe infectious events of the upper and lower airways. There was no difference in overall survival and frequency of CLAD in the two groups.

Computed tomography body composition and clinical outcomes following lung transplantation in cystic fibrosis

BackgroundLow muscle mass is common in patients approaching lung transplantation and may be linked to worse post-transplant outcomes. Existing studies assessing muscle mass and post-transplant outcomes include few patients with cystic fibrosis (CF).MethodsBetween May 1993 and December 2018, 152 adults with CF received lung transplants at our institution. Of these, 83 met inclusion criteria and had usable computed tomography (CT) scans. Using Cox proportional hazards regression, we evaluated the association between pre-transplant thoracic skeletal muscle index (SMI) and our primary outcome of death after lung transplantation. Secondary outcomes, including days to post-transplant extubation and post-transplant hospital and intensive care unit (ICU) length of stay, were assessed using linear regression. We also examined associations between thoracic SMI and pre-transplant pulmonary function and 6-min walk distance.ResultsMedian thoracic SMI was 26.95 cm2/m2 (IQR 23.97, 31.32) for men and 22.83 cm2/m2 (IQR 21.27, 26.92) for women. There was no association between pre-transplant thoracic SMI and death after transplant (HR 1.03; 95% CI 0.95, 1.11), days to post-transplant extubation, or post-transplant hospital or ICU length of stay. There was an association between pre-transplant thoracic SMI and pre-transplant FEV1% predicted (b = 0.39; 95% CI 0.14, 0.63), with higher SMI associated with higher FEV1% predicted.ConclusionsSkeletal muscle index was low for men and women. We did not identify a significant relationship between pre-transplant thoracic SMI and post-transplant outcomes. There was an association between thoracic SMI and pre-transplant pulmonary function, confirming the potential value of sarcopenia as a marker of disease severity.

Advanced Cystic Fibrosis Lung Disease and Lung Transplantation in the Era of Cystic Fibrosis Transmembrane Conductance Regulator Modulators.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have changed the clinical landscape of cystic fibrosis (CF) by improving clinically significant outcome measures and quality of life of people with CF (pwCF). There are now long-term data showing improved 5-year survival with the use of ivacaftor, and the field continues to evolve at a rapid pace with the continued development of highly effective CFTR modulators. While the randomized controlled trials of CFTR modulators excluded patients with severe lung disease (forced expiratory volume in 1 second <40% predicted), observational data based on case reports and registry data show similar benefits in those with advanced lung disease. This has altered clinical practice particularly as it pertains to the role of lung transplantation in CF. This article describes the impact of highly effective modulator therapy (HEMT) on the natural history of CF and the influence on the timing of referral and consideration of listing for lung transplantation. CF clinicians play a pivotal role to ensure that the impetus of the CF foundation consensus guidelines to facilitate timely referral for lung transplantation is not lost among the excitement of anticipated sustained benefit from HEMT. While the widespread availability of elexacaftor/tezacaftor/ivacaftor over the past 2 years has been associated with a sharp drop in the number of people referred for consideration for lung transplantation and the number of people wait-listed for lung transplantation, it is difficult to accurately determine the true impact due to the confounding effect of the coronavirus disease 2019 pandemic. It is expected that lung transplantation will remain an important treatment for a smaller number of pwCF. Lung transplantation offers survival benefits in CF, and there remains an imperative to ensure timely consideration of lung transplantation in patients with advanced disease to further reduce the number of pwCF dying without consideration of lung transplant.

Post-transplant outcomes among cystic fibrosis patients undergoing lung transplantation colonized by Burkholderia: A single center cohort study

Prior infection with Burkholderia cepacia complex (BCC) has been associated with poorer outcomes after lung transplantation, posing an important dilemma for cystic fibrosis (CF). Although current guidelines consider BCC infection to be a relative contraindication, some centers continue to offer lung transplantation to BCC-infected CF patients. We conducted a retrospective cohort study which included all consecutive CF-LTR between 2000 and 2019 to compare the postoperative survival of BCC-infected CF lung transplant recipients (CF-LTR) to BCC-uninfected patients. We used a Kaplan-Meier analysis to compare survival of BCC-infected to BCC-uninfected CF-LTR and fitted a multivariable Cox model, adjusted for age, sex, BMI and year of transplantation as potential confounders. As an exploratory analysis, Kaplan-Meier curves were also stratified by the presence of BCC and urgency of transplantation. A total of 205 patients were included with a mean age of 30.5 years. Seventeen patients (8%) were infected with BCC prior to LT. Patients were infected with the following species: B. multivorans5, B. vietnamiensis3, combined B. multivorans and B. vietnamiensis3 and others4. None of the patients were infected with B. cenocepacia. Three patients were infected with B. gladioli. One-year survival was 91.7% (188/205) for the entire cohort, 82.4% (14/17) among BCC-infected CF-LTR, and 92.5% (173/188) among BCC uninfected CF-LTR (crude HR=2.19; 95%CI 0.99-4.85; p=0.05). In the multivariable model, presence of BCC was not significantly associated with worse survival (adjusted HR 1.89; 95%CI 0.85-4.24; p=0.12). In the stratified analysis for both presence of BCC and urgency of transplantation, urgency of transplantation among BCC-infected CF-LTR appeared to be associated with poorer outcome (p=0.003 across the 4 subgroups). Our results suggest that non-cenocepacia BCC-infected CF-LTR have comparable survival rate to BCC-uninfected CF-LTR.

Changing racial and ethnic differences for lung transplantation in cystic fibrosis.

CFTR modulators, especially (elexacaftor/tezacaftor/ivacaftor), have positively impacted the CF population and quickly decreased LTx numbers. However, no study has investigated if this reduction is universal across all races/ethnicities. Using the UNOS Registry, we explored the frequency/proportions of LTx in WNH and NW (Black, non-Hispanic/Hispanic-Latino/Asian-non Hispanic/American Indian-Alaskan Native-non-Hispanic/Native Hawaiian/Other Pacific Islander-non-Hispanic/Multiracial) in children and adults with CF in the US. Between 1990 and 2019, the annual mean (±SD) number of LTxs for children with CF was 23.2 (±7.7) compared to 5 in 2020 (p < .001) and in 2021 (p < .001). In adults from 1990 to 2019, the mean (±SD) number of LTxs performed was 144.9 (±73.5), which was significantly higher than 2020 (n=73; p < .001) and 2021 (n=45; p < .001). Comparing 1990-2019 to post-2019, the proportion of LTxs performed in both children and adults with CF has decreased from 50.5% (696/1378) to 16.4% (9/55) and from 12.1% (4773/39542) to 2.4% (118/5004), respectively. In WNH pediatric patients, the difference in the percentage of all LTx made up by CF patients between the two eras was 41.2% compared to NW patients where the difference was 11%. Similarly in adults, the difference between the two eras was 10.4% in WNH and 2.4% in NW patients. The recent reduction in LTx for the CF population has had less impact on the NW population in the US, so the continuation of optimal referrals for this group is needed.

144 Computed tomography body composition and clinical outcomes after lung transplantation in cystic fibrosis

144 Computed tomography body composition and clinical outcomes after lung transplantation in cystic fibrosis

Survival difference between high-risk and low-risk CFTR genotypes after lung transplant.

While cystic fibrosis transmembrane conductance regulator (CFTR) genotypes are associated with clinical outcomes in cystic fibrosis patients, it is unknown if genotype impacts lung transplant outcomes. We sought to compare lung transplant survival and time to bronchiolitis obliterans syndrome (BOS) between high-risk, low-risk, and not yet classified CFTR genotypes. We used merged data from the Organ Procurement and Transplantation Network (2005-2017) and United States Cystic Fibrosis Foundation Patient Registry (2005-2016). Cox Proportional Hazards models compared graft failure after lung transplant and time to BOS among high-risk, low-risk, and not yet classified risk CFTR genotype classes. Among 1,830 cystic fibrosis lung transplant recipients, median survival for those with low-risk, high-risk, and not yet classified genotype was 9.83, 6.25, and 5.75 years, respectively. Adjusted Cox models showed recipients with a low-risk genotype had 39% lower risk of death or re-transplant compared to those with high-risk genotype (adjusted HR 0.61, 95% CI=0.40, 0.91). A subset of 1,585 lung transplant recipients were included in the BOS subgroup analysis. Adjusted analyses showed no significant difference of developing BOS among high-risk, low-risk, or not yet classified genotypes. Lung transplant recipients with low-risk CFTR genotype have better survival after transplant compared to recipients with high-risk or not yet classified genotypes. Given these differences, future studies evaluating the mechanism by which CFTR genotype affects post-transplant survival could identify potential targets for intervention.

Macrophage Lysosomal Alkalinization Drives Invasive Aspergillosis in a Mouse Cystic Fibrosis Model of Airway Transplantation.

Cystic fibrosis (CF) lung transplant recipients (LTRs) exhibit a disproportionately high rate of life-threatening invasive aspergillosis (IA). Loss of the cystic fibrosis transmembrane conductance regulator (CFTR-/-) in macrophages (mφs) has been associated with lyosomal alkalinization. We hypothesize that this alkalinization would persist in the iron-laden post-transplant microenvironment increasing the risk of IA. To investigate our hypothesis, we developed a murine CF orthotopic tracheal transplant (OTT) model. Iron levels were detected by immunofluorescence staining and colorimetric assays. Aspergillus fumigatus (Af) invasion was evaluated by Grocott methenamine silver staining. Phagocytosis and killing of Af conidia were examined by flow cytometry and confocal microscopy. pH and lysosomal acidification were measured by LysoSensorTM and LysotrackerTM, respectively. Af was more invasive in the CF airway transplant recipient compared to the WT recipient (p < 0.05). CFTR-/- mφs were alkaline at baseline, a characteristic that was increased with iron-overload. These CFTR-/- mφs were unable to phagocytose and kill Af conidia (p < 0.001). Poly(lactic-co-glycolic acid) (PLGA) nanoparticles acidified lysosomes, restoring the CFTR-/- mφs’ ability to clear conidia. Our results suggest that CFTR-/- mφs’ alkalinization interacts with the iron-loaded transplant microenvironment, decreasing the CF-mφs’ ability to kill Af conidia, which may explain the increased risk of IA. Therapeutic pH modulation after transplantation could decrease the risk of IA.

Longitudinal assessment of renal function after lung transplantation for cystic fibrosis: transition from post-operative acute kidney injury to acute kidney disease and chronic kidney failure

IntroductionThe clinical trajectory of post-operative acute kidney injury (AKI) following lung transplantation for cystic fibrosis is unknown.MethodsIncidence and risk factors for post-operative AKI, acute kidney disease (AKD) and chronic kidney disease (CKD) were retrospectively analyzed in cystic fibrosis patients undergoing lung transplantation. Logistic regressions, Chi-square, Cuzick rank tests, and Cox-proportional hazard models were used.ResultsEighty-three patients were included. Creatinine peaked 3[2–4] days after transplantation, with 15(18%), 15(18%), and 20(24%) patients having post-operative AKI stages 1, 2, and 3, while 15(18%), 19(23%) and 10(12%) developed AKD stage 1, stage 2 and 3, respectively. Higher AKI stage was associated with worsening AKD (p = 0.009) and CKD (p = 0.015) stages. Of the 50 patients with AKI, 32(66%) transitioned to AKD stage > 0, and then 27 (56%) to CKD stage > 1. Female sex, extracorporeal membrane oxygenation support as a bridge to lung transplant and at the end of the surgery, the use of intraoperative blood components, and cold-ischemia time were associated with increased risk of post-operative AKI and AKD. Higher AKI stage prolonged invasive mechanical ventilation (p = 0.0001), ICU stay (p = 0.0001), and hospital stay (p = 0.0001), and increased the incidence of primary graft dysfunction (p = 0.035). Both AKI and AKD stages > 2 worsened long-term survival with risk ratios of 3.71 (1.34–10.2), p = 0.0131 and 2.65(1.02–6.87), p = 0.0443, respectively.DiscussionAKI is frequent in cystic fibrosis patients undergoing lung transplantation, it often evolves to AKD and to chronic kidney disease, thereby worsening short- and long-term outcomes.Graphical abstract

Cystic fibrosis: candidate selection and impact of the cystic fibrosis transmembrane conductance regulator therapy

Over the past decade, the development of highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators has dramatically ameliorated the manifestations of CF for most patients. Perhaps most importantly, CFTR modulators impact the development and progression of advanced lung disease (ALD) and are changing the CF population accessing lung transplant. A recent phase 3 trial of elexacaftor/tezacaftor/ivacaftor (ETI) demonstrated efficacy for individuals with at least one copy of the most common CF mutation, F508del. Studies of CFTR modulator therapy in patients with ALD have demonstrated similar improvements in lung function, nutrition, and pulmonary exacerbation frequency as seen in individuals with higher lung function. Due to improvements with ETI, rates of lung transplant for CF have declined and individuals are achieving stability in lung function. Nevertheless, the Cystic Fibrosis Foundation guidelines for lung transplant referral should be used to guide referral decisions for all individuals with CF, including those on CFTR modulator therapy, to allow remediation of modifiable barriers to transplant. ETI may be used in the posttransplant setting but for selected individuals and with close monitoring. Increasing access to highly effective CFTR modulators has changed the trajectory of lung disease in CF for many, but not all, individuals and there remain individuals who cannot access therapy or whose mutations do not respond to modulators. Lung transplant remains an important treatment option for individuals with advanced CF lung disease. Increasing attention will be required to optimize decisions of when to list for transplant.