Advances in lung transplantation: 60 years on.

Lung transplantation is a well-established treatment for advanced lung disease, improving survival and quality of life. Over the last 60 years all aspects of lung transplantation have evolved significantly and exponential growth in transplant volume. This has been particularly evident over the last decade with a substantial increase in lung transplant numbers as a result of innovations in donor utilization procurement, including the use donation after circulatory death and ex-vivo lung perfusion organs. Donor lungs have proved to be surprisingly robust, and therefore the donor pool is actually larger than previously thought. Parallel to this, lung transplant outcomes have continued to improve with improved acute management as well as microbiological and immunological insights and innovations. The management of lung transplant recipients continues to be complex and heavily dependent on a tertiary care multidisciplinary paradigm. Whilst long term outcomes continue to be limited by chronic lung allograft dysfunction improvements in diagnostics, mechanistic understanding and evolutions in treatment paradigms have all contributed to a median survival that in some centres approaches 10 years. As ongoing studies build on developing novel approaches to diagnosis and treatment of transplant complications and improvements in donor utilization more individuals will have the opportunity to benefit from lung transplantation. As has always been the case, early referral for transplant consideration is important to achieve best results.

Thoraco-abdominal normothermic regional perfusion for thoracic transplantation in the United States: current state and future directions.

PURPOSE OF REVIEW: To provide an update regarding the state of thoracoabdominal normothermic regional perfusion (taNRP) when used for thoracic organ recovery. RECENT FINDINGS: taNRP is growing in its utilization for thoracic organ recovery from donation after circulatory death donors, partly because of its cost effectiveness. taNRP has been shown to yield cardiac allograft recipient outcomes similar to those of brain-dead donors. Regarding the use of taNRP to recover donor lungs, United Network for Organ Sharing (UNOS) analysis shows that taNRP recovered lungs are noninferior, and taNRP has been used to consistently recover excellent lungs at high volume centers. Despite its growth, ethical debate regarding taNRP continues, though clinical data now supports the notion that there is no meaningful brain perfusion after clamping the aortic arch vessels. SUMMARY: taNRP is an excellent method for recovering both heart and lungs from donation after circulatory death donors and yields satisfactory recipient outcomes in a cost-effective manner. taNRP is now endorsed by the American Society of Transplant Surgeons, though ethical debate continues.

[Lung transplantation: current situation and developments]. / Lungentransplantation: aktueller Stand und Entwicklungen.

Lung transplantation is currently the gold standard treatment for end-stage lung diseases. Advances in the preservation of donor lungs, the surgical technique and immunosuppressive therapy have led to lung transplantation now being a routine procedure. Nevertheless, the shortage of donor organs, the acute and particularly chronic lung allograft dysfunction (CLAD) still represent major challenges even in experienced centers. Research in this area is still necessary to improve the long-term survival of lung recipients.

A Single-Center Experience with Lung Transplants During the COVID-19 Pandemic.

BACKGROUND This single-center study analyzed distinctions between lung transplants performed in the Department of Cardiac and Vascular surgery of the University Clinical Center in Gdansk, Poland before and during the COVID-19 pandemic. MATERIAL AND METHODS There were 189 patients who underwent the qualification procedure to lung transplantation in the Department of Cardiac and Vascular Surgery of the University Clinical Center in Gdansk, Poland in the years 2019 and 2020. The control group consisted of 12 patients transplanted in 2019, and the study group consisted of 16 patients transplanted in 2020. RESULTS During 2019, the qualification process was performed in 102 patients with pulmonary end-stage diseases. In 2020, despite the 3-month lockdown related to organizational changes in the hospital, 87 qualification processes were performed. The mortality rate of patients on the waiting list in 2020 was 14.3% (6 patients died), and during 2019 the rate was also 14.3% (4 patients died). Donor qualifications were according to ISHLT criteria. The distribution of donors in both years was similar. There was no relationship between the geographic area of residence and source of donors. In 2019, all 12 patients had double-lung transplant. In 2020, 11 patients had double-lung transplant and 5 patients had single-lung transplant. There was no difference in ventilation time and PGD aside from a shorter ICU stay in 2020. CONCLUSIONS Lung transplants were relatively well-conducted despite the continued obstacles of the COVID-19 pandemic.

Geographic Differences in Lung Transplant Volume and Donor Availability During the COVID-19 Pandemic.

BACKGROUND: Regional variation in lung transplantation practices due to local coronavirus disease 2019 (COVID-19) prevalence may cause geographic disparities in access to lung transplantation. METHODS: Using the United Network for Organ Sharing registry, we conducted a descriptive analysis of lung transplant volume, donor lung volume, new waitlist activations, and waiting list deaths at high-volume lung transplant centers during the first 3 months of the pandemic (March 1. 2020, to May 30, 2020) and we compared it to the same period in the preceding 5 years. RESULTS: Lung transplant volume decreased by 10% nationally and by a median of 50% in high COVID-19 prevalence centers (range -87% to 80%) compared with a median increase of 10% (range -87% to 80%) in low prevalence centers (P-for-trend 0.006). Donation services areas with high COVID-19 prevalence experienced a greater decrease in organ availability (-28% range, -72% to -11%) compared with low prevalence areas (+7%, range -20% to + 55%, P-for-trend 0.001). Waiting list activations decreased at 18 of 22 centers. Waiting list deaths were similar to the preceding 5 years and independent of local COVID-19 prevalence (P-for-trend 0.36). CONCLUSIONS: Regional variation in transplantation and donor availability in the early months of the pandemic varied by local COVID-19 activity.

Ex Vivo Lung Perfusion: Current Achievements and Future Directions.

There is a severe shortage in the availability of donor organs for lung transplantation. Novel strategies are needed to optimize usage of available organs to address the growing global needs. Ex vivo lung perfusion has emerged as a powerful tool for the assessment, rehabilitation, and optimization of donor lungs before transplantation. In this review, we discuss the history of ex vivo lung perfusion, current evidence on its use for standard and extended criteria donors, and consider the exciting future opportunities that this technology provides for lung transplantation.

Trends in Lung Transplantation Practices Across the United States During the COVID-19 Pandemic.

BACKGROUND: The purpose of this study is to examine the effects of the coronavirus disease 2019 (COVID-19) pandemic on adult lung transplants and report practice changes in the United States. METHODS: A retrospective analysis of a public dataset from the United Network for Organ Sharing was performed regarding adult lung transplantation (January 19, 2020-June 30, 2020). Data were stratified into 3 periods: pre-COVID-19 (January 19, 2020-March 14, 2020), first COVID-19 era (March 15, 2020-May 8, 2020), and second COVID-19 era (May 9, 2020-June 30, 2020). Weekly changes in waitlist inactivations (COVID-19 precautions or not), waitlist additions, transplant volume, and donor recovery were examined across eras and changes across era were correlated. RESULTS: During the first COVID-19 era, 301 patients were added to the waitlist, representing a 40% decrease when compared to the prior 8-week period. This was followed by a significant increase in listing during the second COVID-19 era (t = 2.16, P = 0.032). Waitlist inactivations decreased in the second COVID-19 era from the first COVID-19 era (t = 3.60, P < 0.001). There was no difference in waitlist inactivations between the pre-COVID era and the second COVID-19 era (P = 0.10). Weekly volume was not associated with trends in COVID-19 cases across any era, but was negatively associated with waitlist inactivations due to COVID-19 precautions entering the first COVID-19 era (r = -0.73, P = 0.04) and second COVID-19 era (r = -0.89, P = 0.003). CONCLUSIONS: Due to the COVID-19 pandemic, the United States experienced a decrease in lung transplant volume. While overall volume has returned to normal, additional studies are needed to identify areas of improvement to better prepare for future pandemics.

Impact of COVID-19 on Lung Transplant Activity in Germany-A Cross-Sectional Survey.

The current COVID-19 pandemia affects health care systems worldwide, however, to a variable extent depending on the caseload in each country. We aimed to provide a cross-sectional overview of current limitations or adaptions in lung transplant programs in Germany in from January to May 2020 due to the COVID-19 pandemia caused by severe acute respiratory syndrome coronavirus 2. A cross-sectional survey assessing various aspects of lung transplant activity was sent to all active lung transplant programs (n = 12) in Germany. Eight centers (66%) responded to the survey within the requested time frame. Four centers (50%) reported their activity is not restricted at all and four centers (50%) reported on moderate general limitations. The overall lung transplant activity in Germany from January to May 2020 contains 128 bilateral and 11 single lung transplantations, which is similar to the same period in the year 2019 (126 bilateral transplantations and 12 single lung transplantations). The results suggest that the influence of the COVID-19 pandemia on lung transplantation activity in Germany has been moderate so far. Nevertheless, adaptions such as extensive testing of donors and recipients were introduced to reduce the likelihood of infections and increase patient safety. Alertness to changes in COVID-19 reproduction rates might be required until effective antiviral therapy or vaccination is available.

Using Geographic Catchment Areas to Measure Population-based Access to Kidney Transplant in the United States.

BACKGROUND: Monitoring efforts to improve access to transplantation requires a definition of the population attributable to a transplant center. Previously, assessment of variation in transplant care has focused on differences between administrative units-such as states-rather than units derived from observed care patterns. We defined catchment areas (transplant referral regions [TRRs]) from transplant center care patterns for population-based assessment of transplant access. METHODS: We used US adult transplant listings (2006-2016) and Dartmouth Atlas catchment areas to assess the optimal method of defining TRRs. We used US Renal Data System and Scientific Registry of Transplant Recipient data to compare waitlist- and population-based kidney transplant rates. RESULTS: We identified 110 kidney, 67 liver, 85 pancreas, 68 heart, and 43 lung TRRs. Most patients were listed in their assigned TRR (kidney: 76%; liver: 75%; pancreas: 75%; heart: 74%; lung: 72%), although the proportion varied by organ (interquartile range for kidney, 65.7%-82.5%; liver, 58.2%-78.8%; pancreas, 58.4%-81.1%; heart, 63.1%-80.9%; lung, 61.6%-76.3%). Patterns of population- and waitlist-based kidney transplant rates differed, most notably in the Northeast and Midwest. CONCLUSIONS: Patterns of TRR-based kidney transplant rates differ from waitlist-based rates, indicating that current metrics may not reflect transplant access in the broader population. TRRs define populations served by transplant centers and could enable future studies of how transplant centers can improve access for patients in their communities.

Dyspnea, effort and muscle pain during exercise in lung transplant recipients: an analysis of their association with cardiopulmonary function parameters using machine learning.

BACKGROUND: Despite improvement in lung function, most lung transplant (LTx) recipients show an unexpectedly reduced exercise capacity that could be explained by persisting peripheral muscle dysfunction of multifactorial origin. We analyzed the course of symptoms, including dyspnea, muscle effort and muscle pain and its relation with cardiac and pulmonary function parameters during an incremental exercise testing. METHODS: Twenty-four bilateral LTx recipients were evaluated in an observational cross-sectional study. Recruited patients underwent incremental cardio-pulmonary exercise testing (CPET). Arterial blood gases at rest and peak exercise were measured. Dyspnea, muscle effort and muscle pain were scored according to the Borg modified scale. Potential associations between the severity of symptoms and exercise testing parameters were analyzed using a Forest-Tree Machine Learning approach, which accomplishes for a ratio between number of observations and number of screened variables less than unit. RESULTS: Dyspnea score was significantly associated with maximum power output (WR, watts), and minute ventilation (VE, L/min) at peak exercise. In a controlled subgroup analysis, dyspnea score was a limiting symptom only in LTx recipients who reached the higher levels of WR (≥ 101 watts) and VE (≥ 53 L/min). Muscle effort score was significantly associated with breathing reserve as percent of maximal voluntary ventilation (BR%MVV). The lower the BR%MVV at peak exercise (< 32) the higher the muscle effort perception. Muscle pain score was significantly associated with VO2 peak, arterial [HCO3-] at rest, and VE/VCO2 slope. In a subgroup analysis, muscle pain was the limiting symptom in LTx recipients with a lower VO2 peak (< 15 mL/Kg/min) and a higher VE/VCO2 slope (≥ 32). CONCLUSIONS: The majority of our LTx recipients reported peripheral limitation as the prevalent reason for exercise termination. Muscle pain at peak exercise was strictly associated with basal and exercise-induced metabolic altered pathways. The onset of dyspnea (breathing effort) was associated with the intensity of ventilatory response to meet metabolic demands for increasing WR. Our study suggests that only an accurate assessment of symptoms combined with cardio-pulmonary parameters allows a correct interpretation of exercise limitation and a tailored exercise prescription. The role and mechanisms of muscle pain during exercise in LTx recipients requires further investigations.

Time to diagnosis of idiopathic pulmonary fibrosis in the IPF-PRO Registry.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality. Patient characteristics associated with diagnostic delays are not well described. METHODS: Subjects who had not been diagnosed with IPF prior to referral and received a new diagnosis of IPF at an enrolling centre for the IPF-PRO (Idiopathic Pulmonary Fibrosis Prospective Outcomes) Registry were characterised as having a longer (>1 year) or shorter (≤1 year) time from symptom onset to diagnosis and from first imaging evidence of fibrosis to diagnosis. Patient characteristics, evaluations and time to death or lung transplant were compared between these cohorts. RESULTS: Among 347 patients with a symptom onset date, 49% were diagnosed with IPF >1 year after symptom onset. These patients were slightly younger and had more cardiac comorbidities than patients diagnosed ≤1 year after symptom onset. Among 454 patients with a date for imaging evidence of fibrosis, 78% were diagnosed with IPF ≤1 year later. A greater proportion of patients with >1 year versus ≤1 year from imaging evidence of fibrosis to diagnosis had cardiac comorbidities and gastro-oesophageal reflux. There was no significant difference in time to death or lung transplant between groups by time to diagnosis. CONCLUSIONS: The time from symptom onset to diagnosis remains over 1 year in approximately half of the patients with IPF, but once imaging evidence is obtained, most of the patients are diagnosed within a year. Cardiac conditions and gastro-oesophageal disorders were more commonly reported in patients with a longer time to diagnosis.

Current precautions and future directions in lung transplantation during the COVID-19 pandemic - a single center cohort study.

The unprecedented public health emergency caused by the acute viral respiratory coronavirus disease (COVID-19) has drastically changed current practices in solid organ transplantation, markedly so for transplantation of the lungs, the major target of the virus. Although national and state authorities do not recommend postponing transplant procedures, most specialists are reluctant to proceed due to substantial uncertainty and increased risks in the midst of the pandemic. There is an urgent need for evidence-based directions to move forward. Here, we offer our insights as specialists at a high-volume center located in a geographical area with high infection rates.

The need for a holistic approach for SSc-ILD - achievements and ambiguity in a devastating disease.

Systemic sclerosis (SSc) is a multi-organ autoimmune disease with complex interactions between immune-mediated inflammatory processes and vascular pathology leading to small vessel obliteration, promoting uncontrolled fibrosis of skin and internal organs. Interstitial lung disease (ILD) is a common but highly variable manifestation of SSc and is associated with high morbidity and mortality. Treatment approaches have focused on immunosuppressive therapies, which have shown some efficacy on lung function. Recently, a large phase 3 trial showed that treatment with nintedanib was associated with a reduction in lung function decline. None of the conducted randomized clinical trials have so far shown convincing efficacy on other outcome measures including quality of life determined by patient reported outcomes. Little evidence is available for non-pharmacological treatment and supportive care specifically for SSc-ILD patients, including pulmonary rehabilitation, supplemental oxygen, symptom relief and adequate information. Improved management of SSc-ILD patients based on a holistic approach is necessary to support patients in maintaining as much quality of life as possible throughout the disease course and to improve long-term outcomes.

Challenges and Special Aspects of Pulmonary Hypertension in Middle- to Low-Income Regions: JACC State-of-the-Art Review.

Challenges and special aspects related to the management and prognosis of pulmonary hypertension (PH) in middle- to low-income regions (MLIRs) range from late presentation to comorbidities, lack of resources and expertise, cost, and rare options of lung transplantation. Expert consensus recommendations addressing the specific challenges for prevention and therapy of PH in MLIRs with limited resources have been lacking. To date, 6 MLIR-PH registries containing mostly adult patients with PH exist. Importantly, the global prevalence of PH is much higher in MLIRs compared with high-income regions: group 2 PH (left heart disease), pulmonary arterial hypertension associated with unrepaired congenital heart disease, human immunodeficiency virus, or schistosomiasis are highly prevalent. This consensus statement provides selective, tailored modifications to the current PH guidelines to address the specific challenges faced in MLIRs, resulting in the first pragmatic and cost-effective consensus recommendations for PH care providers, patients, and their families.

Human-scale lung regeneration based on decellularized matrix scaffolds as a biologic platform.

Lung transplantation is currently the only curative treatment for patients with end-stage lung disease; however, donor organ shortage and the need for intense immunosuppression limit its broad clinical application. Bioartificial lungs created by combining native matrix scaffolds with patient-derived cells might overcome these problems. Decellularization involves stripping away cells while leaving behind the extracellular matrix scaffold. Cadaveric lungs are decellularized by detergent perfusion, and histologic examination confirms the absence of cellular components but the preservation of matrix proteins. The resulting lung scaffolds are recellularized in a bioreactor that provides biomimetic conditions, including vascular perfusion and liquid ventilation. Cell seeding, engraftment, and tissue maturation are achieved in whole-organ culture. Bioartificial lungs are transplantable, similarly to donor lungs, because the scaffolds preserve the vascular and airway architecture. In rat and porcine transplantation models, successful anastomoses of the vasculature and the airway were achieved, and gas exchange was evident after reperfusion. However, long-term function has not been achieved because of the immaturity of the vascular bed and distal lung epithelia. The goal of this strategy is to create patient-specific transplantable lungs using induced pluripotent stem cell (iPSC)-derived cells. The repopulation of decellularized scaffolds to create transplantable organs is one of possible future clinical applications of iPSCs.

Factors associated with intraoperative extracorporeal membrane oxygenation support during lung transplantation.

BACKGROUND: Intraoperative Extracorporeal membrane oxygenation (ECMO) is increasingly being applied as life-support for lung transplantation patients. However, factors associated with this procedure in lung transplantation patients have not yet been characterized. The aim of this study was to identify preoperative factors of intraoperative ECMO support during lung transplantation and to evaluated the outcome of lung transplantation patients supported with ECMO. METHODS: Patients underwent lung transplantation treated with and without ECMO in Guangzhou Institute of Respiratory Diseases between January 2015 to August 2018 were retrospectively reviewed. Patient demographics and clinical variables were collected and analyzed. Multivariate logistic regression was performed to identify factors independently associated with intraoperative extracorporeal membrane oxygenation support during lung transplantation. RESULTS: During the study period, 138 patients underwent lung transplantation at our institution, the mean LAS was (56.63 ± 18.39) (range, 32.79 to 88.70). Fourty four patients were treated with veno-venous/veno-arterial ECMO. Among the patients, 32 patients wean successfully ECMO after operation, 12 patients remain ECMO after operation, and 32 patients (62.74%) survived to hospital discharge. In multiple analysis, the following factors were associated with intraoperative ECMO support: advanced age, high PAP before operation, duration of mechanical ventilation before operation, a higher APACHE II and primary diagnosis for transplantation. The overall survival rates at 1, 3, and 12 months were 90.91, 72.73, and 56.81% in the ECMO group, and 95.40, 82.76, and 73.56% in the non-ECMO group, respectively (log-rank P = 0.081). Patients who underwent single lung transplant had a lower survival rates in ECMO group as compared with non-ECMO group at 1, 3, and 12 months (90.47% vs 98.25, 71.43% vs 84.21, and 52.38% vs 75.44%) (log-rank P = 0.048). CONCLUSIONS: The preoperative factors of intraoperative ECMO support during lung transplantation included age, high PAP before operation, preoperative mechanical ventilation, a higher APACHE II and primary diagnosis for transplantation based on multivariate analysis.

Xenogeneic Lung Transplantation Models.

Study of lung xenografts has proven useful to understand the remaining barriers to successful transplantation of other organ xenografts. In this chapter, the history and current status of lung xenotransplantation will be briefly reviewed, and two different experimental models, the ex vivo porcine-to-human lung perfusion and the in vivo xenogeneic lung transplantation, will be presented. We will focus on the technical details of these lung xenograft models in sufficient detail, list the needed materials, and mention analysis techniques to allow others to adopt them with minimal learning curve.

Associations between Patient-reported Outcomes and Death or Lung Transplant in Idiopathic Pulmonary Fibrosis. Data from the Idiopathic Pulmonary Fibrosis Prospective Outcomes Registry.

Rationale: Progression of idiopathic pulmonary fibrosis (IPF) is accompanied by worsening of symptoms, exercise capacity, and health-related quality of life. However, the utility of patient-reported outcomes as predictors of mortality remains uncertain.Objectives: To assess whether patient-reported outcomes are independently associated with mortality beyond clinical risk factors in patients with IPF.Methods: Data from the observational IPF Prospective Outcomes Registry were used to examine associations between patient-reported outcomes at enrollment and the composite outcome of death or lung transplant in the following year. Associations were examined using univariable models and models adjusted for age and clinical variables that have been associated with death or lung transplant in patients with IPF in this cohort (oxygen use, forced vital capacity % predicted, and diffusing capacity of the lungs for carbon monoxide % predicted at enrollment).Results: Among 662 patients, 45 died and 12 underwent lung transplant over 1 year. In the model adjusted for age and clinical variables that were associated with death or lung transplant, worse scores on the St. George's Respiratory Questionnaire (SGRQ) total score (hazard ratio [HR], 1.22 [95% confidence interval (CI), 1.01-1.48] per 10-point increase), SGRQ activity score (HR, 1.25 [95% CI, 1.02-1.54] per 10-point increase) and SGRQ symptoms score (HR, 1.17 [95% CI, 1.01-1.36] per 10-point increase) were associated with death or lung transplant over 1 year.Conclusions: Patient-reported outcomes that assess symptoms and physical activity are independently associated with mortality in patients with IPF.

Extracorporeal membrane oxygenation as a bridge to lung transplantation: analysis of Korean organ transplantation registry (KOTRY) data.

BACKGROUND: The use of extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation has greatly increased. However, data regarding the clinical outcomes of this approach are lacking. The objective of this multicenter prospective observational cohort study was to evaluate lung transplantation outcomes in Korean Organ Transplantation Registry (KOTRY) patients for whom ECMO was used as a bridge to transplantation. METHODS: Between March 2015 and December 2017, a total of 112 patients received lung transplantation and were registered in the KOTRY, which is a prospective, multicenter cohort registry. The entire cohort was divided into two groups: the control group (n = 85, 75.9%) and bridge-ECMO group (n = 27, 24.1%). RESULTS: There were no significant differences in pre-transplant and intraoperative characteristics except for poorer oxygenation, more ventilator use, and longer operation time in the bridge-ECMO group. The prevalence of primary graft dysfunction at 0, 24, 48, and 72 h after transplantation did not differ between the two groups. Although postoperative hospital stays were longer in the bridge-ECMO group than in the control group, hospital mortality did not differ between the two groups (25.9% vs. 13.3%, P = 0.212). The majority of patients (70.4% of the bridge-ECMO group and 77.6% of the control group) were discharged directly to their homes. Finally, the use of ECMO as a bridge to lung transplantation did not significantly affect overall survival and graft function. CONCLUSIONS: Short- and long-term post-transplant outcomes of bridge-ECMO patients were comparable to recipients who did not receive ECMO.