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OBJECTIVES: Concomitant heart and lung recovery can result in increased operative complexity, ischemic time, and competition for resources and anatomic territory. Dual thoracic recovery from circulatory death donors may have additional risks that are not fully understood. We investigated the effects of dual heart and lung recovery from circulatory death donors on thoracic transplant outcomes. METHODS: Using the United Network for Organ Sharing database, we categorized all adult thoracic circulatory death donor transplants from 2019 to 2023 by whether the donor heart, lung, or both (dual donors) were recovered. Heart and lung transplant outcomes were compared between dual recovery donors and heart-only or lung-only donors, respectively, using multivariable analyses. RESULTS: Of the 2513 donors included, 42.9% were heart-only, 45.0% were lung-only, and 12.0% were dual donors. Recipients of dual versus heart-only donors had similar likelihood of post-transplant dialysis (18.9% vs 18.3%, P = .84), likelihood of stroke (2.9% vs 4.7%, P = .34), and 2-year risk of mortality (adjusted hazard ratio, 1.15 [95% CI, 0.90-1.47], P = .26), but lower likelihood of acute rejection (10.2% vs 16.1%, P = .04). Recipients of dual and lung-only donors had similar likelihood of predischarge acute rejection (7.6% vs 8.5%, P = .70), intubation at 72 hours (38.9% vs 45.1%, P = .13), and extracorporeal membrane oxygenation at 72 hours (13.1% vs 18.1%, P = .11), as well as 2-year risk of mortality (adjusted hazard ratio, 1.16 [95% CI, 0.74-1.82], P = .52). CONCLUSIONS: Recovering both the heart and lungs from a circulatory death donor does not negatively impact transplant outcomes. Outcomes in this population should continue to be investigated as more data and longer-term follow-up become available.
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BACKGROUND: Ivacaftor (IVA) has been shown to improve lung function and other clinical outcomes in people with cystic fibrosis (CF). A decade of real-world IVA availability has enabled the examination of long-term outcomes with this treatment. This retrospective, longitudinal cohort study investigated the impact of IVA on mortality rate and health outcomes among people with CF in the US. METHODS: Data from the US CF Foundation Patient Registry from January 2010 to December 2019 were analysed. The IVA-treated cohort included people with a CF transmembrane conductance regulator (CFTR) gating mutation (excluding R117H); age-matched comparator cohort included people with a F508del and a minimal function CFTR mutation who had no prior CFTR modulator treatment. Baseline characteristics were balanced between cohorts using standardised mortality ratio weighting generated from propensity scores. Outcomes of interest were overall survival, lung transplant, percent predicted forced expiratory volume in 1 s (ppFEV1), body mass index (BMI), pulmonary exacerbations (PEx), outpatient visits and hospitalisations. FINDINGS: Over a maximum follow-up of 7.9 years, the IVA-treated cohort (N=736) had lower rates of mortality (hazard ratio [HR] (95% CI): 0.22 (0.09 to 0.45)), lung transplant (HR: 0.11 (95% CI 0.02 to 0.28)), PEx (rate ratio: 0.49 (95% CI 0.42 to 0.55)) and all-cause hospitalisations (rate ratio: 0.50 (95% CI 0.43 to 0.56)) as well as better lung function (mean difference in ppFEV1: 8.46 (95% CI 7.34 to 9.75)) and higher BMI/BMI z-scores (mean difference 1.20 (95% CI 0.92 to 1.71) kg/m2 and 0.27 (95% CI 0.25 to 0.40), respectively) than the comparator cohort (N=733). INTERPRETATION: Our analysis suggests that IVA provides sustained clinical benefits in people with CF over a follow-up period of approximately 8 years. These findings reinforce the existing real-world evidence that IVA can slow disease progression and decrease the healthcare burden of CF over the long term.
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Objective: The "July Effect" is a theory that the influx of trainees from July to September negatively impacts patient outcomes. We aimed to study this theoretical phenomenon in lung transplant recipients given the highly technical nature of thoracic procedures. Methods: Adult lung transplant hospitalizations were identified within the National Inpatient Sample (2005-2020). Recipients were categorized as academic Q1 (July to September) or Q2-Q4 (October to June). In-hospital mortality, operator-driven complications (pneumothorax, dehiscence including wound dehiscence, bronchial anastomosis, and others, and vocal cord/diaphragm paralysis, all 3 treated as a composite outcome), length of stay, and inflation-adjusted hospitalization charges were compared between both groups. Multivariable logistic regression was performed to assess the association between academic quarter and in-hospital mortality and operator-driven complications. The models were adjusted for recipient demographics and transplant characteristics. Subgroup analysis was performed between academic and nonacademic hospitals. Results: Of 30,788 lung transplants, 7838 occurred in Q1 and 22,950 occurred in Q2-Q4. Recipient demographic and clinical characteristics were similar between groups. Dehiscence (n = 922, 4% vs n = 236, 3%), post-transplant cardiac arrest (n = 532, 2% vs n = 113, 1%), and pulmonary embolism (n = 712, 3% vs n = 164, 2%) were more common in Q2-Q4 versus Q1 recipients (all P < .05). Other operator-driven complications, in-hospital mortality, and resource use were similar between groups (P > .05). These inferences remained unchanged in adjusted analyses and on subgroup analyses of academic versus nonacademic hospitals. Conclusions: The "July Effect" is not evident in US lung transplantation recipient outcomes during the transplant hospitalization. This suggests that current institutional monitoring systems for trainees across multiple specialties, including surgery, anesthesia, critical care, nursing, and others, are robust.
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BACKGROUND: Ivacaftor (IVA) improves lung function and other extrapulmonary outcomes in people with cystic fibrosis (CF). However, the effect of initiating IVA at earlier versus later ages has not been studied. METHODS: We conducted an observational cohort study of people in the US CF Foundation Patient Registry aged ≥6 years with ≥1 CF transmembrane conductance regulator-gating mutation to compare the effects of initiating IVA at earlier ages on per cent predicted forced expiratory volume in 1 s (ppFEV1) and pulmonary exacerbation (PEx) outcomes. People with CF were grouped by age at IVA initiation (ages 6-10, 11-15, 16-20 and 21-25 years) to perform three analyses of younger versus older IVA initiation (6-10 vs 11-15, 11-15 vs 16-20 and 16-20 vs 21-25 years). For each analysis, baseline characteristics assessed over 1-year periods at the same age prior to IVA initiation were balanced by standardised mortality/morbidity ratio (SMR) weighting. For each analysis, outcomes were compared over a 5-year outcome assessment period when both groups were in the same age range and receiving IVA. FINDINGS: Baseline characteristics were well balanced between younger and older IVA initiator groups after SMR weighting. In the outcome assessment period, younger IVA initiators had significantly higher mean ppFEV1 than older initiators across all comparisons, and those initiating IVA between ages 6-10 and 11-15 years had significantly lower PEx rates. INTERPRETATION: Study findings showed the importance of early IVA initiation in people with CF.
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OBJECTIVE: On November 24, 2017, lung transplant allocation switched from donation service area to a 250-nautical mile radius policy to improve equity in access to lung transplantation. Given the growing consideration of healthcare costs, we evaluated changes in hospitalization costs after this policy change. METHODS: Lung transplant hospitalizations were identified within the National Inpatient Sample from 2005 to 2020. Recipients were categorized as donation service area era (August 2015 to October 2017) or non-donation service area era (December 2017 to February 2020). Median total hospitalization costs (inflation adjusted) were compared by era nationally and regionally. Multivariable generalized linear regression was performed to determine if the removal of the donation service area was associated with total hospitalization costs. The model was adjusted for recipient demographics, Charlson Comorbidity Index, hospitalization region, transplant type (single, double), and use of extracorporeal membrane oxygenation, ex vivo lung perfusion, and mechanical ventilation. RESULTS: We analyzed 12,985 lung transplant recipients (median age of 61 years, 66% were male): 7070 in the donation service area era and 5915 in the non-donation service area era. Demographics were not different between recipients in both eras. Non-donation service area era recipients had greater extracorporeal membrane oxygenation use, mechanical ventilation (<24 hours), and longer length of stay than donation service area era recipients. Median total hospitalization costs for non-donation service area versus donation service area era recipients increased by $24,198 ($157,964 vs $182,162, percentage change = 15.32%, P < .001). Median costs increased in East North Central ($42,281) and Mountain ($35,521) regions (both P < .01). After adjustment, median costs for non-donation service area versus donation service area era recipients still increased ($19,168, 95% CI, 145-38,191, P = .048). CONCLUSIONS: Hospitalization costs for lung transplant hospitalizations have increased from 2015 to 2020. The transition from donation service area-based allocation to the non-donation service area system may have contributed to this increase after 2017 by increasing access to transplant for sicker recipients.
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BACKGROUND: The Lung Allocation Score, implemented in 2005, prioritized lung transplant candidates by medical urgency rather than waiting list time and was expected to improve racial disparities in transplant allocation. We evaluated whether racial disparities in lung transplant persisted after 2005. METHODS: We identified all wait-listed adult lung transplant candidates in the United States from 2005 through 2021 using the Scientific Registry of Transplant Recipients. We evaluated the association between race and receipt of a transplant by using a multivariable competing risk regression model adjusted for demographics, socioeconomic status, Lung Allocation Score, clinical measures, and time. We evaluated interactions between race and age, sex, socioeconomic status, and Lung Allocation Score. RESULTS: We identified 33,158 candidates on the lung transplant waiting list between 2005 and 2021: 27,074 White (82%), 3350 African American (10%), and 2734 Hispanic (8%). White candidates were older, had higher education levels, and had lower Lung Allocation Scores (P < .001). After multivariable adjustment, African American and Hispanic candidates were less likely to receive lung transplants than White candidates (African American: adjusted subhazard ratio, 0.86; 95% CI, 0.82-0.91; Hispanic: adjusted subhazard ratio, 0.82; 95% CI, 0.78-0.87). Lung transplant was significantly less common among Hispanic candidates aged >65 years (P = .003) and non-White candidates from higher-poverty communities (African-American: P = .013; Hispanic: P =.0036). CONCLUSIONS: Despite implementation of the Lung Allocation Score, racial disparities persisted for wait-listed African American and Hispanic lung transplant candidates and differed by age and poverty status. Targeted interventions are needed to ensure equitable access to this life-saving intervention.
Subject(s)
Healthcare Disparities , Lung Transplantation , Waiting Lists , Adult , Humans , Black or African American/statistics & numerical data , Healthcare Disparities/ethnology , Healthcare Disparities/statistics & numerical data , Hispanic or Latino/statistics & numerical data , Lung Transplantation/statistics & numerical data , Outcome Assessment, Health Care , United States/epidemiology , White/statistics & numerical dataABSTRACT
Extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplant (BTT) has been used for critically ill candidates with excellent outcomes, but data on this strategy in older recipients remain limited. We compared outcomes of no BTT, mechanical ventilation (MV)-only BTT, and ECMO BTT in recipients of greater than or equal to 65 years. Lung-only recipients of greater than or equal to 65 years in the United Network for Organ Sharing database between 2008 and 2022 were included and stratified by bridging strategy. Of the 9,936 transplants included, 226 (2.3%) were MV-only BTT and 159 (1.6%) were ECMO BTT. Extracorporeal membrane oxygenation BTT recipients were more likely to have restrictive disease pathology, had higher median lung allocation score, and spent fewer days on the waitlist (all p < 0.001). Compared to no-BTT recipients, ECMO BTT recipients were more likely to be intubated or on ECMO at 72 hours posttransplant and had longer hospital lengths of stay (all p < 0.001). Extracorporeal membrane oxygenation BTT recipients had increased risk of 3 years mortality compared to both no-BTT (adjusted hazard ratio [aHR] = 1.48 [95% confidence interval {CI}: 1.14-1.91], p = 0.003) and MV-only recipients (aHR = 1.50 [95% CI: 1.08-2.07], p = 0.02). Overall, we found that ECMO BTT in older recipients is associated with inferior posttransplant outcomes compared to MV-only or no BTT, but over half of recipients remained alive at 3 years posttransplant.
Subject(s)
Extracorporeal Membrane Oxygenation , Lung Transplantation , Treatment Outcome , Extracorporeal Membrane Oxygenation/adverse effects , Retrospective Studies , Lung Transplantation/adverse effects , Proportional Hazards ModelsABSTRACT
Rationale: Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Prior studies implicated proxy-defined donor smoking as a risk factor for PGD and mortality. Objectives: We aimed to more accurately assess the impact of donor smoke exposure on PGD and mortality using quantitative smoke exposure biomarkers. Methods: We performed a multicenter prospective cohort study of lung transplant recipients enrolled in the Lung Transplant Outcomes Group cohort between 2012 and 2018. PGD was defined as grade 3 at 48 or 72 hours after lung reperfusion. Donor smoking was defined using accepted thresholds of urinary biomarkers of nicotine exposure (cotinine) and tobacco-specific nitrosamine (4-[methylnitrosamino]-1-[3-pyridyl]-1-butanol [NNAL]) in addition to clinical history. The donor smoking-PGD association was assessed using logistic regression, and survival analysis was performed using inverse probability of exposure weighting according to smoking category. Measurements and Main Results: Active donor smoking prevalence varied by definition, with 34-43% based on urinary cotinine, 28% by urinary NNAL, and 37% by clinical documentation. The standardized risk of PGD associated with active donor smoking was higher across all definitions, with an absolute risk increase of 11.5% (95% confidence interval [CI], 3.8% to 19.2%) by urinary cotinine, 5.7% (95% CI, -3.4% to 14.9%) by urinary NNAL, and 6.5% (95% CI, -2.8% to 15.8%) defined clinically. Donor smoking was not associated with differential post-lung transplant survival using any definition. Conclusions: Donor smoking associates with a modest increase in PGD risk but not with increased recipient mortality. Use of lungs from smokers is likely safe and may increase lung donor availability. Clinical trial registered with www.clinicaltrials.gov (NCT00552357).
Subject(s)
Lung Transplantation , Primary Graft Dysfunction , Smoking , Tissue Donors , Humans , Biomarkers , Cotinine , Lung Transplantation/adverse effects , Primary Graft Dysfunction/epidemiology , Prospective Studies , Smoking/adverse effectsABSTRACT
OBJECTIVE: End-stage lung disease from severe COVID-19 infection is an increasingly common indication for lung transplantation (LT), but there are limited data on outcomes. We evaluated 1-year COVID-19 LT outcomes. METHODS: We identified all adult US LT recipients January 2020 to October 2022 in the Scientific Registry for Transplant Recipients, using diagnosis codes to identify recipients transplanted for COVID-19. We used multivariable regression to compare in-hospital acute rejection, prolonged ventilator support, tracheostomy, dialysis, and 1-year mortality between COVID-19 and non-COVID-19 recipients, adjusting for donor, recipient, and transplant characteristics. RESULTS: LT for COVID-19 increased from 0.8% to 10.7% of total LT volume during 2020 to 2021. The number of centers performing LT for COVID-19 increased from 12 to 50. Recipients transplanted for COVID-19 were younger; were more likely to be male and Hispanic; were more likely to be on a ventilator, extracorporeal membrane oxygenation support, and dialysis pre-LT; were more likely to receive bilateral LT; and had higher lung allocation score and shorter waitlist time than other recipients (all P values < .001). COVID-19 LT had higher risk of prolonged ventilator support (adjusted odds ratio, 2.28; P < .001), tracheostomy (adjusted odds ratio 5.3; P < .001), and longer length of stay (median, 27 vs 19 days; P < .001). Risk of in-hospital acute rejection (adjusted odds ratio, 0.99; P = .95) and 1-year mortality (adjusted hazard ratio, 0.73; P = .12) were similar for COVID-19 LTs and LTs for other indications, even accounting for center-level differences. CONCLUSIONS: COVID-19 LT is associated with higher risk of immediate postoperative complications but similar risk of 1-year mortality despite more severe pre-LT illness. These encouraging results support the ongoing use of LT for COVID-19-related lung disease.
Subject(s)
COVID-19 , Lung Diseases , Lung Transplantation , Adult , Humans , Male , Female , Renal Dialysis , Lung Transplantation/adverse effects , Tissue Donors , Lung Diseases/surgery , Retrospective StudiesABSTRACT
OBJECTIVE: To determine whether allograft ischemic times affect outcomes following bilateral, single, and redo lung transplantation. METHODS: A nationwide cohort of lung transplant recipients from 2005 through 2020 was examined using the Organ Procurement and Transplantation Network registry. The effects of standard (<6 hours) and extended (≥6 hours) ischemic times on outcomes following primary bilateral (n = 19,624), primary single (n = 688), redo bilateral (n = 8461), and redo single (n = 449) lung transplantation were analyzed. A priori subgroup analysis was performed in the primary and redo bilateral-lung transplant cohorts by further stratifying the extended ischemic time group into mild (≥6 and <8 hours), moderate (≥8 and <10 hours), and long (≥10 hours) subgroups. Primary outcomes included 30-day mortality, 1-year mortality, intubation at 72 hours' posttransplant, extracorporeal membrane oxygenation (ECMO) support at 72 hours' posttransplant, and a composite variable of intubation or ECMO at 72 hours' posttransplant. Secondary outcomes included acute rejection, postoperative dialysis, and hospital length of stay. RESULTS: Recipients of allografts with ischemic times ≥6 hours experienced increased 30-day and 1-year mortality following primary bilateral-lung transplantation, but increased mortality was not observed following primary single, redo bilateral, or redo single-lung transplants. Extended ischemic times correlated with prolonged intubation or increased postoperative ECMO support in the primary bilateral, primary single, and redo bilateral-lung transplant cohorts but did not affect these outcomes following redo single-lung transplantation. CONCLUSIONS: Since prolonged allograft ischemia correlates with worse transplant outcomes, the decision to use donor lungs with extended ischemic times must consider the specific benefits and risks associated with individual recipient factors and institutional expertise.
Subject(s)
Lung Transplantation , Renal Dialysis , Humans , Retrospective Studies , Time Factors , Lung Transplantation/adverse effects , Ischemia , AllograftsABSTRACT
BACKGROUND: With the increasing age of lung transplant candidates, we studied waitlist and posttransplantation outcomes of candidates ≥70 years during the Lung Allocation Score era. METHODS: Adult lung transplant candidates from 2005 to 2020 in the United Network for Organ Sharing database were included and stratified on the basis of age at listing into 18 to 59 years old, 60 to 69 years old, and ≥70 years old. Baseline characteristics, waitlist outcomes, and posttransplantation outcomes were assessed. RESULTS: A total of 37,623 candidates were included (52.3% aged 18-59 years, 40.6% aged 60-69 years, 7.1% aged ≥70 years). Candidates ≥70 years were more likely than younger candidates to receive a transplant (81.9% vs 72.7% [aged 60-69 years] vs 61.6% [aged 18-59 years]) and less likely to die or to deteriorate on the waitlist within 1 year (9.1% vs 10.1% [aged 60-69 years] vs 12.2% [aged 18-59 years]; P < .001). Donors for older recipients were more likely to be extended criteria (75.7% vs 70.1% [aged 60-69 years] vs 65.7% [aged 18-59 years]; P < .001). Recipients ≥70 years were found to have lower rates of acute rejection (6.7% vs 7.4% [aged 60-69 years] vs 9.2% [aged 18-59 years]; P < .001) and prolonged intubation (21.7% vs 27.4% [aged 60-69 years] vs 34.5% [aged 18-59 years]; P < .001). Recipients aged ≥70 years had increased 1-year (adjusted hazard ratio [aHR], 1.19 [95% CI, 1.06-1.33]; P < .001), 3-year (aHR, 1.28 [95% CI, 1.18-1.39]; P < .001), and 5-year mortality (aHR, 1.29 [95% CI, 1.21-1.38]; P < .001) compared with recipients aged 60 to 69 years. CONCLUSIONS: Candidates ≥70 years had favorable waitlist and perioperative outcomes despite increased use of extended criteria donors. Careful selection of candidates and postoperative surveillance may improve posttransplantation survival in this population.
Subject(s)
Lung Transplantation , Tissue Donors , Adult , Humans , Adolescent , Young Adult , Middle Aged , Aged , Proportional Hazards Models , Registries , Waiting Lists , Lung , Retrospective StudiesABSTRACT
BACKGROUND: Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Accurate prediction of PGD risk could inform donor approaches and perioperative care planning. We sought to develop a clinically useful, generalizable PGD prediction model to aid in transplant decision-making. METHODS: We derived a predictive model in a prospective cohort study of subjects from 2012 to 2018, followed by a single-center external validation. We used regularized (lasso) logistic regression to evaluate the predictive ability of clinically available PGD predictors and developed a user interface for clinical application. Using decision curve analysis, we quantified the net benefit of the model across a range of PGD risk thresholds and assessed model calibration and discrimination. RESULTS: The PGD predictive model included distance from donor hospital to recipient transplant center, recipient age, predicted total lung capacity, lung allocation score (LAS), body mass index, pulmonary artery mean pressure, sex, and indication for transplant; donor age, sex, mechanism of death, and donor smoking status; and interaction terms for LAS and donor distance. The interface allows for real-time assessment of PGD risk for any donor/recipient combination. The model offers decision-making net benefit in the PGD risk range of 10% to 75% in the derivation centers and 2% to 10% in the validation cohort, a range incorporating the incidence in that cohort. CONCLUSION: We developed a clinically useful PGD predictive algorithm across a range of PGD risk thresholds to support transplant decision-making, posttransplant care, and enrich samples for PGD treatment trials.
Subject(s)
Lung Transplantation , Primary Graft Dysfunction , Humans , Risk Factors , Risk Assessment , Primary Graft Dysfunction/diagnosis , Primary Graft Dysfunction/epidemiology , Prospective Studies , Retrospective StudiesABSTRACT
BACKGROUND: This study compared utilization and outcomes of the 2 widely utilized ex vivo lung perfusion (EVLP) platforms in the United States: a static platform and a portable platform. METHODS: Adult (age 18 years or older) bilateral lung-only transplants utilizing EVLP between February 28, 2018, and December 31, 2022, in the United Network for Organ Sharing database were included. Predischarge acute rejection, intubation at 72 hours posttransplant, extracorporeal membrane oxygenation at 72 hours posttransplant, primary graft dysfunction grade 3 at 72 hours posttransplant, 30-day mortality, and 1-year mortality were evaluated using multivariable regressions. RESULTS: Overall, 607 (6.3%) lung transplants during the study period used EVLP (51.2% static, 48.8% portable). Static EVLP was primarily utilized in the eastern United States, whereas portable EVLP was primarily utilized in the western United States. Static EVLP donors were more likely to be donation after circulatory death (33.4% vs 26.0%; P = .005), have a >20 pack-year smoking history (13.5% vs 6.5%; P = .005), and be extended criteria donors (92.3% vs 85.0%; P = .013), whereas portable EVLP donors were more likely to be older than age 55 years (14.2% vs 8.0%; P = .02). Transplants utilizing the static and portable platforms had similar risk of acute rejection, intubation at 72 hours, extracorporeal membrane oxygenation at 72 hours, primary graft dysfunction grade 3 at 72 hours, and posttransplant mortality at 30 days and 1 year (all P values > .05). CONCLUSIONS: The static and portable platforms had significant differences in donor characteristics and geographic distributions of utilization. Despite this, posttransplant survival was similar between the 2 EVLP platforms.
Subject(s)
Lung Transplantation , Perfusion , Humans , Lung Transplantation/mortality , Lung Transplantation/statistics & numerical data , Lung Transplantation/trends , Male , Female , Middle Aged , United States , Adult , Perfusion/methods , Perfusion/mortality , Perfusion/adverse effects , Perfusion/instrumentation , Treatment Outcome , Retrospective Studies , Time Factors , Databases, Factual , Risk Factors , Graft Rejection , Graft Survival , AgedABSTRACT
OBJECTIVE: Lung transplants from donors with hepatitis C (HCV D+) have excellent outcomes, but these organs continue to be declined. We evaluated whether (1) being listed to consider and (2) accepting versus declining HCV D+ offers provided a survival benefit to lung transplant candidates. METHODS: Using the Scientific Registry of Transplant Recipients, we identified all adult (≥18 years) lung transplant candidates 2016-2021 and compared waitlist mortality between those willing versus not willing to consider HCV D+ offers using competing risk regression. We identified all candidates offered an HCV D+ lung that was later accepted and followed them from offer decision until death or end-of-study. We estimated adjusted mortality risk of accepting versus declining an HCV D+ lung offer using propensity-weighted Cox regression. RESULTS: From 2016 to 2021, we identified 21,007 lung transplant candidates, 33.8% of whom were willing to consider HCV D+ offers. Candidates willing to consider HCV D+ offers had a 17% lower risk of waitlist mortality (subhazard ratio, 0.83; 95% confidence interval, 0.75-0.91, P < .001). Over the same period, 665 HCV D+ lung offers were accepted after being declined a total of 2562 times. HCV D+ offer acceptance versus decline was associated with a 20% lower risk of mortality (adjusted hazard ratio, 0.80; 95% confidence interval, 0.66-0.96, P = .02). CONCLUSIONS: Considering HCV D+ lung offers was associated with a 17% lower risk of waitlist mortality, whereas accepting versus declining an HCV D+ lung offer was associated with a 20% lower risk of mortality. Centers and candidates should consider accepting suitable HCV D+ lung offers to optimize outcomes.
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Canonical splice site variants affecting the 5' GT and 3' AG nucleotides of introns result in severe missplicing and account for about 10% of disease-causing genomic alterations. Treatment of such variants has proven challenging due to the unstable mRNA or protein isoforms that typically result from disruption of these sites. Here, we investigate CRISPR-Cas9-mediated adenine base editing for such variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. We validate a CFTR expression minigene (EMG) system for testing base editing designs for two different targets. We then use the EMG system to test non-standard single-guide RNAs with either shortened or lengthened protospacers to correct the most common cystic fibrosis-causing variant in individuals of African descent (c.2988+1G>A). Varying the spacer region length allowed placement of the editing window in a more efficient context and enabled use of alternate protospacer adjacent motifs. Using these modifications, we restored clinically significant levels of CFTR function to human airway epithelial cells from two donors bearing the c.2988+1G>A variant.
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Rationale: Interpretation of spirometry using race-specific reference equations may contribute to health disparities via underestimation of the degree of lung function impairment in Black patients. The use of race-specific equations may differentially affect patients with severe respiratory disease via the use of percentage predicted forced vital capacity (FVCpp) when included in the lung allocation score (LAS), the primary determinant of priority for lung transplantation. Objectives: To determine the impact of a race-specific versus a race-neutral approach to spirometry interpretation on the LAS among adults listed for lung transplantation in the United States. Methods: We developed a cohort from the United Network for Organ Sharing database including all White and Black adults listed for lung transplantation between January 7, 2009, and February 18, 2015. The LAS at listing was calculated for each patient under race-specific and race-neutral approaches, using the FVCpp generated from the Global Lung Function Initiative equation corresponding to each patient's race (race-specific) or from the Global Lung Function Initiative "other" (race-neutral) equation. Differences in LAS between approaches were compared by race, with positive values indicating a higher LAS under the race-neutral approach. Results: In this cohort of 8,982 patients, 90.3% were White and 9.7% were Black. The mean FVCpp was 4.4% higher versus 3.8% lower among White versus Black patients (P < 0.001) under a race-neutral compared with a race-specific approach. Compared with White patients, Black patients had a higher mean LAS under both a race-specific (41.9 vs. 43.9; P < 0.001) and a race-neutral (41.3 vs. 44.3; P < 0.001) approach. However, the mean difference in LAS under a race-neutral approach was -0.6 versus +0.6 for White versus Black patients (P < 0.001). Differences in LAS under a race-neutral approach were most pronounced for those in group B (pulmonary vascular disease) (-0.71 vs. +0.70; P < 0.001) and group D (restrictive lung disease) (-0.78 vs. +0.68; P < 0.001). Conclusions: A race-specific approach to spirometry interpretation has potential to adversely affect the care of Black patients with advanced respiratory disease. Compared with a race-neutral approach, a race-specific approach resulted in lower LASs for Black patients and higher LASs for White patients, which may have contributed to racially biased allocation of lung transplantation. The future use of race-specific equations must be carefully considered.
Subject(s)
Lung Diseases , Lung Transplantation , Adult , Humans , United States , Lung , Vital Capacity , Spirometry , Waiting ListsABSTRACT
Thoracoabdominal normothermic regional perfusion (TA-NRP) has recently begun being utilized in the United States for recovery of cardiothoracic allografts from some donors after circulatory death (DCD), but data on lungs recovered in this method is limited to case reports. We conducted a national retrospective review of lung transplants from DCD donors recovered using TA-NRP. Of the 434 total DCD lung transplants performed between January 2020 and March 2022, 17 were recovered using TA-NRP. Compared to direct recovery DCD transplants, recipients of TA-NRP DCD transplants had lower likelihood of ventilation >48 hours (23.5% vs 51.3%, p = 0.027) and similar likelihood of predischarge acute rejection, requirement for extracorporeal membrane oxygenation at 72 hours, hospital lengths of stay, and survival at 30, 60, and 90 days post-transplant. These early data suggest that DCD lung recovery using TA-NRP might be a safe way to further expand the donor pool and warrant further study.
Subject(s)
Extracorporeal Membrane Oxygenation , Tissue and Organ Procurement , Humans , Graft Survival , Perfusion/methods , Tissue Donors , Lung , Retrospective Studies , Death , Organ Preservation/methodsABSTRACT
OBJECTIVE: The feasibility and 6-month outcome safety of lung transplants (LTs) from hepatitis C virus (HCV)-viremic donors for HCV-seronegative recipients (R-) were established in 2019, but longer-term safety and uptake of this practice nationally remain unknown. METHODS: We identified HCV-seronegative LT recipients (R-) 2015-2020 using the Scientific Registry of Transplant Recipients. We classified donors as seronegative (D-) or viremic (D+). We used χ2 testing, rank-sum testing, and Cox regression to compare posttransplant outcomes between HCV D+/R- and D-/R- LT recipients. RESULTS: HCV D+/R- LT increased from 2 to 97/year; centers performing HCV D+/R- LT increased from 1 to 25. HCV D+/R- versus HCV D-/R- LT recipients had more obstructive disease (35.7% vs 23.3%, P < .001), lower lung allocation score (36.5 vs 41.1, P < .001), and longer waitlist time (P = .002). HCV D+/R- LT had similar risk of acute rejection (adjusted odds ratio [aOR], 0.87; P = .58), extracorporeal membranous oxygenation (aOR, 1.94; P = .10), and tracheostomy (aOR, 0.42; P = .16); similar median hospital stay (P = .07); and lower risk of ventilator > 48 hours (aOR, 0.68; P = .006). Adjusting for donor, recipient, and transplant characteristics, risk of all-cause graft failure and mortality were similar at 30 days, 1 year, and 3 years for HCV D+/R- versus HCV D-/R- LT (all P > .1), as well as for high- (≥20/year) versus low-volume LT centers and high- (≥5/year) versus low-volume HCV D+/R- LT centers (all P > .5). CONCLUSIONS: HCV D+/R- and HCV D-/R- LT have similar outcomes at 3 years posttransplant. These results underscore the safety of HCV D+/R- LT and the potential benefit of expanding this practice further.
Subject(s)
Hepatitis C , Liver Transplantation , Humans , Hepacivirus , Tissue Donors , RegistriesABSTRACT
Single-center studies have suggested that up to 70% of adults with cystic fibrosis (CF) have lower than expected bone mineral density (BMD), substantially higher than the 25% prevalence reported from national registries. We determined the prevalence of low BMD in CF adults at our center and assessed risk factors for low BMD. This retrospective cohort study was conducted in all CF patients ≥18 years of age who had a dual-energy X-ray absorptiometry (DXA) scan performed at the Johns Hopkins Adult Cystic Fibrosis center between 2010 and 2018. Prevalence and incidence of low BMD during the study period were determined. Poisson regression based on generalized estimating equations and robust standard errors were used to evaluate selected risk factors and risk of disease progression. A total of 234 individuals underwent an initial DXA scan. At this scan, prevalence of low BMD was 52.6% (95% confidence interval [CI] 46.0-59.1). A total of 43.6% were at risk for CF-related low BMD (AR-CFLBMD) (95% CI 37.1-50.2) and 9.0% had CF-related low BMD (CFRLBMD) (95% CI 5.6-13.4). Of the 25 with normal BMD at initial scan and a subsequent follow-up scan, 8 (32.0%) progressed to AR-CFLBMD. Of the 53 with AR-CFLBMD on initial scan and a subsequent scan, 6 (11.3%) progressed to CFLBMD, 9 (17.0%) returned to normal BMD, and 38 (71.7%) remained AR-CFLBMD. Older age (relative risk [RR] = 1.01; 95% CI 1.00-1.01) and male sex (RR = 1.32; 95% CI 1.04-1.66) were associated with increased risk of low BMD, while higher forced expiratory volume over 1 second (FEV1%) predicted (RR = 0.99; 95% CI 0.99-1.00) and body mass index (BMI; RR = 0.97; 95% CI 0.94-1.00) were associated with lower risk for low BMD. The fact that more than half of all individuals were found to have lower than expected BMD suggests that the actual prevalence may be higher than currently reported in national registries. This supports the importance of universal bone health screening of all CF adults. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.