Impact of Dual Thoracic Recovery from Circulatory Death Donors on Heart and Lung Transplant Outcomes.

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 (DCD) may have additional risks that are not fully understood. We investigated the effects of dual heart and lung recovery from DCD donors on thoracic transplant outcomes. METHODS: Using the United Network for Organ Sharing database, we categorized all adult thoracic DCD transplants 2019-2023 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 2,513 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=0.84), likelihood of stroke (2.9% vs. 4.7%, p=0.34), and 2-year risk of mortality (aHR 1.15 [95% CI: 0.90-1.47], p=0.26), but lower likelihood of acute rejection (10.2% vs. 16.1%, p=0.04). Recipients of dual and lung-only donors had similar likelihood of pre-discharge acute rejection (7.6% vs. 8.5%, p=0.70), intubation at 72 hours (38.9% vs. 45.1%, p=0.13), and ECMO at 72 hours (13.1% vs. 18.1%, p=0.11), as well as 2-year risk of mortality (aHR 1.16 [95% CI: 0.74-1.82], p=0.52). CONCLUSIONS: Recovering both the heart and lungs from a DCD 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.

Long-term impact of ivacaftor on mortality rate and health outcomes in people with cystic fibrosis.

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.

Debunking the July Effect in lung transplantation recipients.

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.

Impact of age at ivacaftor initiation on pulmonary outcomes among people with cystic fibrosis.

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.

Bigger pies, bigger slices: Increased hospitalization costs for lung transplantation recipients in the non-donation service area allocation era.

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.

Racial Disparities in Waiting List Outcomes of Patients Listed for Lung Transplantation.

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.

Uptake and 1-year outcomes of lung transplantation for COVID-19.

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.

The effect of allograft ischemic time on outcomes following bilateral, single, and reoperative lung transplantation.

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.

Development and validation of primary graft dysfunction predictive algorithm for lung transplant candidates.

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.

The Impact of Donor Smoking on Primary Graft Dysfunction and Mortality after Lung Transplantation.

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).

Outcomes of Lung Transplant Candidates Aged ≥70 Years During the Lung Allocation Score Era.

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.

National utilization, trends, and lung transplant outcomes of static versus portable ex vivo lung perfusion platforms.

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.

To decline or not to decline: Consequences of decision-making regarding lung offers from donors with hepatitis C.

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.

Protospacer modification improves base editing of a canonical splice site variant and recovery of CFTR function in human airway epithelial cells.

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.

Trends in use and three-year outcomes of hepatitis C virus-viremic donor lung transplants for hepatitis C virus-seronegative recipients.

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.

Prevalence and Risk Factors for Low Bone Mineral Density in Adults With Cystic Fibrosis.

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.

CFTR bearing variant p.Phe312del exhibits function inconsistent with phenotype and negligible response to ivacaftor.

The chloride channel dysfunction caused by deleterious cystic fibrosis transmembrane conductance regulator (CFTR) variants generally correlates with severity of cystic fibrosis (CF). However, 3 adults bearing the common severe variant p.Phe508del (legacy: F508del) and a deletion variant in an ivacaftor binding region of CFTR (p.Phe312del; legacy: F312del) manifested only elevated sweat chloride concentration (sw[Cl-]; 87-105 mEq/L). A database review of 25 individuals with F312del and a CF-causing variant revealed elevated sw[Cl-] (75-123 mEq/L) and variable CF features. F312del occurs at a higher-than-expected frequency in the general population, confirming that individuals with F312del and a CF-causing variant do not consistently develop overt CF features. In primary nasal cells, CFTR bearing F312del and F508del generated substantial chloride transport (66.0% ± 4.5% of WT-CFTR) but did not respond to ivacaftor. Single-channel analysis demonstrated that F312del did not affect current flow through CFTR, minimally altered gating, and ablated the ivacaftor response. When expressed stably in CF bronchial epithelial (CFBE41o-) cells, F312del-CFTR demonstrated residual function (50.9% ± 3.3% WT-CFTR) and a subtle decrease in forskolin response compared with WT-CFTR. F312del provides an exception to the established correlation between CFTR chloride transport and CF phenotype and informs our molecular understanding of ivacaftor response.

Lung Volume Reduction Surgery Before Lung Transplantation: A Propensity-Matched Analysis.

BACKGROUND: Lung volume reduction surgery (LVRS) is treatment option for chronic obstructive pulmonary disease, the second most common indication for lung transplantation (LTx) in the United States. Lung volume reduction surgery before LTx is controversial. Single-institution studies report contradicting results, and the impact of undergoing LVRS before LTx on outcomes after LTx is unclear. METHODS: We reviewed the United Network for Organ Sharing database for all adults (aged more than 18 years) who underwent first-time LTx for chronic obstructive pulmonary disease in the lung allocation score era. We used patient demographic and clinical characteristics and lung allocation score to propensity match patients who did and patients who did not undergo LVRS before LTx. The primary exposure was prior LVRS. The primary outcome was graft failure after LTx. Unadjusted Kaplan-Meier and adjusted Cox proportional hazards models were used to assess outcomes. RESULTS: A total of 4905 patients with chronic obstructive pulmonary disease underwent LTx between May 2005 and March 2017. Of them, 107 patients (2.2%) underwent LVRS before LTx. Propensity matching generated 212 matches (106 LVRS+LTx, and 106 LTx only). Median survival was significantly longer in the LTx only cohort (6.5 vs 3.4 years, P = .034). Lung volume reduction surgery before lung transplantation was associated with significantly increased risk of graft failure after lung transplant (hazard ratio 1.72; 95% confidence interval, 1.13 to 2.60; P = .01). CONCLUSIONS: In this national, propensity-matched analysis of LVRS before LTx, we show that LVRS is associated with a significantly increased risk of graft failure. Patients who undergo LVRS and remain in need of LTx should be carefully assessed and followed postoperatively.

Indoor air pollution exposure is associated with greater morbidity in cystic fibrosis.

BACKGROUND: Exposure to higher levels of outdoor air pollution is associated with increased morbidity in individuals with cystic fibrosis. Limited information exist regarding the potential adverse effects of indoor air pollution on those with cystic fibrosis. METHODS: Individuals with cystic fibrosis who were enrolled in the Twin and Sibling Study from 2000-2013, self-reported exposure to four known sources of indoor air pollution (secondhand smoke, forced hot air, wood stove and fireplace). Change in lung function, rates of hospitalizations and pulmonary exacerbations were followed over 4 years to compare outcomes in those who were exposed to those who were not exposed. RESULTS: Of 1432 participants with data on secondhand smoke exposure, 362 (25.3%) were exposed. Of 765 individuals with data on forced hot air exposure, 491 (64.2%) were exposed. Of 1247 participants with data on wood stove exposure and 830 with data on fireplace exposure, 182 (14.6%) and 373 (44.9%) were exposed, respectively. In longitudinal analysis, pediatric individuals either exposed to secondhand smoke or to forced hot air had a 0.60% predicted/year decrease in FEV1% predicted (P=0.002) or a 0.46% predicted/year decrease in FEV1% predicted (P=0.048), respectively compared to individuals who were not exposed. Adults exposed to secondhand smoke had a 42% increased yearly risk of hospitalization compared to those who were not exposed (P=0.045). CONCLUSIONS: Our questionnaire-based data suggest that exposure to sources of indoor air pollution increase morbidity in both the pediatric and adult cystic fibrosis populations. Future studies with quantitative indoor air quality assessments are needed.

Ambient Air Pollution and Adverse Waitlist Events Among Lung Transplant Candidates.

BACKGROUND: Air pollution is associated with cardiopulmonary disease and death in the general population. Fine particulate matter (PM2.5) is particularly harmful due to its ability to penetrate into areas of gas exchange within the lungs. Persons with advanced lung disease are believed to be particularly susceptible to PM2.5 exposure, but only a few studies have examined the effect of exposure on this population. Here we investigate the association between PM2.5 exposure and adverse waitlist events among lung transplant (LT) candidates. METHODS: US registry data were used to identify LT candidates listed between January 1, 2010 and December 31, 2016. Annual PM2.5 concentration at year of listing was estimated for each candidate's ZIP Code using National Aeronautics and Space Administration's (NASA) Socioeconomic Data and Applications Center Global Annual PM2.5 Grids. We estimated crude and adjusted hazard ratios for adverse waitlist events, defined as death or removal, using Cox proportional hazards regression. RESULTS: Of the 15 075 included candidates, median age at listing was 60, 43.8% were female individuals, and 81.7% were non-Hispanic White. Median ZIP Code PM2.5 concentration was 9.06 µg/m3. When compared with those living in ZIP Codes with lower PM2.5 exposure (PM2.5 <10.53 µg/m3), candidates in ZIP Codes in the highest quartile of PM2.5 exposure (≥10.53 µg/m3) had 1.14-fold (95% confidence interval, 1.04-1.25) risk of adverse waitlist events. The result remained significant after adjusting for demographics, education, insurance, smoking, lung allocation score, body mass index, and blood type (hazard ratio, 1.17; 95% confidence interval, 1.07-1.29). CONCLUSIONS: Elevated ambient PM2.5 concentration was associated with adverse waitlist events among LT candidates. These findings highlight the impact of air pollution on clinical outcomes in this critically ill population.