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.

Personalized cardiovascular risk assessment in Rheumatoid Arthritis patients using circulating molecular profiles and their modulation by TNFi, IL6Ri, and JAKinibs.

BACKGROUND & OBJECTIVES: This study aimed to: 1) analyze the inflammatory profile of Rheumatoid Arthritis (RA) patients, identifying clinical phenotypes associated with cardiovascular (CV) risk; 2) evaluate biologic and targeted-synthetic disease-modifying antirheumatic drugs (b-DMARDs and ts-DMARDs': TNFi, IL6Ri, JAKinibs) effects; and 3) characterize molecular mechanisms in immune-cell activation and endothelial dysfunction. PATIENTS & METHODS: A total of 387 RA patients and 45 healthy donors were recruited, forming three cohorts: i) 208 RA patients with established disease but without previous CV events; ii) RA-CVD: 96 RA patients with CV events, and iii) 83 RA patients treated with b-DMARDs/ts-DMARDs for 6 months. Serum inflammatory profiles (cytokines/chemokines/growth factors) and NETosis/oxidative stress-linked biomolecules were evaluated. Mechanistic in vitro studies were performed on monocytes, neutrophils and endothelial cells (EC). RESULTS: In the first RA-cohort, unsupervised clustering unveiled three distinct groups: cluster 3 (C3) displayed the highest inflammatory profile, significant CV-risk score, and greater atheroma plaques prevalence. In contrast, cluster 1 (C1) exhibited the lowest inflammatory profile and CV risk score, while cluster 2 (C2) displayed an intermediate phenotype. Notably, 2nd cohort RA-CVD patients mirrored C3's inflammation. Treatment with b-DMARDs or ts-DMARDs effectively reduced disease-activity scores (DAS28) and restored normal biomolecules levels, controlling CV risk. In vitro, serum from C3-RA or RA-CVD patients increased neutrophils activity and CV-related protein levels in cultured monocytes and EC, which were partially prevented by pre-incubation with TNFi, IL6Ri, and JAKinibs. CONCLUSIONS: Overall, analyzing circulating molecular profiles in RA patients holds potential for personalized clinical management, addressing CV risk and assisting healthcare professionals in tailoring treatment, ultimately improving outcomes.

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.

Better Understanding the Disparity Associated With Black Race in Heart Transplant Outcomes: A National Registry Analysis.

BACKGROUND: Black heart transplant recipients have higher risk of mortality than White recipients. Better understanding of this disparity, including subgroups most affected and timing of the highest risk, is necessary to improve care of Black recipients. We hypothesize that this disparity may be most pronounced among young recipients, as barriers to care like socioeconomic factors may be particularly salient in a younger population and lead to higher early risk of mortality. METHODS: We studied 22 997 adult heart transplant recipients using the Scientific Registry of Transplant Recipients data from January 2005 to 2017 using Cox regression models adjusted for recipient, donor, and transplant characteristics. RESULTS: Among recipients aged 18 to 30 years, Black recipients had 2.05-fold (95% CI, 1.67-2.51) higher risk of mortality compared with non-Black recipients (P<0.001, interaction P<0.001); however, the risk was significant only in the first year post-transplant (first year: adjusted hazard ratio, 2.30 [95% CI, 1.60-3.31], P<0.001; after first year: adjusted hazard ratio, 0.84 [95% CI, 0.54-1.29]; P=0.4). This association was attenuated among recipients aged 31 to 40 and 41 to 60 years, in whom Black recipients had 1.53-fold ([95% CI, 1.25-1.89] P<0.001) and 1.20-fold ([95% CI, 1.09-1.33] P<0.001) higher risk of mortality. Among recipients aged 61 to 80 years, no significant association was seen with Black race (adjusted hazard ratio, 1.12 [95% CI, 0.97-1.29]; P=0.1). CONCLUSIONS: Young Black recipients have a high risk of mortality in the first year after heart transplant, which has been masked in decades of research looking at disparities in aggregate. To reduce overall racial disparities, clinical research moving forward should focus on targeted interventions for young Black recipients during this period.

Evaluation of both exonic and intronic variants for effects on RNA splicing allows for accurate assessment of the effectiveness of precision therapies.

Elucidating the functional consequence of molecular defects underlying genetic diseases enables appropriate design of therapeutic options. Treatment of cystic fibrosis (CF) is an exemplar of this paradigm as the development of CFTR modulator therapies has allowed for targeted and effective treatment of individuals harboring specific genetic variants. However, the mechanism of these drugs limits effectiveness to particular classes of variants that allow production of CFTR protein. Thus, assessment of the molecular mechanism of individual variants is imperative for proper assignment of these precision therapies. This is particularly important when considering variants that affect pre-mRNA splicing, thus limiting success of the existing protein-targeted therapies. Variants affecting splicing can occur throughout exons and introns and the complexity of the process of splicing lends itself to a variety of outcomes, both at the RNA and protein levels, further complicating assessment of disease liability and modulator response. To investigate the scope of this challenge, we evaluated splicing and downstream effects of 52 naturally occurring CFTR variants (exonic = 15, intronic = 37). Expression of constructs containing select CFTR intronic sequences and complete CFTR exonic sequences in cell line models allowed for assessment of RNA and protein-level effects on an allele by allele basis. Characterization of primary nasal epithelial cells obtained from individuals harboring splice variants corroborated in vitro data. Notably, we identified exonic variants that result in complete missplicing and thus a lack of modulator response (e.g. c.2908G>A, c.523A>G), as well as intronic variants that respond to modulators due to the presence of residual normally spliced transcript (e.g. c.4242+2T>C, c.3717+40A>G). Overall, our data reveals diverse molecular outcomes amongst both exonic and intronic variants emphasizing the need to delineate RNA, protein, and functional effects of each variant in order to accurately assign precision therapies.

Lung Transplant Mortality Is Improving in Recipients With a Lung Allocation Score in the Upper Quartile.

BACKGROUND: Since the introduction of the Lung Allocation Score (LAS), the mean LAS has risen. Still, it remains uncertain whether mortality has improved in the most severely ill lung transplant recipients over this time period. METHODS: Using the United Network for Organ Sharing database, we identified 3,548 adult lung transplant recipients from May 4, 2005, to March 31, 2014, with a match-time LAS in the upper quartile (>75th%ile). We divided this population across three eras: 1 = May 4, 2005, to December 31, 2008 (n = 1,280); 2 = January 1, 2009, to December 31, 2011 (n = 1,266); and 3 = January 1, 2012, to March 31, 2014 (n = 1,002). Cox proportional hazards models were constructed for the primary outcomes of 30-day and 1-year mortality to assess the independent impact of the era of transplantation. RESULTS: The mean LAS at time of transplant for patients in the upper quartile in eras 1, 2, and 3 was 63, 73, and 79, respectively (p < 0.001). Later eras of transplantation benefited from a significant improvement in survival at 1 year (log-rank p = 0.001) but not at 30 days (log-rank p = 0.152). After risk adjustment, lung transplantation in more recent eras was associated with improved mortality at both 30 days (era 3 hazard ratio [HR] = 0.50, 95% confidence interval [CI] 0.32% to 0.78%, p = 0.002) and 1 year (era 2 HR = 0.77, 95% CI 0.64% to 0.94%, p = 0.008; era 3 HR = 0.54, 95% CI 0.43% to 0.68%, p < 0.001). CONCLUSIONS: Despite a progressively rising LAS, survival is improving among recipients with the highest LAS at the time of lung transplantation. This calls into question the notion of a maximum LAS beyond which lung transplantation becomes futile, a so-called LAS ceiling.

Early outcomes of antireflux surgery for United States lung transplant recipients.

BACKGROUND: This study aimed to evaluate early outcomes after antireflux surgery for lung transplant (LTx) recipients in the United States. METHODS: Adult patients undergoing elective antireflux surgery between 2003 and 2008 were identified in the Nationwide Inpatient Sample. A propensity-matched analysis compared early outcomes between prior LTx recipients and well-matched control subjects consisting of non-LTx patients undergoing elective antireflux surgery during the same era. The primary outcome was inpatient mortality, and the secondary outcomes were hospital length of stay (LOS), perioperative complications, and hospital costs. RESULTS: During the study period, 401 LTx recipients underwent elective antireflux surgery. These patients were well matched with 401 control patients in terms of age, sex, individual and overall comorbidity burden, hospital teaching status, hospital location, hospital antireflux volume, and open versus laparoscopic approach. The overall operative mortality rate was 1.4 %, with no difference between the groups. The overall and individual morbidity rates also were similar. The LOS and hospital costs were significantly greater in the LTx group. Multivariable logistic regression analysis confirmed that prior LTx did not confer an increased risk of inpatient mortality after antireflux surgery. CONCLUSIONS: To date, this is the largest study to examine outcomes of antireflux surgery for LTx recipients. Operative mortality and morbidity appear to be comparable with those of the general population, although resource utilization is greater. Based on these data, trials to evaluate the role of antireflux surgery in preserving allograft function after LTx should not be hindered by a perceived notion of prohibitive operative risk in this patient population.

Severe acute kidney injury according to the RIFLE (risk, injury, failure, loss, end stage) criteria affects mortality in lung transplantation.

BACKGROUND: The RIFLE criteria (risk, injury, failure, loss, end stage) are new consensus definitions for acute kidney injury (AKI) associated with increased mortality; however, they have not been applied in lung transplantation (LTx). Using the RIFLE criteria, we examined the effect of AKI on outcomes and cost in LTx. METHODS: We retrospectively reviewed all LTx patients at our institution since the lung allocation score (LAS) system was initiated (May 2005-August 2010). Using the Modification of Diet in Renal Disease formula, we assigned appropriate RIFLE class (R, I, F) comparing baseline creatinine to peak levels in the first 7 days after LTx. Generalized linear models assessed the effect of AKI on in-hospital and 1-year mortality. Hospital charges were used to examine the financial effect of AKI. RESULTS: During the study, 106 LTx were performed. Excluding patients bridged to LTx with extracorporeal membrane oxygenation, 84 (86%) lived 1 year. Median LAS was 37.1 (interquartile range, 34.1-45.2). RIFLE status was I or F in 39 (36.7%), and 14 (13.2%) required renal replacement therapy (RRT). After adjusting for LAS, RIFLE-F had an increased relative rate (RR) of in-hospital mortality (RR, 4.76, 95% confidence interval [CI], 1.65-13.7, p = 0.004) and 1-year mortality (RR, 3.17, 95% CI 1.55-6.49, p = 0.002). RIFLE-R and I were not associated with higher in-hospital or 1-year mortality. Post-operative RRT was associated with increased in-hospital (RR, 28.2; 95% CI, 6.18-128.1; p < 0.001) and 1-year mortality (RR, 4.97; 95% CI, 1.54-16.0; p < 0.001). AKI patients had higher median hospital charges of $168,146 vs $143,551 for no AKI (p = 0.02). CONCLUSIONS: This study shows high rates of AKI using the new RIFLE criteria in LTx. RIFLE-F is associated with higher in-hospital and 1-year mortality. Less severe degrees of AKI are not associated with increased mortality. The financial burden associated with AKI is significant.

Society of Thoracic Surgeons Risk Score predicts hospital charges and resource use after aortic valve replacement.

OBJECTIVE: The impact of Society of Thoracic Surgeons predicted mortality risk score on resource use has not been previously studied. We hypothesize that increasing Society of Thoracic Surgeons risk scores in patients undergoing aortic valve replacement are associated with greater hospital charges. METHODS: Clinical and financial data for patients undergoing aortic valve replacement at The Johns Hopkins Hospital over a 10-year period (January 2000 to December 2009) were reviewed. The current Society of Thoracic Surgeons formula (v2.61) for in-hospital mortality was used for all patients. After stratification into risk quartiles, index admission hospital charges were compared across risk strata with rank-sum and Kruskal-Wallis tests. Linear regression and Spearman's coefficient assessed correlation and goodness of fit. Multivariable analysis assessed relative contributions of individual variables on overall charges. RESULTS: A total of 553 patients underwent aortic valve replacement during the study period. Average predicted mortality was 2.9% (±3.4) and actual mortality was 3.4% for aortic valve replacement. Median charges were greater in the upper quartile of patients undergoing aortic valve replacement (quartiles 1-3, $39,949 [interquartile range, 32,708-51,323] vs quartile 4, $62,301 [interquartile range, 45,952-97,103], P < .01]. On univariate linear regression, there was a positive correlation between Society of Thoracic Surgeons risk score and log-transformed charges (coefficient, 0.06; 95% confidence interval, 0.05-0.07; P < .01). Spearman's correlation R-value was 0.51. This positive correlation persisted in risk-adjusted multivariable linear regression. Each 1% increase in Society of Thoracic Surgeons risk score was associated with an added $3000 in hospital charges. CONCLUSIONS: This is the first study to show that increasing Society of Thoracic Surgeons risk score predicts greater charges after aortic valve replacement. As competing therapies, such as percutaneous valve replacement, emerge to treat high-risk patients, these results serve as a benchmark to compare resource use.

Insurance status is an independent predictor of long-term survival after lung transplantation in the United States.

BACKGROUND: Socioeconomic factors such as education, health insurance, and race are known to affect health outcomes. The United Network for Organ Sharing (UNOS) database provides a large cohort of lung transplant (LTx) recipients in which to evaluate the effect of insurance on survival. METHODS: We retrospectively reviewed UNOS data for 11,385 adult primary LTx patients (1998-2008). Patients were stratified by insurance (private/self-pay, Medicare, Medicaid, and other type). All-cause mortality was examined with Cox proportional hazard regression incorporating 14 variables. The Kaplan-Meier method was used to model survival after LTx. RESULTS: Of 11,385 recipients, 7,100 (62.4%) had private insurance/self-pay; 2,966 (26.1%) had Medicare; 815 (7.2%) had Medicaid; and 504 (4.4%) had other type insurance. During the study, 4,943 patients (43.4%) died. Medicare and Medicaid patients had 7.0% and 8.1% lower 10-year survival than did private insurance/self-pay patients, respectively. Insurance did not affect 30-day, 90-day, or 1-year survival. Medicare and Medicaid patients had decreased survival at 3 years and longer. In multivariable analyses, Medicare (hazard ratio, 1.10; 95% confidence interval, 1.03-1.19) and Medicaid (hazard ratio, 1.29; 95% confidence interval, 1.15-1.45) significantly increased risk of death. When deaths in the first year were excluded, survival differences persisted. CONCLUSIONS: This study represents the largest cohort evaluating the effect of insurance on post-LTx survival. Medicare and Medicaid patients have worse survival after LTx compared with private insurance/self-paying patients.

Impact of the lung allocation score on resource utilization after lung transplantation in the United States.

BACKGROUND: The United States lung allocation score (LAS) allows rapid organ allocation to higher acuity patients. Although, wait-list time and wait-list mortality have improved, the costs of lung transplantation (LTx) in these higher acuity patients are largely unknown. We hypothesize that LTx in high LAS recipients is associated with increased charges and resource utilization. METHODS: Clinical and financial data for LTx patients at our institution in the post-LAS era (May 2005 to 2009) were reviewed with follow-up through December 2009. Patients were stratified by LAS quartiles (Q). Total hospital charges for index admission and all admissions within 1 year of LTx were compared between Q4 vs Q1-3 using rank-sum and Kruskal-Wallis tests, as charge data were not normally distributed. RESULTS: Eighty-four LTxs were performed during the study period. Sixty-three (75%) patients survived 1 year; 10 (11.9%) died during the index admission. Median LAS was 37.5 (interquartile range [IQR] 34.3 to 44.8). LAS quartiles were: Q1, 30.1 to 34.3, n = 21; Q2, 34.4 to 37.5, n = 21; Q3, 37.6 to 44.8, n = 21; and Q4, 44.9 to 94.3, n = 21. Charges for index admission were: Q4, $276,668 (IQR 191,301 to 300,156) vs Q1-3, $153,995 (IQR 129,796 to 176,849) (p < 0.001). Index admission median length of stay was greater in Q4 (Q4: 35-day IQR 23 to 46 vs Q1-3: 15-day IQR 11 to 22, p = 0.003). For 1-year charges: Q4, $292,247 (IQR 229,192 to 421,597) vs Q1-3, $188,342 (IQR 153,455 to 252,045) (p = 0.002). Index admission and 1-year charges in Q4 were higher than for other quartiles when examined individually. CONCLUSIONS: This is the first study to show increased charges in high LAS patients. Charges for the index admission and hospital care in the year post-LTx were higher in the highest LAS quartile compared with patients in the lowest 75% of LAS.

The impact of recipient body mass index on survival after lung transplantation.

BACKGROUND: Lung transplant (LTx) candidates are frequently over or underweight. Few studies have examined recipient weight and outcomes after LTx. The United Network for Organ Sharing (UNOS) database provides an opportunity to examine outcomes related to body mass index (BMI) in a large cohort of LTx patients. METHODS: The UNOS data set was retrospectively reviewed for 11,411 adult primary LTx patients (1998 to 2008). Patients were stratified by recipient BMI (kg/m(2)): less than 18.5 (underweight), 18.5 to 24.9 (normal), 25.0 to 29.9 (overweight), more than 30 (obese). All-cause mortality was examined with Cox proportional hazard regression incorporating 15 variables. Survival was modeled using the Kaplan-Meier method. RESULTS: Of 11,411 recipients, 1,355 (11.9%) were underweight, 4,998 (43.8%) were normal weight, 3,662 (62.1%) were overweight, and 1,396 (12.2%) were obese. During the study, 4,959 patients (43.5%) died. Mortality was significantly different between the strata, with incremental increases in death for each BMI category above or below normal. On multivariable analysis, BMI strata predicted death compared with normal weight. Risk of death was increased in recipients who were underweight (hazard ratio [HR], 1.14; 95% confidence interval [CI], 1.03-1.26; p = 0.01), overweight (HR, 1.06; 95% CI, 0.99-1.14; p = 0.1), and obese (HR, 1.16; 95% CI, 1.04-1.28; p = 0.005). Kaplan-Meier modeling showed a significant effect of BMI on survival; however, this effect was no longer significant when first-year deaths were excluded. CONCLUSIONS: Mortality is higher in underweight, overweight, and obese LTx patients than in normal-weight controls. However, this effect appears to be governed by survival in the first year after LTx.

Candidate selection, overall results, and choosing the right operation.

Lung transplantation offers potential improvement in survival and improved quality of life in patients with end-stage lung disease. International guidelines for candidate selection have been agreed upon to aid physicians and providers in selecting appropriate candidates for lung transplantation. In recent years the U.S. lung allocation score (LAS) has been developed and implemented in an attempt to both maximize utility of scarce donor organs and provide benefit to those in need of lung transplantation. This has helped in the process of offering transplantation to those with the greatest need and best chance of survival. Appropriate lung transplantation candidates should have life-threatening lung disease but remain otherwise healthy, because significant comorbidities may increase the risk of poor outcomes after transplantation limiting long-term survival. Improved outcomes are seen through early referrals to a specialized center and vigilant evaluation to select the most appropriate candidates for lung transplantation.

Lung allocation score predicts survival in lung transplantation patients with pulmonary fibrosis.

BACKGROUND: Since 2005, the Organ Procurement and Transplantation Network has used the lung allocation score (LAS) to assign organ allocation priority in lung transplantation. This study was designed to determine whether LAS predicts short-term survival for patients with pulmonary fibrosis. METHODS: Organ Procurement and Transplantation Network data was retrospectively reviewed to identify 1,256 first-time adult lung transplantation recipients with pulmonary fibrosis since initiation of the LAS (May 2005 to December 2007). Patients were stratified by quartiles of LAS. Multivariable Cox proportional hazards regression predicted the risk of 30-day, 90-day, and 1-year mortality. RESULTS: Lung allocation scores ranged from 31.1 to 94.1. Lung allocation score quartiles (Q) were as follows: Q1, 29.8 to 37.8, n = 315; Q2, 37.9 to 42.5, n = 313; Q3, 42.6 to 51.9, n = 314; and Q4, 52.0 to 94.1, n = 314. Lung allocation score correlated strongly with cumulative survival at 90 days and 1 year after lung transplantation. Patients in the highest LAS quartile (LAS Q4, 52.0 to 94.1) had a 10% lower cumulative survival at 1 year after transplantation when compared with patients in the lowest LAS quartile (p = 0.04). On Cox proportional hazards regression, patients in the highest LAS quartile (those above 52.0) had a significant increase in the risk of mortality at both 90 days and 1 year after transplantation (relative to reference Q1: hazard ratio, 2.09; 95% confidence interval, 1.16 to 3.80; p = 0.01 for 90 days; and hazard ratio, 1.59; 95% confidence interval, 1.04 to 2.44; p = 0.03 for 1 year). CONCLUSIONS: An initial examination of survival for pulmonary fibrosis lung transplantation recipients in the post-LAS era was performed. Lung allocation score predicts short-term mortality in this cohort.