Place-based heterogeneity in lung transplant recipient outcomes.

Place is defined as a social or environmental area of residence with meaning to a patient. We hypothesize there is an association between place and the clinical outcomes of lung transplant recipients in the United States. In a retrospective cohort study of transplants between January 1, 2010, and December 31, 2019, in the Scientific Registry of Transplant Recipients, multivariable Cox regression models were used to test the association between place (through social and environmental factors) with readmission, lung rejection, and survival. Among 18,465 recipients, only 20% resided in the same county as the transplant center. Recipients from the most socially vulnerable counties when compared to the least vulnerable were more likely to have COPD as a native disease, Black or African American race, and travel long distances to reach a transplant center. Higher local life expectancy was associated with lower likelihood for readmission (odds ratio [OR] = 0.90, 95% confidence interval [CI]: 0.84, 0.98, p = .01). Higher social vulnerability was associated with a higher likelihood of lung rejection (OR = 1.37, [CI]: 1.07, 1.76, p = .01). There was no association of residence with posttransplant survival. Recipient place-based factors were associated with complications and processes of care after transplant and warrant further investigation.

Plasma CXCL9 and CXCL10 at allograft injury predict chronic lung allograft dysfunction.

Histopathologic lung allograft injuries are putative harbingers for chronic lung allograft dysfunction (CLAD). However, the mechanisms responsible are not well understood. CXCL9 and CXCL10 are potent chemoattractants of mononuclear cells and potential propagators of allograft injury. We hypothesized that these chemokines would be quantifiable in plasma, and would associate with subsequent CLAD development. In this prospective multicenter study, we evaluated 721 plasma samples for CXCL9/CXCL10 levels from 184 participants at the time of transbronchial biopsies during their first-year post-transplantation. We determined the association between plasma chemokines, histopathologic injury, and CLAD risk using Cox proportional hazards models. We also evaluated CXCL9/CXCL10 levels in bronchoalveolar lavage (BAL) fluid and compared plasma to BAL with respect to CLAD risk. Plasma CXCL9/CXCL10 levels were elevated during the injury patterns associated with CLAD, acute rejection, and acute lung injury, with a dose-response relationship between chemokine levels and CLAD risk. Importantly, there were strong interactions between injury and plasma CXCL9/CXCL10, where histopathologic injury associated with CLAD only in the presence of elevated plasma chemokines. We observed similar associations and interactions with BAL CXCL9/CXCL10 levels. Elevated plasma CXCL9/CXCL10 during allograft injury may contribute to CLAD pathogenesis and has potential as a minimally invasive immune monitoring biomarker.

Prognostic implications of and clinical risk factors for acute lung injury and organizing pneumonia after lung transplantation: Data from a multicenter prospective cohort study.

We determined prognostic implications of acute lung injury (ALI) and organizing pneumonia (OP), including timing relative to transplantation, in a multicenter lung recipient cohort. We sought to understand clinical risks that contribute to development of ALI/OP. We analyzed prospective, histologic diagnoses of ALI and OP in 4786 lung biopsies from 803 adult lung recipients. Univariable Cox regression was used to evaluate the impact of early (≤90 days) or late (>90 days) posttransplant ALI or OP on risk for chronic lung allograft dysfunction (CLAD) or death/retransplantation. These analyses demonstrated late ALI/OP conferred a two- to threefold increase in the hazards of CLAD or death/retransplantation; there was no association between early ALI/OP and these outcomes. To determine risk factors for late ALI/OP, we used univariable Cox models considering donor/recipient characteristics and posttransplant events as candidate risks. Grade 3 primary graft dysfunction, higher degree of donor/recipient human leukocyte antigen mismatch, bacterial or viral respiratory infection, and an early ALI/OP event were significantly associated with increased late ALI/OP risk. These data from a contemporary, multicenter cohort underscore the prognostic implications of ALI/OP on lung recipient outcomes, clarify the importance of the timing of these events, and identify clinical risks to target for ALI/OP prevention.

Lung transplant waitlist outcomes in the United States and patient travel distance.

There is a broad range of patient travel distances to reach a lung transplant hospital in the United States. Whether patient travel distance is associated with waitlist outcomes is unknown. We present a cohort study of patients listed between January 1, 2006 and May 31, 2017 using the Scientific Registry of Transplant Recipients. Travel distance was measured from the patient's permanent zip code to the transplant hospital using shared access signature URL access to Google Maps, and assessed using multivariable competing risk regression models. There were 22 958 patients who met inclusion criteria. Median travel distance was 69.7 miles. Among patients who traveled > 60 miles, 41.2% bypassed a closer hospital and sought listing at a more distant hospital. In the adjusted models, when compared to patients who traveled ≤60 miles, patients who traveled >360 miles had a 27% lower subhazard ratio (SHR) for waitlist removal (SHR 0.73, 95% confidence interval [CI]: 0.60, 0.89, P = .002), 16% lower subhazard for waitlist death (SHR 0.84; 95% CI 0.73-0.95, P = .07), and 13% increased likelihood for transplant (SHR 1.13, 95% CI: 1.07, 1.20, P < .001). Many patients bypassed the nearest transplant hospital, and longer patient travel distance was associated with favorable waitlist outcomes.

Correlation between BAL CXCR3 chemokines and lung allograft histopathologies: A multicenter study.

The histopathologic diagnosis of acute allograft injury is prognostically important in lung transplantation with evidence demonstrating a strong and consistent association between acute rejection (AR), acute lung injury (ALI), and the subsequent development of chronic lung allograft dysfunction (CLAD). The pathogenesis of these allograft injuries, however, remains poorly understood. CXCL9 and CXCL10 are CXC chemokines induced by interferon-γ and act as potent chemoattractants of mononuclear cells. We hypothesized that these chemokines are involved in the mononuclear cell recruitment associated with AR and ALI. We further hypothesized that the increased activity of these chemokines could be quantified as increased levels in the bronchoalveolar lavage fluid. In this prospective multicenter study, we evaluate the incidence of histopathologic allograft injury development during the first-year post-transplant and measure bronchoalveolar CXCL9 and CXCL10 levels at the time of the biopsy. In multivariable models, CXCL9 levels were 1.7-fold and 2.1-fold higher during AR and ALI compared with "normal" biopsies without histopathology. Similarly, CXCL10 levels were 1.6-fold and 2.2-fold higher during these histopathologies, respectively. These findings support the association of CXCL9 and CXCL10 with episodes of AR and ALI and provide potential insight into the pathogenesis of these deleterious events.

Risk Factors for Acute Rejection in the First Year after Lung Transplant. A Multicenter Study.

Rationale: Acute rejection, manifesting as lymphocytic inflammation in a perivascular (acute perivascular rejection [AR]) or peribronchiolar (lymphocytic bronchiolitis [LB]) distribution, is common in lung transplant recipients and increases the risk for chronic graft dysfunction.Objectives: To evaluate clinical factors associated with biopsy-proven acute rejection during the first post-transplant year in a present-day, five-center lung transplant cohort.Methods: We analyzed prospective diagnoses of AR and LB from over 2,000 lung biopsies in 400 newly transplanted adult lung recipients. Because LB without simultaneous AR was rare, our analyses focused on risk factors for AR. Multivariable Cox proportional hazards models were used to assess donor and recipient factors associated with the time to the first AR occurrence.Measurements and Main Results: During the first post-transplant year, 53.3% of patients experienced at least one AR episode. Multivariable proportional hazards analyses accounting for enrolling center effects identified four or more HLA mismatches (hazard ratio [HR], 2.06; P ≤ 0.01) as associated with increased AR hazards, whereas bilateral transplantation (HR, 0.57; P ≤ 0.01) was associated with protection from AR. In addition, Wilcoxon rank-sum analyses demonstrated bilateral (vs. single) lung recipients, and those with fewer than four (vs. more than four) HLA mismatches demonstrated reduced AR frequency and/or severity during the first post-transplant year.Conclusions: We found a high incidence of AR in a contemporary multicenter lung transplant cohort undergoing consistent biopsy sampling. Although not previously recognized, the finding of reduced AR in bilateral lung recipients is intriguing, warranting replication and mechanistic exploration.

Disparities in heart and lung transplantation.

PURPOSE OF REVIEW: Cardiothoracic transplantation is the definitive therapy for end-stage heart and lung disease. In service to this population, disparities in access and care must be simultaneously understood and addressed. RECENT FINDINGS: There are sex, race, geographic, age, and underlying disease disparities in both heart and lung transplantation. Women have reduced waitlist survival but improved posttransplant survival when compared with men for both heart and lung transplantation. Black patients have worse outcome compared with other races postheart transplant. Geographic disparities impact the likelihood of receiving heart or lung transplant and the growing number of patients with advanced age seeking transplant complicates discussions on survival benefit. Finally, underlying disease has affected outcomes for both heart and lung transplant and now are incorporated into the allocation system. SUMMARY: Though heart and lung transplantation have several existing disparities, it remains to be seen how advancements in medical technology, changes in donor organ allocation policies, and growing experience in patient selection will impact these concerns.

Highlights from the clinical trials in organ transplantation (CTOT)-20 and CTOT-22 Consortium studies in lung transplant.

Long-term survival after lung transplant lags behind that of other commonly transplanted organs, reflecting the current incomplete understanding of the mechanisms involved in the development of posttransplant lung injury, rejection, infection, and chronic allograft dysfunction. To address this unmet need, 2 ongoing National Institute of Allergy and Infectious Disease funded studies through the Clinical Trials in Organ Transplant Consortium (CTOT) CTOT-20 and CTOT-22 were dedicated to understanding the clinical factors and biological mechanisms that drive chronic lung allograft dysfunction and those that maintain cytomegalovirus polyfunctional protective immunity. The CTOT-20 and CTOT-22 studies enrolled 800 lung transplant recipients at 5 North American centers over 3 years. Given the number and complexity of subjects included, CTOT-20 and CTOT-22 utilized innovative data transfers and capitalized on patient-entered data collection to minimize site manual data entry. The data were coupled with an extensive biosample collection strategy that included DNA, RNA, plasma, serum, bronchoalveolar lavage fluid, and bronchoalveolar lavage cell pellet. This Special Article describes the CTOT-20 and CTOT-22 protocols, data and biosample strategy, initial results, and lessons learned through study execution.

Perspectives on donor lung allocation from both sides of the Atlantic: The United States.

Donor lung allocation in the United States focuses on decreasing waitlist mortality and improving recipient outcomes. The implementation of allocation policy to match deceased donor lungs to waitlisted patients occurs through a unique partnership between government and private organizations, namely the Organ Procurement and Transplantation Network under the Department of Health and Human Services and the United Network for Organ Sharing. In 2005, the donor lung allocation algorithm shifted toward the prioritization of medical urgency of waitlisted patients instead of time accrued on the waitlist. This led to the Lung Allocation Score, which weighs over a dozen clinical variables to predict a 1-year estimate of survival benefit, and is used to prioritize waitlisted patients. In 2017, the use of local allocation boundaries was eliminated in favor of a 250 nautical mile radius from the donor hospital as the first unit of distance used in allocation. The next upcoming iteration of donor allocation policy is expected to use a continuous distribution algorithm where all geographic boundaries are eliminated. There are additional opportunities to improve donor lung allocation, such as for patients with high antibody titers with access to a limited number of donors.

The Association Between Lung Recipient Travel Distance and Posttransplant Survival.

INTRODUCTION: Recipient travel distance may be an unrecognized burden in lung transplantation. DESIGN: Retrospective single-center cohort study of all adult (≥18 years) first-time lung-only transplants from January 1, 2010, until February 28, 2017. Recipient distance to transplant center was calculated using the linear distance from the recipient's home zip code to the Cleveland Clinic in Cleveland, Ohio. RESULTS: 569 recipients met inclusion criteria. Posttransplant graft survival was 85%, 88%, 91%, and 91% at 1 year and 49%, 52%, 57%, and 56% at 5 years posttransplant for recipient travel distances of ≤50, >50 to ≤250, >250 to ≤500, and >500 miles, respectively ( P = .10). DISCUSSION: We found no significant relationship between recipient travel distance and posttransplant graft survival. In carefully selected recipients, travel distance is not a significant barrier to successful posttransplant outcomes which may be important for patient decision-making and donor allocation policy. These data should be validated in a national cohort.

Health effects associated with faulty application of spray polyurethane foam in residential homes.

BACKGROUND: Spray polyurethane foam (SPF) has become a popular form of home insulation in the United States, but there have been adverse health effects reported by home owners. METHODS: We summarized adverse health effects in 13 adults from 10 households (age: 33-82) whose homes were improperly retrofitted with SPF. Subjects either were not asked to leave the premise or were told to return too early. In some cases, proper ventilation was not used or the foams were sprayed using the improper mixing technique. We correlated symptoms with volatile organic compounds (VOCs) in indoor air samples. RESULTS: All subjects reported fishy odors and developed acute watery and burning eyes, burning nose, sinus congestion, throat irritation, cough, dyspnea and chest tightness. Twelve subjects (92.3%) reported acute neuropsychiatric symptoms, including headache, dizziness, forgetfulness, difficulty in concentrating and insomnia. Three subjects (23.0%) had nausea, vomiting and abdominal cramps and three (23.0%) developed skin rash. Subjects continued to experience symptoms long after SPF was done. These symptoms subsided after they left homes, but recurred upon returning. All subjects eventually vacated their homes. The methacholine challenge test was negative in 5 of 7 patients. Analysis of indoor air and headspace gas from the foams showed increased concentrations of VOCs derived from SPF and common indoor air pollutants. The levels of VOCs decreased after SPF was completely removed. CONCLUSIONS: Faulty application of SPF was associated with acute and persistent pulmonary and extra-pulmonary symptoms. These symptoms may be associated with SPF-derived compounds as well as increased concentrations of indoor VOCs.

An acute change in lung allocation score and survival after lung transplantation: a cohort study.

BACKGROUND: Lung transplantation is an effective treatment for patients with advanced lung disease. In the United States, lungs are allocated on the basis of the lung allocation score (LAS), a composite measure of transplantation urgency and utility. Clinical deteriorations result in increases to the LAS; however, whether the trajectory of the LAS has prognostic significance is uncertain. OBJECTIVE: To determine whether an acute increase in the LAS before lung transplantation is associated with reduced posttransplant survival. DESIGN: Retrospective cohort study of adult lung transplant recipients listed for at least 30 days between 4 May 2005 (LAS implementation) and 31 December 2010 in the United Network for Organ Sharing registry. An acute increase in the LAS was defined as an LAS change (LASΔ) greater than 5 units between the 30 days before and the time of transplantation. Multivariable Cox proportional hazard models were used to examine the relationship between an LASΔ >5 and posttransplant graft survival. SETTING: All U.S. lung transplantation centers. PATIENTS: 5749 lung transplant recipients. MEASUREMENTS: Survival time after lung transplantation. RESULTS: 702 (12.2%) patients experienced an LASΔ >5. These patients had significantly worse posttransplant survival (hazard ratio, 1.31 [95% CI, 1.11 to 1.54]; P = 0.001]) after adjustment for the LAS at transplantation (LAS-T) and other clinical covariates. The effect of an LASΔ >5 was independent of the LAS-T, underlying diagnosis, center volume, or donor characteristics. LIMITATION: Analysis was based on center-reported data. CONCLUSION: An acute increase in LAS before transplantation is associated with posttransplant survival after adjustment for LAS-T. Further emphasis on serial assessment of the LAS could improve the ability to offer accurate prediction of survival after transplantation. PRIMARY FUNDING SOURCE: National Institutes of Health.

Residential history, the electronic health record, and clinical medicine: A descriptive study in a lung transplant cohort.

Neighborhood level social determinants of health are commonly measured using a patient's most recent residential location. Not accounting for residential history, and therefore missing accumulated stressors from prior social vulnerabilities, could increase misclassification bias. We tested the hypothesis that the electronic health record could capture the residential history of lung transplant patients -a vulnerable population. After applying the Social Vulnerability Index (SVI) to individual residential histories, the most recent SVI equaled the first SVI in only 15.4% (58/374) of patients. There is a need for databases with residential histories to inform place-based determinants of health and applications to patient care.

Assessing the causal effect of organ transplantation on the distribution of residual lifetime.

Because the number of patients waiting for organ transplants exceeds the number of organs available, a better understanding of how transplantation affects the distribution of residual lifetime is needed to improve organ allocation. However, there has been little work to assess the survival benefit of transplantation from a causal perspective. Previous methods developed to estimate the causal effects of treatment in the presence of time-varying confounders have assumed that treatment assignment was independent across patients, which is not true for organ transplantation. We develop a version of G-estimation that accounts for the fact that treatment assignment is not independent across individuals to estimate the parameters of a structural nested failure time model. We derive the asymptotic properties of our estimator and confirm through simulation studies that our method leads to valid inference of the effect of transplantation on the distribution of residual lifetime. We demonstrate our method on the survival benefit of lung transplantation using data from the United Network for Organ Sharing.

Dynamic hyperinflation correlates with exertional oxygen desaturation in patients with chronic obstructive pulmonary disease.

BACKGROUND: Dynamic hyperinflation (DH) causes exercise limitation and exertional dyspnea in patients with chronic obstructive pulmonary disease (COPD). Exertional desaturation (ED) also occurs commonly in COPD but neither routine physiologic parameters nor imaging predict ED accurately. In this study we evaluated the relationship between DH and ED during 6-min walk testing (6MWT). METHODS: We measured ED and DH in patients with stable COPD. SpO2 was measured by continuous pulse oximetry during 6MWT. ED was defined as a decline in SpO2 (ΔSpO2) ≥4 %. DH was determined by measuring inspiratory capacity (IC) before and after the 6MWT using a handheld spirometer. DH was defined as ΔIC >0.0 L. We correlated DH and ED with clinical and pulmonary physiologic variables by regression analysis, χ (2), and receiver operator curve (ROC) analysis. RESULTS: Thirty males [age = 65 ± 9.4 years, FEV1 % predicted = 48 ± 14 %, and DLCO % predicted = 50 ± 21 % (mean ± SD)] were studied. ΔSpO2 correlated with ΔIC (r = 0.49, p = 0.005) and age (r = 0.39, p = 0.03) by univariate analysis; however, only ΔIC correlated on multivariate regression analysis (p = 0.01). ΔSpO2 did not correlate with FEV1, FVC, FEF25-75, RV, DLCO % predicted, BMI, smoking, BORG score, or distance covered in 6MWT. DH strongly correlated with ED (p = 0.001). On ROC analysis, DH had an area under the curve of 0.92 for the presence of ED (sensitivity = 90 %; specificity = 77 %, p < 0.001). CONCLUSION: Routine pulmonary function test results and clinical variables did not correlate with ED in patients with stable COPD. Dynamic hyperinflation strongly correlates with exertional desaturation and could be a reason for this desaturation.

The Past, Present, and Near Future of Lung Allocation in the United States.

The first official donor lung allocation system in the United States was initiated by the United Network of Organ Sharing in 1990. The initial policy for lung allocation was simple with donor lungs allocated based on ABO match and the amount of time the candidates accrued on the waiting list. Donor offers were first given to candidates' donor service area. In March 2005, the implementation of the lung allocation score (LAS) was the major change in organ allocation. International adoption of the LAS-based allocation system can be seen worldwide.

Application of Place-Based Methods to Lung Transplant Medicine.

Lung transplantation is an increasingly common lifesaving therapy for patients with fatal lung diseases, but this intervention has a critical limitation as median survival after LT is merely 5.5 years. Despite the profound impact of place-based factors on lung health, this has not been rigorously investigated in LT recipients-a vulnerable population due to the lifelong need for daily life-sustaining immunosuppression medications. There have also been longstanding methodological gaps in transplant medicine where both time and place have not been measured; gaps which could be filled by the geospatial sciences. As part of an exploratory analysis, we studied recipients transplanted at our center over a two-year period. The main outcome was at least one episode of rejection within the first year after transplant. We found recipients averaged 1.7 unique residential addresses, a modest relocation rate. Lung rejection was associated with census tracts of predominantly underrepresented minorities or where English was not the primary language as measured by the social vulnerability index. Census tracts likely play an important role in measuring and addressing geographic disparities in transplantation. In a future paradigm, patient spatial data could become an integrated part of real time clinical care to aid in personalized risk stratification and personalized delivery of healthcare.

COVID-19 and lung transplant patients.

COVID-19 is a novel respiratory disease leading to high rates of acute respiratory failure requiring hospital admission. It is unclear if specific patient populations such as lung transplant patients are at higher risk for COVID-19. Some reports suggest that transplant patients may not be at higher risk if proper social distancing and preventive measures are employed. Efforts to ensure the safety of wait-listed patients, transplant recipients, and healthcare workers are underway. Recommendations for the care of lung transplant patients during the COVID-19 pandemic are discussed and will likely change as the pandemic evolves.