Jonathan Paul Singer

Rationale: Primary graft dysfunction (PGD) after lung transplant is associated with increased mortality. Whether PGD increases mortality via long-term effects on allograft function is poorly understood. Objective: Evaluate the association of PGD with potential lung function and chronic lung allograft dysfunction (CLAD). Methods: We included lung transplant recipients enrolled in an 8-center prospective cohort study from 2007-2018. PGD was defined by ISHLT criteria. Linear mixed effects and logistic regression models evaluated the association between PGD and maximum potential forced expiratory volume in 1 second (FEV1) and whether Global Lung Function Initiative defined (GLI) predicted FEV1 was attained, respectively. Flexible parametric survival models evaluated the association between PGD and CLAD, accounting for confounding and mortality as a competing risk. Measurements and Main Results: Among 2419 recipients, 510 had PGD. Recipients with PGD had lower maximum potential FEV1 (-311 ml, 95% CI -245 to -377 ml) and were less likely to achieve GLI-predicted FEV1 (probability difference -12.5%, 95% CI -17 to -8%). 930 recipients developed CLAD (405 obstructive, 525 restrictive) over median (IQR) 5.9 (3.0-8.0 years). The 5-year cumulative incidence of CLAD did not differ by PGD (cumulative difference: -2.2%, 95% CI - 6.4% to 1.9%). This association was not modified by age, sex, BMI, pretransplant diagnosis, or transplant type. PGD was not associated with a difference in cumulative incidence of obstructive or restrictive CLAD (cumulative difference -1.2% and -0.8%, respectively). Conclusion: PGD is associated with reduced lung function and lower likelihood of achieving GLI-predicted maximum potential lung function but not CLAD.

The Lung Transplant Frailty Scale (LT-FS) is a validated binary measure of frailty in lung transplant candidates. We refined the LT-FS Base and Body Composition measures by developing a three-category classification to improve clinical risk stratification and replacing serum C-reactive protein with albumin as a more clinically practical frailty biomarker. We applied a 4-step measure development method to a multicenter prospective cohort study of lung transplant candidates. Low albumin (<3.5 g/dL) replaced high serum C-reactive protein (≥10 mg/L) as the LT-FS biomarker. Cutpoints balancing discrimination, risk prediction, and calibration defined “frail”, “pre-frail”, and “not frail” categories. We then evaluated these category associations with exercise capacity, patient-reported outcomes, and mortality using multivariate linear and Cox regression. Among 419 participants, the refined LT-FS identified a graded increase in mortality risk across frailty categories. Pre-frailty and frailty by LT-FS Body Composition were associated with 2.9-fold (HR 2.9, 95% CI 1.2–6.9) and 7-fold (HR 6.9, 95% CI 2.6–18.2) higher risks of waitlist delisting or death, respectively. After transplant, pre-frailty and frailty by LT-FS Body Composition were associated with 2-fold (HR 2.1, 95% CI 1.2–3.8) and 3.6-fold (HR 3.6, 95% CI 1.8–7.3) higher mortality risk, respectively. Relationships with exercise capacity and disability were less consistent. A refined Lung Transplant Frailty Scale incorporating serum albumin demonstrates strong associations with waitlist and post-transplant mortality. The addition of a pre-frail category better captures the continuum of frailty and improves clinical risk stratification of lung transplant candidates.

Rationale: Supplemental oxygen use in COPD is a readily usable signal for progression to advanced disease and limited prognosis, but it is unclear whether this is reflected in different patterns of end-of-life (EOL) healthcare use or advance care planning (ACP). Objective: To determine whether older adults with COPD using supplemental oxygen have different EOL healthcare use and ACP engagement compared to those without oxygen Methods: We analyzed nationally-representative Health and Retirement Survey data (2012–2018), including decedents aged ≥50 with COPD and self-reported oxygen use. Proxies completed post-death interviews about healthcare use (hospitalization, intensive care, life support equipment [e.g., mechanical ventilation], hospice, palliative care use) and ACP (durable power of attorney, advance directives, care preferences) within the last two years of life. We report adjusted probabilities derived from logistic and linear regression models adjusted for sociodemographics and comorbidities for the associations between oxygen use and EOL healthcare and ACP outcomes. Results: Among 848 decedents (mean age 81, 53% female, 82% White), 47% used supplemental oxygen for a median of 2 years (IQR: 1-4) before death. Compared to those without oxygen, those using oxygen had higher mean hospital days (12.4 vs 9.8 days, p = 0.03), intensive care (54% vs 40%, p = 0.001) and life support use (42% vs 27%, p < 0.001) in the last two years of life. In contrast, rates were similar for use of palliative care (26% vs 24%), hospice (48% vs 48%), and ACP, including completion of durable power of attorney (74% vs 74%) and advance directives (56% vs 56%). Among those who completed advanced directives (n = 464), decedents with and without oxygen use expressed similarly high preferences to limit care (88% vs 88%) and focus on comfort (91% vs 87%). Conclusions: Supplemental oxygen use in older adults with COPD was associated with substantially higher hospital, ICU, and life support use at EOL. Yet, overall ACP engagement and palliative care use was low and those who completed advance directives had strong preferences to limit care. Supplemental oxygen may be an important and under-utilized indicator for integration of timely palliative care among older adults with COPD.

To translate, cross-culturally adapt, and validate the Lung Transplant Quality of Life questionnaire into Brazilian Portuguese. This observational study enrolled 50 participants. Translation and cross-cultural adaptation were conducted in accordance with established guidelines for self-report measures and the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN). The measurement properties assessed included internal consistency, agreement, intra-rater reliability, and convergent validity. Convergent validity was evaluated by comparing the Lung Transplant Quality of Life with the Short Form Health Survey (SF-36) and the Saint George's Respiratory Questionnaire. The Lung Transplant Quality of Life showed adequate internal consistency (Cronbach's alpha=0.86) and excellent intra-rater reliability (intraclass correlation coefficient=0.93). Agreement analysis yielded a standard error of measurement of 8.72. Bland-Altman analysis revealed low mean differences (0.8) between Lung Transplant Quality of Life scores and acceptable limits of agreement (95%CI=-16.9-15.3). Spearman's correlation showed excellent convergent validity with the SF-36 and good validity with the Saint George's Respiratory Questionnaire in both test and retest phases. The Brazilian Portuguese version of the Lung Transplant Quality of Life is a valid and reliable instrument for assessing health-related quality of life in lung transplant patients. Further research is warranted to develop a shorter version while preserving its measurement properties.

Rationale: Clinical features that impact outcomes in lung recipients with chronic lung allograft dysfunction (CLAD) are uncertain and limited by existing approaches to phenotyping that rely on measures inconsistently performed or not standardized across centers. Objective: We used data from the prospective multicenter Lung Transplant Outcomes Group (LTOG) cohort study to determine if routine, objective clinical measures at CLAD diagnosis impact progression to graft loss (death/retransplantation). Methods: The analysis included 2386 adult lung recipients from 9 US centers. Probable CLAD was defined according to International Society for Heart and Lung Transplantation criteria. Cox models were fit for time from probable CLAD to graft loss as a function of each clinical feature of interest including CLAD stage (1-4), CLAD timing (early-onset, <2 years posttransplant), FVC loss (FVCCLAD/FVCBest <0.8), and FEV1/FVC ratio <0.7. Models included a random effect for center and were adjusted for recipient age, sex, transplant type, and native lung disease. Measurements and Main Results: Probable CLAD developed in 1418 patients (59.4%). At onset, 80.7% had stage 1 CLAD, 41.3% had early-onset CLAD, 35.8% had FVC loss, and 46.5% had an FEV1/FVC ratio <0.7. In adjusted analyses, patients with CLAD stage ≥2, early-onset CLAD, and FVC loss had significantly higher hazards for graft loss, while FEV1/FVC <0.7 was associated with reduced graft loss risk. Conclusions: We provide compelling evidence that routine, objective measures at CLAD onset inform CLAD progression risk. Such stratification of disease behavior is important to patient prognostication and may inform the design of future CLAD trials.