Publications by authors named "Steven R Hays"

46 Publications

The association of post-operative delirium with patient-reported outcomes and mortality after lung transplantation.

Clin Transplant 2021 Mar 7:e14275. Epub 2021 Mar 7.

Department of Medicine, University of California San Francisco, San Francisco, CA, USA.

Post-operative delirium after lung transplantation is common. Its associations with health-related quality of life (HRQL), depression, and mortality remains unknown. In 236 lung transplant recipients, HRQL and depressive symptoms were assessed as part of a structured survey battery before and after transplantation. Surveys included the Geriatric Depressive Scale (GDS) and Short Form 12 (SF12). Delirium was assessed throughout the post-operative intensive care unit (ICU) stay with Confusion Assessment Method for ICU. Delirium and mortality data were extracted from electronic medical records. We examined associations between delirium and changes in depressive symptoms and HRQL using linear mixed effects models and association between delirium and mortality with Cox-proportional hazard models. Post-operative delirium occurred in 34 participants (14%). Delirium was associated with attenuated improvements in SF12-PCS (difference ₋4.0; 95%CI: -7.4, -0.7) but not SF12-MCS (difference 2.2; 95%CI: -0.7,5.7) or GDS (difference ₋0.4; 95%CI: -1.5,0.7). Thirty-two participants died during the study period. Delirium was associated with increased adjusted hazard risk of mortality (HR 17.9, 95%CI: 4.4,72.5). Delirium after lung transplantation identifies a group at increased risk for poorer HRQL and death within the first post-operative year. Further studies should investigate potential causal links between delirium, and poorer HRQL and mortality risk after lung transplantation.
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http://dx.doi.org/10.1111/ctr.14275DOI Listing
March 2021

Construct and Predictive Validity of Sarcopenia in Lung Transplant Candidates.

Ann Am Thorac Soc 2021 Feb 10. Epub 2021 Feb 10.

UC San Francisco, Pulmonary and Critical Care Medicine, San Francisco, California, United States.

Rationale: Sarcopenia is associated with disability and death. The optimal definition and clinical relevance of sarcopenia in lung transplantation remain unknown.

Objective: To assess the construct and predictive validity of sarcopenia definitions in lung transplant candidates.

Methods: In a multicenter prospective cohort of 424 lung transplant candidates, we evaluated limited (muscle mass only) and expanded (muscle mass and quality) sarcopenia definitions from the European Working Group on Sarcopenia in Older People 2 (EWGSOP2), Foundation for the National Institutes of Health (FNIH), and a cohort-specific distribution-based lowest quartile definition. We assessed construct validity using associations with conceptually related factors. We evaluated the relationship between sarcopenia and frailty using generalized additive models. We also evaluated associations between sarcopenia definitions and key pre-transplant outcomes including disability (quantified by the Lung Transplant Valued Life Activities scale [range 0-3, higher scores = worse disability; minimally important difference: 0.3]) and waitlist delisting/death by multivariate linear and Cox regression, respectively.

Results: Sarcopenia prevalence ranged from 6-13% by definition used. The limited EWGSOP2 definition demonstrated the highest construct validity, followed by the expanded EWGSOP2 and both limited and expanded FNIH and lowest quartile definitions. Sarcopenia exhibited a linear association with the risk of frailty. The EWGSOP2 and expanded lowest quartile definitions were associated with disability, ranging from 0.20 to 0.25 higher LT-VLA scores. Sarcopenia was associated with increased risk of waitlist delisting or death by the limited and expanded lowest quartile definitions (HR: 3.8; 95%CI: 1.4, 9.9 and HR: 3.5; 95%CI: 1.1, 11.0, respectively) and the EWGSOP2 limited definition (HR 2.8; 95%CI: 0.9, 8.6) but not with the three other candidate definitions.

Conclusions: The prevalence and validity of sarcopenia vary by definition; the EWGSOP2 limited definition exhibited the broadest validity in lung transplant candidates. The linear relationship between low muscle mass and frailty highlights sarcopenia's contribution to frailty and also questions the clinical utility of a sarcopenia cut-point in advanced lung disease. The associations between sarcopenia and important pre-transplant outcomes support further investigation into using body composition for candidate risk stratification.
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http://dx.doi.org/10.1513/AnnalsATS.202007-796OCDOI Listing
February 2021

Mobile health technology to improve emergent frailty after lung transplantation.

Clin Transplant 2021 Feb 2:e14236. Epub 2021 Feb 2.

Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California San Francisco, San Francisco, CA, USA.

We evaluated the feasibility, safety, and efficacy of a mHealth-supported physical rehabilitation intervention to treat frailty in a pilot study of 18 lung transplant recipients. Frail recipients were defined by a short physical performance battery (SPPB score ≤7). The primary intervention modality was Aidcube, a customizable rehabilitation mHealth platform. Our primary aims included tolerability, feasibility, and acceptability of use of the platform, and secondary outcomes were changes in SPPB and in scores of physical activity, and disability measured using the Duke Activity Status Index (DASI) and Lung Transplant-Value Life Activities (LT-VLA). Notably, no adverse events were reported. Subjects reported the app was easy to use, usability improved over time, and the app enhanced motivation to engage in rehabilitation. Comments highlighted the complexities of immediate post-transplant rehabilitation, including functional decline, pain, tremor, and fatigue. At the end of the intervention, SPPB scores improved a median of 5 points from a baseline of 4. Physical activity and patient-reported disability also improved. The DASI improved from 4.5 to 19.8 and LT-VLA score improved from 2 to 0.59 at closeout. Overall, utilization of a mHealth rehabilitation platform was safe and well received. Remote rehabilitation was associated with improvements in frailty, physical activity and disability. Future studies should evaluate mHealth treatment modalities in larger-scale randomized trials of lung transplant recipients.
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http://dx.doi.org/10.1111/ctr.14236DOI Listing
February 2021

Rapid molecular detection of airway pathogens in lung transplant recipients.

Transpl Infect Dis 2021 Feb 1:e13579. Epub 2021 Feb 1.

Department of Medicine, University of California, San Francisco, CA, USA.

Background: Airway infections are difficult to distinguish from acute rejection in lung transplant recipients. Traditional culture techniques take time that may delay treatment. We hypothesized that a rapid multiplex molecular assay could improve time to diagnosis and appropriate clinical decision making.

Methods: In a prospective observational study of recipients undergoing bronchoscopy, we assessed the BioFire FilmArray Pneumonia Panel (BFPP) in parallel to standard of care (SOC) diagnostics. Research clinicians performed shadow (research only) clinical decision making in real time. Time to report and interpretation were reported as median and interquartile ranges and compared by Wilcoxon signed-ranked test. Agreement was defined based on detection of any species targeted in the molecular assay.

Results: For the 150 enrolled subjects, BFPP results were available 3.8 hours (IQR 2.8-5.1) following bronchoscopy, compared to 13 hours for viral SOC (IQR 10-34, P < .001) results and 48 hours for bacterial SOC (IQR 46-70, P < .001) results. Positive BFPP results were interpreted in 9 hours (IQR 5-20) following bronchoscopy, compared to 74 hours for SOC (IQR 37-110, P < .001). Assays agreed for 138 (92%) of the 150 subjects. Of 22 BFPP diagnoses, five (23%) resulted in a shadow antibiotic recommendation. Notable BFPP deficiencies included fungal species and H parainfluenzae, accounting for 15 (27%) and 13 (23%) of the 56 actionable SOC results, respectively.

Conclusions: This molecular diagnostic including bacterial targets has the potential to shorten time to diagnosis and augment current clinical decision making but cannot replace SOC culture methods.
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http://dx.doi.org/10.1111/tid.13579DOI Listing
February 2021

Natural killer cells activated through NKG2D mediate lung ischemia-reperfusion injury.

J Clin Invest 2021 Feb;131(3)

Department of Medicine, University of California, San Francisco, California.

Pulmonary ischemia-reperfusion injury (IRI) is a clinical syndrome of acute lung injury that occurs after lung transplantation or remote organ ischemia. IRI causes early mortality and has no effective therapies. While NK cells are innate lymphocytes capable of recognizing injured cells, their roles in acute lung injury are incompletely understood. Here, we demonstrated that NK cells were increased in frequency and cytotoxicity in 2 different IRI mouse models. We showed that NK cells trafficked to the lung tissue from peripheral reservoirs and were more mature within lung tissue. Acute lung ischemia-reperfusion injury was blunted in a NK cell-deficient mouse strain but restored with adoptive transfer of NK cells. Mechanistically, NK cell NKG2D receptor ligands were induced on lung endothelial and epithelial cells following IRI, and antibody-mediated NK cell depletion or NKG2D stress receptor blockade abrogated acute lung injury. In human lung tissue, NK cells were increased at sites of ischemia-reperfusion injury and activated NK cells were increased in prospectively collected human bronchoalveolar lavage in subjects with severe IRI. These data support a causal role for recipient peripheral NK cells in pulmonary IRI via NK cell NKG2D receptor ligation. Therapies targeting NK cells may hold promise in acute lung injury.
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http://dx.doi.org/10.1172/JCI137047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852842PMC
February 2021

Type-1 immunity and endogenous immune regulators predominate in the airway transcriptome during chronic lung allograft dysfunction.

Am J Transplant 2020 Oct 20. Epub 2020 Oct 20.

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Chronic lung allograft dysfunction (CLAD) remains the major complication limiting long-term survival among lung transplant recipients (LTRs). Limited understanding of CLAD immunopathogenesis and a paucity of biomarkers remain substantial barriers for earlier detection and therapeutic interventions for CLAD. We hypothesized the airway transcriptome would reflect key immunologic changes in disease. We compared airway brush-derived transcriptomic signatures in CLAD (n = 24) versus non-CLAD (n = 21) LTRs. A targeted assessment of the proteome using concomitant bronchoalveolar lavage (BAL) fluid for 24 cytokines/chemokines and alloimmune T cell responses was performed to validate the airway transcriptome. We observed an airway transcriptomic signature of differential genes expressed (DGEs) in CLAD marked by Type-1 immunity and striking upregulation of two endogenous immune regulators: indoleamine 2, 3 dioxygenase 1 (IDO-1) and tumor necrosis factor receptor superfamily 6B (TNFRSF6B). Advanced CLAD staging was associated with a more intense airway transcriptome signature. In a validation cohort using the identified signature, we found an area under the curve (AUC) of 0.77 for CLAD LTRs. Targeted proteomic analyses revealed a predominant Type-1 profile with detection of IFN-γ, TNF-α, and IL-1β as dominant CLAD cytokines, correlating with the airway transcriptome. The airway transcriptome provides novel insights into CLAD immunopathogenesis and biomarkers that may impact diagnosis of CLAD.
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http://dx.doi.org/10.1111/ajt.16360DOI Listing
October 2020

Treatment of immunocompromised COVID-19 patients with convalescent plasma.

Transpl Infect Dis 2020 Sep 29:e13477. Epub 2020 Sep 29.

Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.

Immunosuppressed patients such as solid organ transplant and hematologic malignancy patients appear to be at increased risk for morbidity and mortality due to coronavirus disease 2019 (COVID-19) caused by SARS coronavirus 2 (SARS-CoV-2). Convalescent plasma, a method of passive immunization that has been applied to prior viral pandemics, holds promise as a potential treatment for COVID-19. Immunocompromised patients may experience more benefit from convalescent plasma given underlying deficits in B and T cell immunity as well as contraindications to antiviral and immunomodulatory therapy. We describe our institutional experience with four immunosuppressed patients (two kidney transplant recipients, one lung transplant recipient, and one chronic myelogenous leukemia patient) treated with COVID-19 convalescent plasma through the Expanded Access Program (NCT04338360). All patients clinically improved after administration (two fully recovered and two discharged to skilled nursing facilities) and none experienced a transfusion reaction. We also report the characteristics of convalescent plasma product from a local blood center including positive SARS-CoV-2 IgG and negative SARS-CoV-2 PCR in all samples tested. This preliminary evidence suggest that convalescent plasma may be safe among immunosuppressed patients with COVID-19 and emphasizes the need for further data on the efficacy of convalescent plasma as either primary or adjunctive therapy for COVID-19.
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http://dx.doi.org/10.1111/tid.13477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537112PMC
September 2020

Chronic lung allograft dysfunction small airways reveal a lymphocytic inflammation gene signature.

Am J Transplant 2021 01 22;21(1):362-371. Epub 2020 Sep 22.

Department of Medicine, University of California, San Francisco, California, USA.

Chronic lung allograft dysfunction (CLAD) is the major barrier to long-term survival following lung transplantation, and new mechanistic biomarkers are needed. Lymphocytic bronchitis (LB) precedes CLAD and has a defined molecular signature. We hypothesized that this LB molecular signature would be associated with CLAD in small airway brushings independent of infection. We quantified RNA expression from small airway brushings and transbronchial biopsies, using RNAseq and digital RNA counting, respectively, for 22 CLAD cases and 27 matched controls. LB metagene scores were compared across CLAD strata by Wilcoxon rank sum test. We performed unbiased host transcriptome pathway and microbial metagenome analysis in airway brushes and compared machine-learning classifiers between the two tissue types. This LB metagene score was increased in CLAD airway brushes (p = .002) and improved prediction of graft failure (p = .02). Gene expression classifiers based on airway brushes outperformed those using transbronchial biopsies. While infection was associated with decreased microbial alpha-diversity (p ≤ .04), neither infection nor alpha-diversity was associated with LB gene expression. In summary, CLAD was associated with small airway gene expression changes not apparent in transbronchial biopsies in this cohort. Molecular analysis of airway brushings for diagnosing CLAD merits further examination in multicenter cohorts.
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http://dx.doi.org/10.1111/ajt.16293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009189PMC
January 2021

Primary graft dysfunction attenuates improvements in health-related quality of life after lung transplantation, but not disability or depression.

Am J Transplant 2021 02 5;21(2):815-824. Epub 2020 Sep 5.

Division of Pulmonary and Critical Care, Department of Medicine, School of Medicine, University of California, San Francisco, California, USA.

Disability, depressive symptoms, and impaired health-related quality of life (HRQL) are common among patients with life-threatening respiratory compromise. We sought to determine if primary graft dysfunction (PGD), a syndrome of acute lung injury, attenuates improvements in patient-reported outcomes after transplantation. In a single-center prospective cohort, we assessed disability, depressive symptoms, and HRQL before and at 3- to 6-month intervals after lung transplantation. We estimated the magnitude of change in disability, depressive symptoms, and HRQL with hierarchical segmented linear mixed-effects models. Among 251 lung transplant recipients, 50 developed PGD Grade 3. Regardless of PGD severity, participants had improvements in disability and depressive symptoms, as well as generic-physical, generic-mental, respiratory-specific, and health-utility HRQL, exceeding 1- to 4-fold the minimally clinically important difference across all instruments. Participants with PGD Grade 3 had a lower magnitude of improvement in generic-physical HRQL and health-utility than in all other participants. Among participants with PGD Grade 3, prolonged mechanical ventilation was associated with greater attenuation of improvements. PGD remains a threat to the 2 primary aims of lung transplantation, extending survival and improving HRQL. Attenuation of improvement persists long after hospital discharge. Future studies should assess if interventions can mitigate the impact of PGD on patient-reported outcomes.
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http://dx.doi.org/10.1111/ajt.16257DOI Listing
February 2021

Cystic Fibrosis Lung Transplant Recipients Have Suppressed Airway Interferon Responses during Infection.

Cell Rep Med 2020 Jul;1(4)

Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.

Lung transplantation can be lifesaving in end-stage cystic fibrosis (CF), but long-term survival is limited by chronic lung allograft dysfunction (CLAD). Persistent upper airway (PsA) colonization can seed the allograft. While PsA infection is associated with CLAD in non-CF recipients, this association is less clear for CF recipients experiencing PsA recolonization. Here, we evaluate host and pathogen contributions to this phenomenon. In the context of PsA infection, brushings from the airways of CF recipients demonstrate type 1 interferon gene suppression. Airway epithelial cell (AEC) cultures demonstrate similar findings in the absence of pathogens or immune cells, contrasting with the pre-transplant CF AEC phenotype. Type 1 interferon promoters are relatively hypermethylated in CF AECs. CF subjects in this cohort have more mucoid PsA, while non-CF PsA subjects have decreased microbiome α diversity. Peri-transplant protocols may benefit from consideration of this host and microbiome equilibrium.
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http://dx.doi.org/10.1016/j.xcrm.2020.100055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402593PMC
July 2020

Complement activation on endothelium initiates antibody-mediated acute lung injury.

J Clin Invest 2020 11;130(11):5909-5923

Department of Medicine, UCSF, San Francisco, California, USA.

Antibodies targeting human leukocyte antigen (HLA)/major histocompatibility complex (MHC) proteins limit successful transplantation and transfusion, and their presence in blood products can cause lethal transfusion-related acute lung injury (TRALI). It is unclear which cell types are bound by these anti-leukocyte antibodies to initiate an immunologic cascade resulting in lung injury. We therefore conditionally removed MHC class I (MHC I) from likely cellular targets in antibody-mediated lung injury. Only the removal of endothelial MHC I reduced lung injury and mortality, related mechanistically to absent endothelial complement fixation and lung platelet retention. Restoration of endothelial MHC I rendered MHC I-deficient mice susceptible to lung injury. Neutrophil responses, including neutrophil extracellular trap (NET) release, were intact in endothelial MHC I-deficient mice, whereas complement depletion reduced both lung injury and NETs. Human pulmonary endothelial cells showed high HLA class I expression, and posttransfusion complement activation was increased in clinical TRALI. These results indicate that the critical source of antigen for anti-leukocyte antibodies is in fact the endothelium, which reframes our understanding of TRALI as a rapid-onset vasculitis. Inhibition of complement activation may have multiple beneficial effects of reducing endothelial injury, platelet retention, and NET release in conditions where antibodies trigger these pathogenic responses.
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http://dx.doi.org/10.1172/JCI138136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598054PMC
November 2020

Skeletal muscle adiposity and outcomes in candidates for lung transplantation: a lung transplant body composition cohort study.

Thorax 2020 09 1;75(9):801-804. Epub 2020 Jun 1.

Medicine, University of California, San Francisco, California, USA.

CT measurement of body composition may improve lung transplant candidate selection. We assessed whether skeletal muscle adipose deposition on abdominal and thigh CT scans was associated with 6 min walk distance (6MWD) and wait-list survival in lung transplant candidates. Each ½-SD decrease in abdominal muscle attenuation (indicating greater lipid content) was associated with 14 m decrease in 6MWD (95% CI -20 to -8) and 20% increased risk of death or delisting (95% CI 10% to 40%). Each ½-standard deviation decrease in thigh muscle attenuation was associated with 15 m decrease in 6MWD (95% CI -21 to -10). CT imaging may improve candidate risk stratification.
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http://dx.doi.org/10.1136/thoraxjnl-2019-214461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888552PMC
September 2020

Clinical outcomes and serologic response in solid organ transplant recipients with COVID-19: A case series from the United States.

Am J Transplant 2020 11 17;20(11):3225-3233. Epub 2020 Jul 17.

Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, California, USA.

The coronavirus disease 2019 (COVID-19) pandemic caused by SARS coronavirus 2 (SARS-CoV-2) has caused significant morbidity and mortality for patients and stressed healthcare systems worldwide. The clinical features, disease course, and serologic response of COVID-19 among immunosuppressed patients such as solid organ transplant (SOT) recipients, who are at presumed risk for more severe disease, are not well characterized. We describe our institutional experience with COVID-19 among 10 SOT patients, including the clinical presentation, treatment modalities, and outcomes of 7 renal transplant recipients, 1 liver transplant recipient, 1 heart transplant recipient, and 1 lung transplant recipient. In addition, we report the serologic response in SOT recipients, documenting a positive IgG response in all 7 hospitalized patients. We also review the existing literature on COVID-19 in SOT recipients to consolidate the current knowledge on COVID-19 in the SOT population for the transplant community.
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http://dx.doi.org/10.1111/ajt.16079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300859PMC
November 2020

Frailty after lung transplantation is associated with impaired health-related quality of life and mortality.

Thorax 2020 08 6;75(8):669-678. Epub 2020 May 6.

Medicine, University of California San Francisco, San Francisco, California, USA.

Background: Lung transplantation and related medications are associated with pathobiological changes that can induce frailty, a state of decreased physiological reserve. Causes of persistent or emergent frailty after lung transplantation, and whether such transplant-related frailty is associated with key outcomes, are unknown.

Methods: Frailty and health-related quality of life (HRQL) were prospectively measured repeatedly for up to 3 years after lung transplantation. Frailty, quantified by the Short Physical Performance Battery (SPPB), was tested as a time-dependent binary and continuous predictor. The association of transplant-related frailty with HRQL and mortality was evaluated using mixed effects and Cox regression models, respectively, adjusting for age, sex, ethnicity, diagnosis, and for body mass index and lung function as time-dependent covariates. We tested the association between measures of body composition, malnutrition, renal dysfunction and immunosuppressants on the development of frailty using mixed effects models with time-dependent predictors and lagged frailty outcomes.

Results: Among 259 adults (56% male; mean age 55.9±12.3 years), transplant-related frailty was associated with lower HRQL. Frailty was also associated with a 2.5-fold higher mortality risk (HR 2.51; 95% CI 1.21 to 5.23). Further, each 1-point worsening in SPPB was associated, on average, with a 13% higher mortality risk (HR 1.13; 95% CI 1.04 to 1.23). Secondarily, we found that sarcopenia, underweight and obesity, malnutrition, and renal dysfunction were associated with the development of frailty after transplant.

Conclusions: Transplant-related frailty is associated with lower HRQL and higher mortality in lung recipients. Abnormal body composition, malnutrition and renal dysfunction may contribute to the development of frailty after transplant. Confirming the role of these potential contributors and developing interventions to mitigate frailty may improve lung transplant success.
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http://dx.doi.org/10.1136/thoraxjnl-2019-213988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023537PMC
August 2020

Improvements in frailty contribute to substantial improvements in quality of life after lung transplantation in patients with cystic fibrosis.

Pediatr Pulmonol 2020 06 1;55(6):1406-1413. Epub 2020 Apr 1.

Department of Medicine, University of California San Francisco, San Francisco, California.

Background: While lung transplantation (LTx) improves health-related quality of life (HRQL) in cystic fibrosis (CF), the determinants of this improvement are unknown. In other populations, frailty-a syndrome of vulnerability to physiologic stressors-is associated with disability and poor HRQL. We hypothesized that improvements in frailty would be associated with improved disability and HRQL in adults with CF undergoing LTx.

Methods: In a single-center prospective cohort study from 2010 to 2017, assessments of frailty, disability, and HRQL were performed before and at 3- and 6-months after LTx. We assessed frailty by the short physical performance battery (SPPB). We assessed disability with the Lung Transplant Valued Life Activities scale (LT-VLA) and HRQL by the Medical Outcomes Study Short Form Physical and Mental Component Summary scales (SF12-PCS, -MCS), the Airway Questionnaire 20-Revised (AQ20R), and the Euroqol 5D (EQ5D). We tested the association of concurrent changes in frailty and lung function on disability and HRQL by linear mixed-effects models adjusted for sex and body mass index.

Results: Among 23 participants with CF, improvements in frailty and lung function were independently associated with improved disability and some HRQL measures. For example, each 1-point improvement in SPPB or 200 mL improvement in FEV1 was associated with improved LT-VLA disability by 0.14 (95%CI: 0.08-0.20) and 0.07 (95%CI: 0.05-0.09) points and improved EQ5D by 0.05 (95%CI: 0.03 to 0.07) and 0.02 (95%CI: 0.01-0.03) points, respectively.

Conclusion: Improvement in frailty is a novel determinant of improved disability and HRQL in adults with CF undergoing LTx.
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http://dx.doi.org/10.1002/ppul.24747DOI Listing
June 2020

Tacrolimus trough monitoring guided by mass spectrometry without accounting for assay differences is associated with acute kidney injury in lung transplant recipients.

Am J Health Syst Pharm 2019 12;76(24):2019-2027

Division of Pulmonary and Critical Care, Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA.

Purpose: Tacrolimus is a nephrotoxic immunosuppressant historically monitored via enzyme-based immunoassay (IA). After 2011, the 2 largest laboratory companies in the United States implemented tacrolimus quantification by liquid chromatography-mass spectrometry (LC-MS); this method excludes metabolites, potentially resulting in lower quantified drug concentrations. We sought to determine if tacrolimus therapeutic drug monitoring via LC-MS, as performed using trough targets originally derived from IA values, influences clinical outcomes.

Methods: In a single-center retrospective cohort study of lung transplant recipients, risks of acute kidney injury, acute renal failure, and new-onset diabetes after transplantation, as well as chronic lung allograft dysfunction-free survival, were compared in 82 subjects monitored by LC-MS and 102 subjects monitored by IA using Cox proportional hazard models adjusted for age, sex, baseline renal function, and race.

Results: LC-MS-based monitoring was associated with a greater risk of acute kidney injury (adjusted hazard ratio, 1.65; 95% confidence interval, 1.02-2.67). No statistically significant differences in risks of acute renal failure and new-onset diabetes after transplantation were observed.

Conclusion: Although LC-MS provides a more accurate representation of the blood concentration of the parent compound tacrolimus exclusive of metabolite, established cut points for tacrolimus dosing may need to be adjusted to account for the increased risk of renal injury.
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http://dx.doi.org/10.1093/ajhp/zxz243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170730PMC
December 2019

Mitochondrial DNA Stimulates TLR9-Dependent Neutrophil Extracellular Trap Formation in Primary Graft Dysfunction.

Am J Respir Cell Mol Biol 2020 03;62(3):364-372

Department of Medicine.

The immune system is designed to robustly respond to pathogenic stimuli but to be tolerant to endogenous ligands to not trigger autoimmunity. Here, we studied an endogenous damage-associated molecular pattern, mitochondrial DNA (mtDNA), during primary graft dysfunction (PGD) after lung transplantation. We hypothesized that cell-free mtDNA released during lung ischemia-reperfusion triggers neutrophil extracellular trap (NET) formation via TLR9 signaling. We found that mtDNA increases in the BAL fluid of experimental PGD (prolonged cold ischemia followed by orthotopic lung transplantation) and not in control transplants with minimal warm ischemia. The adoptive transfer of mtDNA into the minimal warm ischemia graft immediately before lung anastomosis induces NET formation and lung injury. TLR9 deficiency in neutrophils prevents mtDNA-induced NETs, and TLR9 deficiency in either the lung donor or recipient decreases NET formation and lung injury in the PGD model. Compared with human lung transplant recipients without PGD, severe PGD was associated with high levels of BAL mtDNA and NETs, with evidence of relative deficiency in DNaseI. We conclude that mtDNA released during lung ischemia-reperfusion triggers TLR9-dependent NET formation and drives lung injury. In PGD, DNaseI therapy has a potential dual benefit of neutralizing a major NET trigger (mtDNA) in addition to dismantling pathogenic NETs.
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http://dx.doi.org/10.1165/rcmb.2019-0140OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055700PMC
March 2020

Dectin-1 genetic deficiency predicts chronic lung allograft dysfunction and death.

JCI Insight 2019 11 14;4(22). Epub 2019 Nov 14.

Department of Medicine, UCSF, San Francisco, California, USA.

BACKGROUNDInnate immune activation impacts lung transplant outcomes. Dectin-1 is an innate receptor important for pathogen recognition. We hypothesized that genotypes reducing dectin-1 activity would be associated with infection, graft dysfunction, and death in lung transplant recipients.METHODSWe assessed the rs16910526 CLEC7A gene polymorphism Y238X, which results in dectin-1 truncation, in 321 lung allograft recipients at a single institution and in 1,129 lung allograft recipients in the multicenter Lung Transplant Outcomes Group (LTOG) cohort. Differences in dectin-1 mRNA, cytokines, protein levels, immunophenotypes, and clinical factors were assessed.RESULTSY238X carriers had decreased dectin-1 mRNA expression (P = 0.0001), decreased soluble dectin-1 protein concentrations in bronchoalveolar lavage (P = 0.008) and plasma (P = 0.04), and decreased monocyte surface dectin-1 (P = 0.01) compared with wild-type subjects. Y238X carriers had an increased risk of fungal pathogens (HR 1.17, CI 1.0-1.4), an increased risk of graft dysfunction or death (HR 1.6, CI 1.0-2.6), as well increased mortality in the UCSF cohort (HR 1.8, CI 1.1-3.8) and in the LTOG cohort (HR 1.3, CI 1.1-1.6), compared with wild-type CLEC7A subjects.CONCLUSIONIncreased rates of graft dysfunction and death associated with this dectin-1 polymorphism may be amplified by immunosuppression that drives higher fungal burden from compromised pathogen recognition.FUNDINGThe UCSF Nina Ireland Program for Lung Health Innovative Grant program, the Clinical Sciences Research & Development Service of the VA Office of Research and Development, and the Joel D. Cooper Career Development Award from the International Society for Heart and Lung Transplantation.
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http://dx.doi.org/10.1172/jci.insight.133083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948872PMC
November 2019

Adipose tissue quantification and primary graft dysfunction after lung transplantation: The Lung Transplant Body Composition study.

J Heart Lung Transplant 2019 12 10;38(12):1246-1256. Epub 2019 Aug 10.

Department of Medicine, Columbia University Medical Center, New York, New York; Department of Epidemiology, Mailman School of Public Health, Columbia University Medical Center, New York, New York. Electronic address:

Background: Obesity is associated with an increased risk of primary graft dysfunction (PGD) after lung transplantation. The contribution of specific adipose tissue depots is unknown.

Methods: We performed a prospective cohort study of adult lung transplant recipients at 4 U.S. transplant centers. We measured cross-sectional areas of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) on chest and abdominal computed tomography (CT) scans and indexed each measurement to height. We used logistic regression to examine the associations of adipose indices and adipose classes with grade 3 PGD at 48 or 72 hours, and Cox proportional hazards models to examine survival. We used latent class analyses to identify the patterns of adipose distribution. We examined the associations of adipose indices with plasma biomarkers of obesity and PGD.

Results: A total of 262 and 117 subjects had available chest CT scans and underwent protocol abdominal CT scans, respectively. In the adjusted models, a greater abdominal SAT index was associated with an increased risk of PGD (odds ratio 1.9, 95% CI 1.02-3.4, p = 0.04) but not with survival time. VAT indices were not associated with PGD risk or survival time. A greater abdominal SAT index correlated with greater pre- and post-transplant leptin (r = 0.61, p < 0.001, and r = 0.44, p < 0.001), pre-transplant IL-1RA (r = 0.25, p = 0.04), and post-transplant ICAM-1 (r = 0.25, p = 0.04). We identified 3 latent patterns of adiposity. The class defined by high thoracic and abdominal SAT had the greatest risk of PGD.

Conclusions: Subcutaneous, but not visceral, adiposity is associated with an increased risk of PGD after lung transplantation.
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http://dx.doi.org/10.1016/j.healun.2019.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883162PMC
December 2019

Management and clinical outcomes after lung transplantation in patients with pre-transplant Mycobacterium abscessus infection: A single center experience.

Transpl Infect Dis 2019 Jun 16;21(3):e13084. Epub 2019 Apr 16.

Department of Medicine, University of California, San Francisco.

Background: Preoperative Mycobacterium abscessus infection is often considered a contraindication to lung transplantation because of its association with poor outcomes after transplant. Detailed strategies for bridging to transplant, post-operative management, and data regarding outcomes are lacking.

Methods: We reviewed outcomes in subjects with M abscessus infection who underwent lung transplantation between 2010 and 2018 at the University of California San Francisco. M abscessus infection was defined by American Thoracic Society (ATS) criteria. Data collected included age, FEV , BMI, LAS, antibiotic regimens, and other management decisions. Time to chronic lung allograft dysfunction (CLAD) and survival were also assessed.

Results: Of 387 lung transplant recipients, seven were infected with M abscessus at the time of listing. All received multiple antibiotics before transplant. While all subjects converted to smear negative for acid-fast bacilli before listing, five of the seven remained culture-positive at the time of transplant. After transplant, subjects received a median of 6 months of a multi-antibiotic regimen. One subject developed a post-operative M abscessus soft tissue infection that was treated medically. Six of the seven subjects survived the observation period; one died unrelated to M abscessus. Time to CLAD and survival were similar to a contemporary comparator group of CF transplant recipients.

Conclusion: Lung transplant recipients with M abscessus infection have a low incidence of recurrent infection, excellent survival, and freedom from CLAD when an aggressive management and surveillance strategy is utilized. Given these findings, M abscessus infection may not be considered a contraindication to lung transplantation.
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http://dx.doi.org/10.1111/tid.13084DOI Listing
June 2019

Gene signatures common to allograft rejection are associated with lymphocytic bronchitis.

Clin Transplant 2019 05 27;33(5):e13515. Epub 2019 Mar 27.

Medical Service, Veterans Affairs Health Care System, San Francisco, California.

Lymphocytic bronchitis (LB) precedes chronic lung allograft dysfunction. The relationships of LB (classified here as Endobronchial or E-grade rejection) to small airway (A- and B-grade) pathologies are unclear. We hypothesized that gene signatures common to allograft rejection would be present in LB. We studied LB in two partially overlapping lung transplant recipient cohorts: Cohort 1 included large airway brushes (6 LB cases and 18 post-transplant referents). Differential expression using DESeq2 was used for pathway analysis and to define an LB-associated metagene. In Cohort 2, eight biopsies for each pathology subtype were matched with pathology-free biopsies from the same subject (totaling 48 samples from 24 subjects). These biopsies were analyzed by multiplexed digital counting of immune transcripts. Metagene score differences were compared by paired t tests. Compared to referents in Cohort 1, LB demonstrated upregulation of allograft rejection pathways, and upregulated genes in these cases characterized an LB-associated metagene. We observed statistically increased expression in Cohort 2 for this LB-associated metagene and four other established allograft rejection metagenes in rejection vs paired non-rejection biopsies for both E-grade and A-grade subtypes, but not B-grade pathology. Gene expression-based categorization of allograft rejection may prove useful in monitoring lung allograft health.
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http://dx.doi.org/10.1111/ctr.13515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545574PMC
May 2019

Development and Preliminary Validation of the Lung Transplant Quality of Life (LT-QOL) Survey.

Am J Respir Crit Care Med 2019 04;199(8):1008-1019

4 Institute for Health & Aging, University of California, San Francisco, San Francisco, California.

Rationale: Although lung transplantation aims to improve health-related quality of life (HRQL), existing instruments fail to include health domains considered important in this population.

Objectives: We aimed to develop a comprehensive lung transplant-specific instrument to address this shortcoming.

Methods: We developed a pool of 126 candidate items addressing domains previously identified as important by lung transplant recipients. Through cognitive interviews conducted in 43 transplant recipients, items deemed irrelevant or redundant were dropped. The 84 remaining items were field tested in lung transplant recipients. Exploratory and confirmatory factor analyses were used to evaluate the factor structure, and scales were evaluated for internal consistency and construct validity.

Measurements And Main Results: The 84-item preliminary survey was administered to 201 lung transplant recipients with a mean age of 57.9 (±12.7) years; 46% were female. After factor analyses and internal consistency evaluation, we retained 60 items comprising the Lung Transplant Quality of Life (LT-QOL) Survey. The LT-QOL contains 10 scales that measure symptoms, health perceptions, functioning, and well-being. The confirmatory factor analysis model had good approximate fit (comparative fit index = 0.990; standardized root-mean-square residual = 0.062). Cronbach αs for the 10 scales ranged from 0.75 to 0.95. Interscale correlations were consistent with hypothesized relationships. Subjects with severe chronic lung allograft dysfunction (n = 13) reported significantly worse HRQL than subjects without chronic lung allograft dysfunction (n = 168) on 6 of the 10 LT-QOL scales.

Conclusions: The LT-QOL is a new, multidimensional instrument that characterizes and quantifies HRQL in lung transplant recipients.
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http://dx.doi.org/10.1164/rccm.201806-1198OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467318PMC
April 2019

Pirfenidone-Induced Sarcoid-Like Reaction: A Novel Complication.

Chest 2018 10;154(4):e89-e92

Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA.

Idiopathic pulmonary fibrosis is the most common idiopathic interstitial pneumonia. Prognosis is poor with a median survival <3 years. Pirfenidone is one of two US Food and Drug Administration-approved medications that slow disease progression. We describe the development of lymphadenopathy or a sarcoid-like reaction following initiation of pirfenidone, a complication not previously reported.
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http://dx.doi.org/10.1016/j.chest.2018.03.048DOI Listing
October 2018

NKG2C Natural Killer Cells in Bronchoalveolar Lavage Are Associated With Cytomegalovirus Viremia and Poor Outcomes in Lung Allograft Recipients.

Transplantation 2019 03;103(3):493-501

Department of Medicine, University of California, San Francisco, CA.

Background: Cytomegalovirus (CMV) infection is a risk factor for chronic lung allograft dysfunction (CLAD), which limits survival in lung allograft recipients. Natural killer (NK) cells that express the NKG2C receptor mediate CMV-specific immune responses. We hypothesized that NKG2C NK cells responding to CMV in the lung allograft would reduce CMV-related inflammation and would improve CLAD-free survival.

Methods: We prospectively followed 130 subjects who underwent lung transplantation from 2012 to 2016. Bronchoalveolar lavage (BAL) NK cells were immunophenotyped for NKG2C, maturation, and proliferation markers. CMV viral load, serologies, serial spirometry, and mortality were recorded from medical records. Natural killer cell subset association with CMV endpoints were made using generalized estimating equation-adjusted linear models. BAL NKG2C NK cell association with CLAD-free survival was assessed by Cox proportional hazards modeling.

Results: NKG2C NK cells were more mature and proliferative than NKG2C NK cells and represented a median of 7.8% of BAL NK cells. The NKG2C NK cell proportion increased prior to the first detection of viremia and was nearly tripled in subjects with high level viremia (>1000 copies/mL) compared with no detected viremia. Subjects with increased BAL NKG2C NK cells, relative to the median, had a significantly increased risk for CLAD or death (hazard ratio, 4.2; 95% confidence interval, 1.2-13.3).

Conclusions: The BAL NKG2C NK cell proportion may be a relevant biomarker for assessing risk of CMV viremia and quantifying potential CMV-related graft injury that can lead to CLAD or death.
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http://dx.doi.org/10.1097/TP.0000000000002450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389428PMC
March 2019

Genotypes associated with tacrolimus pharmacokinetics impact clinical outcomes in lung transplant recipients.

Clin Transplant 2018 08 4;32(8):e13332. Epub 2018 Jul 4.

Department of Medicine, University of California, San Francisco, California.

Most lung transplantation immunosuppression regimens include tacrolimus. Single nucleotide polymorphisms (SNPs) in genes important to tacrolimus bioavailability and clearance (ABCB1, CYP3A4, and CYP3A5) are associated with differences in tacrolimus pharmacokinetics. We hypothesized that polymorphisms in these genes would impact immunosuppression-related outcomes. We categorized ABCB1, CYP3A4, and CYP3A5 SNPs for 321 lung allograft recipients. Genotype effects on time to therapeutic tacrolimus level, interactions with antifungal medications, concentration to dose (C /D), acute kidney injury, and rejection were assessed using linear models adjusted for subject characteristics and repeat measures. Compared with CYP3A poor metabolizers (PM), time to therapeutic tacrolimus trough was increased by 5.1 ± 1.6 days for CYP3A extensive metabolizers (EM, P < 0.001). In the post-operative period, CYP3A intermediate metabolizers spent 1.2 ± 0.5 days less (P = 0.01) and EM spent 2.1 ± 0.5 days less (P < 0.001) in goal tacrolimus range than CYP3A PM. Azole antifungals interacted with CYP3A genotype in predicting C /D (P < 0.001). Increased acute kidney injury rates were observed in subjects with high ABCB1 function (OR 3.0, 95% CI 1.1-8.6, P = 0.01). Lower rates of acute cellular rejection were observed in subjects with low ABCB1 function (OR 0.36, 95% CI 0.07-0.94, P = 0.02). Recipient genotyping may help inform tacrolimus dosing decisions and risk of adverse clinical outcomes.
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http://dx.doi.org/10.1111/ctr.13332DOI Listing
August 2018

A mobile health technology enabled home-based intervention to treat frailty in adult lung transplant candidates: A pilot study.

Clin Transplant 2018 06 20;32(6):e13274. Epub 2018 Jun 20.

Department of Medicine, University of California, San Francisco, CA, USA.

Background: Frailty is prevalent in lung transplant candidates (LTC) and is associated with waitlist delisting or death. We performed a pilot study to assess the safety and feasibility of a home-based, mobile health technology-facilitated intervention to treat frailty in LTC.

Methods: We performed an 8-week, nonrandomized, home-based exercise and nutrition intervention in LTC with Short Physical Performance Battery (SPPB) frailty scores of ≤11. The intervention utilized a customized, mobile device application ("app") enabling monitoring and progression of the intervention in real time. We aimed to evaluate key process measures. Secondarily, we tested whether the intervention could improve frailty scores quantified by the SPPB and Fried Frailty Phenotype (FFP).

Results: A total of 15 subjects enrolled were 63 ± 5.7 years old; oxygen requirements ranged from 3 to 15LPM. Thirteen subjects completed the intervention. Over 108 subject-weeks, there were no adverse events. Subjects found the app engaging and easy to work with. SPPB frailty improved in 7 (54%) and FFP improved in 8 (62%). There was a strong trend toward improved frailty scores (SPPB change 1.0 ± 1.9; P = .08; FFP change -0.6 ± 1.0; P = .07).

Conclusion: In this pilot study, we found that a home-based prehabilitation program that leverages mobile health technology to target frailty in LTC is well received, safe, and capable of improving physical frailty scores.
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http://dx.doi.org/10.1111/ctr.13274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066279PMC
June 2018

Suppressed calcineurin-dependent gene expression identifies lung allograft recipients at increased risk of infection.

Am J Transplant 2018 08 22;18(8):2043-2049. Epub 2018 May 22.

Department of Surgery, University of California, San Francisco, CA, USA.

Lung transplant immunosuppression regimens generally include the calcineurin inhibitor tacrolimus. We hypothesized that mean residual expression (MRE) of calcineurin-dependent genes assesses rejection and infection risk better than does tacrolimus trough. We prospectively followed 44 lung allograft recipients at 2 to 18 months posttransplant and measured changes in whole blood interleukin-2, interferon-γ, and granulocyte-macrophage colony-stimulating factor gene expression following a tacrolimus dose. Posttransplant duration, immunosuppressive medication levels, and bronchoscopic rejection and infection assessments were compared with MRE by using generalized-estimating equation-adjusted models. Prednisolone effect on MRE was assessed ex vivo in blood samples from nontransplanted controls. Tacrolimus concentration inhibiting 50% of cytokine production (IC ) was measured in a pretransplant subset. Results showed that MRE did not change with diagnosis of rejection but that airway infection was associated with a 20% absolute decrease (95% confidence interval 11%-29%). MRE increased with time after transplant but was not associated with tacrolimus trough. Interestingly, MRE correlated inversely with corticosteroid dose in the study cohort and ex vivo. Pretransplant tacrolimus IC depended on the cytokine measured and varied between individuals, suggesting a range in baseline responses to tacrolimus. We conclude that MRE identifies infection risk in lung allograft recipients, potentially integrating calcineurin inhibitor and steroid effects on lymphocyte effector function.
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http://dx.doi.org/10.1111/ajt.14886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699504PMC
August 2018

Improvement in patient-reported outcomes after lung transplantation is not impacted by the use of extracorporeal membrane oxygenation as a bridge to transplantation.

J Thorac Cardiovasc Surg 2018 07 22;156(1):440-448.e2. Epub 2018 Feb 22.

Division of Pulmonary and Critical Care, Department of Medicine, University of California San Francisco School of Medicine, San Francisco, Calif.

Objective: Extracorporeal membrane oxygenation (ECMO) is increasingly used as a bridge to lung transplantation. The impact of preoperative ECMO on health-related quality of life (HRQL) and depressive symptoms after lung transplantation remains unknown, however.

Methods: In a single-center prospective cohort study, we assessed HRQL and depressive symptoms before and at 3, 6, and 12 months after lung transplantation using the Short Form 12 Physical and Mental Component Scores (SF12-PCS and SF12-MCS), Airway Questionnaire 20-Revised (AQ20R), EuroQol 5D (EQ5D), and Geriatric Depression Scale (GDS). Changes in HRQL were quantified by segmented linear mixed-effects models controlling for age, sex, diagnosis, preoperative forced expiratory volume in 1 second, 6-minute walk distance, and Lung Allocation Score. We compared changes in HRQL among subjects bridged with ECMO, subjects hospitalized but not on ECMO, and subjects called in for transplantation as outpatients.

Results: Out of 189 subjects, 17 were bridged to transplantation with ECMO. In all groups, improvements in HRQL following lung transplantation exceeded the minimally clinically important difference using the SF12-PCS, AQ20R, EQ5D, and GDS. HRQL defined by SF12-MCS did not change after transplantation. Improvements were generally similar among the groups, except for EQ5D, which showed a trend toward less benefit in the outpatients, possibly due to their better HRQL before lung transplantation.

Conclusions: Subjects ill enough to require ECMO as a bridge to lung transplantation appear to achieve similar improvements in HRQL and depressive symptoms as those who do not. It is reassuring to both providers and patients that lung transplantation provides substantial improvements in HRQL, even for those patients who are critically ill in the run up to transplantation.
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http://dx.doi.org/10.1016/j.jtcvs.2018.01.101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013366PMC
July 2018

Short lung transplant donor telomere length is associated with decreased CLAD-free survival.

Thorax 2017 11 26;72(11):1052-1054. Epub 2017 Apr 26.

University of California, San Francisco, California, USA.

Telomere length (TL) decreases with cellular ageing and biological stressors. As advanced donor and recipient ages are risk factors for chronic lung allograft dysfunction (CLAD), we hypothesised that decreased age-adjusted donor TL would predict earlier onset of CLAD. Shorter donor TL was associated with increased risk of CLAD or death (HR 1.26 per 1 kb TL decrease, 95% CI 1.03 to 1.54), particularly for young donors. Recipient TL was associated with cytopenias but not CLAD. Shorter TL was also seen in airway epithelium for subjects progressing to CLAD (p=0.02). Allograft TL may contribute to CLAD pathogenesis and facilitate risk stratification.
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http://dx.doi.org/10.1136/thoraxjnl-2016-209897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550329PMC
November 2017

Refining Low Physical Activity Measurement Improves Frailty Assessment in Advanced Lung Disease and Survivors of Critical Illness.

Ann Am Thorac Soc 2017 Aug;14(8):1270-1279

1 Department of Medicine, College of Physicians & Surgeons.

Rationale: The frail phenotype has gained popularity as a clinically relevant measure in adults with advanced lung disease and in critical illness survivors. Because respiratory disease and chronic illness can greatly limit physical activity, the measurement of participation in traditional leisure time activities as a frailty component may lead to substantial misclassification of frailty in pulmonary and critical care patients.

Objectives: To test and validate substituting the Duke Activity Status Index (DASI), a simple 12-item questionnaire, for the Minnesota Leisure Time Physical Activity (MLTA) questionnaire, a detailed questionnaire covering 18 leisure time activities, as the measure of low activity in the Fried frailty phenotype (FFP) instrument.

Methods: In separate multicenter prospective cohort studies of adults with advanced lung disease who were candidates for lung transplant and older survivors of acute respiratory failure, we assessed the FFP using either the MLTA or the DASI. For both the DASI and MLTA, we evaluated content validity by testing floor effects and construct validity through comparisons with conceptually related factors. We tested the predictive validity of substituting the DASI for the MLTA in the FFP assessment using Cox models to estimate associations between the FFP and delisting/death before transplant in those with advanced lung disease and 6-month mortality in older intensive care unit (ICU) survivors.

Results: Among 618 adults with advanced lung disease and 130 older ICU survivors, the MLTA had a substantially greater floor effect than the DASI (42% vs. 1%, and 49% vs. 12%, respectively). The DASI correlated more strongly with strength and function measures than did the MLTA in both cohorts. In models adjusting for age, sex, comorbidities, and illness severity, substitution of the DASI for the MLTA led to stronger associations of the FFP with delisting/death in lung transplant candidates (FFP-MLTA hazard ratio [HR], 1.42; 95% confidence interval [CI], 0.55-3.65; FFP-DASI HR, 2.99; 95% CI, 1.03-8.65) and with mortality in older ICU survivors (FFP-MLTA HR, 2.68; 95% CI, 0.62-11.6; FFP-DASI HR, 5.71; 95% CI, 1.34-24.3).

Conclusions: The DASI improves the construct and predictive validity of frailty assessment in adults with advanced lung disease or recent critical illness. This simple questionnaire should replace the more complex MLTA in assessing the frailty phenotype in these populations.
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http://dx.doi.org/10.1513/AnnalsATS.201612-1008OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566272PMC
August 2017