Publications by authors named "Jasleen Kukreja"

77 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

Lung transplantation from swimming pool drowning victims: A case series.

Am J Transplant 2021 Jan 28. Epub 2021 Jan 28.

Division of Cardiothoracic Surgery, University of California, San Francisco, California, USA.

The use of donor lungs from victims of drowning remains a rare occurrence, given concerns over lung parenchymal injury and microbial contamination secondary to aspiration. Given this infrequency, there is a relative paucity of literature surrounding the use of organs from drowned donors, with the few that exist on this subject focusing primarily on cases of drowning in naturally occurring bodies of water (i.e., drowning at sea). Little is known regarding the outcomes of utilizing donor lungs from victims of drowning in artificial bodies of water (i.e., swimming pools). Here, we describe three cases of bilateral lung transplantation from donors who drowned in swimming pools, with good short- and long-term outcomes. These cases lend further evidence to the feasibility of using such organs that have traditionally been viewed with much trepidation. With continually growing demand for donor organs, the use of drowned donor lungs may serve as a means to expand the donor pool and lessen the burden of waitlist mortality.
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http://dx.doi.org/10.1111/ajt.16510DOI Listing
January 2021

An Analysis of Successful Features of Anesthesiology Journal Clubs.

J Educ Perioper Med 2020 Oct-Dec;22(4):E648. Epub 2020 Oct 1.

Background: No studies have examined how journal clubs (JCs) are implemented in anesthesiology residency training programs. The goal of the study was to close this gap by (1) examining the format, content, and goals of JCs; (2) identifying features associated with higher resident attendance and JC success; and (3) examining program directors' perspectives on JCs.

Methods: A 41-question survey was sent to anesthesiology program directors. Answers were analyzed using multivariable logistic regression, multivariable linear regression, and exploratory factor analysis.

Results: Out of 117 surveys sent across the United States, 80 program directors responded (68.4% response rate). Of the 80 programs, 77 (96.3%) programs have a JC, with 93.2% of them existing for more than 2 years. Most JCs (62.5%) neither formally appraised articles before meetings, nor formally evaluated their JC (59.7%). Faculty alone organized 44.4% and moderated 69.9% of the JCs. The role of residents was primarily limited to presenting selected articles with faculty guidance (83.3%). The average resident attendance was 49.7%. A multivariable linear regression analysis identified mandatory resident attendance, faculty turnout of >5 members, and longer intervals between JC meetings as features associated with higher resident attendance. Only 49.3% of JCs were successful as defined a priori by resident attendance >50% and longevity of ≥2 years. Features associated with JC success based on multivariable logistic regression included mandatory resident attendance and complimentary food.

Conclusions: This largest survey of JCs in anesthesiology found that while JCs are widely established, half of them could be improved.
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http://dx.doi.org/10.46374/volxxii-issue4-brzezinskiDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792583PMC
October 2020

Molecular markers of telomere dysfunction and senescence are common findings in the usual interstitial pneumonia pattern of lung fibrosis.

Histopathology 2021 Jan 11. Epub 2021 Jan 11.

Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Denver, CO, USA.

Aims: Idiopathic pulmonary fibrosis (IPF) is a genetically mediated, age-associated, progressive form of pulmonary fibrosis characterised pathologically by a usual interstitial pneumonia (UIP) pattern of fibrosis. The UIP pattern is also found in pulmonary fibrosis attributable to clinical diagnoses other than IPF (non-IPF UIP), whose clinical course is similarly poor, suggesting common molecular drivers. This study investigates whether IPF and non-IPF UIP lungs similarly express markers of telomere dysfunction and senescence.

Methods And Results: To test whether patients with IPF and non-IPF UIP share molecular drivers, lung tissues from 169 IPF patients and 57 non-IPF UIP patients were histopathologically and molecularly compared. Histopathological changes in both IPF and non-IPF UIP patients included temporal heterogeneity, microscopic honeycombing, fibroblast foci, and dense collagen fibrosis. Non-IPF UIP lungs were more likely to have lymphocytic infiltration, non-caseating granulomas, airway-centred inflammation, or small airways disease. Telomeres were shorter in alveolar type II (AECII) cells of both IPF and non-IPF UIP lungs than in those of age-similar, unused donor, controls. Levels of molecular markers of senescence (p16 and p21) were elevated in lysates of IPF and non-IPF UIP lungs. Immunostaining localised expression of these proteins to AECII cells. The mucin 5B (MUC5B) gene promoter variant minor allele frequency was similar between IPF and non-IPF UIP patients, and MUC5B expression was similar in IPF and non-IPF UIP lungs.

Conclusions: Molecular markers of telomere dysfunction and senescence are pathologically expressed in both IPF and non-IPF UIP lungs. These findings suggest that common molecular drivers may contribute to the pathogenesis of UIP-associated pulmonary fibrosis, regardless of the clinical diagnosis.
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http://dx.doi.org/10.1111/his.14334DOI Listing
January 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

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

Airway Epithelial Telomere Dysfunction Drives Remodeling Similar to Chronic Lung Allograft Dysfunction.

Am J Respir Cell Mol Biol 2020 10;63(4):490-501

Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine.

Telomere dysfunction is associated with multiple fibrotic lung processes, including chronic lung allograft dysfunction (CLAD)-the major limitation to long-term survival following lung transplantation. Although shorter donor telomere lengths are associated with an increased risk of CLAD, it is unknown whether short telomeres are a cause or consequence of CLAD pathology. Our objective was to test whether telomere dysfunction contributes to the pathologic changes observed in CLAD. Histopathologic and molecular analysis of human CLAD lungs demonstrated shortened telomeres in lung epithelial cells quantified by teloFISH, increased numbers of surfactant protein C immunoreactive type II alveolar epithelial cells, and increased expression of senescence markers (β-galactosidase, p16, p53, and p21) in lung epithelial cells. (telomere repeat binding factor 1 flox/flox) mice were crossed with tamoxifen-inducible SCGB1a1-cre mice to generate mice. Following 9 months of tamoxifen-induced deletion of TRF1 in club cells, mice developed mixed obstructive and restrictive lung physiology, small airway obliteration on microcomputed tomography, a fourfold decrease in telomere length in airway epithelial cells, collagen deposition around bronchioles and adjacent lung parenchyma, increased type II aveolar epithelial cell numbers, expression of senescence-associated β-galactosidase in epithelial cells, and decreased SCGB1a1 expression in airway epithelial cells. These findings demonstrate that telomere dysfunction isolated to airway epithelial cells leads to airway-centric lung remodeling and fibrosis similar to that observed in patients with CLAD and suggest that lung epithelial cell telomere dysfunction may be a molecular driver of CLAD.
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http://dx.doi.org/10.1165/rcmb.2019-0374OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528921PMC
October 2020

Donor heart and lung procurement: A consensus statement.

J Heart Lung Transplant 2020 06 21;39(6):501-517. Epub 2020 Apr 21.

Department of Surgery, Division of Thoracic Surgery, University of Washington, Seattle, Washington.

Heart and lung procurements are multiphased processes often accompanied by an array of complex logistics. Approaches to donor evaluation and management, organ procurement, and organ preservation vary among individual procurement teams. Because early graft failure remains a major cause of mortality in contemporary thoracic organ transplant recipients, we sought to establish some standardization in the procurement process. This paper, in this vein, represents an international consensus statement on donor heart and lung procurement and is designed to serve as a guide for physicians, surgeons, and other providers who manage donors to best optimize the clinical status for the procurement of both heart and lungs for transplantation. Donation after brain death (DBD) and donation after circulatory determination death (referred to as donation after circulatory death [DCD] for the remainder of the paper) for both heart and lung transplantation will be discussed in this paper. Although the data available on DCD heart donation are limited, information regarding the surgical technique for procurement is included within this consensus statement. Furthermore, this paper will focus on adult DBD and DCD heart and lung procurement. Currently, no certification, which is either recognized and/or endorsed by the transplant community at large, exists for the training of a cardiothoracic procurement surgeon. Nevertheless, establishing a training curriculum and credentialing requirements are beyond the scope of this paper.
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http://dx.doi.org/10.1016/j.healun.2020.03.020DOI Listing
June 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

Risk Factors and Outcomes of Extracorporeal Membrane Oxygenation as a Bridge to Lung Transplantation.

Semin Thorac Cardiovasc Surg 2020 Winter;32(4):772-785. Epub 2020 May 20.

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

This study aimed to identify outcome determinants for extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation (BTT) at our institution.This retrospective single-center study reviewed patients on ECMO between 2010 and 2018 and compared clinical characteristics between patients who underwent successful-BTT and those who did not. Additionally, we examined differences between actively versus emergently listed patients and reasons for failure-to-list. Seventy-six patients were placed on ECMO with the intent to bridge to transplant. Of those, 42 were actively on the waitlist (AWL) prior to ECMO initiation, 20 were emergently evaluated and waitlisted (EWL) after ECMO initiation, and 14 failed-to-list. Of the 62 listed patients, 42 (68%) were successfully transplanted. Risk factors of failed-BTT included right ventricular dysfunction prior to ECMO initiation, longer ECMO duration, reduced mobility status, shorter stature, higher prevalence of blood type B, worse kidney and liver function, and increased transfusion requirements. The number of patients transitioned to central VA-ECMO was higher in the failed-BTT group. Thirty-day survival post-transplantation was 98%, with 90% successfully discharged; 1-year survival conditional upon discharge was 97%. AWL and EWL groups had comparable outcomes. Reasons for failure-to-list are not readily modifiable. ECMO-BTT has become a viable option with satisfactory 1-year survival in patients with irreversible lung injury. Our results support rescue transplant for emergently evaluated and waitlisted patients on ECMO. Our data suggests that modification in national organ allocation policies especially as they pertain to high-acuity recipients with rare blood types and short stature could enhance successful outcome.
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http://dx.doi.org/10.1053/j.semtcvs.2020.05.008DOI Listing
March 2021

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

Lung transplant programs in developing countries: challenges, solutions, and outcomes.

Curr Opin Organ Transplant 2020 06;25(3):299-304

Division of Cardiothoracic Surgery, University of California, San Francisco, California, USA.

Purpose Of Review: The majority of lung transplants (LT) performed are in developed countries. In contrast, little is known about the status of LT in developing nations. The objective is to summarize the challenges, present solutions, and review outcomes of LT in developing countries. We hope this review will guide healthcare providers in such countries that are contemplating embarking on this journey.

Recent Findings: The key challenges that programs in developing countries encountered included shortage and marginal quality of donated organs, lack of dedicated multi-disciplinary LT team, limited availability of advanced technology and high risk of post-transplant infections. Education and collaboration among government, public, and healthcare sectors was seen as fundamental to building and maintaining a successful program. Despite minimal resources and huge challenges, LT survival rates in developing countries improved and were comparable with outcomes reported by the International Society for Heart and Lung Transplantation (ISHLT) Registry.

Summary: Starting a new LT program is a daunting task that is complex and resource intensive, especially in developing countries. Improving outcomes indeed provide impetus to continue to persevere in this endeavor with support from all sectors. The findings presented here could help new programs to better anticipate and tackle challenges.
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http://dx.doi.org/10.1097/MOT.0000000000000766DOI Listing
June 2020

Redefining marginality: donor lung criteria.

Curr Opin Organ Transplant 2020 06;25(3):280-284

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

Purpose Of Review: Despite an increase in lung transplantation globally, the waitlist mortality persists due to organ shortage. In order to keep up with the demand, the marginal lung donor criteria need to be revisited. The goal of this review is to redefine the lung donor criteria based on the most recent data.

Recent Findings: Recent evidence indicates that lungs from donor with traditional extended criteria such as, age more than 55, PaO2/FiO2 threshold of less than 300, ischemia time more than 6 h, positive sputum microbiology, abnormal radiography no longer represent contraindications to lung transplantation by themselves. In addition, the introduction of new antiviral agents, organs from Hepatitis C positive donors, though not extended in the traditional sense, have shown positive outcomes.

Summary: The decision to use such organs, including those with smoking history, should be taken in totality weighing both donor and recipient characteristics. Hence, authors would advocate removing the term 'marginal' or 'extended' from lung donor criteria.
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http://dx.doi.org/10.1097/MOT.0000000000000764DOI Listing
June 2020

Improved survival after lung transplantation for adults requiring preoperative invasive mechanical ventilation: A national cohort study.

J Thorac Cardiovasc Surg 2020 Nov 4;160(5):1385-1395.e6. Epub 2020 Mar 4.

Department of Surgery, University of California San Francisco, San Francisco, Calif.

Objective: Early survival after lung transplantation has improved in the last decade. Mechanically ventilated recipients are known to be at greater risk for early post-transplant mortality. We hypothesized that post-transplant survival in mechanically ventilated recipients has improved over time.

Methods: Using a national registry, we compared hazard of death at 30 days, 4 and 14 months, 3 and 5 years, and overall for adults on mechanical ventilation who underwent lung or heart-lung transplantation from May 4, 2011, to April 4, 2018 (modern group) with those undergoing transplantation from May 4, 2005, to May 3, 2011 (early group). We quantified the impact of mechanical ventilation on survival using population-attributable fractions. We also compared mechanically ventilated recipients with nonmechanically ventilated recipients.

Results: Mechanically ventilated recipients from the modern group had lower hazard of death than recipients in the early group at all time-points, lowest at 30-days post-transplant (hazard ratio, 0.04; 95% confidence interval, 0.02-0.08). In the modern period, mechanically ventilated recipients had greater hazard of death than nonmechanically ventilated recipients at 30 days' post-transplant (9.53; 4.57-19.86). For mechanically ventilated recipients, the population attributable fraction was lower in the modern group compared to the earlier group (0.6% vs 5.7%).

Conclusions: While mechanically ventilated recipients remain at high risk, survival in this patient population has improved over time. This may reflect improvements in perioperative recipient management.
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http://dx.doi.org/10.1016/j.jtcvs.2020.02.080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485564PMC
November 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048765PMC
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

Portable normothermic ex-vivo lung perfusion, ventilation, and functional assessment with the Organ Care System on donor lung use for transplantation from extended-criteria donors (EXPAND): a single-arm, pivotal trial.

Lancet Respir Med 2019 11 1;7(11):975-984. Epub 2019 Aug 1.

Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium.

Background: Donor lung use for transplantation is the lowest among solid organ tranplants because of several complex and multifactorial reasons; one area that could have a substantial role is the limited capabilities of cold ischaemic storage. The aim of the EXPAND trial was to evaluate the efficacy of normothermic portable Organ Care System (OCS) Lung perfusion and ventilation on donor lung use from extended-criteria donors and donors after circulatory death, which are rarely used.

Methods: In this single-arm, pivotal trial done in eight institutions across the USA, Germany, and Belgium, lungs from extended-criteria donors were included if fulfilling one or more of the following criteria: a ratio of partial pressure of arterial oxygen (PaO) to fractional concentration of oxygen inspired air (FiO) in the donor lung of 300 mm Hg or less; expected ischaemic time longer than 6 h; donor age 55 years or older; or lungs from donors after circulatory death that were recruited and assessed using OCS Lung. Lungs were transplanted if they showed stability of OCS Lung variables, PaO:FiO was more than 300 mm Hg, and they were accepted by the transplanting surgeon. Patients were adult bilateral lung transplant recipients. The primary efficacy endpoint was a composite of patient survival at day 30 post-transplant and absence of The International Society for Heart & Lung Tranplantation primary-graft dysfunction grade 3 (PGD3) within 72 h post-transplantation, with a prespecified objective performance goal of 65%. The primary analysis population was all transplanted recipients. This trial is registered with ClinicalTrials.gov, number NCT01963780, and is now complete.

Findings: Between Jan 23, 2014, and Oct 23, 2016, 93 lung pairs were perfused, ventilated, and assessed on the OCS Lung. 12 lungs did not meet OCS transplantation criteria so 81 lungs were suitable for transplantation. Two lungs were excluded for logistical reasons, hence 79 (87%) of eligible lungs were transplanted. The primary endpoint was achieved in 43 (54%) of 79 patients and did not meet the objective performance goal. 35 (44%) of 79 patients had PGD3 within the initial 72 h. 78 (99%) of 79 patients had survived at 30 days post-transplant. The mean number of lung graft-related serious adverse events (respiratory failure and major pulmonary-related infection) was 0·3 events per patient (SD 0·5).

Interpretation: Despite missing the objective primary endpoint, the portable OCS Lung resulted in 87% donor lung use for transplantation with excellent clinical outcomes. Many lungs declined by other transplant centres were successfully transplanted using this new technology, which implies its use has the potential to increase the number of lung transplants performed worldwide. Whether similar outcomes could be obtained if these lungs were preserved on ice is unknown and remains an area for future research.

Funding: TransMedics Inc.
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http://dx.doi.org/10.1016/S2213-2600(19)30200-0DOI Listing
November 2019

A nonlinear relationship between visceral adipose tissue and frailty in adult lung transplant candidates.

Am J Transplant 2019 11 24;19(11):3155-3161. Epub 2019 Jul 24.

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

Frailty is a state of decreased physiologic reserve associated with poor outcomes before and after lung transplantation. Obesity, particularly central obesity characterized by excess proinflammatory visceral adipose tissue (VAT), is associated with incident frailty in middle-aged and older adults. The association between VAT and frailty in advanced lung disease, however, is unknown. In two, nonoverlapping multicenter cohorts of adults listed for lung transplantation, we measured VAT area on bioelectrical impedance assay (BIA) in one cohort and cross-sectional VAT and subcutaneous adipose tissue (SAT) areas on abdominal computed tomography (CT) in the other. We identified a nonlinear relationship between greater VAT by BIA and frailty. In fully adjusted piecewise regression models, every 20 cm increase in VAT area was associated with 50% increased odds of frailty in subjects with high VAT (95% CI 1.2-1.9, P < .001), and 10% decreased odds of frailty (95% CI 0.7-1.04, P = .12) in subjects with low VAT. Compared to frail subjects with low VAT, those with high VAT were more likely to have low grip strength and less likely to have weight loss, suggesting that mechanisms of frailty may differ by VAT. Further investigation of mechanisms linking VAT and frailty may identify new targets for prevention and treatment.
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http://dx.doi.org/10.1111/ajt.15525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863776PMC
November 2019

Frailty trajectories in adult lung transplantation: A cohort study.

J Heart Lung Transplant 2019 07 18;38(7):699-707. Epub 2019 Mar 18.

Departments of Medicine.

Background: Frailty is common in adults with advanced lung disease and is associated with death before and after lung transplantation. We aimed to determine whether frailty changes from before to after the lung transplant.

Methods: In a single-center, prospective cohort study among adults undergoing lung transplantation from 2010 to 2017, we assessed frailty by the Short Physical Performance Battery (SPPB; higher scores reflect less frailty) and Fried Frailty Phenotype (FFP; higher scores reflect greater frailty) before and repeatedly up to 36 months after transplant. We tested for changes in frailty scores over time using segmented mixed effects models, adjusting for age, sex, and diagnosis. We quantified the proportion of subjects transitioning between frailty states (frail vs not frail) from before to after the transplant.

Results: In 246 subjects, changes in frailty occurred within the first 6 post-operative months and remained stable thereafter. The overall change in frailty was attributable to improvements among those subjects who were frail before transplant. They experienced a 5.1-point improvement in SPPB (95% confidence interval [CI] 4.6-5.7) and a 1.8-point improvement in FFP (95% CI -2.1 to -1.6) during the early period. Frailty by SPPB and FFP did not change in those who were not frail before transplant. Approximately 84% of survivors who were frail before transplant became not frail after transplant.

Conclusions: Pre-operative frailty resolves in many patients after lung transplantation. Because a large proportion of frailty may be attributable to advanced lung disease, frailty alone should not be an absolute contraindication to transplantation.
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http://dx.doi.org/10.1016/j.healun.2019.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612595PMC
July 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