Publications by authors named "John R Greenland"

48 Publications

Longitudinal single-cell epitope and RNA-sequencing reveals the immunological impact of type 1 interferon autoantibodies in critical COVID-19.

bioRxiv 2021 Mar 10. Epub 2021 Mar 10.

Type I interferon (IFN-I) neutralizing autoantibodies have been found in some critical COVID-19 patients; however, their prevalence and longitudinal dynamics across the disease severity scale, and functional effects on circulating leukocytes remain unknown. Here, in 284 COVID-19 patients, we found IFN-I autoantibodies in 19% of critical, 6% of severe and none of the moderate cases. Longitudinal profiling of over 600,000 peripheral blood mononuclear cells using multiplexed single-cell epitope and transcriptome sequencing from 54 COVID-19 patients, 15 non-COVID-19 patients and 11 non-hospitalized healthy controls, revealed a lack of IFN-I stimulated gene (ISG-I) response in myeloid cells from critical cases, including those producing anti-IFN-I autoantibodies. Moreover, surface protein analysis showed an inverse correlation of the inhibitory receptor LAIR-1 with ISG-I expression response early in the disease course. This aberrant ISG-I response in critical patients with and without IFN-I autoantibodies, supports a unifying model for disease pathogenesis involving ISG-I suppression via convergent mechanisms.
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http://dx.doi.org/10.1101/2021.03.09.434529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987018PMC
March 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

Frailty and aging-associated syndromes in lung transplant candidates and recipients.

Am J Transplant 2020 Dec 9. Epub 2020 Dec 9.

Medical Affairs-Pulmonary, Veracyte Inc, South San Francisco, California, USA.

Many lung transplant candidates and recipients are older and frailer compared to previous eras. Older patients are at increased risk for pre- and posttransplant mortality, but this risk is not explained by numerical age alone. This manuscript represents the product of the American Society of Transplantation (AST) conference on frailty. Experts in the field reviewed the latest published research on assessment of elderly and frail lung transplant candidates. Physical frailty, often defined as slowness, weakness, low physical activity, shrinking, and exhaustion, and frailty evaluation is an important tool for evaluation of age-associated dysfunction. Another approach is assessment by cumulative deficits, and both types of frailty are common in lung transplant candidates. Frailty is associated with death or delisting before transplant, and may be associated with posttransplant mortality. Sarcopenia, cognitive dysfunction, depression, and nutrition are other important components for patient evaluation. Aging-associated inflammation, telomere dysfunction, and adaptive immune system senescence may also contribute to frailty. Developing tools for frailty assessment and interventions holds promise for improving patient outcomes before and after lung transplantation.
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http://dx.doi.org/10.1111/ajt.16439DOI Listing
December 2020

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

Transcriptome-based diagnostics for chronic lung allograft dysfunction: A socratic question revisited.

Authors:
John R Greenland

J Heart Lung Transplant 2020 12 21;39(12):1338-1340. Epub 2020 Oct 21.

Department of Medicine, University of California, San Francisco, San Francisco, California; Medical Service, San Francisco VA Health Care System, San Francisco, California. Electronic address:

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http://dx.doi.org/10.1016/j.healun.2020.09.007DOI Listing
December 2020

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

The impact of belatacept on the phenotypic heterogeneity of renal T cell-mediated alloimmune response: The critical role of maintenance treatment and inflammatory load.

Clin Transplant 2020 11 19;34(11):e14084. Epub 2020 Oct 19.

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

Belatacept offers superior long-term outcome relative to calcineurin inhibitor (CNI)-based immunosuppression. However, the higher frequency of early T cell-mediated rejection (TCMR) in belatacept-treated patients hampered the widespread adoption of costimulation blockade. Here, we applied gene expression analysis and whole-slide inflammatory cell quantification to assess the impact of belatacept on intragraft immune signature. We studied formalin-fixed, paraffin-embedded renal biopsies from 92 patients stratified by histopathologic diagnosis (TCMR, borderline changes, or normal) and immunosuppression regimen (belatacept, CNI). An interaction model was built to explore maintenance treatment-dependent expression level changes of immune response-related genes across diagnostic categories of normal, borderline changes, and TCMR. Ninety-one percent of genes overexpressed in TCMR showed significant correlation with whole section inflammatory load. There were 27 genes that had a positive association with belatacept treatment. These were mostly related to myeloid cells and innate immunity. Genes negatively associated with costimulation blockade (n = 14) could be linked to B-cell differentiation and proliferation. We concluded that expression levels of genes characteristic of TCMR are strongly interconnected with quantitative changes of the biopsy inflammatory load. Our results might suggest differential involvement of the innate immune system, and an altered B-cell engagement during TCMR in belatacept-treated patients relative to CNI-treated referents.
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http://dx.doi.org/10.1111/ctr.14084DOI Listing
November 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

International Society for Heart and Lung Transplantation consensus statement for the standardization of bronchoalveolar lavage in lung transplantation.

J Heart Lung Transplant 2020 Jul 15. Epub 2020 Jul 15.

Lung Transplant Program, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.

Bronchoalveolar lavage (BAL) is a key clinical and research tool in lung transplantation (LTx). However, BAL collection and processing are not standardized across LTx centers. This International Society for Heart and Lung Transplantation-supported consensus document on BAL standardization aims to clarify definitions and propose common approaches to improve clinical and research practice standards. The following 9 areas are covered: (1) bronchoscopy procedure and BAL collection, (2) sample handling, (3) sample processing for microbiology, (4) cytology, (5) research, (6) microbiome, (7) sample inventory/tracking, (8) donor bronchoscopy, and (9) pediatric considerations. This consensus document aims to harmonize clinical and research practices for BAL collection and processing in LTx. The overarching goal is to enhance standardization and multicenter collaboration within the international LTx community and enable improvement and development of new BAL-based diagnostics.
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http://dx.doi.org/10.1016/j.healun.2020.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361106PMC
July 2020

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

COVID-19 Infection: Perioperative Implications: Reply.

Anesthesiology 2020 09;133(3):678-679

San Francisco VA Health Care System and University of California (J.R.G.), San Francisco, California.

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http://dx.doi.org/10.1097/ALN.0000000000003424DOI Listing
September 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

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

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

Pathobiology of frailty in lung disease.

Transl Res 2020 07 3;221:1-22. Epub 2020 May 3.

Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, UC San Francisco, San Francisco, California.

Frailty is a clinical state of vulnerability to stressors resulting from cumulative alterations in multiple physiological and molecular systems. Frailty assessment in patients with chronic disease is useful for identifying those who are at increased risk for poor clinical and patient reported outcomes. Due to biobehavioral changes purported to cause both frailty and certain chronic lung diseases, patients with lung disease appear susceptible to frailty and prone to developing it decades earlier than community dwelling healthy populations. Herein, we review the literature and potential pathobiological mechanisms underpinning associations between frailty in lung disease and age, sex, comorbidity and symptom burden, severity of lung disease, inflammatory biomarkers, various clinical parameters, body composition measures, and physical activity levels. We also propose a multipronged program of future research focused on improving the accuracy and precision of frailty measurement in lung disease, identifying blood-based biomarkers and measures of body composition for frailty, determining whether subphenotypes of frailty with distinct pathobiology exist, and developing personalized interventions that target the specific underlying mechanisms causing frailty.
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http://dx.doi.org/10.1016/j.trsl.2020.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321864PMC
July 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

COVID-19 Infection: Implications for Perioperative and Critical Care Physicians.

Anesthesiology 2020 06;132(6):1346-1361

From Pulmonary and Critical Care Medicine (J.R.G.) Anesthesia and Perioperative Care (M.D.M., M.J.L.), San Francisco Veterans Administration Health Care System, San Francisco, California Laboratory Medicine (L.W.) University of California, San Francisco, California (J.R.G., M.D.M., M.J.L.).

Healthcare systems worldwide are responding to Coronavirus Disease 2019 (COVID-19), an emerging infectious syndrome caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus. Patients with COVID-19 can progress from asymptomatic or mild illness to hypoxemic respiratory failure or multisystem organ failure, necessitating intubation and intensive care management. Healthcare providers, and particularly anesthesiologists, are at the frontline of this epidemic, and they need to be aware of the best available evidence to guide therapeutic management of patients with COVID-19 and to keep themselves safe while doing so. Here, the authors review COVID-19 pathogenesis, presentation, diagnosis, and potential therapeutics, with a focus on management of COVID-19-associated respiratory failure. The authors draw on literature from other viral epidemics, treatment of acute respiratory distress syndrome, and recent publications on COVID-19, as well as guidelines from major health organizations. This review provides a comprehensive summary of the evidence currently available to guide management of critically ill patients with COVID-19.
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http://dx.doi.org/10.1097/ALN.0000000000003303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155909PMC
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

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

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

Natural killer cells in lung transplantation.

Thorax 2019 04 31;74(4):397-404. Epub 2018 Oct 31.

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

Natural killer (NK) cells are innate lymphoid cells that have been increasingly recognised as important in lung allograft tolerance and immune defence. These cells evolved to recognise alterations in self through a diverse set of germline-encoded activating and inhibitory receptors and display a broad range of effector functions that play important roles in responding to infections, malignancies and allogeneic tissue. Here, we review NK cells, their diverse receptors and the mechanisms through which NK cells are postulated to mediate important lung transplant clinical outcomes. NK cells can promote tolerance, such as through the depletion of donor antigen-presenting cells. Alternatively, these cells can drive rejection through cytotoxic effects on allograft tissue recognised as 'non-self' or 'stressed', via killer cell immunoglobulin-like receptor (KIR) or NKG2D receptor ligation, respectively. NK cells likely mediate complement-independent antibody-mediated rejection of allografts though CD16A Fc receptor-dependent activation induced by graft-specific antibodies. Finally, NK cells play an important role in response to infections, particularly by mediating cytomegalovirus infection through the CD94/NKG2C receptor. Despite these sometimes-conflicting effects on allograft function, enumeration of NK cells may have an important role in diagnosing allograft dysfunction. While the effects of immunosuppression agents on NK cells may currently be largely unintentional, further understanding of NK cell biology in lung allograft recipients may allow these cells to serve as biomarkers of graft injury and as therapeutic targets.
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http://dx.doi.org/10.1136/thoraxjnl-2018-212345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420386PMC
April 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

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

Where the Chromosome Ends: Telomeres and Cytomegalovirus Risk in Lung Transplant Recipients.

Authors:
John R Greenland

Am J Respir Crit Care Med 2019 02;199(3):265-267

1 Department of Medicine VA Health Care System and University of California San Francisco, California.

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http://dx.doi.org/10.1164/rccm.201808-1472EDDOI Listing
February 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