Publications by authors named "Jason D Christie"

263 Publications

The lung microbiome in lung transplantation.

J Heart Lung Transplant 2021 May 7. Epub 2021 May 7.

Division of Pulmonary, Allergy and Critical Care Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

Culture-independent study of the lower respiratory tract after lung transplantation has enabled an understanding of the microbiome - that is, the collection of bacteria, fungi, and viruses, and their respective gene complement - in this niche. The lung has unique features as a microbial environment, with balanced entry from the upper respiratory tract, clearance, and local replication. There are many pressures impacting the microbiome after transplantation, including donor allograft factors, recipient host factors such as underlying disease and ongoing exposure to the microbe-rich upper respiratory tract, and transplantation-related immunosuppression, antimicrobials, and postsurgical changes. To date, we understand that the lung microbiome after transplant is dysbiotic; that is, it has higher biomass and altered composition compared to a healthy lung. Emerging data suggest that specific microbiome features may be linked to host responses, both immune and non-immune, and clinical outcomes such as chronic lung allograft dysfunction (CLAD), but many questions remain. The goal of this review is to put into context our burgeoning understanding of the lung microbiome in the postlung transplant patient, the interactions between microbiome and host, the role the microbiome may play in post-transplant complications, and critical outstanding research questions.
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http://dx.doi.org/10.1016/j.healun.2021.04.014DOI Listing
May 2021

Integrative omics provide biological and clinical insights into acute respiratory distress syndrome.

Intensive Care Med 2021 07 25;47(7):761-771. Epub 2021 May 25.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, 655 Huntington Avenue, Boston, MA, 02115, USA.

Purpose: Acute respiratory distress syndrome (ARDS) is accompanied by a dysfunctional immune-inflammatory response following lung injury, including during coronavirus disease 2019 (COVID-19). Limited causal biomarkers exist for ARDS development. We sought to identify novel genetic susceptibility targets for ARDS to focus further investigation on their biological mechanism and therapeutic potential.

Methods: Meta-analyses of ARDS genome-wide association studies were performed with 1250 cases and 1583 controls in Europeans, and 387 cases and 387 controls in African Americans. The functionality of novel loci was determined in silico using multiple omics approaches. The causality of 114 factors potentially involved in ARDS development was assessed using Mendelian Randomization analysis.

Results: There was distinct genetic heterogeneity in ARDS between Europeans and African Americans. rs7967111 at 12p13.2 was functionally associated with ARDS susceptibility in Europeans (odds ratio = 1.38; P = 2.15 × 10). Expression of two genes annotated at this locus, BORCS5 and DUSP16, was dynamic but ultimately decreased during ARDS development, as well as downregulated in immune cells alongside COVID-19 severity. Causal inference implied that comorbidity of inflammatory bowel disease and elevated levels of C-reactive protein and interleukin-10 causally increased ARDS risk, while vitamin D supplementation and vasodilator use ameliorated risk.

Conclusion: Our findings suggest a novel susceptibility locus in ARDS pathophysiology that implicates BORCS5 and DUSP16 as potentially acting in immune-inflammatory processes. This locus warrants further investigation to inform the development of therapeutic targets and clinical care strategies for ARDS, including those induced by COVID-19.
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http://dx.doi.org/10.1007/s00134-021-06410-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144871PMC
July 2021

The Supportive Care Needs of Primary Caregivers of Lung Transplant Candidates.

J Pain Symptom Manage 2021 May 13. Epub 2021 May 13.

University of Pennsylvania School of Nursing (P.C.P., N.P.B., L.A.M., S.A., M.E.), Philadelphia, PA; Department of Veterans Affairs, Corporal Michael J. Crescenz VA Medical Center - Philadelphia (M.E.), University of Pennsylvania School of Nursing, Philadelphia, PA, USA.

Context: Caring for people with advanced illness has an impact on caregivers' physical, psychological, and emotional health. Patients being evaluated for lung transplantation or those on the transplant waitlist are required to have identified social support. However, little is known about the caregivers' specific supportive care needs.

Objective: The aim of this study was to determine the supportive care needs of informal caregivers of patients who are being evaluated for or awaiting lung transplantation.

Methods: A cross sectional survey of the caregivers of lung transplant candidates using the Carers' Support Needs Assessment Tool (CSNAT) was conducted.

Results: The sample (n = 78) included caregivers from a single-center academic institution in the United States. Participants were predominantly Caucasian and female, mean age 58 years (SD:13). Most were the patient's spouse or partner and over half reported needs in the following areas: what to expect in the future; who to call with healthcare concerns; financial, legal and work issues; and caregivers' feelings and worries. When asked if they need more support in these areas, up to one-third indicated they needed "quite a bit more" or "very much more," with substantial needs regarding what to expect in the future, who to call with healthcare concerns, and financial, legal, or work issues.

Conclusion: A substantial portion of lung transplant caregivers express need for more support. Future research should focus on testing strategies to promote regular assessment of these needs and examining the effectiveness of interdisciplinary interventions to address them.
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http://dx.doi.org/10.1016/j.jpainsymman.2021.05.004DOI Listing
May 2021

COVID-19 and the Early-Career Physician-Scientist. Fostering Resilience beyond the Pandemic.

ATS Sch 2020 Oct 23;2(1):19-28. Epub 2020 Oct 23.

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

The coronavirus disease (COVID-19) pandemic has created significant stressors for the academic and scientific community, with unique challenges for early-career physician-scientists. The pandemic-related disruptions have significantly affected research productivity, access to mentoring, professional development and networking opportunities, funding, and personal wellness. This is especially true for pulmonary and critical care medicine faculty because of the burden of specialized clinical care responsibilities that the COVID-19 pandemic has demanded. Departmental, institutional, and national leadership should foster open dialogue to identify and mitigate these challenges to promote ongoing career development of early-career physician-scientists. Implementation of thoughtful interventions to address these challenges will provide essential support for junior faculty and help retain a generation of physician-scientists.
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http://dx.doi.org/10.34197/ats-scholar.2020-0104PSDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043276PMC
October 2020

Plasma Nucleosomes Are Associated With Mortality in Pediatric Acute Respiratory Distress Syndrome.

Crit Care Med 2021 Jul;49(7):1149-1158

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine and Center for Translational Lung Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

Objectives: Circulating nucleosomes and their component histones have been implicated as pathogenic in sepsis and acute respiratory distress syndrome in adults. However, their role in pediatric acute respiratory distress syndrome is unknown.

Design: We performed a prospective cohort study in children with acute respiratory distress syndrome, with plasma collection within 24 hours of acute respiratory distress syndrome onset. We associated nucleosome levels with severity of acute respiratory distress syndrome and with nonpulmonary organ failures and tested for association of nucleosomes with PICU mortality and ventilator-free days at 28 days in univariate and multivariable analyses. We also performed proteomics of DNA-bound plasma proteins in a matched case-control study of septic children with and without acute respiratory distress syndrome in order to identify specific histone proteins elevated in acute respiratory distress syndrome.

Setting: Large academic tertiary-care PICU.

Patients: Intubated children meeting Berlin criteria for acute respiratory distress syndrome.

Interventions: None.

Measurements And Main Results: We enrolled 333 children with acute respiratory distress syndrome, with 69 nonsurvivors (21%). Plasma nucleosomes were correlated with acute respiratory distress syndrome severity and with the number of nonpulmonary organ failures at acute respiratory distress syndrome onset. Nucleosomes were higher (p < 0.001) in nonsurvivors (0.40 [interquartile range, 0.20-0.71] arbitrary units) relative to survivors (0.10 [interquartile range, 0.04-0.25] arbitrary units). Nucleosomes were associated with PICU mortality in multivariable analysis (adjusted odds ratio 1.84 per 1 sd increase; 95% CI, 1.38-2.45; p < 0.001). Nucleosomes were also associated with a lower probability of being extubated alive by day 28 after multivariable adjustment (adjusted subdistribution hazard ratio, 0.74; 95% CI, 0.63-0.88; p = 0.001). Proteomic analysis demonstrated higher levels of the core nucleosome histones H2A, H2B, H3, and H4 in septic children with acute respiratory distress syndrome, relative to septic children without acute respiratory distress syndrome.

Conclusions: Plasma nucleosomes are associated with acute respiratory distress syndrome severity, nonpulmonary organ failures, and worse outcomes in pediatric acute respiratory distress syndrome.
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http://dx.doi.org/10.1097/CCM.0000000000004923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217097PMC
July 2021

Risk of primary graft dysfunction following lung transplantation in selected adults with connective tissue disease-associated interstitial lung disease.

J Heart Lung Transplant 2021 May 23;40(5):351-358. Epub 2021 Jan 23.

Division of Rheumatology, Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, New York. Electronic address:

Background: Previous studies have reported similarities in long-term outcomes following lung transplantation for connective tissue disease-associated interstitial lung disease (CTD-ILD) and idiopathic pulmonary fibrosis (IPF). However, it is unknown whether CTD-ILD patients are at increased risk of primary graft dysfunction (PGD), delays in extubation, or longer index hospitalizations following transplant compared to IPF patients.

Methods: We performed a multicenter retrospective cohort study of CTD-ILD and IPF patients enrolled in the Lung Transplant Outcomes Group registry who underwent lung transplantation between 2012 and 2018. We utilized mixed effects logistic regression and stratified Cox proportional hazards regression to determine whether CTD-ILD was independently associated with increased risk for grade 3 PGD or delays in post-transplant extubation and hospital discharge compared to IPF.

Results: A total of 32.7% (33/101) of patients with CTD-ILD and 28.9% (145/501) of patients with IPF developed grade 3 PGD 48-72 hours after transplant. There were no significant differences in odds of grade 3 PGD among patients with CTD-ILD compared to those with IPF (adjusted OR 1.12, 95% CI 0.64-1.97, p = 0.69), nor was CTD-ILD independently associated with a longer post-transplant time to extubation (adjusted HR for first extubation 0.87, 95% CI 0.66-1.13, p = 0.30). However, CTD-ILD was independently associated with a longer post-transplant hospital length of stay (median 23 days [IQR 14-35 days] vs17 days [IQR 12-28 days], adjusted HR for hospital discharge 0.68, 95% CI 0.51-0.90, p = 0.008).

Conclusion: Patients with CTD-ILD experienced significantly longer postoperative hospitalizations compared to IPF patients without an increased risk of grade 3 PGD.
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http://dx.doi.org/10.1016/j.healun.2021.01.1391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102314PMC
May 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

Characteristics, Outcomes, and Trends of Patients With COVID-19-Related Critical Illness at a Learning Health System in the United States.

Ann Intern Med 2021 05 19;174(5):613-621. Epub 2021 Jan 19.

University of Pennsylvania Health System, Philadelphia, Pennsylvania (G.L.A., J.J., M.O.H., J.H.A., J.B., C.B., P.J.B., C.L.C., L.M.C., M.F.C., J.M.C., J.D.C., T.C., K.R.C., B.D.F., E.G., J.C.G., S.G., A.H., C.W.H., M.H., P.K., Z.N.K., G.B.K., M.L., N.D.M., M.E.M., D.N., J.L.P., M.B.P., S.C.P., Z.A.Q., J.P.R., J.S., W.D.S., M.J.S., M.G.S., C.P.S., J.K.W., W.W., A.A.W., B.J.A., J.T.G.).

Background: The coronavirus disease 2019 (COVID-19) pandemic continues to surge in the United States and globally.

Objective: To describe the epidemiology of COVID-19-related critical illness, including trends in outcomes and care delivery.

Design: Single-health system, multihospital retrospective cohort study.

Setting: 5 hospitals within the University of Pennsylvania Health System.

Patients: Adults with COVID-19-related critical illness who were admitted to an intensive care unit (ICU) with acute respiratory failure or shock during the initial surge of the pandemic.

Measurements: The primary exposure for outcomes and care delivery trend analyses was longitudinal time during the pandemic. The primary outcome was all-cause 28-day in-hospital mortality. Secondary outcomes were all-cause death at any time, receipt of mechanical ventilation (MV), and readmissions.

Results: Among 468 patients with COVID-19-related critical illness, 319 (68.2%) were treated with MV and 121 (25.9%) with vasopressors. Outcomes were notable for an all-cause 28-day in-hospital mortality rate of 29.9%, a median ICU stay of 8 days (interquartile range [IQR], 3 to 17 days), a median hospital stay of 13 days (IQR, 7 to 25 days), and an all-cause 30-day readmission rate (among nonhospice survivors) of 10.8%. Mortality decreased over time, from 43.5% (95% CI, 31.3% to 53.8%) to 19.2% (CI, 11.6% to 26.7%) between the first and last 15-day periods in the core adjusted model, whereas patient acuity and other factors did not change.

Limitations: Single-health system study; use of, or highly dynamic trends in, other clinical interventions were not evaluated, nor were complications.

Conclusion: Among patients with COVID-19-related critical illness admitted to ICUs of a learning health system in the United States, mortality seemed to decrease over time despite stable patient characteristics. Further studies are necessary to confirm this result and to investigate causal mechanisms.

Primary Funding Source: Agency for Healthcare Research and Quality.
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http://dx.doi.org/10.7326/M20-5327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901669PMC
May 2021

Peripheral blood transcriptomic sub-phenotypes of pediatric acute respiratory distress syndrome.

Crit Care 2020 12 7;24(1):681. Epub 2020 Dec 7.

Department of Biostatistics, Center for Clinical Epidemiology and Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA, USA.

Background: Acute respiratory distress syndrome (ARDS) is heterogeneous and may be amenable to sub-phenotyping to improve enrichment for trials. We aimed to identify subtypes of pediatric ARDS based on whole blood transcriptomics.

Methods: This was a prospective observational study of children with ARDS at the Children's Hospital of Philadelphia (CHOP) between January 2018 and June 2019. We collected blood within 24 h of ARDS onset, generated expression profiles, and performed k-means clustering to identify sub-phenotypes. We tested the association between sub-phenotypes and PICU mortality and ventilator-free days at 28 days using multivariable logistic and competing risk regression, respectively.

Results: We enrolled 106 subjects, of whom 96 had usable samples. We identified three sub-phenotypes, dubbed CHOP ARDS Transcriptomic Subtypes (CATS) 1, 2, and 3. CATS-1 subjects (n = 31) demonstrated persistent hypoxemia, had ten subjects (32%) with immunocompromising conditions, and 32% mortality. CATS-2 subjects (n = 29) had more immunocompromising diagnoses (48%), rapidly resolving hypoxemia, and 24% mortality. CATS-3 subjects (n = 36) had the fewest comorbidities and also had rapidly resolving hypoxemia and 8% mortality. The CATS-3 subtype was associated with lower mortality (OR 0.18, 95% CI 0.04-0.86) and higher probability of extubation (subdistribution HR 2.39, 95% CI 1.32-4.32), relative to CATS-1 after adjustment for confounders.

Conclusions: We identified three sub-phenotypes of pediatric ARDS using whole blood transcriptomics. The sub-phenotypes had divergent clinical characteristics and prognoses. Further studies should validate these findings and investigate mechanisms underlying differences between sub-phenotypes.
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http://dx.doi.org/10.1186/s13054-020-03410-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720038PMC
December 2020

The palliative care needs of lung transplant candidates.

Clin Transplant 2020 12 15;34(12):e14092. Epub 2020 Oct 15.

Department of Veterans Affairs, Corporal Michael J. Crescenz VA Medical Center - Philadelphia, University of Pennsylvania School of Nursing, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Background: Little is known about the palliative care needs of patients awaiting lung transplantation. The aim of this study was to describe these needs in patients undergoing evaluation for or awaiting lung transplantation.

Methods: Cross-sectional survey using an adapted version of the Needs at the End-of-life Screening Tool (NEST-13) at a US-based transplant program.

Results: Among the 111 participants, 83.5% were White, 60.0% were female, and almost three-quarters had either restrictive or obstructive lung disease. The greatest palliative care needs included difficulty being physically active (mean: 7.9/10; SD: 2.6; median: 9.0), physical symptoms (mean: 7.4/10; SD: 2.6; median: 8.0), missing work due to illness (mean: 6.2/10; SD: 4.0; median: 8.0), and concerns that life might end (mean: 5.1/10; SD: 3.6; median: 5.0). Participants reported that religious/spiritual beliefs contribute to their sense of purpose (mean: 4.1/10; SD: 3.9) but had few unmet needs in this area (mean: 0.9/10; median: 0.0). Only 6.4% reported seeing a palliative care specialist, and 48.2% were unsure what a palliative care specialist is.

Conclusion: There are substantial palliative care needs among lung transplant candidates, particularly physical symptoms and end-of-life concerns. These findings support integrating palliative care and end-of-life discussions in the management of lung transplant candidates.
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http://dx.doi.org/10.1111/ctr.14092DOI Listing
December 2020

The ABO histo-blood group, endothelial activation, and acute respiratory distress syndrome risk in critical illness.

J Clin Invest 2021 Jan;131(1)

Division of Pulmonary, Allergy, and Critical Care.

BACKGROUNDThe ABO histo-blood group is defined by carbohydrate modifications and is associated with risk for multiple diseases, including acute respiratory distress syndrome (ARDS). We hypothesized that genetically determined blood subtype A1 is associated with increased risk of ARDS and markers of microvascular dysfunction and coagulation.METHODSWe conducted analyses in 3 cohorts of critically ill trauma and sepsis patients (n = 3710) genotyped on genome-wide platforms to determine the association of the A1 blood type genotype with ARDS risk. We subsequently determined whether associations were present in FUT2-defined nonsecretors who lack ABO antigens on epithelium, but not endothelium. In a patient subgroup, we determined the associations of blood type with plasma levels of endothelial glycoproteins and disseminated intravascular coagulation (DIC). Lastly, we tested whether blood type A was associated with less donor lung injury recovery during human ex vivo lung perfusion (EVLP).RESULTSThe A1 genotype was associated with a higher risk of moderate to severe ARDS relative to type O in all 3 populations. In sepsis, this relationship was strongest in nonpulmonary infections. The association persisted in nonsecretors, suggesting a vascular mechanism. The A1 genotype was also associated with higher DIC risk as well as concentrations of thrombomodulin and von Willebrand factor, which in turn were associated with ARDS risk. Blood type A was also associated with less lung injury recovery during EVLP.CONCLUSIONWe identified a replicable association between ABO blood type A1 and risk of ARDS among the critically ill, possibly mediated through microvascular dysfunction and coagulation.FUNDINGNIH HL122075, HL125723, HL137006, HL137915, DK097307, HL115354, HL101779, and the University of Pennsylvania McCabe Fund Fellowship Award.
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http://dx.doi.org/10.1172/JCI139700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773362PMC
January 2021

Local complement activation is associated with primary graft dysfunction after lung transplantation.

JCI Insight 2020 09 3;5(17). Epub 2020 Sep 3.

Department of Medicine, Perlman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

BACKGROUNDThe complement system plays a key role in host defense but is activated by ischemia/reperfusion injury (IRI). Primary graft dysfunction (PGD) is a form of acute lung injury occurring predominantly due to IRI, which worsens survival after lung transplantation (LTx). Local complement activation is associated with acute lung injury, but whether it is more reflective of allograft injury compared with systemic activation remains unclear. We proposed that local complement activation would help identify those who develop PGD after LTx. We also aimed to identify which complement activation pathways are associated with PGD.METHODSWe performed a multicenter cohort study at the University of Pennsylvania and Washington University School of Medicine. Bronchoalveolar lavage (BAL) and plasma specimens were obtained from recipients within 24 hours after LTx. PGD was scored based on the consensus definition. Complement activation products and components of each arm of the complement cascade were measured using ELISA.RESULTSIn both cohorts, sC4d and sC5b-9 levels were increased in BAL of subjects with PGD compared with those without PGD. Subjects with PGD also had higher C1q, C2, C4, and C4b, compared with subjects without PGD, suggesting classical and lectin pathway involvement. Ba levels were higher in subjects with PGD, suggesting alternative pathway activation. Among lectin pathway-specific components, MBL and FCN-3 had a moderate-to-strong correlation with the terminal complement complex in the BAL but not in the plasma.CONCLUSIONComplement activation fragments are detected in the BAL within 24 hours after LTx. Components of all 3 pathways are locally increased in subjects with PGD. Our findings create a precedent for investigating complement-targeted therapeutics to mitigate PGD.FUNDINGThis research was supported by the NIH, American Lung Association, Children's Discovery Institute, Robert Wood Johnson Foundation, Cystic Fibrosis Foundation, Barnes-Jewish Hospital Foundation, Danish Heart Foundation, Danish Research Foundation of Independent Research, Svend Andersen Research Foundation, and Novo Nordisk Research Foundation.
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http://dx.doi.org/10.1172/jci.insight.138358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526453PMC
September 2020

Discovery through Diversity: Insights into the Genetics of Lung Function in Latino Youth.

Am J Respir Crit Care Med 2020 10;202(7):913-914

Division of Pulmonary, Allergy, and Critical Care Medicine and Center for Translational Lung Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.

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http://dx.doi.org/10.1164/rccm.202006-2404EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528776PMC
October 2020

Genetic variation implicates plasma angiopoietin-2 in the development of acute kidney injury sub-phenotypes.

BMC Nephrol 2020 07 17;21(1):284. Epub 2020 Jul 17.

Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, 325 9th Avenue, Seattle, WA, 98104, USA.

Background: We previously identified two acute kidney injury (AKI) sub-phenotypes (AKI-SP1 and AKI-SP2) with different risk of poor clinical outcomes and response to vasopressor therapy. Plasma biomarkers of endothelial dysfunction (tumor necrosis factor receptor-1, angiopoietin-1 and 2) differentiated the AKI sub-phenotypes. However, it is unknown whether these biomarkers are simply markers or causal mediators in the development of AKI sub-phenotypes.

Methods: We tested for associations between single-nucleotide polymorphisms within the Angiopoietin-1, Angiopoietin-2, and Tumor Necrosis Factor Receptor 1A genes and AKI- SP2 in 421 critically ill subjects of European ancestry. Top performing single-nucleotide polymorphisms (FDR < 0.05) were tested for cis-biomarker expression and whether genetic risk for AKI-SP2 is mediated through circulating biomarkers. We also completed in vitro studies using human kidney microvascular endothelial cells. Finally, we calculated the renal clearance of plasma biomarkers using 20 different timed urine collections.

Results: A genetic variant, rs2920656C > T, near ANGPT2 was associated with reduced risk of AKI-SP2 (odds ratio, 0.45; 95% CI, 0.31-0.66; adjusted FDR = 0.003) and decreased plasma angiopoietin-2 (p = 0.002). Causal inference analysis showed that for each minor allele (T) the risk of developing AKI-SP2 decreases by 16%. Plasma angiopoietin-2 mediated 41.5% of the rs2920656 related risk for AKI-SP2. Human kidney microvascular endothelial cells carrying the T allele of rs2920656 produced numerically lower levels of angiopoietin-2 although this was not statistically significant (p = 0.07). Finally, analyses demonstrated that angiopoietin-2 is minimally renally cleared in critically ill subjects.

Conclusion: Genetic mediation analysis provides supportive evidence that angiopoietin-2 plays a causal role in risk for AKI-SP2.
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http://dx.doi.org/10.1186/s12882-020-01935-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368773PMC
July 2020

Thoracic Visceral Adipose Tissue Area and Pulmonary Hypertension in Lung Transplant Candidates. The Lung Transplant Body Composition Study.

Ann Am Thorac Soc 2020 11;17(11):1393-1400

Department of Medicine and.

Obesity is associated with an increased risk of pulmonary hypertension (PH); however, regional adipose tissue deposition is heterogeneous with distinct cardiovascular phenotypes. To determine the association of body mass index (BMI) and thoracic visceral and subcutaneous adipose tissue areas (VAT and SAT, respectively) with PH in patients with advanced lung disease referred for lung transplantation. We studied patients undergoing evaluation for lung transplantation at three centers from the Lung Transplant Body Composition Study. PH was defined as mean pulmonary artery pressure >20 mm Hg and pulmonary vascular resistance ≥3 Wood units. VAT and SAT were measured on chest computed tomography and normalized to height squared. One hundred thirty-seven (34%) of 399 patients included in our study had PH. Doubling of thoracic VAT was associated with significantly lower pulmonary vascular resistance (β, -0.24; 95% confidence interval [95% CI], -0.46 to -0.02;  = 0.04), higher pulmonary arterial wedge pressure (β, 0.79; 95% CI, 0.32 to 1.26;  = 0.001), and decreased risk of PH (relative risk, 0.86; 95% CI, 0.74 to 0.99;  = 0.04) after multivariate adjustment. Vaspin levels were higher in patients without PH (median, 101.8 vs. 92.0 pg/ml;  < 0.001) but did not mediate the association between VAT and the risk of PH. SAT and BMI were not independently associated with risk of PH. Lower thoracic VAT was associated with a higher risk of PH in patients with advanced lung disease undergoing evaluation for lung transplantation. The role of adipokines in the pulmonary vascular disease remains to be evaluated.
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http://dx.doi.org/10.1513/AnnalsATS.202003-247OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640728PMC
November 2020

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

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

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

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

Relationship of body mass index, serum creatine kinase, and acute kidney injury after severe trauma.

J Trauma Acute Care Surg 2020 07;89(1):179-185

From the Department of Surgery (C.R.V., D.N.H.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Hackensack Meridian School of Medicine at Seton Hall University (T.D.), Nutley, New Jersey; Pulmonary, Allergy, and Critical Care Division (J.P.R., C.M.F., P.N.L., J.D.C., M.G.S.S.), Center for Clinical Epidemiology and Biostatistics (D.N.H., Q.W., J.D.C., M.G.S.S.), Division of Traumatology, Surgical Critical Care, and Emergency Surgery (D.N.H.), and Center for Translational Lung Biology (J.P.R., J.D.C., M.G.S.S.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Objectives: Body mass index (BMI) is associated with acute kidney injury (AKI) after trauma, but underlying mechanisms are unclear. Body mass index correlates with both excess adiposity and increased muscle mass. Since the latter could predispose to severe rhabdomyolysis after trauma, we hypothesized that the BMI-AKI association may be partially explained by a direct relationship of BMI with serum creatine kinase (CK).

Methods: Prospective cohort study of 463 critically ill patients admitted to a level I trauma center from 2005 to 2015 with Injury Severity Score of >15 and serum CK measured in the first 7 days. We defined AKI by AKI Network creatinine criteria. We used simple linear regression to determine the association of BMI with peak CK and multivariable logistic regression to adjust the BMI-AKI association for peak CK and confounders.

Results: Median age was 43 years, 350 (76%) were male, 366 (79%) had blunt mechanism, and median Injury Severity Score was 24. Body mass index was associated with peak CK (R = 0.05, p < 0.001). Acute kidney injury developed in 148 patients (32%), and median time to peak CK was 29 hours (interquartile range, 15-56 hours) after presentation. Body mass index was significantly associated with AKI in multivariable models adjusted for age, race, sex, diabetes, injury mechanism and severity, and red blood cell transfusions (odds ratio [OR], 1.31 per 5 kg/m; 95% confidence interval [CI], 1.09-1.58; p = 0.004). Adding peak CK to the model partially attenuated the association of BMI with AKI (OR, 1.26 per 5 kg/m; 95% CI, 1.04-1.52; p = 0.018), and peak CK was also associated with AKI (OR, 1.19 per natural log; 95% CI, 1.00-1.41; p = 0.049). Peak CK remained associated with AKI when restricted to patients with values of <5,000 U/L (OR, 1.31 per natural log; 95% CI, 1.01-1.69; p = 0.043).

Conclusion: Serum CK correlated with BMI and partially attenuated the association of BMI with AKI after major trauma, suggesting that excess muscle injury may contribute to the BMI-AKI association.

Level Of Evidence: Epidemiologic study, level III.
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http://dx.doi.org/10.1097/TA.0000000000002714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830741PMC
July 2020

Locally Informed Simulation to Predict Hospital Capacity Needs During the COVID-19 Pandemic.

Ann Intern Med 2020 07 7;173(1):21-28. Epub 2020 Apr 7.

University of Pennsylvania, Philadelphia, Pennsylvania (G.E.W., M.Z.L., G.L.A., P.J.B., J.D.C., C.W.H., M.E.M., S.D.H.).

Background: The coronavirus disease 2019 (COVID-19) pandemic challenges hospital leaders to make time-sensitive, critical decisions about clinical operations and resource allocations.

Objective: To estimate the timing of surges in clinical demand and the best- and worst-case scenarios of local COVID-19-induced strain on hospital capacity, and thus inform clinical operations and staffing demands and identify when hospital capacity would be saturated.

Design: Monte Carlo simulation instantiation of a susceptible, infected, removed (SIR) model with a 1-day cycle.

Setting: 3 hospitals in an academic health system.

Patients: All people living in the greater Philadelphia region.

Measurements: The COVID-19 Hospital Impact Model (CHIME) (http://penn-chime.phl.io) SIR model was used to estimate the time from 23 March 2020 until hospital capacity would probably be exceeded, and the intensity of the surge, including for intensive care unit (ICU) beds and ventilators.

Results: Using patients with COVID-19 alone, CHIME estimated that it would be 31 to 53 days before demand exceeds existing hospital capacity. In best- and worst-case scenarios of surges in the number of patients with COVID-19, the needed total capacity for hospital beds would reach 3131 to 12 650 across the 3 hospitals, including 338 to 1608 ICU beds and 118 to 599 ventilators.

Limitations: Model parameters were taken directly or derived from published data across heterogeneous populations and practice environments and from the health system's historical data. CHIME does not incorporate more transition states to model infection severity, social networks to model transmission dynamics, or geographic information to account for spatial patterns of human interaction.

Conclusion: Publicly available and designed for hospital operations leaders, this modeling tool can inform preparations for capacity strain during the early days of a pandemic.

Primary Funding Source: University of Pennsylvania Health System and the Palliative and Advanced Illness Research Center.
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http://dx.doi.org/10.7326/M20-1260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153364PMC
July 2020

An Integrative Review of the Role of Palliative Care in Lung Transplantation.

Prog Transplant 2020 06 3;30(2):147-154. Epub 2020 Apr 3.

Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Background: Lung transplant patients experience significant physical symptoms and psychological stress that affect their quality of life. Palliative care is an interdisciplinary specialty associated with improved symptom management and enhanced quality of life. Little, however, is known about the palliative care needs of lung transplant patients and the role it plays in their care.

Aim: The aim of this integrative review was to synthesize the literature describing the palliative care needs, the current role, and factors influencing the integration of palliative care in the care of lung transplant patients.

Design/data Sources: We searched PubMed, Scopus, CINAHL, and Embase to identify English-language, primary studies focused on palliative care in adult lung transplantation. Study quality was evaluated using Strengthening the Report of Observational studies in Epidemiology and Consolidated Criteria for Reporting Qualitative Research criteria.

Results: Seven articles were included in the review. Most were single-center, descriptive studies. Two studies used qualitative and 5 used quantitative methodologies. Collectively, these studies suggest that palliative care is typically consulted for physical and psychological symptom management, although consultation is uncommon and often occurs late in the lung transplant process. We found no studies that systematically assessed palliative needs. Misperceptions about palliative care, communication challenges, and unrealistic patient/family expectations are identified barriers to the integration. While limited, evidence suggests that palliative care can be successfully integrated into lung transplant patient management.

Conclusions: Empirical literature about palliative care in lung transplantation is sparse. Further research is needed to define the needs and opportunities for integration into the care of these patients.
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http://dx.doi.org/10.1177/1526924820913512DOI Listing
June 2020

Clinical Impact of an Electronic Dashboard and Alert System for Sedation Minimization and Ventilator Liberation: A Before-After Study.

Crit Care Explor 2019 Oct 30;1(10):e0057. Epub 2019 Oct 30.

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pennsylvania, Philadelphia, PA.

Sedation minimization and ventilator liberation protocols improve outcomes but are challenging to implement. We sought to demonstrate proof-of-concept and impact of an electronic application promoting sedation minimization and ventilator liberation.

Design: Multi-ICU proof-of-concept study and a single ICU before-after study.

Setting: University hospital ICUs.

Patients: Adult patients receiving mechanical ventilation.

Interventions: An automated application consisting of 1) a web-based dashboard with real-time data on spontaneous breathing trial readiness, sedation depth, sedative infusions, and nudges to wean sedation and ventilatory support and 2) text-message alerts once patients met criteria for a spontaneous breathing trial and spontaneous awakening trial. Pre-intervention, sedation minimization, and ventilator liberation were reviewed daily during a multidisciplinary huddle. Post-intervention, the dashboard was used during the multidisciplinary huddle, throughout the day by respiratory therapists, and text alerts were sent to bedside providers.

Measurements And Main Results: We enrolled 115 subjects in the proof-of-concept study. Spontaneous breathing trial alerts were accurate (98.3%), usually sent while patients were receiving mandatory ventilation (88.5%), and 61.9% of patients received concurrent spontaneous awakening trial alerts. We enrolled 457 subjects in the before-after study, 221 pre-intervention and 236 post-intervention. After implementation, patients were 28% more likely to be extubated (hazard ratio, 1.28; 95% CI, 1.01-1.63; = 0.042) and 31% more likely to be discharged from the ICU (hazard ratio, 1.31; 95% CI, 1.03-1.67; = 0.027) at any time point. After implementation, the median duration of mechanical ventilation was 2.20 days (95% CI, 0.09-4.31 d; = 0.042) shorter and the median ICU length of stay was 2.65 days (95% CI, 0.13-5.16 d; = 0.040) shorter, compared with the expected durations without the application.

Conclusions: Implementation of an electronic dashboard and alert system promoting sedation minimization and ventilator liberation was associated with reductions in the duration of mechanical ventilation and ICU length of stay.
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http://dx.doi.org/10.1097/CCE.0000000000000057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063891PMC
October 2019

Cardiac complications and failure to rescue after injury in a mature state trauma system: Towards identifying opportunities for improvement.

Injury 2020 May 16;51(5):1216-1223. Epub 2020 Feb 16.

The University of Pennsylvania, Division of Traumatology, Critical Care and Emergency, Philadelphia, PA, United States. Electronic address:

Introduction: Cardiac complications (CC) after injury are rare but contribute disproportionately to mortality. Variability in rates of CC and failure to rescue (FTR) after CC (FTR-C) within trauma systems may suggest opportunities for improvement, but we have not yet demonstrated the ability to identify high and low performers. We examined center-level rates of CC and FTR-C in a mature trauma system with the hypothesis that high-performing centers for each of these outcomes could be identified.

Methods: Using a statewide trauma registry from 2007-2015, we developed multivariable logistic regression models on CC and FTR-C including patient demographics, physiology, comorbidity, and injury data. Predicted probabilities of each outcome were summed to generate expected event rates, which were compared to observed event rates to generate centerlevel observed-to-expected (O:E) ratios. We measured internal consistency between CC and FTR-C for centers using Cronbach's alpha.

Results: Cardiac complications occurred in 5,079/278,042 (1.8%; center-level range: 0.9-3.8%) of included patients (median age 55 (IQR 34-76), 84% Caucasian, 60% male, 92% blunt, median ISS 9 (IQR5-16)). Death after CC occurred in 982/5,097 patients for an FTR-C rate of 19.3% (center-level range: 7.8-30.4%). 10/27 centers were high-performers (95% confidence interval for O:E ratio <1) for CC and 2/27 centers were high-performers for FTR-C, but internal consistency between these metrics was poor (alpha = 0.31).

Conclusion: Rates of CC and FTR-C vary significantly between hospitals in mature trauma systems but high-performing centers can be identified. Inconsistent performance between metrics suggests unknown institutional factors underlie performance for CC and FTR.
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http://dx.doi.org/10.1016/j.injury.2020.02.003DOI Listing
May 2020

Plasma sTNFR1 and IL8 for prognostic enrichment in sepsis trials: a prospective cohort study.

Crit Care 2019 12 9;23(1):400. Epub 2019 Dec 9.

Division of Pulmonary, Allergy and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, 5036 Gates Building, Philadelphia, PA, 19104, USA.

Background: Enrichment strategies improve therapeutic targeting and trial efficiency, but enrichment factors for sepsis trials are lacking. We determined whether concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1), interleukin-8 (IL8), and angiopoietin-2 (Ang2) could identify sepsis patients at higher mortality risk and serve as prognostic enrichment factors.

Methods: In a multicenter prospective cohort study of 400 critically ill septic patients, we derived and validated thresholds for each marker and expressed prognostic enrichment using risk differences (RD) of 30-day mortality as predictive values. We then used decision curve analysis to simulate the prognostic enrichment of each marker and compare different prognostic enrichment strategies.

Measurements And Main Results: An admission sTNFR1 concentration > 8861 pg/ml identified patients with increased mortality in both the derivation (RD 21.6%) and validation (RD 17.8%) populations. Among immunocompetent patients, an IL8 concentration > 94 pg/ml identified patients with increased mortality in both the derivation (RD 17.7%) and validation (RD 27.0%) populations. An Ang2 level > 9761 pg/ml identified patients at 21.3% and 12.3% increased risk of mortality in the derivation and validation populations, respectively. Using sTNFR1 or IL8 to select high-risk patients improved clinical trial power and efficiency compared to selecting patients with septic shock. Ang2 did not outperform septic shock as an enrichment factor.

Conclusions: Thresholds for sTNFR1 and IL8 consistently identified sepsis patients with higher mortality risk and may have utility for prognostic enrichment in sepsis trials.
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http://dx.doi.org/10.1186/s13054-019-2684-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902425PMC
December 2019

Plasma Mitochondrial DNA Levels Are Associated With ARDS in Trauma and Sepsis Patients.

Chest 2020 01 14;157(1):67-76. Epub 2019 Oct 14.

Pulmonary, Allergy and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Center for Translational Lung Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Background: Critically ill patients who develop ARDS have substantial associated morbidity and mortality. Circulating mitochondrial DNA (mtDNA) released during critical illness causes endothelial dysfunction and lung injury in experimental models. This study hypothesized that elevated plasma mtDNA is associated with ARDS in critically ill patients with trauma and sepsis.

Methods: Plasma mtDNA concentrations were measured at ED presentation and approximately 48 h later in separate prospective cohorts of critically ill patients with trauma and sepsis. ARDS was classified according to the Berlin definition. The association of mtDNA with ARDS was tested by using multivariable logistic regression, adjusted for covariates previously shown to contribute to ARDS risk in each population.

Results: ARDS developed in 41 of 224 (18%) trauma patients and in 45 of 120 (38%) patients with sepsis. Forty-eight-hour mtDNA levels were significantly associated with ARDS (trauma: OR, 1.58/log copies/μL; 95% CI, 1.14-2.19 [P = .006]; sepsis: OR, 1.52/log copies/μL; 95% CI, 1.12-2.06 [P = .007]). Plasma mtDNA on presentation was not significantly associated with ARDS in either cohort. In patients with sepsis, 48-h mtDNA was more strongly associated with ARDS among those with a nonpulmonary infectious source (OR, 2.20/log copies/μL; 95% CI, 1.36-3.55 [P = .001], n = 69) than those with a pulmonary source (OR, 1.04/log copies/μL; 95% CI, 0.68-1.59 [P = .84], n = 51; P = .014 for interaction).

Conclusions: Plasma mtDNA levels were associated with incident ARDS in two critical illness populations. Given supportive preclinical data, our findings suggest a potential link between circulating mtDNA and lung injury and merit further investigation as a potentially targetable mediator of ARDS.
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http://dx.doi.org/10.1016/j.chest.2019.09.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965693PMC
January 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

Early Tacrolimus Concentrations After Lung Transplant Are Predicted by Combined Clinical and Genetic Factors and Associated With Acute Kidney Injury.

Clin Pharmacol Ther 2020 02 20;107(2):462-470. Epub 2019 Oct 20.

Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Tacrolimus exhibits unpredictable pharmacokinetics (PKs) after lung transplant, partly explained by cytochrome P450 (CYP)-enzyme polymorphisms. However, whether exposure variability during the immediate postoperative period affects outcomes is unknown, and pharmacogenetic dosing may be limited by residual PK variability. We estimated adjusted associations between early postoperative tacrolimus concentrations and acute kidney injury (AKI) and acute cellular rejection (ACR), and identified clinical and pharmacogenetic factors that explain postoperative tacrolimus concentration variability in 484 lung transplant patients. Increasing tacrolimus concentration was associated with higher AKI risk (hazard ratio (HR) 1.54; 95% confidence interval (CI) 1.20-1.96 per 5-mg/dL); and increasing AKI severity (odds ratio 1.29; 95% CI 1.04-1.60 per 5-mg/dL), but not ACR (HR 1.02; 95% CI 0.73-1.42). A model with clinical and pharmacogenetic factors explained 42% of concentration variance compared with 19% for pharmacogenetic factors only. Early tacrolimus exposure was independently associated with AKI after lung transplantation, but not ACR. Clinical factors accounted for substantial residual tacrolimus concentration variability not explained by CYP-enzyme polymorphisms.
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http://dx.doi.org/10.1002/cpt.1629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980920PMC
February 2020

Plasma sRAGE Acts as a Genetically Regulated Causal Intermediate in Sepsis-associated Acute Respiratory Distress Syndrome.

Am J Respir Crit Care Med 2020 01;201(1):47-56

Pulmonary, Allergy, and Critical Care Medicine Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.

Acute respiratory distress syndrome (ARDS) lacks known causal biomarkers. Plasma concentrations of sRAGE (soluble receptor for advanced glycation end products) strongly associate with ARDS risk. However, whether plasma sRAGE contributes causally to ARDS remains unknown. Evaluate plasma sRAGE as a causal intermediate in ARDS by Mendelian randomization (MR), a statistical method to infer causality using observational data. We measured early plasma sRAGE in two critically ill populations with sepsis. The cohorts were whole-genome genotyped and phenotyped for ARDS. To select validated genetic instruments for MR, we regressed plasma sRAGE on genome-wide genotypes in both cohorts. The causal effect of plasma sRAGE on ARDS was inferred using the top variants with significant associations in both populations ( < 0.01,  > 0.02). We applied the inverse variance-weighted method to obtain consistent estimates of the causal effect of plasma sRAGE on ARDS risk. There were 393 European and 266 African ancestry patients in the first cohort and 843 European ancestry patients in the second cohort. Plasma sRAGE was strongly associated with ARDS risk in both populations (odds ratio, 1.86; 95% confidence interval [1.54-2.25]; 2.56 [2.14-3.06] per log increase). Using genetic instruments common to both populations, plasma sRAGE had a consistent causal effect on ARDS risk with a β estimate of 0.50 (95% confidence interval [0.09-0.91] per log increase). Plasma sRAGE is genetically regulated during sepsis, and MR analysis indicates that increased plasma sRAGE leads to increased ARDS risk, suggesting plasma sRAGE acts as a causal intermediate in sepsis-related ARDS.
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http://dx.doi.org/10.1164/rccm.201810-2033OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938154PMC
January 2020

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, Vanderbilt University Medical Center, Nashville, Tennessee.

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

RNA sequencing of transplant-stage idiopathic pulmonary fibrosis lung reveals unique pathway regulation.

ERJ Open Res 2019 Jul 12;5(3). Epub 2019 Aug 12.

Pulmonary and Critical Care Medicine, University of Pennsylvania, Philadelphia PA, USA.

Idiopathic pulmonary fibrosis (IPF), the scarring of lung parenchyma resulting in the loss of lung function, remains a fatal disease with a significant unmet medical need. Patients with severe IPF often develop acute exacerbations resulting in the rapid deterioration of lung function, requiring transplantation. Understanding the pathophysiological mechanisms contributing to IPF is key to develop novel therapeutic approaches for end-stage disease. We report here RNA-sequencing analyses of lung tissues from a cohort of patients with transplant-stage IPF (n=36), compared with acute lung injury (ALI) (n=11) and nondisease controls (n=19), that reveal a robust gene expression signature unique to end-stage IPF. In addition to extracellular matrix remodelling pathways, we identified pathways associated with T-cell infiltration/activation, tumour development, and cholesterol homeostasis, as well as novel alternatively spliced transcripts that are differentially regulated in the advanced IPF lung ALI or nondisease controls. Additionally, we show a subset of genes that are correlated with percent predicted forced vital capacity and could reflect disease severity. Our results establish a robust transcriptomic fingerprint of an advanced IPF lung that is distinct from previously reported microarray signatures of moderate, stable or progressive IPF and identifies hitherto unknown candidate targets and pathways for therapeutic intervention in late-stage IPF as well as biomarkers to characterise disease progression and enable patient stratification.
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http://dx.doi.org/10.1183/23120541.00117-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689672PMC
July 2019

Upper Respiratory Dysbiosis with a Facultative-dominated Ecotype in Advanced Lung Disease and Dynamic Change after Lung Transplant.

Ann Am Thorac Soc 2019 11;16(11):1383-1391

Department of Medicine.

The oropharyngeal microbiome is a primary source of lung microbiota, contributes to lower respiratory infection, and is also a driver of oral health. We sought to understand oropharyngeal microbial communities in advanced lung disease, community dynamics after lung transplantation, and ecological features of dysbiosis. Oropharyngeal wash samples were obtained from individuals with end-stage disease awaiting transplantation ( = 22) and longitudinally from individuals at 6 weeks, 3 months, and 6 months after transplantation ( = 33), along with healthy control subjects ( = 14). Bacterial 16S and fungal internal transcribed spacer rRNA regions were deep-sequenced, and bacterial community respiratory patterns were imputed from taxonomic composition. Healthy subjects' oropharyngeal microbiomes showed a gradient of community types reflecting relative enrichment of strictly anaerobic, aerobic, or facultative anaerobic bacteria. Patients with end-stage lung disease showed severe dysbiosis by both taxonomic composition and respiration phenotypes, with reduced richness and diversity, increased facultative and decreased aerobic bacteria, and absence of communities characterized by obligate aerobes. In patients at 6 weeks and 3 months post-transplant, richness and diversity were intermediate between healthy and pretransplant subjects, with near-normal distribution of community types. However, by 6 months post-transplant, oropharyngeal wash resembled the low-diversity facultative-dominated profile of pretransplant subjects. Community ecotype correlated with abundance. End-stage lung disease is associated with marked upper respiratory tract dysbiosis involving both community structure and respiratory metabolism profiles of constituent bacteria. Dynamic changes occur after lung transplantation, with partial normalization early but later appearance of severe dysbiosis similar to pretransplant patients. Aberrant oropharyngeal communities may predispose to abnormal lung microbiota and infection risk both in advanced lung disease and after transplantation.
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http://dx.doi.org/10.1513/AnnalsATS.201904-299OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945465PMC
November 2019