Publications by authors named "Janet S Lee"

94 Publications

Characteristics of patients discharged and readmitted after COVID-19 hospitalisation within a large integrated health system in the United States.

Infect Dis (Lond) 2021 May 8:1-5. Epub 2021 May 8.

Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, USA.

Background: Limited studies have explored post-discharge outcomes following Coronavirus Disease 2019 (COVID-19) hospitalisation. We sought to characterise patients discharged following a COVID-19 hospitalisation within a large integrated health system in the United States.

Methods: We performed a retrospective study of 2180 COVID-19 patients discharged between 1 April 2020 and 31 July 2020. The primary endpoint was all-cause observation stay or inpatient readmission within 30 days from discharge. Bivariate and multivariable logistic regression analyses were performed to estimate the association between key socio-demographic and clinical characteristics with risk of 30-day readmission.

Results: The 30-day readmission rate was 7.6% ( = 166); 30-day mortality rate was 1% ( = 19). Most readmissions were respiratory-related (58%) and occurred at a median time of 5 days post discharge. Adjusted models showed that prior hospitalisations (Odds Ratio = 2.36, [95% Confidence Interval: 1.59-3.50]), chronic pulmonary disease (1.57 [1.09-2.28]), and discharge to home health (1.46 [1.01-2.11]) were significantly associated with 30-day readmission. Longer duration from diagnosis to index admission was borderline associated with lower odds of readmission (0.95 [0.91-1.00]).

Conclusion: Readmission and mortality rates for COVID-19 following discharge are low. Most readmissions occur early and are due to respiratory causes and may reflect the prolonged acute disease course.
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http://dx.doi.org/10.1080/23744235.2021.1924398DOI Listing
May 2021

Elastase Activity From Pseudomonas aeruginosa Respiratory Isolates and ICU Mortality.

Chest 2021 Apr 17. Epub 2021 Apr 17.

Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA. Electronic address:

Background: Pseudomonas aeruginosa (PA) is a common cause of respiratory infection and morbidity. Pseudomonas elastase is an important virulence factor regulated by the lasR gene. Whether PA elastase activity is associated with worse clinical outcomes in ICU patients is unknown.

Research Question: Is there an association between PA elastase activity and worse host outcomes in a cohort of ICU patients?

Methods: PA respiratory isolates from 238 unique ICU patients from two tertiary-care centers within the University of Pittsburgh Medical Center health system were prospectively collected and screened for total protease and elastase activity, biofilm production, antimicrobial resistance, and polymicrobial status. The association between pathogen characteristics and 30-day and 90-day mortality were calculated using logistic regression. For subgroup analysis, the two patterns of early (<72h) and late sample (>72h) collections from index ICU admission were distinguished using a finite mixture model. Lung inflammation and injury was evaluated in a mouse model using a PA high elastase vs low elastase producer.

Results: PA elastase activity was common in ICU respiratory isolates representing 75% of samples and was associated with increased 30-day mortality (adjusted OR [95%CI]. 1.39 [1.05-1.83]). Subgroup analysis demonstrated that elastase activity is a risk factor for 30- and 90-day mortality in the early sample group, whereas antimicrobial resistance was a risk factor for 90-day mortality in the late sample group. Whole genome sequencing of high and low elastase producers showed that predicted loss-of-function lasR genotypes were less common among high elastase producers. Mice infected with a high elastase producer showed increased lung bacterial burden and inflammatory profile compared with mice infected with a low elastase producer.

Interpretation: Elastase activity is associated with 30-day ICU mortality. A high elastase producing clinical isolate confers increased lung tissue inflammation compared with a low elastase producer in vivo.
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http://dx.doi.org/10.1016/j.chest.2021.04.015DOI Listing
April 2021

Inclusion in the Pulmonary, Critical Care, and Sleep Medicine Physician-Scientist Workforce. Building with Intention.

ATS Sch 2020 Aug 12;1(4):353-363. Epub 2020 Aug 12.

Division of Pulmonary, Allergy, and Critical Care Medicine, and Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania; and.

Physician-scientists comprise an exceedingly small fraction of the physician workforce. As the fields of pulmonary, critical care, and sleep medicine continue to invest in the development of the physician-scientist workforce, recruitment and retention strategies need to consider the temporal trend in the decline in numbers of trainees pursuing basic research, the challenges of trainees from underrepresented groups in medicine, and opportunities for career and scientific advancement of women physician-scientists. In this perspective article, we examine the headwinds in the training and education of physician-scientists and highlight potential solutions to reverse these trends.
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http://dx.doi.org/10.34197/ats-scholar.2020-0026PSDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015761PMC
August 2020

Thrombospondin-1 Restricts Interleukin-36γ-Mediated Neutrophilic Inflammation during Pseudomonas aeruginosa Pulmonary Infection.

mBio 2021 04 6;12(2). Epub 2021 Apr 6.

Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

Interleukin-36γ (IL-36γ), a member of the IL-1 cytokine superfamily, amplifies lung inflammation and impairs host defense during acute pulmonary infection. To be fully active, IL-36γ is cleaved at its N-terminal region by proteases such as neutrophil elastase (NE) and cathepsin S (CatS). However, it remains unclear whether limiting extracellular proteolysis restrains the inflammatory cascade triggered by IL-36γ during infection. Thrombospondin-1 (TSP-1) is a matricellular protein with inhibitory activity against NE and the pathogen-secreted elastase LasB-both proteases implicated in amplifying inflammation. We hypothesized that TSP-1 tempers the inflammatory response during lung infection by inhibiting the proteolytic environment required for IL-36γ activation. Compared to wild-type (WT) mice, TSP-1-deficient (Thbs1) mice exhibited a hyperinflammatory response in the lungs during infection, with increased cytokine production and an unrestrained extracellular proteolytic environment characterized by higher free NE and LasB, but not CatS activity. LasB cleaved IL-36γ proximally to M at a cleavage site distinct from those generated by NE and CatS, which cleave IL-36γ proximally to Y and S, respectively. N-terminal truncation experiments predicted that the M and the S isoforms bind the IL-36R complex almost identically. IL-36γ neutralization ameliorated the hyperinflammatory response and improved lung immunity in Thbs1 mice during infection. Moreover, administration of cleaved IL-36γ induced cytokine production and neutrophil recruitment and activation that was accentuated in Thbs1 mice lungs. Collectively, our data show that TSP-1 regulates lung neutrophilic inflammation and facilitates host defense by restraining the extracellular proteolytic environment required for IL-36γ activation. pulmonary infection can lead to exaggerated neutrophilic inflammation and tissue destruction, yet host factors that regulate the neutrophilic response are not fully known. IL-36γ is a proinflammatory cytokine that dramatically increases in bioactivity following N-terminal processing by proteases. Here, we demonstrate that thrombospondin-1, a host matricellular protein, limits N-terminal processing of IL-36γ by neutrophil elastase and the -secreted protease LasB. Thrombospondin-1-deficient mice (Thbs1) exhibit a hyperinflammatory response following infection. Whereas IL-36γ neutralization reduces inflammatory cytokine production, limits neutrophil activation, and improves host defense in Thbs1 mice, cleaved IL-36γ administration amplifies neutrophilic inflammation in Thbs1 mice. Our findings indicate that thrombospondin-1 guards against feed-forward neutrophilic inflammation mediated by IL-36γ in the lung by restraining the extracellular proteolytic environment.
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http://dx.doi.org/10.1128/mBio.03336-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092289PMC
April 2021

Bifurcated monocyte states are predictive of mortality in severe COVID-19.

bioRxiv 2021 Feb 10. Epub 2021 Feb 10.

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection presents with varied clinical manifestations , ranging from mild symptoms to acute respiratory distress syndrome (ARDS) with high mortality . Despite extensive analyses, there remains an urgent need to delineate immune cell states that contribute to mortality in severe COVID-19. We performed high-dimensional cellular and molecular profiling of blood and respiratory samples from critically ill COVID-19 patients to define immune cell genomic states that are predictive of outcome in severe COVID-19 disease. Critically ill patients admitted to the intensive care unit (ICU) manifested increased frequencies of inflammatory monocytes and plasmablasts that were also associated with ARDS not due to COVID-19. Single-cell RNAseq (scRNAseq)-based deconvolution of genomic states of peripheral immune cells revealed distinct gene modules that were associated with COVID-19 outcome. Notably, monocytes exhibited bifurcated genomic states, with expression of a cytokine gene module exemplified by (MIP-1β) associated with survival and an interferon signaling module associated with death. These gene modules were correlated with higher levels of MIP-1β and CXCL10 levels in plasma, respectively. Monocytes expressing genes reflective of these divergent modules were also detectable in endotracheal aspirates. Machine learning algorithms identified the distinctive monocyte modules as part of a multivariate peripheral immune system state that was predictive of COVID-19 mortality. Follow-up analysis of the monocyte modules on ICU day 5 was consistent with bifurcated states that correlated with distinct inflammatory cytokines. Our data suggests a pivotal role for monocytes and their specific inflammatory genomic states in contributing to mortality in life-threatening COVID-19 disease and may facilitate discovery of new diagnostics and therapeutics.
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http://dx.doi.org/10.1101/2021.02.10.430499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885916PMC
February 2021

Finding Order in the Chaos: Outstanding Questions in Klebsiella pneumoniae Pathogenesis.

Infect Immun 2021 Mar 17;89(4). Epub 2021 Mar 17.

Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

are Gram-negative facultative anaerobes that are found within host-associated commensal microbiomes, but they can also cause a wide range of infections that are often difficult to treat. These infections are caused by different pathotypes of , called either classical or hypervirulent strains. These two groups are genetically distinct, inhabit nonoverlapping geographies, and cause different types of harmful infections in humans. These distinct bacterial groups have also been found to interact differently with the host immune system. Initial innate immune defenses against infection include complement, macrophages, neutrophils, and monocytes; these defenses are primary strategies employed by the host to clear infections. pathogenesis depends upon the interactions between the microbe and each of these host defenses, and it is becoming increasingly apparent that bacterial genetic diversity impacts the outcomes of these interactions. Here, we highlight recent advances in our understanding of pathogenesis, with a focus on how bacterial evolution and diversity impact interactions with mammalian innate immune host defenses. We also discuss outstanding questions regarding how can frustrate normal immune responses, capitalize upon states of immunocompromise, and cause infections with high mortality.
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http://dx.doi.org/10.1128/IAI.00693-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090965PMC
March 2021

COVID-19 versus Non-COVID ARDS: Comparison of Demographics, Physiologic Parameters, Inflammatory Biomarkers and Clinical Outcomes.

Ann Am Thorac Soc 2021 Feb 5. Epub 2021 Feb 5.

UPMC Presbyterian, 25817, Pulmonary and Critical Care Medicine, Pittsburgh, Pennsylvania, United States;

Rationale: There is an urgent need for improved understanding of the mechanisms and clinical characteristics of acute respiratory distress syndrome (ARDS) due to COVID-19.

Objectives: To compare key demographic and physiologic parameters, biomarkers and clinical outcomes of COVID-19 ARDS and ARDS secondary to direct lung injury from other etiologies of pneumonia.

Methods: We enrolled 27 patients with COVID-19 ARDS in a prospective, observational cohort study, and compared them with a historical, pre-COVID-19 cohort of patients with viral ARDS (n=14), bacterial ARDS (n=21), and ARDS due to culture-negative pneumonia (n=30). We recorded clinical demographics, measured respiratory mechanical parameters, collected serial peripheral blood specimens for measurement of plasma interleukin-(IL)-6, IL-8, and IL-10, and followed patients prospectively for patient-centered outcomes. We conducted between group comparisons with non-parametric tests and analyzed time-to-event outcomes with Kaplan-Meier and Cox proportional hazards models.

Results: Patients with COVID-19 ARDS had higher body mass index and were more likely to be Black, or residents of skilled nursing facilities, compared to non-COVID-19 ARDS (p<0.05). COVID-19 patients had lower delivered minute ventilation compared to bacterial and culture-negative ARDS (post-hoc p<0.01), but not compared to viral ARDS. We found no differences in static compliance, hypoxemic indices or carbon dioxide clearance between groups. COVID-19 patients had lower IL-6 levels compared to bacterial and culture-negative ARDS at early time points post-intubation, but no differences in IL-6 levels compared to viral ARDS. COVID-19 patients had longer duration of mechanical ventilation but similar 60-day mortality, both in unadjusted and adjusted analyses.

Conclusions: COVID-19 ARDS bears several similarities to viral ARDS but demonstrates lower minute ventilation and lower systemic levels of IL-6 compared to bacterial and culture-negative ARDS. COVID-19 ARDS was associated with longer dependence on mechanical ventilation compared to non-COVID ARDS. Such detectable differences of COVID-19 do not merit deviation from evidence-based management of ARDS but suggest priorities for clinical research to better characterize and treat this new clinical entity.
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http://dx.doi.org/10.1513/AnnalsATS.202008-1026OCDOI Listing
February 2021

COPD Comorbidity Profiles and 2-Year Trajectory of Acute and Postacute Care Use.

Chest 2021 Jun 19;159(6):2233-2243. Epub 2021 Jan 19.

Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA. Electronic address:

Background: Multiple morbidity is the norm in advanced COPD and contributes to high symptom burden and worse outcomes.

Research Question: Can distinct comorbidity profiles be identified and validated in a community-based sample of patients with COPD from a large integrated health care system using a standard, commonly used diagnostic code-based comorbidity index and downstream 2-year health care use data?

Study Design And Methods: In this retrospective cohort study, we used latent class analysis (LCA) to identify comorbidity profiles in a population-based sample of 91,453 patients with a COPD diagnosis between 2011 and 2015. We included specific comorbid conditions from the Charlson Comorbidity Index (CCI) and accounted for variation in underlying prevalence of different comorbidities across the three study sites. Sociodemographic, clinical, and health-care use data were obtained from electronic health records (EHRs). Multivariate logistic regression analysis was used to compare rates of acute and postacute care use by class.

Results: The mean age was 71 ± 11 years, 55% of patients were women, 23% of patients were people of color, and 80% of patients were former or current smokers. LCA identified four distinct comorbidity profiles with progressively higher CCI scores: low morbidity (61%; 1.9 ± 1.4), metabolic renal (21%; 4.7 ± 1.8), cardiovascular (12%; 4.6 ± 1.9), and multimorbidity (7%; 7.5 ± 1.7). In multivariate models, during 2 years of follow-up, a significant, nonoverlapping increase was found in the odds of having any all-cause acute (hospitalizations, observation stays, and ED visits) and postacute care use across the comorbidity profiles.

Interpretation: Distinct comorbidity profiles can be identified in patients with COPD using standard EHR-based diagnostic codes, and these profiles are associated with subsequent acute and postacute care use. Population-based risk stratification schemes for end-to-end, comprehensive COPD management should consider integrating comorbidity profiles such as those found in this study.
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http://dx.doi.org/10.1016/j.chest.2021.01.020DOI Listing
June 2021

Brief Report: Hydroxychloroquine does not induce hemolytic anemia or organ damage in a "humanized" G6PD A- mouse model.

PLoS One 2020 2;15(10):e0240266. Epub 2020 Oct 2.

Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America.

Background: Hydroxychloroquine (HCQ) is widely used in the treatment of malaria, rheumatologic disease such as lupus, and most recently, COVID-19. These uses raise concerns about its safe use in the setting of glucose-6-phosphate dehydrogenase (G6PD) deficiency, especially as 11% of African American men carry the G6PD A- variant. However, limited data exist regarding the safety of HCQ in this population.

Study Design And Methods: Recently, we created a novel "humanized" mouse model containing the G6PD deficiency A- variant (Val68Met) using CRISPR technology. We tested the effects of high-dose HCQ administration over 5 days on hemolysis in our novel G6PD A- mice. In addition to standard hematologic parameters including plasma hemoglobin, erythrocyte methemoglobin, and reticulocytes, hepatic and renal function were assessed after HCQ.

Results: Residual erythrocyte G6PD activity in G6PD A- mice was ~6% compared to wild-type (WT) littermates. Importantly, we found no evidence of clinically significant intravascular hemolysis, methemoglobinemia, or organ damage in response to high-dose HCQ.

Conclusions: Though the effects of high doses over prolonged periods was not assessed, this study provides early, novel safety data of the use of HCQ in the setting of G6PD deficiency secondary to G6PD A-. In addition to novel safety data for HCQ, to our knowledge, we are the first to present the creation of a "humanized" murine model of G6PD deficiency.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240266PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531777PMC
October 2020

Stressed erythrophagocytosis induces immunosuppression during sepsis through heme-mediated STAT1 dysregulation.

J Clin Invest 2021 Jan;131(1)

Acute Lung Injury Center of Excellence.

Macrophages are main effectors of heme metabolism, increasing transiently in the liver during heightened disposal of damaged or senescent RBCs (sRBCs). Macrophages are also essential in defense against microbial threats, but pathological states of heme excess may be immunosuppressive. Herein, we uncovered a mechanism whereby an acute rise in sRBC disposal by macrophages led to an immunosuppressive phenotype after intrapulmonary Klebsiella pneumoniae infection characterized by increased extrapulmonary bacterial proliferation and reduced survival from sepsis in mice. The impaired immunity to K. pneumoniae during heightened sRBC disposal was independent of iron acquisition by bacterial siderophores, in that K. pneumoniae mutants lacking siderophore function recapitulated the findings observed with the WT strain. Rather, sRBC disposal induced a liver transcriptomic profile notable for suppression of Stat1 and IFN-related responses during K. pneumoniae sepsis. Excess heme handling by macrophages recapitulated STAT1 suppression during infection that required synergistic NRF1 and NRF2 activation but was independent of heme oxygenase-1 induction. Whereas iron was dispensable, the porphyrin moiety of heme was sufficient to mediate suppression of STAT1-dependent responses in human and mouse macrophages and promoted liver dissemination of K. pneumoniae in vivo. Thus, cellular heme metabolism dysfunction negatively regulated the STAT1 pathway, with implications in severe infection.
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http://dx.doi.org/10.1172/JCI137468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773401PMC
January 2021

Lower respiratory tract myeloid cells harbor SARS-CoV-2 and display an inflammatory phenotype.

medRxiv 2020 Aug 14. Epub 2020 Aug 14.

SARS-CoV-2 pneumonia may induce an aberrant immune response with brisk recruitment of myeloid cells into the lower respiratory tract, which may contribute to morbidity and mortality. We describe endotracheal aspirate samples from seven patients with SARS-CoV-2 pneumonia requiring mechanical ventilation. We note SARS-CoV-2 virions within lower respiratory tract myeloid cells shown by electron tomography, immunofluorescence confocal imaging, and immuno-electron microscopy. Endotracheal aspirates are primarily composed of mononuclear and polymorphonuclear leukocytes. These myeloid cells that harbor virus are frequently positive for CD14 and/or CD16 and most display an inflammatory phenotype marked by expression of IL-6 and tissue factor mRNA transcript and protein expression.
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http://dx.doi.org/10.1101/2020.08.11.20171967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430612PMC
August 2020

Single cell RNA sequencing identifies an early monocyte gene signature in acute respiratory distress syndrome.

JCI Insight 2020 07 9;5(13). Epub 2020 Jul 9.

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

Acute respiratory distress syndrome (ARDS) results from overwhelming pulmonary inflammation. Prior bulk RNA sequencing provided limited insights into ARDS pathogenesis. We used single cell RNA sequencing to probe ARDS at a higher resolution. PBMCs of patients with pneumonia and sepsis with early ARDS were compared with those of sepsis patients who did not develop ARDS. Monocyte clusters from ARDS patients revealed multiple distinguishing characteristics in comparison with monocytes from patients without ARDS, including downregulation of SOCS3 expression, accompanied by a proinflammatory signature with upregulation of multiple type I IFN-induced genes, especially in CD16+ cells. To generate an ARDS risk score, we identified upregulation of 29 genes in the monocytes of these patients, and 17 showed a similar profile in cells of patients in independent cohorts. Monocytes had increased expression of RAB11A, known to inhibit neutrophil efferocytosis; ATP2B1, a calcium pump that exports Ca2+ implicated in endothelial barrier disruption; and SPARC, associated with processing of procollagen to collagen. These data show that monocytes of ARDS patients upregulate expression of genes not just restricted to those associated with inflammation. Together, our findings identify molecules that are likely involved in ARDS pathogenesis that may inform biomarker and therapeutic development.
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http://dx.doi.org/10.1172/jci.insight.135678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406263PMC
July 2020

Practical Guidelines for Collection, Manipulation and Inactivation of SARS-CoV-2 and COVID-19 Clinical Specimens.

Curr Protoc Cytom 2020 06;93(1):e77

Department of Environmental Health and Safety, University of Pittsburgh, Pittsburgh, Pennsylvania.

SARS-CoV-2 is a novel coronavirus that causes the acute respiratory disease-Coronavirus disease 2019 (COVID-19)-which has led to a global health crisis. Currently, no prophylactics or therapies exist to control virus spread or mitigate the disease. Thus, the risk of infection for physicians and scientists is high, requiring work to be conducted in Biosafety Level-3 (BSL-3) facilities if virus will be isolated or propagated. However, inactivation of the virus can enable safe handling at a reduced biosafety level, making samples accessible to a diverse array of institutions and investigators. Institutions of all types have an immediate need for guidelines that outline safe collection, handling, and inactivation of samples suspected to contain active virus. Here we provide a practical guide for physicians and researchers wishing to work with materials from patients who are COVID-19 positive or suspected positive. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Practical guidelines for the safe collection and handling of specimens collected from COVID-19 and suspected COVID-19 patients Basic Protocol 2: Inactivating SARS-CoV-2.
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http://dx.doi.org/10.1002/cpcy.77DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300551PMC
June 2020

Association between self-reported moderate to vigorous physical activity and the rate of outpatient treated COPD exacerbations: retrospective cohort study.

BMJ Open Respir Res 2020 05;7(1)

Research and Evaluation, Kaiser Permanente Southern California Research and Evaluation, Pasadena, California, USA.

Introduction: Little has been published regarding the relationship between physical activity (PA) and outpatient treated, mild to moderate acute exacerbation of chronic obstructive pulmonary disease exacerbations (AECOPD). The purpose of this study was to determine the association between self-reported PA and outpatient treated AECOPD over 2 years using real-world data obtained from existing electronic medical records (EMRs).

Methods: We included 44 896 patients with a chronic obstructive pulmonary disease diagnosis from the EMR in this retrospective cohort study. Moderate to vigorous PA was measured via patient self-report, obtained during routine clinical care; patients were classified as inactive (0 min/week), insufficiently active (1-149 min/week) or active (≥150 min/week). AECOPDs were measured using both encounter and prescription fill (antibiotics and/or oral steroids) data. We used Poisson regression models to compare the unadjusted and adjusted rates of outpatient treated AECOPD over 2 years across the PA categories.

Results: In adjusted models, the 2-year AECOPD incidence rate ratio (IRR) was not different between the inactive and insufficiently inactive groups (IRR 0.98, 95% CI 0.96 to 1.01) and only marginally meaningful lower for the active group (IRR 0.97, 95% CI 0.95 to 0.98). Sensitivity analyses of patients meeting or not meeting obstructive criteria produced similar results with generally weak or non-significant associations.

Conclusion: The lack of an association between PA and AECOPD contrasts with previous published findings of a strong relationship between moderate to vigorous PA and hospitalisations for severe AECOPD. This difference could partially be attributed to the imprecision of our measurements for both the exposure and outcome.
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http://dx.doi.org/10.1136/bmjresp-2020-000590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264694PMC
May 2020

Hepatitis C Screening Rates and Care Cascade in a Large US Insured Population, 2010-2016: Gaps to Elimination.

Popul Health Manag 2021 Apr 11;24(2):198-206. Epub 2020 May 11.

Gastroenterology & Hepatology, University of Southern California, Los Angeles, California, USA.

Understanding the health care system's ability to move patients through the hepatitis C virus (HCV) care cascade from screening to treatment is essential for HCV elimination. This retrospective study describes real-world HCV screening rates and care cascade steps to identify gaps in care for patients with HCV in the United States. Eligible patients were aged ≥18 years as of the measurement year (calendar year between January 1, 2010-December 31, 2016) and were commercial and Medicare Advantage with Part D members in the Optum Research database with continuous health plan enrollment 5 years prior to and during the measurement year. Incident and prevalent screening rates were calculated for each measurement year. Care cascade steps were analyzed via Kaplan-Meier analysis and logistic regression among patients with a positive HCV ribonucleic acid test. Cohorts were selected based on birth year (pre-1945 birth cohort, 1945-1965 birth cohort, post-1965 birth cohort). Among the 1945-1965 birth cohort, incident and prevalent screening rates increased from 1.6% to 4.7% and 10% to 18%, respectively, from 2010 to 2016. The proportion of patients attaining each independent cascade step within 1 year of screening increased significantly over time for genotype testing ( = 0.0283) and receipt of treatment ( < 0.0001). Median time from screening to treatment decreased from 1627 days (95% CI 1335-1871) in 2010 to 282 days (95% CI 223-498) in 2015. HCV screening and completion of the care cascade has improved for certain patient populations; however, gaps remain, highlighting the urgent need to address barriers to meeting HCV elimination goals.
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http://dx.doi.org/10.1089/pop.2019.0237DOI Listing
April 2021

Increased Alternative Complement Pathway Function and Improved Survival during Critical Illness.

Am J Respir Crit Care Med 2020 07;202(2):230-240

Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine.

Complement is crucial for host defense but may also drive dysregulated inflammation. There is limited understanding of alternative complement function, which can amplify all complement activity, during critical illness. We examined the function and key components of the alternative complement pathway in a series of critically ill patients and in a mouse pneumonia model. Total classical (CH50) and alternative complement (AH50) function were quantified in serum from 321 prospectively enrolled critically ill patients and compared with clinical outcomes. Alternative pathway (AP) regulatory factors were quantified by ELISA ( = 181) and examined via transcriptomics data from external cohorts. Wild-type, , and mice were infected intratracheally with (KP) and assessed for extrapulmonary dissemination. AH50 greater than or equal to median, but not CH50 greater than or equal to median, was associated with decreased 30-day mortality (adjusted odds ratio [OR], 0.53 [95% confidence interval (CI), 0.31-0.91]), independent of chronic liver disease. One-year survival was improved in patients with AH50 greater than or equal to median (adjusted hazard ratio = 0.59 [95% CI, 0.41-0.87]). Patients with elevated AH50 had increased levels of AP factors B, H, and properdin, and fewer showed a "hyperinflammatory" subphenotype (OR, 0.30 [95% CI, 0.18-0.49]). Increased expression of proximal AP genes was associated with improved survival in two external cohorts. AH50 greater than or equal to median was associated with fewer bloodstream infections (OR, 0.67 [95% CI, 0.45-0.98). Conversely, depletion of AP factors, or AH50 less than median, impaired serum control of KP that was restored by adding healthy serum. mice demonstrated increased extrapulmonary dissemination and serum inflammatory markers after intratracheal KP infection compared with wild type. Elevated AP function is associated with improved survival during critical illness, possibly because of enhanced immune capacity.
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http://dx.doi.org/10.1164/rccm.201910-2083OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365364PMC
July 2020

The evolution of radiographic edema in ARDS and its association with clinical outcomes: A prospective cohort study in adult patients.

J Crit Care 2020 04 13;56:222-228. Epub 2020 Jan 13.

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Center for Medicine and the Microbiome, University of Pittsburgh, USA. Electronic address:

Purpose: To assess the longitudinal evolution of radiographic edema using chest X-rays (CXR) in patients with Acute Respiratory Distress Syndrome (ARDS) and to examine its association with prognostic biomarkers, ARDS subphenotypes and outcomes.

Materials And Methods: We quantified radiographic edema on CXRs from patients with ARDS or cardiogenic pulmonary edema (controls) using the Radiographic Assessment of Lung Edema (RALE) score on day of intubation and up to 10 days after. We measured baseline plasma biomarkers and recorded clinical variables.

Results: The RALE score had good inter-rater agreement (r = 0.83, p < 0.0001) applied on 488 CXRs from 129 patients, with higher RALE scores in patients with ARDS (n = 108) compared to controls (n = 21, p = 0.01). Baseline RALE scores were positively correlated with levels of the receptor for end-glycation end products (RAGE) in ARDS patients (p < 0.05). Baseline RALE scores were not predictive of 30- or 90-day survival. Persistently elevated RALE scores were associated with prolonged need for mechanical ventilation (p = 0.002).

Conclusions: The RALE score is easily implementable with high inter-rater reliability. Longitudinal RALE scoring appears to be a reproducible approach to track the evolution of radiographic edema in patients with ARDS and can potentially predict prolonged need for mechanical ventilation.
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http://dx.doi.org/10.1016/j.jcrc.2020.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136845PMC
April 2020

Host-Response Subphenotypes Offer Prognostic Enrichment in Patients With or at Risk for Acute Respiratory Distress Syndrome.

Crit Care Med 2019 12;47(12):1724-1734

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA.

Objectives: Classification of patients with acute respiratory distress syndrome into hyper- and hypoinflammatory subphenotypes using plasma biomarkers may facilitate more effective targeted therapy. We examined whether established subphenotypes are present not only in patients with acute respiratory distress syndrome but also in patients at risk for acute respiratory distress syndrome (ARFA) and then assessed the prognostic information of baseline subphenotyping on the evolution of host-response biomarkers and clinical outcomes.

Design: Prospective, observational cohort study.

Setting: Medical ICU at a tertiary academic medical center.

Patients: Mechanically ventilated patients with acute respiratory distress syndrome or ARFA.

Interventions: None.

Measurements And Main Results: We performed longitudinal measurements of 10 plasma biomarkers of host injury and inflammation. We applied unsupervised latent class analysis methods utilizing baseline clinical and biomarker variables and demonstrated that two-class models (hyper- vs hypoinflammatory subphenotypes) offered improved fit compared with one-class models in both patients with acute respiratory distress syndrome and ARFA. Baseline assignment to the hyperinflammatory subphenotype (39/104 [38%] acute respiratory distress syndrome and 30/108 [28%] ARFA patients) was associated with higher severity of illness by Sequential Organ Failure Assessment scores and incidence of acute kidney injury in patients with acute respiratory distress syndrome, as well as higher 30-day mortality and longer duration of mechanical ventilation in ARFA patients (p < 0.0001). Hyperinflammatory patients exhibited persistent elevation of biomarkers of innate immunity for up to 2 weeks postintubation.

Conclusions: Our results suggest that two distinct subphenotypes are present not only in patients with established acute respiratory distress syndrome but also in patients at risk for its development. Hyperinflammatory classification at baseline is associated with higher severity of illness, worse clinical outcomes, and trajectories of persistently elevated biomarkers of host injury and inflammation during acute critical illness compared with hypoinflammatory patients. Our findings provide strong rationale for examining treatment effect modifications by subphenotypes in randomized clinical trials to inform precision therapeutic approaches in critical care.
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http://dx.doi.org/10.1097/CCM.0000000000004018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865808PMC
December 2019

Effect of Physical Activity Coaching on Acute Care and Survival Among Patients With Chronic Obstructive Pulmonary Disease: A Pragmatic Randomized Clinical Trial.

JAMA Netw Open 2019 08 2;2(8):e199657. Epub 2019 Aug 2.

Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena.

Importance: While observational studies show that physical inactivity is associated with worse outcomes in chronic obstructive pulmonary disease (COPD), there are no population-based trials to date testing the effectiveness of physical activity (PA) interventions to reduce acute care use or improve survival.

Objective: To evaluate the long-term effectiveness of a community-based PA coaching intervention in patients with COPD.

Design, Setting, And Participants: Pragmatic randomized clinical trial with preconsent randomization to the 12-month Walk On! (WO) intervention or standard care (SC). Enrollment occurred from July 1, 2015, to July 31, 2017; follow-up ended in July 2018. The setting was Kaiser Permanente Southern California sites. Participants were patients 40 years or older who had any COPD-related acute care use in the previous 12 months; only patients assigned to WO were approached for consent to participate in intervention activities.

Interventions: The WO intervention included collaborative monitoring of PA step counts, semiautomated step goal recommendations, individualized reinforcement, and peer/family support. Standard COPD care could include referrals to pulmonary rehabilitation.

Main Outcomes And Measures: The primary outcome was a composite binary measure of all-cause hospitalizations, observation stays, emergency department visits, and death using adjusted logistic regression in the 12 months after randomization. Secondary outcomes included self-reported PA, COPD-related acute care use, symptoms, quality of life, and cardiometabolic markers.

Results: All 2707 eligible patients (baseline mean [SD] age, 72 [10] years; 53.7% female; 74.3% of white race/ethnicity; and baseline mean [SD] percent forced expiratory volume in the first second of expiration predicted, 61.0 [22.5]) were randomly assigned to WO (n = 1358) or SC (n = 1349). The intent-to-treat analysis showed no differences between WO and SC on the primary all-cause composite outcome (odds ratio [OR], 1.09; 95% CI, 0.92-1.28; P = .33) or in the individual outcomes. Prespecified, as-treated analyses compared outcomes between all SC and 321 WO patients who participated in any intervention activities (23.6% [321 of 1358] uptake). The as-treated, propensity score-weighted model showed nonsignificant positive estimates in favor of WO participants compared with SC on all-cause hospitalizations (OR, 0.84; 95% CI, 0.65-1.10; P = .21) and death (OR, 0.62; 95% CI, 0.35-1.11; P = .11). More WO participants reported engaging in PA compared with SC (47.4% [152 of 321] vs 30.7% [414 of 1349]; P < .001) and had improvements in the Patient-Reported Outcomes Measurement Information System 10 physical health domain at 6 months. There were no group differences in other secondary outcomes.

Conclusions And Relevance: Participation in a PA coaching program by patients with a history of COPD exacerbations was insufficient to effect improvements in acute care use or survival in the primary analysis.

Trial Registration: ClinicalTrials.gov identifier: NCT02478359.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.9657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704745PMC
August 2019

Frontline Science: Rev-Erbα links blue light with enhanced bacterial clearance and improved survival in murine Klebsiella pneumoniae pneumonia.

J Leukoc Biol 2020 01 4;107(1):11-25. Epub 2019 Aug 4.

Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

The wavelength of light is a critical determinant of light's capacity to entrain adaptive biological mechanisms, such as enhanced immune surveillance, that precede and prepare us for the active circadian day, a time when the risk of encountering pathogen is highest. Light rich in the shorter wavelength visible blue spectrum maximally entrains these circadian rhythms. We hypothesized that exposure to blue light during sepsis will augment immunity and improve outcome. Using a clinically relevant Klebsiella pneumoniae acute lower respiratory tract infection model, we show that blue spectrum light shifts autonomic tone toward parasympathetic predominance and enhances immune competence, as characterized by accelerated pathogen clearance that is accompanied by reduced alveolar neutrophil influx, inflammation, and improved survival. Blue light functioned through an optic-cholinergic pathway and expansion of splenic Ccr2 monocytes to increase control of the infection and improve survival. The "keystone" mediating these effects is the circadian clock protein Rev-Erbα, and biochemical activation with Rev-Erbα agonist SR9009 enhanced mononuclear cell phagocytosis in vitro and recapitulated the enhanced pathogen elimination in vivo observed with blue light. These findings underscore the potential therapeutic value of blue light and modulating Rev-Erbα to enhance host immunity against infection.
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http://dx.doi.org/10.1002/JLB.4HI0519-155RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456460PMC
January 2020

Impact of pill burden on adherence to hepatitis C medication.

Curr Med Res Opin 2019 11 25;35(11):1937-1944. Epub 2019 Sep 25.

Optum , Eden Prairie , MN , USA.

To describe pill burden before and after hepatitis C virus (HCV) treatment initiation among patients newly treated for HCV infection, and to evaluate the association between HCV pill burden and gaps in HCV therapy. This was a retrospective administrative claims study of patients treated with direct-acting antivirals (DAAs) for HCV from 1 November 2013 to 31 July 2016. HCV pill burden was defined as the pill count per day for the index HCV regimen. Mean overall pill burden (HCV medications plus non-HCV medications) was calculated in the 90 days before and after DAA initiation. Gaps in the index HCV regimen were assessed in the 6 months after DAA initiation. Multivariable logistic regression was used to compare the odds of a gap in HCV therapy across HCV pill burden categories (1 pill/day, 2 pills/day, and ≥3 pills/day). Among 9815 patients who met the study criteria, mean overall pill burdens before and after DAA treatment initiation were 5.4 and 7.7, respectively ( < .001). The adjusted odds ratio (OR) of a ≥15-day gap in HCV therapy was 1.75 (95% confidence interval [CI] = 1.38-2.22) for patients with 2 HCV pills/day and 2.11 (95% CI = 1.78-2.51) for patients with ≥3 pills/day, compared with patients with 1 HCV pill/day. Patients with HCV have a substantial pill burden even before initiating HCV treatment. As higher HCV pill burden was associated with lower medication adherence, pill burden should be an important consideration in HCV treatment selection.
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http://dx.doi.org/10.1080/03007995.2019.1643160DOI Listing
November 2019

End-of-Life Care in Patients Exposed to Home-Based Palliative Care vs Hospice Only.

J Am Geriatr Soc 2019 06 4;67(6):1226-1233. Epub 2019 Mar 4.

Pasadena Regional Office, Kaiser Permanente Southern California, Pasadena, CA.

Objectives: The current evidence base regarding the effectiveness of home-based palliative care (HomePal) on outcomes of importance to multiple stakeholders remains limited. The purpose of this study was to compare end-of-life care in decedents who received HomePal with two cohorts that either received hospice only (HO) or did not receive HomePal or hospice (No HomePal-HO).

Design: Retrospective cohorts from an ongoing study of care transition from hospital to home. Data were collected from 2011 to 2016.

Setting: Kaiser Permanente Southern California.

Participants: Decedents 65 and older who received HomePal (n = 7177) after a hospitalization and two comparison cohorts (HO only = 25 102; No HomePal-HO = 22 472).

Measurements: Utilization data were extracted from administrative, clinical, and claims databases, and death data were obtained from state and national indices. Days at home was calculated as days not spent in the hospital or in a skilled nursing facility (SNF).

Results: Patients who received HomePal were enrolled for a median of 43 days and had comparable length of stay on hospice as patients who enrolled only in hospice (median days = 13 vs 12). Deaths at home were comparable between HomePal and HO (59% vs 60%) and were higher compared with No HomePal-HO (16%). For patients who survived at least 6 months after HomePal admission (n = 2289), the mean number of days at home in the last 6 months of life was 163 ± 30 vs 161 ± 30 (HO) vs 149 ± 40 (No HomePal-HO). Similar trends were also noted for the last 30 days of life, 25 ± 8 (HomePal, n = 5516), 24 ± 8 (HO), and 18 ± 11 (No HomePal-HO); HomePal patients had a significantly lower risk of hospitalizations (relative risk [RR] = .58-.87) and SNF stays (RR = .32-.77) compared with both HO and No HomePal-HO patients.

Conclusion: Earlier comprehensive palliative care in patients' home in place of or preceding hospice is associated with fewer hospitalizations and SNF stays and more time at home in the final 6 months of life. J Am Geriatr Soc, 2019.
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http://dx.doi.org/10.1111/jgs.15844DOI Listing
June 2019

Platelets inhibit apoptotic lung epithelial cell death and protect mice against infection-induced lung injury.

Blood Adv 2019 02;3(3):432-445

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

Thrombocytopenia is associated with worse outcomes in patients with acute respiratory distress syndrome, which is most commonly caused by infection and marked by alveolar-capillary barrier disruption. However, the mechanisms by which platelets protect the lung alveolar-capillary barrier during infectious injury remain unclear. We found that natively thrombocytopenic mice deficient in the thrombopoietin receptor sustain severe lung injury marked by alveolar barrier disruption and hemorrhagic pneumonia with early mortality following acute intrapulmonary (PA) infection; barrier disruption was attenuated by platelet reconstitution. Although PA infection was associated with a brisk neutrophil influx, depletion of airspace neutrophils failed to substantially mitigate PA-triggered alveolar barrier disruption in mice. Rather, PA cell-free supernatant was sufficient to induce lung epithelial cell apoptosis in vitro and in vivo and alveolar barrier disruption in both platelet-depleted mice and mice in vivo. Cell-free supernatant from PA with genetic deletion of the type 2 secretion system, but not the type 3 secretion system, mitigated lung epithelial cell death in vitro and lung injury in mice. Moreover, platelet releasates reduced poly (ADP ribose) polymerase cleavage and lung injury in mice, and boiling of platelet releasates, but not apyrase treatment, abrogated PA supernatant-induced lung epithelial cell cytotoxicity in vitro. These findings indicate that while neutrophil airspace influx does not potentiate infectious lung injury in the thrombocytopenic host, platelets and their factors protect against severe pulmonary complications from pathogen-secreted virulence factors that promote host cell death even in the absence of overt infection.
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http://dx.doi.org/10.1182/bloodadvances.2018026286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373758PMC
February 2019

Pseudomonas aeruginosa utilizes host polyunsaturated phosphatidylethanolamines to trigger theft-ferroptosis in bronchial epithelium.

J Clin Invest 2018 10 10;128(10):4639-4653. Epub 2018 Sep 10.

Department of Environmental and Occupational Health and Center for Free Radical and Antioxidant Health and.

Ferroptosis is a death program executed via selective oxidation of arachidonic acid-phosphatidylethanolamines (AA-PE) by 15-lipoxygenases. In mammalian cells and tissues, ferroptosis has been pathogenically associated with brain, kidney, and liver injury/diseases. We discovered that a prokaryotic bacterium, Pseudomonas aeruginosa, that does not contain AA-PE can express lipoxygenase (pLoxA), oxidize host AA-PE to 15-hydroperoxy-AA-PE (15-HOO-AA-PE), and trigger ferroptosis in human bronchial epithelial cells. Induction of ferroptosis by clinical P. aeruginosa isolates from patients with persistent lower respiratory tract infections was dependent on the level and enzymatic activity of pLoxA. Redox phospholipidomics revealed elevated levels of oxidized AA-PE in airway tissues from patients with cystic fibrosis (CF) but not with emphysema or CF without P. aeruginosa. We believe that the evolutionarily conserved mechanism of pLoxA-driven ferroptosis may represent a potential therapeutic target against P. aeruginosa-associated diseases such as CF and persistent lower respiratory tract infections.
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http://dx.doi.org/10.1172/JCI99490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159971PMC
October 2018

Translational Sepsis Research: Spanning the Divide.

Crit Care Med 2018 09;46(9):1497-1505

Department of Surgery, University of Pittsburgh, Pittsburgh, PA.

Objective: Our knowledge of the molecular mechanisms of sepsis has attained exponential growth. Yet, the pillars of its care remain antibiotics, fluid resuscitation, and physiologic support of failing organ systems. The inability to bring biologic breakthroughs to the bedside is not for lack of effort. Over 60 clinical trials of novel therapies, each heavily supported by the momentum of biologic data suggesting clinical utility, have been conducted and have failed to identify benefit. This mass of "negative" clinical data abut an equally towering mound of knowledge of sepsis biology, which collectively have led investigators to ask, "what happened?"

Data Sources: Review of published scientific literature via MEDLINE searches using key terms related to the article topics.

Study Selection: Original articles, review articles, and systematic reviews were considered.

Data Extraction: Articles were selected for inclusion based upon author consensus.

Data Synthesis: Here, we present a synthetic review of some of the challenges in translating experimental animal models of sepsis to the bedside. We commence with the concept that the heterogeneity in the kinetics of the sepsis response serves as an important, often underappreciated but surmountable, source of translational impedance. Upon this groundwork, we discuss distinctions between animal experimentation and clinical trial design in the elements for hypothesis testing: cohort selection, power and sample size, randomization and blinding, and timing of intervention. From this concept, we develop a contextual framework for advancing the paradigm of animal-based investigations to facilitate science that transitions from molecule to medicine.

Conclusions: A persistent divide exists between the laboratory and clinical research arenas, which may be addressable via systematic targeting of identified translational gaps.
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http://dx.doi.org/10.1097/CCM.0000000000003271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097250PMC
September 2018

Respiratory Microbiome Profiling for Etiologic Diagnosis of Pneumonia in Mechanically Ventilated Patients.

Front Microbiol 2018 10;9:1413. Epub 2018 Jul 10.

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, United States.

Etiologic diagnosis of bacterial pneumonia relies on identification of causative pathogens by cultures, which require extended incubation periods and have limited sensitivity. Next-generation sequencing of microbial DNA directly from patient samples may improve diagnostic accuracy for guiding antibiotic prescriptions. In this study, we hypothesized that enhanced pathogen detection using sequencing can improve upon culture-based diagnosis and that certain sequencing profiles correlate with host response. We prospectively collected endotracheal aspirates and plasma within 72 h of intubation from patients with acute respiratory failure. We performed 16S rRNA gene sequencing to determine pathogen abundance in lung samples and measured plasma biomarkers to assess host responses to detected pathogens. Among 56 patients, 12 patients (21%) had positive respiratory cultures. Sequencing revealed lung communities with low diversity ( < 0.02) dominated by taxa (>50% relative abundance) corresponding to clinically isolated pathogens (concordance = 0.009). Importantly, sequencing detected dominant pathogens in 20% of the culture-negative patients exposed to broad-spectrum empiric antibiotics. Regardless of culture results, pathogen dominance correlated with increased plasma markers of host injury (receptor of advanced glycation end-products-RAGE) and inflammation (interleukin-6, tumor necrosis factor receptor 1-TNFR1) ( < 0.05), compared to subjects without dominant pathogens in their lung communities. Machine-learning algorithms identified pathogen abundance by sequencing as the most informative predictor of culture positivity. Thus, enhanced detection of pathogenic bacteria by sequencing improves etiologic diagnosis of pneumonia, correlates with host responses, and offers substantial opportunity for individualized therapeutic targeting and antimicrobial stewardship. Clinical translation will require validation with rapid whole meta-genome sequencing approaches to guide real-time antibiotic prescriptions.
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http://dx.doi.org/10.3389/fmicb.2018.01413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048198PMC
July 2018

Label-free Neutrophil Enrichment from Patient-derived Airway Secretion Using Closed-loop Inertial Microfluidics.

J Vis Exp 2018 06 7(136). Epub 2018 Jun 7.

Research Laboratory of Electronics, Massachusetts Institute of Technology; Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology; Department of Biological Engineering, Massachusetts Institute of Technology;

Airway secretions contain a large number of immune-related cells, e.g., neutrophils, macrophages, and lymphocytes, which can be used as a major resource to evaluate a variety of pulmonary diseases, both for research and clinical purposes. However, due to the heterogeneous and viscous nature of patient mucus, there is currently no reliable dissociation method that does not damage the host immune cells in the patient airway secretion. In this research, we introduce a sample preparation method that uses inertial microfluidics for the patient's immune assessment. Regardless of the heterogeneous fluidic properties of the clinical samples, the proposed method recovers more than 95% of neutrophils from airway secretion samples that are diluted 1,000-fold with milliliters of clean saline. By recirculating the concentrated output stream to the initial sample reservoir, a high concentration, recovery, and purity of the immune cells are provided; recirculation is considered a trade-off to the single-run syringe-based operation of inertial microfluidics. The closed-loop operation of spiral microfluidics provides leukocytes without physical or chemical disturbance, as demonstrated by the phorbol 12-myristate 13-acetate (PMA)-induced elastase release of sorted neutrophils.
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http://dx.doi.org/10.3791/57673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6101596PMC
June 2018

Impact of Inpatient Palliative Care on Quality of End-of-Life Care and Downstream Acute and Postacute Care Utilization.

J Palliat Med 2018 07 13;21(7):913-923. Epub 2018 Mar 13.

3 Department of Research and Evaluation, Kaiser Permanente Southern California , Pasadena, California.

Background: Additional evidence is needed regarding the impact of inpatient palliative care (IPC) on the quality of end-of-life care and downstream utilization.

Aim: Examine the effects of IPC on quality of end-of-life care and acute and postacute care use in a large integrated system.

Design: Retrospective cohort design.

Setting/participants: Adult decedents from January 1, 2012, to December 31, 2014, who had at least one hospitalization at 11 Kaiser Permanente Southern California medical centers in the 12 months before death and not hospitalized for a trauma-related condition or receiving home-based PC or hospice were included in the cohort.

Materials And Methods: Inverse probability of treatment weighting of propensity scores was used to compare outcomes between patients exposed to IPC (n = 3742) and controls (n = 12,755) who never received IPC before death.

Results: Patients who received IPC were more likely to enroll in home-based PC or hospice (69% vs. 43%) and were less likely to die in a hospital (15% vs. 29%) or intensive care (2% vs. 9%) compared with controls (all, p < 0.001). IPC exposure was associated with higher risk for rehospitalization (HR: 1.18, 95% CI 1.11-1.25) and more frequent emergency department visits (RR: 1.16, 95% CI 1.07-1.26) with no increase in postacute care use compared with controls. Stratified analyses showed that IPC effects on acute care utilization were dependent on code status.

Conclusion: IPC exposure was associated with higher enrollment in home-based PC/hospice and more deaths at home. The increased acute care utilization by the IPC group may reflect persistent confounding by indication.
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http://dx.doi.org/10.1089/jpm.2017.0275DOI Listing
July 2018